Preface

Hemophilia is a rare inherited disease due to a deficiency of coagulation factors VIII and IX. It was initially detected in the royal families of the UK, Russia, Spain, and Germany; hence, it is labeled a royal disease. Though known since biblical times, the term hemophilia was ascribed to Schonlein in the 1820s. Low levels of factor VIII were identified in 1947. Decreased levels of factor IX were shown in Hemophilia B in 1952. A lot of knowledge was acquired later and management progressed from plasma to FFP to cryoprecipitate to purified plasma-derived factors to recombinant factors—first, second, and third generation. There had been significant improvement in first aid measures for the management of multiple complications like arthropathy and the development of inhibitors. Improvement in treatment has seen various phases—from general therapy with plasma to specific therapy with recombinant factors. Now efforts are being made to prolong the halflife of factors VIII and IX to genetic therapy by targeting the affected gene.

It gives me immense pleasure to be associated with and edit a book on hemophilia, a disease for which research is making rapid advances. I have been associated with hemophilia for a long time and have organized hemophilia care in the state of Haryana in India and initiated steps for the free supply of factors VIII and IX for poor and needy patients.

This book covers various important aspects of hemophilia management. State-ofthe-art chapters have been written by various authors. The chapter on genotypephenotype correlation describes the changing concepts of multiple mutations in hemophilia and emphasizes the role of gene-environment interaction. In the chapter on the perioperative management of hemophilia A, authors have discussed intraoperative and postoperative factor replacement therapy in hemophilia A patients undergoing minor and major surgeries. Factor replacement in hemophilia is discussed in detail. Hemophilia A and B being X-linked disorders are by and large considered as strictly affecting the male population. The chapter on women's issues in inherited bleeding disorders highlights that a significant number of heavy menstrual bleeders can be hemophilia A and B carriers, in addition to more common causes of von Willebrand disease (VWD), platelet disorders, and some rare bleeding disorders. This can pose serious life threats, especially after surgery or postpartum.

This book on hemophilia highlights the latest literature and many important aspects of this disease. A few decades ago, little was known about hemophilia. At present, we are able to save many lives and also alleviate morbidity and prevent disability due to rapid advances in first aid measures, physical therapy, and prophylaxis. Prophylaxis will undoubtedly prove the turning point in hemophilia management.

I sincerely hope this book will provide a guide to students, scientists, and clinicians working in hemophilia, benefitting all of us.

> **Dr. Pankaj Abrol** Professor & Head, Pediatric Hematologist Oncologist, Department of Pediatrics, SGT Medical College Hospital & Research Institute, Gurgaon (Haryana), India

> > **1**

**Chapter 1**

*Pankaj Abrol*

**1. Introduction**

**1.1 Pathophysiology**

normal in hemophilia.

minimal trauma.

**1.2 Classification**

**1.3 Clinical presentation**

hemophilia) is approximately 400,000 [1].

5% of the activity, i.e., >5–40 U/dL of plasma.

Introductory Chapter: Hemophilia

Hemophilia disease is caused by deficiency of coagulation factors VIII and IX. Former is called hemophilia A (80–85%) whereas latter is labeled hemophilia B (10–15%). Hemophilia A and B are X-linked disorders, have common clinical presentation, with no racial predilection and are seen in all ethnic groups. The incidence is 1 in 5000 male births. A rare variety of hemophilia—hemophilia C or Rosenthal syndrome (factor XI deficiency) is seen in Jews of Ashkenazi descent. It is a milder form of hemophilia and because of autosomal transmission affects both the sexes. As per annual global surveys by WFH number of PWH (people with

Factors VIII and IX along with phospholipid and calcium activate factor activating complex. This factor X activating complex or factor VII in presence of tissue factor activate factor IX initiating coagulation cascade. In laboratory prothrombin time (PT) measures activation of factor X by factor VII and is therefore

After any injury, initial hemostatic response of the human body is to form a platelet plug and formation of fibrin clot to stop bleeding. In hemophilia clot formation is delayed. The clot is soft and not robust. Bleeding in open space leads to hemorrhage and significant blood loss. Bleeding in closed joint leads to tamponade effect. When the soft clot is lysed, rebleeding can occur following

Hemophilia is classified as per baseline level of factors VIII or IX in blood. One unit is defined as amount present in 1 mL of normal plasma. Severe hemophilia means that coagulation factor is <1% of normal activity, i.e., <1 U/dL of plasma. Moderate hemophilia is between 1 and 5% of normal coagulant activity, i.e., 1–5 U/dL of plasma. And mild hemophilia when coagulant activity is higher than

Factor VIII and IX cannot cross placenta. So a neonate can bleed at birth or even a fetus can have bleeding in utero. Thirty percent of hemophilia patients may bleed after circumcision. Up to 3% may have ICH or intracranial hemorrhage [2], and half the number getting ECH (extracranial hemorrhage). Some may get ICH as well as ECH. All efforts should be made to prevent head trauma during delivery and

### **Chapter 1**

## Introductory Chapter: Hemophilia

*Pankaj Abrol*

### **1. Introduction**

Hemophilia disease is caused by deficiency of coagulation factors VIII and IX. Former is called hemophilia A (80–85%) whereas latter is labeled hemophilia B (10–15%). Hemophilia A and B are X-linked disorders, have common clinical presentation, with no racial predilection and are seen in all ethnic groups. The incidence is 1 in 5000 male births. A rare variety of hemophilia—hemophilia C or Rosenthal syndrome (factor XI deficiency) is seen in Jews of Ashkenazi descent. It is a milder form of hemophilia and because of autosomal transmission affects both the sexes. As per annual global surveys by WFH number of PWH (people with hemophilia) is approximately 400,000 [1].

#### **1.1 Pathophysiology**

Factors VIII and IX along with phospholipid and calcium activate factor activating complex. This factor X activating complex or factor VII in presence of tissue factor activate factor IX initiating coagulation cascade. In laboratory prothrombin time (PT) measures activation of factor X by factor VII and is therefore normal in hemophilia.

After any injury, initial hemostatic response of the human body is to form a platelet plug and formation of fibrin clot to stop bleeding. In hemophilia clot formation is delayed. The clot is soft and not robust. Bleeding in open space leads to hemorrhage and significant blood loss. Bleeding in closed joint leads to tamponade effect. When the soft clot is lysed, rebleeding can occur following minimal trauma.

#### **1.2 Classification**

Hemophilia is classified as per baseline level of factors VIII or IX in blood. One unit is defined as amount present in 1 mL of normal plasma. Severe hemophilia means that coagulation factor is <1% of normal activity, i.e., <1 U/dL of plasma. Moderate hemophilia is between 1 and 5% of normal coagulant activity, i.e., 1–5 U/dL of plasma. And mild hemophilia when coagulant activity is higher than 5% of the activity, i.e., >5–40 U/dL of plasma.

#### **1.3 Clinical presentation**

Factor VIII and IX cannot cross placenta. So a neonate can bleed at birth or even a fetus can have bleeding in utero. Thirty percent of hemophilia patients may bleed after circumcision. Up to 3% may have ICH or intracranial hemorrhage [2], and half the number getting ECH (extracranial hemorrhage). Some may get ICH as well as ECH. All efforts should be made to prevent head trauma during delivery and discourage forceps or vacuum extraction. Mostly hemophilia is suspected at birth because of family history but in one-third, it may be due to spontaneous mutation and therefore giving no clue from family history.

When a toddler tries to cruise, he starts getting symptoms like easy bruising following minor traumas, hematomas and bleeding in to joints. In early years when child tries to stand and walk, ankle joint followed by knee joint become the target joint for bleeding and hemarthrosis becomes main symptom He may also bleed from mouth because of torn frenulum. By 1 year of age 90% hemophiliacs present with excessive bleeding [3]. In older children and adolescents hemarthrosis in knee and elbow joints becomes more common and these joints become target joints. Hinged joints like ankle knee and elbow are more often involved. In 70–80% of cases, hemarthrosis is the main presentation. Bleeding into muscles occurs in 10–20%. Less than 5% bleed in CNS. At the time of bleeding in joints, there is feeling of tingling or warmth. This is followed by increasing pain and loss of motion. In a younger child pain and swelling of the joints present earlier but as the child grows older and bleeding occurs in the joints, pain and swelling of joint decreases. The patient comes to know of bleeding earlier. They are able to tell their parents that they are bleeding in to joints and the treatment should be started. When a child continues to have repeated hemarthrosis, chronic effusion and hyperemia appears in joints. If not managed properly with coagulation factors, chronic arthropathy occurs. As the age advances more PWH (people with hemophilia) get crippled because of repeated hemarthrosis in resource restrained countries [4]. Hemophilia patients may also present with hematuria or GIT bleeding.

MUSCLES: hemophilia patients bleed deep inside muscles and these hematomas are difficult to palpate. The patient gets vague feeling of pain on movement and there is increase in circumference of the affected limb. If not managed properly it can lead to fibrosis and contractures with muscular atrophy and pseudotumor formation. Bleeding in to iliopsoas muscle is particularly notorious. Such a patient has vague pain and discomfort in lower abdomen and upper part of thigh, with internally rotated thigh. These patients may have massive internal hemorrhage in the muscles requiring urgent specific aggressive management with factors for a fortnight followed prophylaxis for several months [2].

#### **1.4 Life-threatening hemorrhages in hemophilia**


Bleeding in CNS and around airway can cause pressure symptoms in vital areas and airway compression. Exsanguinating hemorrhages can also cause shock and death. Such episodes require urgent therapy on slightest suspicion.

#### **1.5 Hemophilia in female carriers**

Because of lyonization of X chromosome, some female hemophilia carriers have sufficient reduction in level of factor VIII or IX and have mild bleeding disorder. Carriers with factor level of 40–60% may have bleeding tendency [5]. Levels of factor VIII or IX should be determined in all these carriers to determine the need for treatment when they go for surgery or have bleeding episode. There is also 50% probability of birth of female hemophilia patient when a male hemophilia patient marries a female hemophilia carrier.

**3**

*Introductory Chapter: Hemophilia*

**1.6 Laboratory evaluation**

factor levels are very low [6].

**1.7 Genetic testing**

**1.8 Treatment**

incidence of chronic complications.

*DOI: http://dx.doi.org/10.5772/intechopen.84687*

require repeated tests of coagulation times.

It is easy to diagnose severe hemophilia. Prothrombin time (PT) is normal and partial thromboplastin time (PTT) is 2–3 times prolonged. Mild hemophilia is difficult to diagnosis as PTT may be normal or slightly prolonged. In a newborn, PTT may be slightly prolonged due to deficiency of vitamin K dependent factor IX and raised level of factor VIII due to stress of delivery. So diagnosis of hemophilia may

Diagnosis of factor IX deficiency is more difficult as available commercial PTT reagents are more sensitive to factor VIII deficiency. PTT may be normal even with factor IX level as low as 15–20 U/dL. So it is advisable to perform factor IX assay even when PTT is normal in suspected hemophilia B. Specific functional assays of factors VIII and IX are done by mixing studies to confirm the diagnosis of hemophilia A and B. When mixed 1:1 with normal plasma PTT becomes normal in hemophilia. If PTT is not corrected, one should suspect presence of inhibitors to factor VIII or IX. Other causes are presence of lupus inhibitor or heparin. If inhibitors are present, quantitative Bethesda assay should be performed to measure antibody titer. Immunoassays of factors VIII and IX can also be done to identify dysfunctional

proteins called cross-reacting material (CRM). Immunoassays are usually not required for management of hemophilia patients. Clot waveform analysis and thrombin generation assay are also recommended for accurate estimation of factor VIII and IX activity during management of hemophilia patients especially when the

Both hemophilia A and B are X-linked traits, and the encoding genes F8 and F9 map to the distal portion of long arm of chromosomes [7]. Commonest genetic alteration is inversion and mostly originating in male germ cells. Family history is present in approximately two third of patients and mutations constitute one third of cases. Genetic resting is available and performed on proband first. African Americans have different haplotype and therefore have higher level of inhibitor formation. Prenatal testing can be done by amniocentesis or chorionic villous biopsy. Factor IX gene is smaller. Missense point mutation is seen in more than 60% of patients. In case genetic testing is not helping, coagulation based assay can also

Hallmark of treatment is prompt and appropriate management of bleeding episode; and prophylactic therapy to prevent future hemorrhages decreasing the

Supportive care: In general hemophilia patients should be advised to avoid trauma, but it is very difficult to advise a child in growing age of activity to completely do so. They can be advised to avoid risk prone behavior, use seat belts and bike helmets while driving. Ask them to avoid contact sports like, boxing and wrestling. They can do swimming and play table tennis, badminton, etc. In mild and moderate hemophilia these measures may help but in severe hemophilia there can be bleeding without trauma. Psychosocial counseling may help the child to achieve a balance. Hemophiliacs should be advised to avoid nonsteroidal anti-inflammatory drugs like aspirin, as these drugs interfere with platelet functions and aggregation, making him prone to bleeding. These patients should be immunized against hepatitis B and those on plasma-derived

be used to detect carrier state and it is 90% accurate [8].

products should be screened periodically for HIV, hepatitis B and C.

#### **1.6 Laboratory evaluation**

*Hemophilia - Recent Advances*

and therefore giving no clue from family history.

discourage forceps or vacuum extraction. Mostly hemophilia is suspected at birth because of family history but in one-third, it may be due to spontaneous mutation

When a toddler tries to cruise, he starts getting symptoms like easy bruising following minor traumas, hematomas and bleeding in to joints. In early years when child tries to stand and walk, ankle joint followed by knee joint become the target joint for bleeding and hemarthrosis becomes main symptom He may also bleed from mouth because of torn frenulum. By 1 year of age 90% hemophiliacs present with excessive bleeding [3]. In older children and adolescents hemarthrosis in knee and elbow joints becomes more common and these joints become target joints. Hinged joints like ankle knee and elbow are more often involved. In 70–80% of cases, hemarthrosis is the main presentation. Bleeding into muscles occurs in 10–20%. Less than 5% bleed in CNS. At the time of bleeding in joints, there is feeling of tingling or warmth. This is followed by increasing pain and loss of motion. In a younger child pain and swelling of the joints present earlier but as the child grows older and bleeding occurs in the joints, pain and swelling of joint decreases. The patient comes to know of bleeding earlier. They are able to tell their parents that they are bleeding in to joints and the treatment should be started. When a child continues to have repeated hemarthrosis, chronic effusion and hyperemia appears in joints. If not managed properly with coagulation factors, chronic arthropathy occurs. As the age advances more PWH (people with hemophilia) get crippled because of repeated hemarthrosis in resource restrained countries [4]. Hemophilia patients may also present with hematuria or GIT bleeding. MUSCLES: hemophilia patients bleed deep inside muscles and these hematomas

are difficult to palpate. The patient gets vague feeling of pain on movement and there is increase in circumference of the affected limb. If not managed properly it can lead to fibrosis and contractures with muscular atrophy and pseudotumor formation. Bleeding in to iliopsoas muscle is particularly notorious. Such a patient has vague pain and discomfort in lower abdomen and upper part of thigh, with internally rotated thigh. These patients may have massive internal hemorrhage in the muscles requiring urgent specific aggressive management with factors for a

3.All exsanguinating hemorrhages including bleeding in iliopsoas muscles.

death. Such episodes require urgent therapy on slightest suspicion.

Bleeding in CNS and around airway can cause pressure symptoms in vital areas and airway compression. Exsanguinating hemorrhages can also cause shock and

Because of lyonization of X chromosome, some female hemophilia carriers have sufficient reduction in level of factor VIII or IX and have mild bleeding disorder. Carriers with factor level of 40–60% may have bleeding tendency [5]. Levels of factor VIII or IX should be determined in all these carriers to determine the need for treatment when they go for surgery or have bleeding episode. There is also 50% probability of birth of female hemophilia patient when a male hemophilia patient

fortnight followed prophylaxis for several months [2].

**1.4 Life-threatening hemorrhages in hemophilia**

2.Bleeding in and around airway.

**1.5 Hemophilia in female carriers**

marries a female hemophilia carrier.

1.Bleeding in CNS.

**2**

It is easy to diagnose severe hemophilia. Prothrombin time (PT) is normal and partial thromboplastin time (PTT) is 2–3 times prolonged. Mild hemophilia is difficult to diagnosis as PTT may be normal or slightly prolonged. In a newborn, PTT may be slightly prolonged due to deficiency of vitamin K dependent factor IX and raised level of factor VIII due to stress of delivery. So diagnosis of hemophilia may require repeated tests of coagulation times.

Diagnosis of factor IX deficiency is more difficult as available commercial PTT reagents are more sensitive to factor VIII deficiency. PTT may be normal even with factor IX level as low as 15–20 U/dL. So it is advisable to perform factor IX assay even when PTT is normal in suspected hemophilia B. Specific functional assays of factors VIII and IX are done by mixing studies to confirm the diagnosis of hemophilia A and B. When mixed 1:1 with normal plasma PTT becomes normal in hemophilia. If PTT is not corrected, one should suspect presence of inhibitors to factor VIII or IX. Other causes are presence of lupus inhibitor or heparin. If inhibitors are present, quantitative Bethesda assay should be performed to measure antibody titer.

Immunoassays of factors VIII and IX can also be done to identify dysfunctional proteins called cross-reacting material (CRM). Immunoassays are usually not required for management of hemophilia patients. Clot waveform analysis and thrombin generation assay are also recommended for accurate estimation of factor VIII and IX activity during management of hemophilia patients especially when the factor levels are very low [6].

#### **1.7 Genetic testing**

Both hemophilia A and B are X-linked traits, and the encoding genes F8 and F9 map to the distal portion of long arm of chromosomes [7]. Commonest genetic alteration is inversion and mostly originating in male germ cells. Family history is present in approximately two third of patients and mutations constitute one third of cases. Genetic resting is available and performed on proband first. African Americans have different haplotype and therefore have higher level of inhibitor formation. Prenatal testing can be done by amniocentesis or chorionic villous biopsy. Factor IX gene is smaller. Missense point mutation is seen in more than 60% of patients. In case genetic testing is not helping, coagulation based assay can also be used to detect carrier state and it is 90% accurate [8].

#### **1.8 Treatment**

Hallmark of treatment is prompt and appropriate management of bleeding episode; and prophylactic therapy to prevent future hemorrhages decreasing the incidence of chronic complications.

Supportive care: In general hemophilia patients should be advised to avoid trauma, but it is very difficult to advise a child in growing age of activity to completely do so. They can be advised to avoid risk prone behavior, use seat belts and bike helmets while driving. Ask them to avoid contact sports like, boxing and wrestling. They can do swimming and play table tennis, badminton, etc. In mild and moderate hemophilia these measures may help but in severe hemophilia there can be bleeding without trauma. Psychosocial counseling may help the child to achieve a balance. Hemophiliacs should be advised to avoid nonsteroidal anti-inflammatory drugs like aspirin, as these drugs interfere with platelet functions and aggregation, making him prone to bleeding. These patients should be immunized against hepatitis B and those on plasma-derived products should be screened periodically for HIV, hepatitis B and C.

#### *Hemophilia - Recent Advances*

Half-life of factor VIII is 8–12 h and that of factor IX is 18–24 h. In event of mild to moderate hemorrhage, level of factor VIII or IX has to be raised to hemostatic level of 35–50% range. In life threatening or severe hemorrhage, hemostatic level of factor should be raised to 100% [3].

Dose of recombinant factor VIII (rFVIII) in IU: Body weight (kg) × 0.5 × %age of desired rise in rFVIII. (1) Dose of recombinant factor IX (rFIX) in IU: Body weight (kg) × 1.4 × %age of desired rise in rFIX. (2)

Endogenous factor VIII can be released by desmopressin acetate (DDAVP, 1-deamino-8-*d*-arginine vasopressin) in mild hemophilia. Intranasal preparation of concentrated preparation of desmopressin acetate 150 μg/puff is given as one puff to the patient weighing <50 kg and two puffs (300 μg) to patient >50 kg. Desmopressin is not effective in hemophilia B.

#### **1.9 Recombinant factors**

Development of recombinant factors is a major advance in treatment of hemophilia patients. Three generations—first, second and third generations are currently available [9]. First generation factor concentrates are stabilized with human albumin, second generation is stabilized with sucrose, and third generation is stabilized with/without additional human or animal plasma proteins. Efforts are still being made to get better recombinant factors with longer half-life and less immunogenicity, so that the frequency of prophylactic infusion may be further decreased [10]. With use of plasma derived factors, inhibitor formation is less, and after 150 EDs (exposure days) inhibitor formation is negligible [11]. In some centers, initial prophylaxis is given with plasma derived factors VIII and IX, and with recombinant factors after 150 EDs. Recombinant factor VIII is available in all three generations, but for factor IX, only third generation recombinant factor is available.

#### **1.10 Adjunctive management**


#### **1.11 Long-term complications**

These are chronic arthropathy, development of inhibitors to factors VIII or IX and the risk of transfusion-transmitted infections.

**5**

two types.

*Introductory Chapter: Hemophilia*

*DOI: http://dx.doi.org/10.5772/intechopen.84687*

a.Chronic arthropathy: hemarthrosis in target joints is commonest presentation in hemophilia. After every such episode, proteolytic enzymes are released by white blood cells in the joint space. Heme released from blood induces macrophage proliferation leading to synovitis. Thickened synovium develops frond like projections which on getting pinched induces further hemorrhage. Cartilaginous surface of the affected joint gets eroded and exposes bone surface leading to articular fusion and ankylosis. Because of repeated hemarthrosis, synovium gets more and more thickened leading to narrowing of joint space, little space to accommodate more blood and causing intense pain. Such patients need to be put on short-term or long-term prophylaxis to prevent progression of arthropathy.

b.Development of inhibitors: repeated infusion of factors VIII or IX may induce immune response leading to formation of inhibitor antibodies to the deficient factor. Such patients fail to respond to appropriate factor replacement after bleeding episode. Incidence of inhibitor development may be as high as 25–30% in hemophilia A and somewhat lower in hemophilia B. Risk of development of inhibitors is minimal after 150 exposure days to coagulation factors. MASAC (USA) advises inhibitor assay only up to 150 exposure days [11]. With recombinant factor VIII incidence of inhibitor development is 87% higher and 69% higher incidence of high titer inhibitor compared to plasma derived factors. Some inhibitors to factor IX may also cause anaphylaxis. Incidence of development of inhibitors is higher with recombinant factors than plasma derived factors. Such patients may lose inhibitors and respond after continued administration of factors. Some others may require desensitization by infusing higher dose of factor VIII or IX, saturating antibodies and inducing immune tolerance induction. Alternatives are rituximab, steroids and cyclophosphamide. In patients who do not respond to these agents, recombinant factor VIIa or prothrombin complex concentrate may be used to bypass factor VIII.

c.Risk of transfusion transmitted infections: in past, there had been many incidences of transmission of hepatitis B and C and even HIV when plasma derived factors VIII and IX were used. Now with advent of recombinant factors VIII and IX, such a risk is minimal but one must immunize these patients for

Hemophilia A patients with inhibitors: these patients can be divided in to

a.Low responding factor VIII inhibitors: inhibitor titer is <5 Bethesda units. These can be treated with factor VIII at higher doses. Continuous administration of factor VIII is more effective. For common muscle and joint hemor-

b.High responding factor VIII inhibitors: inhibitor titer is more than five

Bethesda units. Requires management in a tertiary hemophilia care centers by hemophilia experts. Treatment is more aggressive. Alternatives are porcine factor VIII concentrates, recombinant factor VIIa, prothrombin complex concentrate or activated prothrombin complex concentrate (commercially available

Hemophilia B patients with inhibitors: incidence of inhibitor formation is much lower but can cause anaphylaxis. Activated prothrombin complex concentrate and recombinant factor VII are very effective. In patients who have developed anaphylaxis,

hepatitis B and monitor immunization status of the patient.

rhages, double dose of factor VIII is usually effective.

FEIBA or factor VIII inhibitor bypassing activity).

#### *Introductory Chapter: Hemophilia DOI: http://dx.doi.org/10.5772/intechopen.84687*

*Hemophilia - Recent Advances*

**1.9 Recombinant factors**

**1.10 Adjunctive management**

of factor VIII and IX.

hemarthrosis [12].

**1.11 Long-term complications**

factor should be raised to 100% [3].

Dose of recombinant factor VIII (rFVIII) in IU:

Dose of recombinant factor IX (rFIX) in IU:

Desmopressin is not effective in hemophilia B.

Half-life of factor VIII is 8–12 h and that of factor IX is 18–24 h. In event of mild to moderate hemorrhage, level of factor VIII or IX has to be raised to hemostatic level of 35–50% range. In life threatening or severe hemorrhage, hemostatic level of

Endogenous factor VIII can be released by desmopressin acetate (DDAVP, 1-deamino-8-*d*-arginine vasopressin) in mild hemophilia. Intranasal preparation of concentrated preparation of desmopressin acetate 150 μg/puff is given as one puff to the patient weighing <50 kg and two puffs (300 μg) to patient >50 kg.

Development of recombinant factors is a major advance in treatment of hemophilia patients. Three generations—first, second and third generations are currently available [9]. First generation factor concentrates are stabilized with human albumin, second generation is stabilized with sucrose, and third generation is stabilized with/without additional human or animal plasma proteins. Efforts are still being made to get better recombinant factors with longer half-life and less immunogenicity, so that the frequency of prophylactic infusion may be further decreased [10]. With use of plasma derived factors, inhibitor formation is less, and after 150 EDs (exposure days) inhibitor formation is negligible [11]. In some centers, initial prophylaxis is given with plasma derived factors VIII and IX, and with recombinant factors after 150 EDs. Recombinant factor VIII is available in all three generations,

1.More important in resource limited conditions, when there is less availability

2.First aid measures are important in management of acute bleeding episode presenting as musculoskeletal hemorrhage like hemarthrosis. Protection (splint), rest, ice, compression and elevation (**PRICE**) are very useful in acute

3.Pain killers: NSAID drugs like aspirin should be avoided. Paracetamol is safest analgesic. Some COX-2 inhibitors can be judiciously used in arthropathy.

5.Antifibrinolytic drugs like tranexamic acid and epsilon aminocaproic acid can

These are chronic arthropathy, development of inhibitors to factors VIII or IX

but for factor IX, only third generation recombinant factor is available.

4.Physiotherapy/rehabilitation after pain decreases.

be used in mucosal bleeds and dental extraction.

and the risk of transfusion-transmitted infections.

Body weight (kg) × 0.5 × %age of desired rise in rFVIII. (1)

Body weight (kg) × 1.4 × %age of desired rise in rFIX. (2)

**4**


Hemophilia A patients with inhibitors: these patients can be divided in to two types.


Hemophilia B patients with inhibitors: incidence of inhibitor formation is much lower but can cause anaphylaxis. Activated prothrombin complex concentrate and recombinant factor VII are very effective. In patients who have developed anaphylaxis, use of activated prothrombin complex concentrate is contraindicated as this contains some factor IX, use of factor VIIa is the answer [2]. Immune tolerance is not effective as some of the patients develop nephrotic syndrome if higher dose of factor IX is given.

#### **1.12 Hemophilia prophylaxis**

Hemophilia prophylaxis is regular administration of factors VIII or IX to the patient to prevent bleeding. It was observed that mid and moderate hemophilia patients, who have coagulation factor level >1% rarely had spontaneous hemorrhage. And if we can maintain factors VIII or IX level >1%, patient will not have spontaneous hemorrhage, thereby decreasing moribund and debilitating complications with much better preservation of joint functions. Prophylaxis requires insertion of central catheter to ensure venous access, is expensive, requires more of costly factors but reduces complications and preserves joints. Hemophilia prophylaxis can be primary, secondary or tertiary [9].


Prophylaxis can also be classified as intermittent or continuous:


In a patient with repeated hemarthrosis or bleeding, short-term prophylaxis for 4–8 weeks is recommended to interrupt the bleeding cycle. Whether adults require long-term prophylaxis is not yet clear. More studies are required to confirm this. Some young adults can do well off prophylaxis. Prophylaxis does not reverse the damage already done to the affected joint, but it slows the progression of arthropathy and improves quality of life. It is also cost-effective as it helps to avoid the subsequent costly management of damaged joints.

Dose schedule for prophylaxis [12]:


Many countries follow different protocols. Protocol should be individualized. It is best given in the morning to cover activity of whole day.

**7**

**Author details**

Pankaj Abrol

modified.

provided the original work is properly cited.

Hospital and Research Institute, Gurgaon, Haryana, India

\*Address all correspondence to: abrolpankaj1@gmail.com

*Introductory Chapter: Hemophilia*

**1.13 Home therapy of hemophilia**

*DOI: http://dx.doi.org/10.5772/intechopen.84687*

With home therapy treatment is started earlier, so onset of complications is delayed. A certificate program shall be helpful. Family and patient need to be educated about general information and perspective of hemophilia. They need to know about first aid measures; dosage calculation, storage and administration of coagulation factors. Knowledge about aseptic technique, central catheters, proper storage and disposal of needles, record keeping and management of blood spills is mandatory. Comprehensive care team should monitor all this by making frequent follow up visits. Family members should be motivated to take care of young chil-

Hemophilia treatment centers must provide comprehensive medical care to hemophilia patients. Multiple disciplines should be involved providing state of art medical care. The center should have hematologist, pediatrician, nurses, dentist, psychologist, social worker, physical therapist and orthopedist. Even patients and their families should be part of the team. Every year the patient should be assessed for individual and potential problems, so that if required his treatment can be

dren. Older children and young adults can learn self-infusion and care.

**1.14 Comprehensive hemophilia treatment centers (CHTC)**

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Pediatrics, Pediatric Hematologist Oncologist, SGT Medical College

#### **1.13 Home therapy of hemophilia**

*Hemophilia - Recent Advances*

**1.12 Hemophilia prophylaxis**

examination.

45 weeks in a year.

clinical and radiological examination.

(85%) of the year under consideration.

subsequent costly management of damaged joints.

is best given in the morning to cover activity of whole day.

Dose schedule for prophylaxis [12]:

twice a week for hemophilia B.

twice a week for hemophilia B.

use of activated prothrombin complex concentrate is contraindicated as this contains some factor IX, use of factor VIIa is the answer [2]. Immune tolerance is not effective as some of the patients develop nephrotic syndrome if higher dose of factor IX is given.

Hemophilia prophylaxis is regular administration of factors VIII or IX to the patient to prevent bleeding. It was observed that mid and moderate hemophilia patients, who have coagulation factor level >1% rarely had spontaneous hemorrhage. And if we can maintain factors VIII or IX level >1%, patient will not have spontaneous hemorrhage, thereby decreasing moribund and debilitating complications with much better preservation of joint functions. Prophylaxis requires insertion of central catheter to ensure venous access, is expensive, requires more of costly factors but reduces complications and preserves joints.

a.Primary regular prophylaxis: prophylaxis treatment started regularly before second clinically relevant large joint bleed and before 3 years of age. There is no documented osteochondral joint disease on clinical and radiological

b.Secondary regular prophylaxis: prophylaxis treatment after two or more joint bleeds in to large joints and before the onset of joint disease, confirmed by

c.Tertiary regular prophylaxis: prophylaxis treatment after onset of joint disease

a.Intermittent (Periodic): prophylactic factors given for periods not exceeding

b.Continuous: with an intent to treat for 52 weeks/year and for at least 45 weeks

In a patient with repeated hemarthrosis or bleeding, short-term prophylaxis for 4–8 weeks is recommended to interrupt the bleeding cycle. Whether adults require long-term prophylaxis is not yet clear. More studies are required to confirm this. Some young adults can do well off prophylaxis. Prophylaxis does not reverse the damage already done to the affected joint, but it slows the progression of arthropathy and improves quality of life. It is also cost-effective as it helps to avoid the

a.Malmo protocol: 25–40 IU/kg per dose thrice a week for hemophilia A and

b.Utrecht protocol: 15–30 IU/kg per dose thrice a week for hemophilia A and

Many countries follow different protocols. Protocol should be individualized. It

documented after clinical and/or plain radiograph of affected joint.

Prophylaxis can also be classified as intermittent or continuous:

Hemophilia prophylaxis can be primary, secondary or tertiary [9].

**6**

With home therapy treatment is started earlier, so onset of complications is delayed. A certificate program shall be helpful. Family and patient need to be educated about general information and perspective of hemophilia. They need to know about first aid measures; dosage calculation, storage and administration of coagulation factors. Knowledge about aseptic technique, central catheters, proper storage and disposal of needles, record keeping and management of blood spills is mandatory. Comprehensive care team should monitor all this by making frequent follow up visits. Family members should be motivated to take care of young children. Older children and young adults can learn self-infusion and care.

#### **1.14 Comprehensive hemophilia treatment centers (CHTC)**

Hemophilia treatment centers must provide comprehensive medical care to hemophilia patients. Multiple disciplines should be involved providing state of art medical care. The center should have hematologist, pediatrician, nurses, dentist, psychologist, social worker, physical therapist and orthopedist. Even patients and their families should be part of the team. Every year the patient should be assessed for individual and potential problems, so that if required his treatment can be modified.

### **Author details**

Pankaj Abrol

Department of Pediatrics, Pediatric Hematologist Oncologist, SGT Medical College Hospital and Research Institute, Gurgaon, Haryana, India

\*Address all correspondence to: abrolpankaj1@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References** Chapter 2

[1] Stonebraker JS, Bolton-Maggs PH, Sourice JM, Walker I, Brooker M. A study of variations in reported hemophilia A prevalence around the world. Hemophilia. 2010;**16**(1):20-32

[2] Paula JD, Montgomery RR, Gill JC, Flood V. Hemophilia and von Willebrand disease. In: Nathan and Oski's Hematology and Oncology of Infancy and Childhood. 8th ed. Philadelphia: Elsevier Saunders; 2015. pp. 1028-1054

[3] Scott JP, Flood VH. Hereditary clotting factor deficiencies (bleeding disorders). In: Nelson Textbook of Pediatrics. 20th ed. Philadelphia: Elsevier; 2015. pp. 2384-2389

[4] Kar A, Mirkazemi R, Singh P, Potnis-Lele M, Lohade S, Lalwani A, et al. Disability in Indian patients with haemophilia. Hemophilia. 2007;**13**(4):398-404

[5] Plug I, Eveline P, Mauser-Bunschoten EP, Annette HJ, Brocker-Vriends AH, Hans KP, et al. Bleeding in carriers of hemophilia. Blood. 2006;**108**(1):52-56

[6] Matsumoto T, Shima M, Takeyama M, Yoshida K, Tanaka I, Sakurai Y, et al. The measurement of low level of factor VIII or factor IX in hemophilia A and hemophilia B plasma by clot waveform analysis and thrombin generation assay. Journal of Thrombosis and Haemostasis. 2006;**4**:377-384

[7] Goodeve AC, Perry DJ, Cumming T, et al. Genetics of haemostasis. Haemophilia. 2012;**18**(Suppl 4):73-80

[8] Graw J, Brackmann H, Oldenberg J, et al. Hemophilia A: From mutations analysis to new therapies. Nature Reviews. Genetics. 2005;**6**:488-501

[9] Morfini M, Coppola A, Franchini M, Minno GD. Clinical use of factor

VIII and factor IX concentrates. Blood Transfusion. 2013;**11**(Suppl 4):s55-s63

Genotype-Phenotype

Abstract

haemophilia

1.1 Background

9

1. Phenotypic variation

1.2 Phenotypic variation in haemophilia

Heterogeneity in Haemophilia

Muhammad Tariq Masood Khan and Abid Sohail Taj

Haemophilia was previously regarded as a classical example of Mendelian inheritance, with mutation in only a single gene (F8 or F9) causing the disease phenotype. The disease manifests complete penetrance. Studies, however, revealed the striking genetic and phenotypic heterogeneities of the disease. With further sophistication of clinical and molecular techniques, the disease was also found to have allele heterogeneity, phenotypic plasticity and variation in expressivity. The variations are more pronounced in F9 variants with five distinct phenotypes. All these phenomena advocate a rather complex genotype-phenotype relationship for the disease. A keen insight into the matter may unveil new avenues of therapeutics.

Keywords: genotype-phenotype correlation, genotype-phenotype heterogeneity,

A phenotype is defined as an observable characteristic which is expressed by an underlying genotype interacting with the environment [1]. Phenotype, in clinical scenario, hence represents the observable interface of the disease in terms of clinical features (laboratory findings, signs and symptoms) [2]. In contrast to genotype which is a stable entity, phenotype is dynamic and influenced by both the genotype and environment [3, 4]. Hence, in strict terms, the exact disease phenotype may be difficult to ascertain in many cases. This uncertainty usually underlies contemporary processes, directly or indirectly affecting the disease, with their own genetic and/or environmental influences [2]. Precise definition for a specific phenotype, therefore, needs development of a standardised comprehensive checklist of signs, symptoms and laboratory findings [3]. This is considerably convenient in case of monogenic disorders. Phenotypes for multigenic disorders or genetic diseases significantly influenced by environmental interactions are difficult to delineate [5].

Haemophilia is known to mankind since ancient times with references from Babylonian history [6]. The first vague description of cases appeared in the tenth century [7]. The first modern description of the disease was made in the eighteenth

[10] Lieuw K. Many factor VIII products available in the treatment of hemophilia A: An embarrassment of riches? Journal of Blood Medicine. 2017;**8**:67-73

[11] Hermans C, Astermark J, de Moerloose P. Exposure to factor VIII and prediction of inhibitor development: Exposure days vs. danger days, or both? Journal of Thrombosis and Haemostasis. 2012;**10**:2194-2196

[12] Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Blackwell Publishing Ltd; 2012. [Epub Jul 6, 2012]

#### **References** Chapter 2

## Genotype-Phenotype Heterogeneity in Haemophilia

Muhammad Tariq Masood Khan and Abid Sohail Taj

#### Abstract

Haemophilia was previously regarded as a classical example of Mendelian inheritance, with mutation in only a single gene (F8 or F9) causing the disease phenotype. The disease manifests complete penetrance. Studies, however, revealed the striking genetic and phenotypic heterogeneities of the disease. With further sophistication of clinical and molecular techniques, the disease was also found to have allele heterogeneity, phenotypic plasticity and variation in expressivity. The variations are more pronounced in F9 variants with five distinct phenotypes. All these phenomena advocate a rather complex genotype-phenotype relationship for the disease. A keen insight into the matter may unveil new avenues of therapeutics.

Keywords: genotype-phenotype correlation, genotype-phenotype heterogeneity, haemophilia

#### 1. Phenotypic variation

#### 1.1 Background

A phenotype is defined as an observable characteristic which is expressed by an underlying genotype interacting with the environment [1]. Phenotype, in clinical scenario, hence represents the observable interface of the disease in terms of clinical features (laboratory findings, signs and symptoms) [2]. In contrast to genotype which is a stable entity, phenotype is dynamic and influenced by both the genotype and environment [3, 4]. Hence, in strict terms, the exact disease phenotype may be difficult to ascertain in many cases. This uncertainty usually underlies contemporary processes, directly or indirectly affecting the disease, with their own genetic and/or environmental influences [2]. Precise definition for a specific phenotype, therefore, needs development of a standardised comprehensive checklist of signs, symptoms and laboratory findings [3]. This is considerably convenient in case of monogenic disorders. Phenotypes for multigenic disorders or genetic diseases significantly influenced by environmental interactions are difficult to delineate [5].

#### 1.2 Phenotypic variation in haemophilia

Haemophilia is known to mankind since ancient times with references from Babylonian history [6]. The first vague description of cases appeared in the tenth century [7]. The first modern description of the disease was made in the eighteenth

**8**

*Hemophilia - Recent Advances*

[1] Stonebraker JS, Bolton-Maggs PH, Sourice JM, Walker I, Brooker M. A study of variations in reported hemophilia A prevalence around the world. Hemophilia. 2010;**16**(1):20-32 VIII and factor IX concentrates. Blood Transfusion. 2013;**11**(Suppl 4):s55-s63

[10] Lieuw K. Many factor VIII products available in the treatment of hemophilia A: An embarrassment of riches? Journal

Moerloose P. Exposure to factor VIII and prediction of inhibitor development: Exposure days vs. danger days, or both? Journal of Thrombosis and Haemostasis.

[12] Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Blackwell

Publishing Ltd; 2012. [Epub Jul 6, 2012]

of Blood Medicine. 2017;**8**:67-73

[11] Hermans C, Astermark J, de

2012;**10**:2194-2196

[2] Paula JD, Montgomery RR, Gill JC, Flood V. Hemophilia and von Willebrand disease. In: Nathan and Oski's Hematology and Oncology of Infancy and Childhood. 8th ed. Philadelphia: Elsevier Saunders; 2015.

[3] Scott JP, Flood VH. Hereditary clotting factor deficiencies (bleeding disorders). In: Nelson Textbook of Pediatrics. 20th ed. Philadelphia: Elsevier; 2015. pp. 2384-2389

[4] Kar A, Mirkazemi R, Singh P, Potnis-Lele M, Lohade S, Lalwani A, et al. Disability in Indian patients with haemophilia. Hemophilia.

[5] Plug I, Eveline P, Mauser-Bunschoten EP, Annette HJ, Brocker-Vriends AH, Hans KP, et al. Bleeding in carriers of hemophilia. Blood. 2006;**108**(1):52-56

[6] Matsumoto T, Shima M, Takeyama M, Yoshida K, Tanaka I, Sakurai Y, et al. The measurement of low level of factor VIII or factor IX in hemophilia A and hemophilia B plasma by clot waveform analysis and thrombin generation assay. Journal of Thrombosis and Haemostasis.

[7] Goodeve AC, Perry DJ, Cumming T, et al. Genetics of haemostasis. Haemophilia. 2012;**18**(Suppl 4):73-80

[8] Graw J, Brackmann H, Oldenberg J, et al. Hemophilia A: From mutations analysis to new therapies. Nature Reviews. Genetics. 2005;**6**:488-501

[9] Morfini M, Coppola A, Franchini M, Minno GD. Clinical use of factor

2007;**13**(4):398-404

2006;**4**:377-384

pp. 1028-1054

century, and the term haemophilia was first used in 1828 by Johann Lukas Schönlein and his student Friedrich Hopff [6].

The two diseases, haemophilia A (HA) and haemophilia B (HB), were initially regarded as the same and attributed to fragility of vessels [8]. The idea later shifted to abnormalities in platelets in the 1930s. It was in 1937, when Patek and Taylor found the 'anti-haemophilic globulin', extracted from plasma, to be the factor responsible. The two diseases were, however, first discriminated in 1944 by Pavlosky of Buenos Aires [8].

In haemophilia, the phenotype is expressed at three distinct levels: the coagulation activity, the factor antigen level and the clinical outcome in terms of bleeding and its complications. Plasma procoagulant level, determined by coagulation activity, is the most important clinical entity determining severity of the disease. Employing this parameter, the Scientific and Standardisation Committee classified haemophilia A and haemophilia B into three major classes, that is, mild, moderate and severe [9]. Each phenotype has a distinct clinical impact (Table 1). Patients with severe phenotype (plasma factor level < 0.01 IU/ml; <1% of normal) commonly present with frequent (two to five bleeding episodes per month) spontaneous bleeding into the joints or deep muscles. Patients with moderate severity of the disease (plasma factor level 0.01–0.05 IU/ml; 1–5% of normal) would bleed following mild trauma; spontaneous bleeding is seen uncommonly. Diagnosis is usually established in the first 5–6 years of life. Bleeding frequency ranges from once a month to once a year. In mild severity of the disease (plasma factor level >0.05 to <0.40 IU/ml; >5 to <40% of normal), bleeding occurs as a result of major trauma, e.g., surgery or accident. Bleeding is infrequent in these patients [10, 11].

This is, however, noteworthy that patients with a specific severity of the disease do not always behave as anticipated. Studies have reported a significant number of severe haemophilia cases with a milder phenotype [1, 12, 13]. In such cases, bleeding phenotype resembles that of moderate severity. These cases are hence treated like moderate haemophilia; prophylactic treatment is often not needed.

mutations are reported in F9 [14]. These mutations, summarised in Table 2, include all the major types of mutations. Point mutations are the most frequent, followed by small indel mutations. Repeat variants are not yet reported to associate with the disease. In majority of the cases, specific mutations result in the same disease severity, a phenomenon referred to as genotype-phenotype correlation [13, 15].

Mutation type F8 F9 Missense/nonsense 1674 748 Splicing 193 101 Regulatory 10 28 Small deletions 489 161 Small insertions 160 52 Small indels 38 17 Gross deletions 260 75 Gross insertions/duplications 40 7 Complex rearrangements 20 13 Repeat variations 0 0 Total 2884 1202

Penetrance refers to the appearance of disease in affected individuals, whereas expressivity is the degree of severity of disease in patients [16]. Haemophilia is an X-linked recessive genetic disorder with complete penetrance in most of the cases, that is, male individuals with pathogenic variants in F8 or F9 are mostly fated to have haemophilia. This stands true particularly in case of F8. Patients from the same family have approximately the same severity status. However, the severity, as described earlier, is not the same in all patients. Cases with the same mutations exhibiting different levels of coagulation factor activity advocate variable expressivity for the specific genotype. This variation is believed to be the outcome factors including genetic alterations or polymorphisms in other genes (especially those related to haemostasis, inflammation and immune response) and environmental factors [17]. It has been established that the same genotype subjected to different environments expresses diverse phenotypes [18]. This interaction between geno-

type and environment is called gene–environment interaction [19, 20].

Large structural changes in the protein, by default, tend to generate a severe phenotype. Nonsense mutations, particularly those occurring in the early gene segments, have a similar tendency. Almost all the nonsense mutations reported within the initial part of the gene are associated with severe disease phenotype. Frameshift mutations in F8/F9 gene are again usually associated with an adverse

Approximately 30% of the female individuals with heterozygous mutation have a coagulation factor activity less than 40% [22]. Increased bleeding tendency among

the carriers, in comparison to normal females, is well documented [23, 24].

2.1 Disease penetrance and expressivity

Frequency of different types of mutations reported in F8 and F9.

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

F8, factor VIII gene; F9, factor IX gene.

Table 2.

phenotype [21].

11


Table 1.

Haemophilia severity classification on the basis of FVIII:C/FIX:C levels.

#### 2. Genetic heterogeneity in haemophilia

Haemophilia was previously regarded as a classical example of Mendelian inheritance, with mutation in only one gene (F8 or F9) causing the disease phenotype. The concept, however, has significantly evolved in the last couple of decades, and the two diseases are now recognised to have a heterogeneous spectrum of mutations. More than 2800 mutations are reported in F8, whereas more than 1200


#### Table 2.

century, and the term haemophilia was first used in 1828 by Johann Lukas Schönlein

The two diseases, haemophilia A (HA) and haemophilia B (HB), were initially regarded as the same and attributed to fragility of vessels [8]. The idea later shifted to abnormalities in platelets in the 1930s. It was in 1937, when Patek and Taylor found the 'anti-haemophilic globulin', extracted from plasma, to be the factor responsible. The two diseases were, however, first discriminated in 1944 by

In haemophilia, the phenotype is expressed at three distinct levels: the coagulation activity, the factor antigen level and the clinical outcome in terms of bleeding and its complications. Plasma procoagulant level, determined by coagulation activity, is the most important clinical entity determining severity of the disease. Employing this parameter, the Scientific and Standardisation Committee classified haemophilia A and haemophilia B into three major classes, that is, mild, moderate and severe [9]. Each phenotype has a distinct clinical impact (Table 1). Patients with severe phenotype (plasma factor level < 0.01 IU/ml; <1% of normal) commonly present with frequent (two to five bleeding episodes per month) spontaneous bleeding into the joints or deep muscles. Patients with moderate severity of the disease (plasma factor level 0.01–0.05 IU/ml; 1–5% of normal) would bleed following mild trauma; spontaneous bleeding is seen uncommonly. Diagnosis is usually established in the first 5–6 years of life. Bleeding frequency ranges from once a month to once a year. In mild severity of the disease (plasma factor level >0.05 to <0.40 IU/ml; >5 to <40% of normal), bleeding occurs as a result of major trauma,

e.g., surgery or accident. Bleeding is infrequent in these patients [10, 11].

like moderate haemophilia; prophylactic treatment is often not needed.

haemostatic challenge

FVIII:C, factor VIII coagulation activity; FIX:C, factor IX coagulation activity.

Haemophilia severity classification on the basis of FVIII:C/FIX:C levels.

Haemophilia was previously regarded as a classical example of Mendelian inheritance, with mutation in only one gene (F8 or F9) causing the disease phenotype. The concept, however, has significantly evolved in the last couple of decades, and the two diseases are now recognised to have a heterogeneous spectrum of mutations. More than 2800 mutations are reported in F8, whereas more than 1200

2. Genetic heterogeneity in haemophilia

This is, however, noteworthy that patients with a specific severity of the disease do not always behave as anticipated. Studies have reported a significant number of severe haemophilia cases with a milder phenotype [1, 12, 13]. In such cases, bleeding phenotype resembles that of moderate severity. These cases are hence treated

Age at diagnosis Bleeding and haemarthroses

Severe ≤1 ≤2 years Spontaneous haemorrhages and haemarthroses since

Moderate 2–5 <6 years Haemorrhage are usually secondary to minor trauma or

early childhood

surgery; spontaneous haemarthrosis is unusual

Haemorrhage secondary to surgery or major trauma; spontaneous bleedings are rare

and his student Friedrich Hopff [6].

Hemophilia - Recent Advances

Pavlosky of Buenos Aires [8].

Severity FVIII:C/FIX: C level (%)

Table 1.

10

Mild 6–40 Subject to

Frequency of different types of mutations reported in F8 and F9.

mutations are reported in F9 [14]. These mutations, summarised in Table 2, include all the major types of mutations. Point mutations are the most frequent, followed by small indel mutations. Repeat variants are not yet reported to associate with the disease. In majority of the cases, specific mutations result in the same disease severity, a phenomenon referred to as genotype-phenotype correlation [13, 15].

#### 2.1 Disease penetrance and expressivity

Penetrance refers to the appearance of disease in affected individuals, whereas expressivity is the degree of severity of disease in patients [16]. Haemophilia is an X-linked recessive genetic disorder with complete penetrance in most of the cases, that is, male individuals with pathogenic variants in F8 or F9 are mostly fated to have haemophilia. This stands true particularly in case of F8. Patients from the same family have approximately the same severity status. However, the severity, as described earlier, is not the same in all patients. Cases with the same mutations exhibiting different levels of coagulation factor activity advocate variable expressivity for the specific genotype. This variation is believed to be the outcome factors including genetic alterations or polymorphisms in other genes (especially those related to haemostasis, inflammation and immune response) and environmental factors [17]. It has been established that the same genotype subjected to different environments expresses diverse phenotypes [18]. This interaction between genotype and environment is called gene–environment interaction [19, 20].

Large structural changes in the protein, by default, tend to generate a severe phenotype. Nonsense mutations, particularly those occurring in the early gene segments, have a similar tendency. Almost all the nonsense mutations reported within the initial part of the gene are associated with severe disease phenotype. Frameshift mutations in F8/F9 gene are again usually associated with an adverse phenotype [21].

Approximately 30% of the female individuals with heterozygous mutation have a coagulation factor activity less than 40% [22]. Increased bleeding tendency among the carriers, in comparison to normal females, is well documented [23, 24].

In case of F9 sequence variants, besides classical HB, four other phenotypes are reported. These are described in the following sections.

disrupts the binding site to variable extents of severity. The mutation c.-55G>C, however, occurs at a site which is overlapped by the HNF4 binding site and another

The F9 mutation c.1151G>T is associated with several fold increase in FIX:C activity [40]. The mutant FIX has leucine substituted for arginine at p.Arg384Leu. This alteration increases the affinity for FX to bind at this site. Patients might present with thromboembolic complications. This variant was named 'factor IX Padua'. Studies have also demonstrated that Arg-338 is part of an exosite (a secondary binding site) that binds factor X and heparin at the same time [41]. People with FIX:C levels more than 129 U/dL are 2–3 times more at risk of developing DVT in comparison to those with lower FIX:C levels. The risk is higher in females [42]. Variations in F9-associated single-nucleotide polymorphisms

The Malmo polymorphism, c.580G>A (p. Ala194Thr), has an allele frequency of

All vitamin K-dependent clotting factors [including FII, FVII, FIX, FX, protein C

Phenotypic plasticity is defined as 'the ability of individual genotypes to produce different phenotypes when exposed to different environmental conditions' [47]. In the current scenario, this refers to presentation of the same mutation with different

It has been found that the mutations with varying phenotypes (MVPs) mostly occur at the less conserved sites with Arg being the usual mutated residue. It is also noted that these mutations commonly occur at the CpG dinucleotides. In comparison, mutations with uniform phenotypes (MUPs) occur in more conserved sites, with cysteine as the most frequently mutated amino acid residue. Intrinsic protein structural changes have been reported with reduced severity in cases of MVPs. No significant structural variations are identified between the two groups. The phenomenon is hypothesised to be a function of multiple factors including modifier

(PC), protein S (PS) and protein Z (PZ)] possess an 18 amino acid propeptide sequence which serves as a binding site for the γ-glutamyl carboxylase enzyme. This enzyme catalyses modification of certain glutamate residues in the amino terminus of the mentioned clotting factors [46]. It has been determined that mutations at this

site reduce the affinity vitamin K-dependent γ-carboxylase for the proteins.

0.32 in the Western population. It has been found that people with the G allele (F9 Malmo) have a 15–43% decreased risk of developing DVT in comparison to those with A allele [44]. This protective role of F9 Malmo has been extensively studied and confirmed [45]. The biochemical mechanisms behind this phenomenon

regulatory region, the androgen-responsive element (ARE) [39].

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

(SNPs) do not explain this raise in FIX antigen levels [43].

2.1.2 Thrombophilia

2.1.3 Protection against DVT

are still obscure.

2.1.4 Warfarin sensitivity

3. Phenotypic plasticity

severities of the disease.

13

3.1 Genetic basis of phenotypic plasticity

#### 2.1.1 Haemophilia B Leyden

Haemophilia B Leyden is a specific type of HB in which the patient presents with decreased FIX:C levels in the early childhood, but the levels progressively increase after puberty. The disease is postulated to occur as a result of mutation in the 50 bp region that spans the transcriptional start site [25]. A total of 23 promoter region mutations have been identified until now (Table 3).

The mutation at c.-55G>C (or c. -26G>C in legacy nucleotide numbering) found in the promoter region of F9 gene is also called the haemophilia B Brandenburg mutation [38]. Unlike HB Leyden this variant does not exhibit improvement in FIX: C levels with age. The promoter region sequence located at c.-34 to -10 of the F9 gene serves as a binding site for the hepatocyte nuclear factor 4 (HNF4). The liverenriched HNF4 is a member of the steroid hormone receptor superfamily of transcription factors (also called the nuclear receptor superfamily). Mutation at HNF4


#### Table 3.

F9 promoter site mutations associated with HB Leyden (mutation c.-55G>C is an exception).

disrupts the binding site to variable extents of severity. The mutation c.-55G>C, however, occurs at a site which is overlapped by the HNF4 binding site and another regulatory region, the androgen-responsive element (ARE) [39].

#### 2.1.2 Thrombophilia

In case of F9 sequence variants, besides classical HB, four other phenotypes are

Haemophilia B Leyden is a specific type of HB in which the patient presents with decreased FIX:C levels in the early childhood, but the levels progressively increase after puberty. The disease is postulated to occur as a result of mutation in the 50 bp region that spans the transcriptional start site [25]. A total of 23 promoter region

The mutation at c.-55G>C (or c. -26G>C in legacy nucleotide numbering) found in the promoter region of F9 gene is also called the haemophilia B Brandenburg mutation [38]. Unlike HB Leyden this variant does not exhibit improvement in FIX: C levels with age. The promoter region sequence located at c.-34 to -10 of the F9 gene serves as a binding site for the hepatocyte nuclear factor 4 (HNF4). The liverenriched HNF4 is a member of the steroid hormone receptor superfamily of transcription factors (also called the nuclear receptor superfamily). Mutation at HNF4

HGVS cDNA name Legacy nucleotide no. Nature of mutation Disease severity Reference c.-55G>A -26 Substitution Moderate [26] c.-55G>C -26 Substitution Severe [27] c.-55G>T -26 Substitution Severe [28] c.-53A>G -24 Substitution Not reported [21] c.-52C>G -23 Substitution Not reported [21] c.-52C>T -23 Substitution Not reported [29] c.-50T>G -21 Substitution Not reported [30] c.-49T>A -20 Substitution Moderate/mild [31] c.-49T>C -20 Substitution Mild [32] c.-48G>C -19 Substitution Moderate/mild [29] c.-35G>A -6 Substitution Mild [33] c.-35G>C -6 Substitution Mild [34] c.-34A>G -5 Substitution Mild [26] c.-34A>T -5 Substitution Moderate [35] c.-24T>A 6 Substitution Mild [34] c.-23T>C 7 Substitution Not reported [21] c.-22T>C/c 8 Substitution Mild [36] c.-22delT 8 Deletion Moderate [21] c.-21C>G 9 Substitution Not reported [21] c.-18A>G 12 Substitution Moderate [21] c.-17A>C 13 Substitution Severe [26] c.-17A>G 13 Substitution Mild [37] c.-17delA 13 Deletion Mild [37]

reported. These are described in the following sections.

mutations have been identified until now (Table 3).

HGVS, Human Genome Variation Society; no., number.

F9 promoter site mutations associated with HB Leyden (mutation c.-55G>C is an exception).

Table 3.

12

2.1.1 Haemophilia B Leyden

Hemophilia - Recent Advances

The F9 mutation c.1151G>T is associated with several fold increase in FIX:C activity [40]. The mutant FIX has leucine substituted for arginine at p.Arg384Leu. This alteration increases the affinity for FX to bind at this site. Patients might present with thromboembolic complications. This variant was named 'factor IX Padua'. Studies have also demonstrated that Arg-338 is part of an exosite (a secondary binding site) that binds factor X and heparin at the same time [41].

People with FIX:C levels more than 129 U/dL are 2–3 times more at risk of developing DVT in comparison to those with lower FIX:C levels. The risk is higher in females [42]. Variations in F9-associated single-nucleotide polymorphisms (SNPs) do not explain this raise in FIX antigen levels [43].

#### 2.1.3 Protection against DVT

The Malmo polymorphism, c.580G>A (p. Ala194Thr), has an allele frequency of 0.32 in the Western population. It has been found that people with the G allele (F9 Malmo) have a 15–43% decreased risk of developing DVT in comparison to those with A allele [44]. This protective role of F9 Malmo has been extensively studied and confirmed [45]. The biochemical mechanisms behind this phenomenon are still obscure.

#### 2.1.4 Warfarin sensitivity

All vitamin K-dependent clotting factors [including FII, FVII, FIX, FX, protein C (PC), protein S (PS) and protein Z (PZ)] possess an 18 amino acid propeptide sequence which serves as a binding site for the γ-glutamyl carboxylase enzyme. This enzyme catalyses modification of certain glutamate residues in the amino terminus of the mentioned clotting factors [46]. It has been determined that mutations at this site reduce the affinity vitamin K-dependent γ-carboxylase for the proteins.

#### 3. Phenotypic plasticity

Phenotypic plasticity is defined as 'the ability of individual genotypes to produce different phenotypes when exposed to different environmental conditions' [47]. In the current scenario, this refers to presentation of the same mutation with different severities of the disease.

#### 3.1 Genetic basis of phenotypic plasticity

It has been found that the mutations with varying phenotypes (MVPs) mostly occur at the less conserved sites with Arg being the usual mutated residue. It is also noted that these mutations commonly occur at the CpG dinucleotides. In comparison, mutations with uniform phenotypes (MUPs) occur in more conserved sites, with cysteine as the most frequently mutated amino acid residue. Intrinsic protein structural changes have been reported with reduced severity in cases of MVPs. No significant structural variations are identified between the two groups. The phenomenon is hypothesised to be a function of multiple factors including modifier


HGVS cDNA

15

c.1639T>C c.1702G>A c.1754T>C c.1804C>T c.1809C>G c.2015\_2017del

c.2048A>G c.206\_212del

c.2090T>A c.2114-?\_5219+?del

c.2159G>A c.2182delT c.2373G>A c.2440C>T

c.266G>A c.2945dupA

c.296T>A c.3143G>A c.3300dupA

c.353A>G c.3637delA c.3637dupA

p.Ile1213Asnfs\*28

p.Glu1101Argfs\*17

p.His118Arg p.Ile1213Phefs\*5

p.Asn982Lysfs\*9

p.Val99Asp p.Trp1048\*

p.Gly720Asp p.Ser728Leufs\*23

p.Trp791\* p.Arg814\* p.Gly89Asp

Missense Frameshift

Nonsense Nonsense Missense Frameshift

Missense Nonsense Frameshift

Missense Frameshift Frameshift

Large structural change (>50 bp)

p.Leu69Glnfs\*21

p.Val697Asp

 p.Phe672del p.Tyr683Cys

Missense Frameshift

Missense

Substitution

Deletion

Substitution

 Deletion Substitution

Deletion

Substitution

Substitution

Substitution

Duplication

Substitution

Substitution

Duplication

Substitution

Deletion

Duplication

 14

 B

X

X

 14

 B

X

X

 3

 A1

X

X

 14

 B

X

X

 14

 B

X

X

 3

 A1

X

X

 14

 B

X

X

 3

 A1

X

X

 14

 B

X

X

 14

 B

X

X

 14

 A2

X

X

 14

 A2

X

X

 14

 A3

X

X

 13

 A2

X

X

 2

 A1

X

X

 13

 A2

X

X

 Small structural change (in-frame, <50 bp) Deletion

p.Cys547Arg p.Gly568Ser p.Ile585Thr

p.Arg602\* p.Ser603Arg

 HGVS protein

Mutation type

Missense Missense Missense Nonsense Missense

Mechanism

Substitution

Substitution

Substitution

Substitution

Substitution

 12

 13

 A2

X

X

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

> A2

X

X

 12

 A2

X

X

 12

 A2

X

X

 11

 A2

X

X

 11

 A2

X

X

 Exon

 Domain

 Severe (<1 U/dL) Moderate (1–5 U/dL) Mild (>5 U/dL)

#### Hemophilia - Recent Advances


#### Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

HGVS cDNA

14

c.1171C>T c.1172G>A c.1492G>A

c.396A>C c.4380delT

c.5122C>T c.5219+3A>G

c.5399G>A c.5663G>T

c.590T>G c.6356A>G c.6371A>G c.6506G>A c.6545G>A c.6683G>A c.6977G>A

c.902G>A c.1063C>T c.1226A>G c.1316G>T c.143+1567A>G

c.1475A>G

p.Tyr492Cys

p.Arg1800His

p.Arg1888Ile p.Val197Gly p.Gln2119Arg p.Tyr2124Cys p.Arg2169His p.Arg2182His p.Arg2228Gln p.Arg2326Gln

p.Arg301His

p.Arg355\* p.Glu409Gly p.Gly439Val

p.Asn1460Lysfs\*5

p.Arg1708Cys

 HGVS protein

p.Arg391Cys p.Arg391His p.Gly498Arg p.Glu132Asp

Mutation type

Missense Missense Missense Missense Frameshift

Missense Splice site change

Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Nonsense Missense Missense Splice site change

Missense

Mechanism

Substitution

Substitution

Substitution

Substitution

Deletion

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 10

 A2

X

X

 Intron 1

 9

 A2

X X

X

X

 8

 A2

X

X

 8

 A1

X

X

 7

 A1

X

X

X

 26

 C2

X

X

X

 24

 C2

X

X

X

 23

 C1

X

X

X

 23

 C1

X

X

X

 22

 C1

X

X

X

 22

 C1

X

X

X

 4

 A1

X

X

X

 17

 A3

X

X

X

 16

 A3

X

X

X

 Intron 14

 14

 a3

X X

X

X

X

X

 14

 B

X

X

X

 4

 A1

X

X

X

 10

 A2

X

X

X

Hemophilia - Recent Advances

 8

 a1

X

X

X

 8

 a1

X

X

X

 Exon

 Domain


HGVS cDNA

17

c.5999-?\_6429+?dup

c.602-?\_787+?del

c.6046C>T c.6133G>A c.6172G>C c.6274-?\_6429+?del

c.6403C>T c.6429+?\_6430-?inv

c.6481C>T c.6485C>T c.6496C>T c.6544C>T c.6593G>T c.6682C>G c.6682C>T c.670+5G>A

c.6742T>A c.6875\_6876del

c.6967C>T c.6977G>T c.6994T>C

c.764G>C

p.Phe2294Serfs\*90

p.Arg2323Cys p.Arg2326Leu p.Trp2332Arg

p.Gly255Ala

p.Trp2248Arg

p.Pro2161Ser p.Pro2162Leu

p.Arg2166\* p.Arg2182Cys p.Gly2198Val p.Arg2228Gly

p.Arg2228\*

Missense Missense Nonsense Missense Missense Missense Nonsense Splice site change

Missense Frameshift

Missense Missense Missense Missense

Large structural change (>50 bp)

p.Arg2135\*

Nonsense

Large structural change (>50 bp)

p.Arg2016Trp p.Gly2045Arg p.Ala2058Pro

Missense Missense Missense

 HGVS protein

Mutation type Large structural change (>50 bp) Large structural change (>50 bp)

Mechanism

 Duplication

 Deletion Substitution

Substitution

Substitution

 Deletion Substitution

 Inversion Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Deletion

Substitution

Substitution

Substitution

Substitution

 6

 A1

X

X

 26

 C2

X

X

 26

 C2

X

X

 26

 C2

X

X

 25

 C2

X

X

 25

 C2

X

X

 Intron 5

 24

 C2

X X

X

X

 24

 C2

X

X

 24

 C2

X

X

 23

 C1

X

X

 23

 C1

X

X

 23

 C1

X

X

 23

 C1

X

X

 Intron 22

 22

 C1

X X

X

X

 22

 C1

X

X

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

> 20

 C1

X

X

 20

 C1

X

X

 19

 A3

 5–6

X

X

XX

 19–22

 Exon

 Domain

 Severe (<1 U/dL) Moderate (1–5 U/dL) Mild (>5 U/dL)

X

X


#### Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

HGVS cDNA

16

c.3702\_3705del

c.388G>C c.421G>A c.4296\_4300del

c.4379dupA

c.43C>T c.4796G>A c.4825dupA

c.491G>A c.5113C>T

c.515G>T c.5219G>T c.5471dupA

c.5536A>T

c.556G>T c.5606G>T c.5685delT

c.5719A>T c.5878C>T c.5953C>T c.5973\_5976del

c.5998+1G>A

p.Met1992Hisfs\*37

p.Phe1895Leufs\*50

p.Ser1907Cys

p.Arg1960\* p.Arg1985\*

p.Asn1824Lysfs\*6

p.Lys1846\* p.Asp186Tyr p.Gly1869Val

p.Thr1609Asnfs\*4

p.Gly164Asp

p.Gln1705\* p.Cys172Phe p.Arg1740Met

p.Asn1460Lysfs\*2

p.Arg15\* p.Trp1599\*

p.His1434Serfs\*6

p.His1234Glnfs\*2

p.Gly130Arg p.Glu141Lys

 HGVS protein

Mutation type

Frameshift

Missense Missense Frameshift Frameshift

Nonsense Nonsense Frameshift

Missense Nonsense Missense Missense Frameshift

Nonsense Missense Missense Frameshift

Missense Nonsense Nonsense Frameshift Splice site change

Mechanism

Deletion

Substitution

Substitution

Deletion

Duplication

Substitution

Substitution

Duplication

Substitution

Substitution

Substitution

Substitution

Duplication

Substitution

Substitution

Substitution

Deletion

Substitution

Substitution

Substitution

Deletion

Substitution

 Intron 18

 18

 A3

X X

X

X

 18

 A3

X

X

 18

 A3

X

X

 17

 A3

X

X

 17

 A3

X

X

 17

 A3

X

X

 4

 A1

X

X

 16

 A3

X

X

 16

 A3

X

X

 14

 A3

X

X

 4

 A1

X

X

 14

 a3

X

X

 4

 A1

X

X

 14

 B

X

X

 14

 B

X

X

 1

 Signal

X

X

 14

 B

X

X

 14

 B

X

X

 4

 A1

X

X

Hemophilia - Recent Advances

 3

 A1

X

X

 14

 B

X

X

 Exon

 Domain


HGVS cDNA

19

c.1569G>T c.1636C>T c.1648C>T c.1660A>G c.1834C>T c.2044G>T c.2149C>T c.2167G>A

c.274G>A

c.311T>A c.410C>T c.5096A>T c.5143C>G c.5339C>A c.5393C>T c.5398C>G

c.541G>A c.5428T>C c.5526G>A c.5557G>A c.5618C>T c.5825G>C c.5879G>A

p.= p.Arg546Trp p.Arg550Cys p.Ser554Gly p.Arg612Cys p.Val682Phe p.Arg717Trp p.Ala723Thr

p.Gly92Ser p.Val104Asp

p.Thr137Ile p.Tyr1699Phe p.Arg1715Gly p.Pro1780Gln p.Ala1798Val p.Arg1800Gly

p.Val181Met p.Ser1810Pro p.Met1842Ile p.Ala1853Thr p.Pro1873Leu p.Gly1942Ala p.Arg1960Gln

 HGVS protein

Mutation type

Synonymous

Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense

Mechanism

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 18

 A3

 18

 A3

 17

 A3

 16

 A3

 16

 A3

 16

 A3

 4

 A1

 16

 A3

 16

 A3

 15

 A3

 14

 A3

 14

 a3

 4

 A1

 3

 A1

 3

 A1

 14

 A2

 14

 A2

 13

 A2

 12

 A2

 11

 A2

 11

 A2

 11

 A2

 11

 A2

X X X X X X X X X X X X X X X X X X X X X X X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

X

X

X

X

X

 Exon

 Domain


#### Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

HGVS cDNA

18

c.785C>T c.787+3A>G

c.822G>C c.901C>T c.954\_955del

c.991\_992del

c.1043G>A

c.121G>T c.1409C>T c.1751A>G c.1910A>G c.3870dupA

c.437A>C c.5150A>G c.5183A>G c.6273+1G>T

c.677G>T c.6967C>G

c.902G>T

c.923C>T c.1293G>T c.1348T>A c.1408C>A

p.Ser226Ile p.Arg2323Gly p.Arg301Leu p.Ser308Leu p.Leu431Phe p.Tyr450Asn p.Pro470Thr

p.Gly1291Argfs\*29

p.Lys146Thr p.Tyr1717Cys p.Tyr1728Cys

p.Ile331Leufs\*6

p.Cys348Tyr

p.Gly41Cys p.Pro470Leu p.Gln584Arg p.Asn637Ser

p.Leu319Aspfs\*18

p.Trp274Cys p.Arg301Cys

 HGVS protein

p.Pro262Leu

Mutation type

Missense Splice site change

Missense Missense Frameshift Frameshift

Missense Missense Missense Missense Missense Frameshift

Missense Missense Missense Splice site change

Missense Missense Missense Missense Missense Missense Missense

Mechanism

Substitution

Substitution

Substitution

Substitution

Deletion

Deletion

Substitution

Substitution

Substitution

Substitution

Substitution

Duplication

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 9

 A2

 9

 A2

 9

 A2

X

X

X

X

X

X

 7

 A1

X

 7

 A1

X

 26

 C2

X

 6

 A1

X

 Intron 21

 14

 A3

X

X

 14

 A3

X

 4

 A1

X

 14

 B

X

 13

 A2

X

 11

 A2

X

 9

 A2

X

 1

 A1

X

 8

 A1

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

 7

 A1

X

X

 7

 A1

X

X

 7

 A1

X

X

 7

 A1

X

X

Hemophilia - Recent Advances

 Intron 6

 6

 A1

X

X

X

X

 Exon

 Domain


Table 4. of F8 mutations reported with phenotypic plasticity.

List HGVS cDNA name HGVS protein name

21

c.87A>G c.127C>T c.128G>A c.172G>A c.173G>A c.191G>A c.259T>G c.301C>G c.316G>A c.412A>C c.415G>A

c.571C>T c.572G>A c.720G>T c.755G>A c.797C>T c.835G>A c.838G>C c.881G>A c.914A>G c.987C>G c.1009G>A

p.Thr29Thr p.Arg43Trp p.Arg43Gln p.Gly58Arg p.Gly58Glu p.Cys64Tyr p.Phe87Val p.Pro101Ala p.Gly106Ser p.Asn138His p.Gly139Ser p.Arg191Cys p.Arg191His p.Trp240Cys p.Cys252Tyr p.Ala266Val p.Ala279Thr p.Gly280Arg p.Arg294Gln p.Tyr305Cys p.Ser329Arg p.Ala337Thr

Synonymous

Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 7

 Protease

 X

 7

 Protease

 X

 7

 Protease

 X

 7

 Protease

 X

 6

 Protease

 X

 6

 Linker

 X

 6

 Linker

 X

 5

 EGF2

 X

 5

 EGF2

 X

 4

 EGF1

 X

 4

 EGF1

 X

 3

 GLA

 X

 2

 GLA

 X

 2

 GLA

 X

 2

 GLA

 X

 2

 PRO

 X

 2

 PRO

 X

 1

 PRO

 X

X X X X X X X X X X X X X X X X X X X X X X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

X

X

X

X

Mutation type

Mechanism

 Exon

 Domain

 Severe

Moderate (1–5 U/dL) Mild (>5 U/dL)


#### Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

HGVS cDNA

20

c.5921C>T c.5954G>A c.601+1632G>A

c.6113A>G c.6119G>A c.6212G>C c.6278A>G c.6350T>G c.6413C>A c.6443A>G c.6520C>G c.6532C>T

c.668A>C c.670+6T>C

c.6744G>T

c.67A>G c.6915T>G c.6920A>C c.6956C>T

c.755C>T c.871G>A

Table 4. List of F8 mutations reported with phenotypic

 plasticity.

p.Trp2248Cys

p.Arg23Gly p.Asn2305Lys p.Asp2307Ala p.Pro2319Leu

p.Thr252Ile p.Glu291Lys

p.Asn2038Ser p.Cys2040Tyr p.Arg2071Thr p.Asp2093Gly

p.Ile2117Ser p.Ser2138Tyr p.Asn2148Ser p.His2174Asp p.Arg2178Cys

p.Glu223Ala

p.Ser1974Phe p.Arg1985Gln

 HGVS protein

Mutation type

Missense Missense Splice site change

Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Splice site change

Missense Missense Missense Missense Missense Missense Missense

Mechanism

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 7

 A1

 6

 A1

 26

 C2

 26

 C2

 26

 C2

 1

 A1

 25

 C2

 Intron 5

 5

 A1

 23

 C1

 23

 C1

 23

 C1

 22

 C1

 22

 C1

 22

 C1

 21

 C1

 20

 C1

 19

 A3

 Intron 4

 18

 A3

 18

 A3

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Hemophilia - Recent Advances

X

X

 Exon

 Domain


HGVS cDNA name HGVS protein name

23

c.226G>A c.260T>G c.263G>A c.291T>G c.304T>C c.305G>A c.350G>A c.383G>A c.392delA c.414T>A c.422G>A c.423C>A c.423C>G c.427C>G c.434G>A c.464G>T c.470G>A c.470G>C c.479G>T c.482A>G c.484C>T c.509G>A

p.Glu76Lys p.Phe87Cys

p.Trp88\* p.Cys97Trp p.Cys102Arg p.Cys102Tyr p.Cys117Tyr p.Cys128Tyr

p.Asp131fs p.Asn138Lys p.Cys141Tyr

p.Cys141\* p.Cys141Trp p.Gln143Glu p.Cys145Tyr p.Cys155Phe p.Cys157Tyr p.Cys157Ser p.Gly160Val p.Tyr161Cys

p.Arg162\* p.Ser170Tyr

Missense Missense Nonsense Missense Missense Missense Missense Missense Frameshift

Missense Missense Nonsense Missense Missense Missense Missense Missense Missense Missense Missense Nonsense Missense

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Deletion

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 5

 EGF2

 X

 4

 EGF1

 X

 4

 EGF1

 X

 4

 EGF1

 X

 4

 EGF1

 X

 4

 EGF1

 X

 3

 GLA

 X

 3

 GLA

 X

 2

 GLA

 X

X

X

X

X

X

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Mutation type

Mechanism

 Exon

 Domain

 Severe

Moderate (1–5 U/dL) Mild (>5 U/dL)

> (< 1 U/dL)

Hemophilia - Recent Advances


Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

HGVS cDNA name HGVS protein name

22

c.1025C>T c.1135C>T c.1136G>A c.1187G>C c.1235G>A c.1240C>A

c.1275A>C c.1304G>A c.1306G>A

c.1328T>C c.\*2545A>G

c.-17A>G c.-35G>A c.-35G>C

c.50T>A c.83G>A c.128G>T c.138G>T c.190T>C c.199G>A c.219A>C c.223C>T

p.Ile17Asn p.Cys28Tyr p.Arg43Leu p.Arg47Ser p.Cys64Arg p.Glu67Lys p.Glu73Asp p.Arg75Stop

p.Thr342Met

p.Arg379\* p.Arg379Gln p.Cys396Ser p.Gly412Glu p.Pro414Thr p.Leu425Phe p.Cys435Tyr p.Ala436Thr

p.Ile443Thr

Missense Nonsense Missense Missense Missense Missense Missense Missense Missense Missense

30UTR Promoter Promoter Promoter Missense Missense Missense Missense Missense Missense Missense Nonsense

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 2

 GLA

 X

 2

 GLA

 X

 2

 GLA

 X

 2

 GLA

 X

 2

 PRO

 X

 2

 PRO

 X

 1 Signal peptide

 1 Signal peptide

 X

 X

 50UTR

 50UTR

 1

 30UTR

 8

 Protease

 X X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Hemophilia - Recent Advances

X

X

Mutation type

Mechanism

 Exon

 Domain

 Severe

Moderate (1–5 U/dL) Mild (>5 U/dL)


HGVS cDNA name HGVS protein name

25

c.871G>A c.880C>T c.881G>T c.892C>T c.946A>T c.990C>A c.1004G>T c.1009G>C c.1068G>C c.1069G>A c.1070G>A c.1076T>G c.1097C>A c.1108C>T c.1113C>A c.1120G>T c.1135C>G c.1144T>C c.1147C>T c.1150C>T c.1168A>T c.1169T>G

p.Glu291Lys

p.Arg294\* p.Arg294Leu

p.Arg298\* p.Ile316Phe

p.Tyr330\* p.Cys335Tyr p.Ala337Pro p.Trp356Cys p.Gly357Arg p.Gly357Glu p.Val359Gly p.Ala366Asp

p.Gln370\* p.Tyr371\* p.Val374Glu p.Arg379Gly p.Cys382Arg p.Leu383Phe

p.Arg384\* p.Ile390Phe p.Ile390Ser

Missense Nonsense Missense Nonsense Missense Nonsense Missense Missense Missense Missense Missense Missense Missense Nonsense Nonsense Missense Missense Missense Missense Nonsense Missense Missense

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

X

X

X

X

X

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Mutation type

Mechanism

 Exon

 Domain

 Severe

Moderate (1–5 U/dL) Mild (>5 U/dL)


#### Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

HGVS cDNA name HGVS protein name

24

c.520G>A

c.532T>C c.535G>A c.545\_546del

c.547delG c.676C>T c.677G>A c.677G>T c.688\_690del

c.706G>T c.707G>A c.711A>G c.719G>A c.719G>T c.721C>T c.723G>A c.727\_728delinsA

c.757G>A c.789\_790InsT

c.799C>T c.839G>T

p.Gly253Arg

p.Thr264fs p.His267Tyr p.Gly280Val

Missense Frameshift

Missense Missense

 p.Val243fs

p.Val174Met p.Cys178Arg p.Gly179Arg p.Ser182Cysfs\*6

p.Val183fs p.Arg226Trp p.Arg226Gln p.Arg226Leu p.Gly230del

p.Gly236Cys p.Gly236Asp p.Gln237Gln

p.Trp240\* p.Trp240Leu

p.Gln241\* p.Gln241Gln

Missense Missense Synonymous

Nonsense Missense Nonsense Synonymous

Frameshift

 Small structural change (in-frame, <50 bp)

Missense Missense Missense Frameshift Frameshift

Missense Missense Missense

Substitution

Substitution

Substitution

Deletion

Deletion

Substitution

Substitution

Substitution

 Deletion Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Insertion/

7

 Protease

 X

deletion

Substitution

Insertion

Substitution

Substitution

 8

 Protease

 X

 7

 Protease

 X

 7

 Protease

 X

 7

 Protease

 X

X

X

X

X

 6

 Protease

 X

 6

 Protease

 X

 6

 Protease

 X

 6

 Protease

 X

 6

 Protease

 X

 6

 Protease

 X

 6

 Protease

 X

 6

 Protease

 X

 6

 Activation

 X

 6

 Activation

 X

 6

 Activation

 X

 6

 Linker

 X

 6

 Linker

 X

 6

 Linker

 X

 6

 Linker

 X

 5

 EGF2

 X

X

X

X

Hemophilia - Recent Advances

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Mutation type

Mechanism

 Exon

 Domain

 Severe

Moderate (1–5 U/dL) Mild (>5 U/dL)


HGVS cDNA name HGVS protein name

27

c.1307C>T c.1318A>G c.1324G>A

c.1357T>C c.1361T>C c.\*1157A>G c.252+3\_252+6del

c.252+6T>C c.253-25A>G

c.277+2T>C c.277+5G>A c.392-1G>C c.392-2A>G c.521-3T>G

c.-55G>A c.723+1G>A c.839-4A>G c.88+1\_88+4del

c.88+1G>T c.88+5G>C c.88+5G>T

c.19A>T

p.Ile7Phe

p.Ala436Val p.Lys440Glu p.Gly442Arg p.Trp453Arg

p.Ile454Thr

Missense Missense Missense Missense Missense

30UTR Splice site change Splice site change Splice site change Splice site change Splice site change Splice site change Splice site change Splice site change

Promoter Splice site change Splice site change Splice site change Splice site change Splice site change Splice site change

Missense

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Deletion

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Deletion

Substitution

Substitution

Substitution

Substitution

 1 Signal peptide

 X

 Intron 1

 Intron 1

 Intron 1

 Intron 1

 Intron 7

 Intron 6

 50UTR

 Intron 5

 Intron 4

 Intron 4

 Intron 3

 Intron 3

 Intron 2

 Intron 2

 Intron 2

 30UTR

 8

 Protease

 X X X X X X X X X X X X X X X X X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

X

X

X

X

X

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

Mutation type

Mechanism

 Exon

 Domain

 Severe

Moderate (1–5 U/dL) Mild (>5 U/dL)


#### Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

HGVS cDNA name HGVS protein name

26

c.1181T>A c.1204G>A

c.1217C>G c.1217C>T c.1219T>C c.1226G>A c.1228G>A c.1228G>C c.1232G>A c.1237G>A c.1241C>T c.1245T>A c.1256T>A c.1258G>T c.1291T>C c.1293G>T c.1294G>A c.1295G>A c.1295G>C c.1295G>T c.1297G>A c.1298A>C

p.Met394Lys p.Gly402Arg

p.Ser406\* p.Ser406Leu p.Cys407Arg p.Gly409Glu p.Asp410Asn p.Asp410His p.Ser411Asn p.Gly413Arg p.Pro414Leu p.His415Gln p.Val419Glu

p.Glu420\* p.Trp431Arg p.Trp431Cys p.Gly432Ser p.Gly432Asp p.Gly432Ala p.Gly432Val p.Glu433Lys p.Glu433Ala

Missense Missense Nonsense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Nonsense Missense Missense Missense Missense Missense Missense Missense Missense

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

X

X

X

Hemophilia - Recent Advances

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Mutation type

Mechanism

 Exon

 Domain

 Severe

Moderate (1–5 U/dL) Mild (>5 U/dL)


HGVS cDNA name HGVS protein name

29

c.484C>A c.572G>C c.785T>C c.786T>G c.839G>C c.872A>G c.950C>T c.997C>A c.1067G>T c.1097C>T

c.1127T>C c.1180A>G

c.1187G>T c.1193G>C c.1348T>C

c.-48G>C c.-49T>A c.520+13A>G

c.88+5G>A

Table 5. List of F9 mutations reported with phenotypic

 plasticity.

p.Arg162Arg p.Arg191Pro p.Ile262Thr p.Ile262Met p.Gly280Ala p.Glu291Gly p.Ala317Val p.Pro333Thr p.Trp356Leu p.Ala366Val p.Leu376Pro p.Met394Val p.Cys396Phe p.Gly398Ala p.Tyr450His

Synonymous

Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Promoter Promoter Splice site change Splice site change

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 Intron 1

 Intron 5

 50UTR

 50UTR

 8

 Protease

 8

 Protease

 8

 Protease

 8

 Protease

 8

 Protease

 8

 Protease

 8

 Protease

 8

 Protease

 8

 Protease

 8

 Protease

 8

 Protease

 7

 Protease

 7

 Protease

 6

 Linker

 5

 EGF2

X X X X X X X X X X X X X X X X X X X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

X

X

X

X

Mutation type

Mechanism

 Exon

 Domain

 Severe

Moderate (1–5 U/dL) Mild (>5 U/dL)

> (< 1 U/dL)

#### Hemophilia - Recent Advances


#### Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

Table 5. ListofF9mutations

reported with phenotypic

 plasticity.

HGVS cDNA name HGVS protein name

28

c.164T>G c.339T>A c.466T>C c.676C>G c.685G>A c.907C>T c.942T>G c.1045G>T c.1072A>G c.1079T>C c.1109A>C c.1174A>G c.1238G>A c.252+5G>A c.839-1G>A

c.82T>C c.151A>G c.163T>A c.279T>A c.335T>C c.479G>A c.479G>C

p.Cys28Arg p.Lys51Glu p.Phe55Ile p.Asp93Glu p.Ile112Thr p.Gly160Glu p.Gly160Ala

p.Phe55Cys p.Asn113Lys p.Ser156Phe p.Arg226Gly p.Gly229Ser p.His303Tyr p.His314Gln

p.Gly349\* p.Arg358Gly p.Phe360Ser p.Gln370Pro p.Asn392Asp p.Gly413Glu

Missense Missense Missense Missense Missense Missense Missense Nonsense Missense Missense Missense Missense Missense Splice site change Splice site change

Missense Missense Missense Missense Missense Missense Missense

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

Substitution

 5

 EGF2

 5

 EGF2

 4

 EGF1

 4

 EGF1

 2

 GLA

 2

 GLA

 1 Signal peptide

 Intron 7

 Intron 2

 8

 Protease

 X X X X X X X X X X

X

X

X

X

X

X

X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 8

 Protease

 X

 6

 Protease

 X

 6

 Activation

 X

 5

 EGF2

 X

 4

 EGF1

 X

 2

 GLA

 X

X

X

X

Hemophilia - Recent Advances

X

X

X

X

X

X

X

X

X

X

X

X

Mutation type

Mechanism

 Exon

 Domain

 Severe

Moderate (1–5 U/dL) Mild (>5 U/dL)

#### Hemophilia - Recent Advances

genes, epigenetic influences and environmental effects. These factors may act individually or in combination [48].

Tables 4 and 5 depict F8 and F9 mutations, respectively, reported with phenotypic plasticity [49, 50]. A total of 351 mutations are presented here with cases reported from at least two severity classes. The most significant are the 85 cases (32 from F8 and 53 from F9) wherein patients from both severe and mild categories are reported.

References

(3–4):131-138

2006;8(3):462-476

160(4):636-645

(Supp. 1):S4-S9

[1] Jayandharan GR, Srivastava A. The phenotypic heterogeneity of severe hemophilia. Seminars in Thrombosis and Hemostasis. 2008;34(1):128-141

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

> GeneReviews®. Seattle, WA: University of Washington, Seattle. 2000. Available from: https://www.ncbi.nlm.nih.gov/

> [11] Konkle BA, Huston H, Nakaya Fletcher S. Hemophilia A. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, et al., editors. GeneReviews((R)). Seattle (WA): University of Washington, Seattle; 1993. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved

[12] van den Berg HM, De Groot PH, Fischer K. Phenotypic heterogeneity in

Thrombosis and Haemostasis. 2007;5

[13] Khan MTM, Naz A, Ahmed J, Shamsi T, Ahmed S, Ahmed N, et al. Mutation spectrum and genotypephenotype analyses in a Pakistani cohort with hemophilia B. Clinical and Applied Thrombosis/Hemostasis: Official Journal of the International Academy of Clinical and Applied Thrombosis/ Hemostasis. 2018;24(5):741-748

[14] Zhao H, Yang Y, Lu Y, Mort M, Cooper DN, Zuo Z, et al. Quantitative mapping of genetic similarity in human heritable diseases by shared mutations. Human Mutation. 2018;

[15] Graw J, Brackmann HH, Oldenburg J, Schramm W, Schwaab R, editors. Genotype-phenotype correlation in hemophilia A. In: 30th Hemophilia Symposium Hamburg 1999; Berlin/

Heidelberg: Springer; 2001

[16] Zlotogora J. Penetrance and expressivity in the molecular age. Genetics in Medicine: Official Journal of

the American College of Medical Genetics. 2003;5(5):347-352

severe hemophilia. Journal of

(Supp. 1):151-156

39(2):292-301

books/NBK1495/

[3] Schulze TG, McMahon FJ. Defining the phenotype in human genetic studies:

phenotyping. Human Heredity. 2004;58

[4] Winawer MR. Phenotype definition in epilepsy. Epilepsy & Behavior: E&B.

[5] Gottesman II, Gould TD. The endophenotype concept in psychiatry: Etymology and strategic intentions. The American Journal of Psychiatry. 2003;

[6] Schramm W. The history of haemophilia—A short review. Thrombosis Research. 2014;134

[7] Ingram GI. The history of haemophilia. Journal of Clinical Pathology. 1976;29(6):469-479

Rare Diseases. 2012;7:24

Definitions in hemophilia. Recommendation of the scientific

[8] Franchini M, Mannucci PM. Past, present and future of hemophilia: A narrative review. Orphanet Journal of

[9] White GC 2nd, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J.

subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thrombosis

[10] Konkle BA, Josephson NC, Nakaya

and Haemostasis. 2001;85(3):560

Fletcher S. Hemophilia B. In:

31

[2] Wojczynski MK, Tiwari HK. Definition of phenotype. Advances in

Genetics. 2008;60:75-105

Forward genetics and reverse

Taking into account the significant amount of phenotypic plasticity in haemophilia, researchers have proposed to recognise the disease phenotype, in terms of coagulation activity, a continuous variable and abandoning of the classical categorical classification [51]. With the evolving concepts of personalised medicine, this may prove realistic… and the future.

#### Author details

Muhammad Tariq Masood Khan<sup>1</sup> \* and Abid Sohail Taj<sup>2</sup>


\*Address all correspondence to: drtariqmsd@gmail.com

<sup>© 2019</sup> The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

### References

genes, epigenetic influences and environmental effects. These factors may act

Taking into account the significant amount of phenotypic plasticity in haemophilia, researchers have proposed to recognise the disease phenotype, in terms of coagulation activity, a continuous variable and abandoning of the classical categorical classification [51]. With the evolving concepts of personalised medicine,

Tables 4 and 5 depict F8 and F9 mutations, respectively, reported with phenotypic plasticity [49, 50]. A total of 351 mutations are presented here with cases reported from at least two severity classes. The most significant are the 85 cases (32 from F8 and 53 from F9) wherein patients from both severe and mild categories are

\* and Abid Sohail Taj<sup>2</sup>

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

individually or in combination [48].

Hemophilia - Recent Advances

this may prove realistic… and the future.

reported.

Author details

30

Muhammad Tariq Masood Khan<sup>1</sup>

1 Northwest School of Medicine, Peshawar, Pakistan

\*Address all correspondence to: drtariqmsd@gmail.com

2 Peshawar General Hospital, Peshawar, Pakistan

provided the original work is properly cited.

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[2] Wojczynski MK, Tiwari HK. Definition of phenotype. Advances in Genetics. 2008;60:75-105

[3] Schulze TG, McMahon FJ. Defining the phenotype in human genetic studies: Forward genetics and reverse phenotyping. Human Heredity. 2004;58 (3–4):131-138

[4] Winawer MR. Phenotype definition in epilepsy. Epilepsy & Behavior: E&B. 2006;8(3):462-476

[5] Gottesman II, Gould TD. The endophenotype concept in psychiatry: Etymology and strategic intentions. The American Journal of Psychiatry. 2003; 160(4):636-645

[6] Schramm W. The history of haemophilia—A short review. Thrombosis Research. 2014;134 (Supp. 1):S4-S9

[7] Ingram GI. The history of haemophilia. Journal of Clinical Pathology. 1976;29(6):469-479

[8] Franchini M, Mannucci PM. Past, present and future of hemophilia: A narrative review. Orphanet Journal of Rare Diseases. 2012;7:24

[9] White GC 2nd, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thrombosis and Haemostasis. 2001;85(3):560

[10] Konkle BA, Josephson NC, Nakaya Fletcher S. Hemophilia B. In:

GeneReviews®. Seattle, WA: University of Washington, Seattle. 2000. Available from: https://www.ncbi.nlm.nih.gov/ books/NBK1495/

[11] Konkle BA, Huston H, Nakaya Fletcher S. Hemophilia A. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, et al., editors. GeneReviews((R)). Seattle (WA): University of Washington, Seattle; 1993. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved

[12] van den Berg HM, De Groot PH, Fischer K. Phenotypic heterogeneity in severe hemophilia. Journal of Thrombosis and Haemostasis. 2007;5 (Supp. 1):151-156

[13] Khan MTM, Naz A, Ahmed J, Shamsi T, Ahmed S, Ahmed N, et al. Mutation spectrum and genotypephenotype analyses in a Pakistani cohort with hemophilia B. Clinical and Applied Thrombosis/Hemostasis: Official Journal of the International Academy of Clinical and Applied Thrombosis/ Hemostasis. 2018;24(5):741-748

[14] Zhao H, Yang Y, Lu Y, Mort M, Cooper DN, Zuo Z, et al. Quantitative mapping of genetic similarity in human heritable diseases by shared mutations. Human Mutation. 2018; 39(2):292-301

[15] Graw J, Brackmann HH, Oldenburg J, Schramm W, Schwaab R, editors. Genotype-phenotype correlation in hemophilia A. In: 30th Hemophilia Symposium Hamburg 1999; Berlin/ Heidelberg: Springer; 2001

[16] Zlotogora J. Penetrance and expressivity in the molecular age. Genetics in Medicine: Official Journal of the American College of Medical Genetics. 2003;5(5):347-352

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[28] Belvini D, Salviato R, Radossi P, Pierobon F, Mori P, Castaldo G, et al. Molecular genotyping of the Italian cohort of patients with hemophilia B. Haematologica. 2005;90(5):635-642

[29] Ketterling RP, Liu JZ, Liao D, Kasper CK, Ambriz R, Paredes R, et al. Two novel factor IX promoter mutations: Incremental progress towards 'saturation in vivo mutagenesis' of a human promoter region. Human Molecular Genetics. 1995;4(4):769-770

[30] Reijnen MJ, Peerlinck K, Maasdam D, Bertina RM, Reitsma PH. Hemophilia B Leyden: Substitution of thymine for guanine at position 21 results in a disruption of a hepatocyte nuclear factor 4 binding site in the factor IX promoter. Blood. 1993;82(1):151-158

[31] Reitsma PH, Bertina RM, Ploos van Amstel JK, Riemens A, Briet E. The putative factor IX gene promoter in hemophilia B Leyden. Blood. 1988; 72(3):1074-1076

[32] Ghanem N, Costes B, Martin J, Vidaud M, Rothschild C, Foyer-Gazengel C, et al. Twenty-four novel hemophilia B mutations revealed by rapid scanning of the whole factor IX gene in a French population sample. European Journal of Human Genetics. 1993;1(2):144-155

Genotype-Phenotype Heterogeneity in Haemophilia DOI: http://dx.doi.org/10.5772/intechopen.81429

[33] Hirosawa S, Fahner JB, Salier JP, Wu CT, Lovrien EW, Kurachi K. Structural and functional basis of the developmental regulation of human coagulation factor IX gene: Factor IX Leyden. Proceedings of the National Academy of Sciences of the United States of America. 1990;87(12):4421-4425

[17] Pavlova A, Oldenburg J. Defining severity of hemophilia: More than factor levels. Seminars in Thrombosis and Hemostasis. 2013;39(7):702-710

Hemophilia - Recent Advances

a haemophilia B Leyden factor IX mutation. Nature Genetics. 1993;3(2):

Research. 1996;24(1):103-118

[27] Crossley M, Winship PR, Austen DE, Rizza CR, Brownlee GG. A less severe form of haemophilia B Leyden. Nucleic Acids Research. 1990;18(15):

[28] Belvini D, Salviato R, Radossi P, Pierobon F, Mori P, Castaldo G, et al. Molecular genotyping of the Italian cohort of patients with hemophilia B. Haematologica. 2005;90(5):635-642

[29] Ketterling RP, Liu JZ, Liao D, Kasper CK, Ambriz R, Paredes R, et al.

towards 'saturation in vivo mutagenesis' of a human promoter region. Human Molecular Genetics. 1995;4(4):769-770

[30] Reijnen MJ, Peerlinck K, Maasdam D, Bertina RM, Reitsma PH. Hemophilia B Leyden: Substitution of thymine for guanine at position 21 results in a disruption of a hepatocyte nuclear factor 4 binding site in the factor IX promoter. Blood. 1993;82(1):151-158

[31] Reitsma PH, Bertina RM, Ploos van Amstel JK, Riemens A, Briet E. The putative factor IX gene promoter in hemophilia B Leyden. Blood. 1988;

[32] Ghanem N, Costes B, Martin J, Vidaud M, Rothschild C, Foyer-Gazengel C, et al. Twenty-four novel hemophilia B mutations revealed by rapid scanning of the whole factor IX gene in a French population sample. European Journal of Human Genetics.

72(3):1074-1076

1993;1(2):144-155

Two novel factor IX promoter mutations: Incremental progress

[26] Giannelli F, Green PM, Sommer SS, Poon MC, Ludwig M, Schwaab R, et al. Haemophilia B (sixth edition): A database of point mutations and short additions and deletions. Nucleic Acids

175-179

4633

[18] Baye TM, Abebe T, Wilke RA. Genotype-environment interactions and

[19] Chanda P, Sucheston L, Liu S, Zhang A, Ramanathan M. Information-

theoretic gene-gene and geneenvironment interaction analysis of quantitative traits. BMC Genomics.

[20] Guo SW. Gene-environment interaction and the mapping of complex traits: Some statistical models and their implications. Human Heredity. 2000;

[21] Rallapalli PM, Kemball-Cook G, Tuddenham EG, Gomez K, Perkins SJ. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. Journal of Thrombosis and Haemostasis. 2013;

[22] Plug I, Mauser-Bunschoten EP, Brocker-Vriends AH, van Amstel HK, van der Bom JG, van Diemen-Homan JE, et al. Bleeding in carriers of hemophilia. Blood. 2006;108(1):52-56

[23] Paroskie A, Gailani D, DeBaun MR, Sidonio RF Jr. A cross-sectional study of bleeding phenotype in haemophilia A carriers. British Journal of Haematology.

[24] Khan MTM, Naz A, Ahmed J, Shamsi TS, Taj AS. Diagnosis and phenotypic assessment of Pakistani haemophilia B carriers. Pakistan Journal of Medical Sciences. 2017;33(3):738-742

[25] Picketts DJ, Lillicrap DP, Mueller CR. Synergy between transcription factors DBP and C/EBP compensates for

2009;10:509

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Personalized Medicine. 2011;8(1):59-70

their translational implications.

[34] Stenson PD, Mort M, Ball EV, Howells K, Phillips AD, Thomas NS, et al. The human gene mutation database: 2008 update. Genome Medicine. 2009;1(1):13

[35] Picketts DJ, D'Souza C, Bridge PJ, Lillicrap D. An A to T transversion at position 5 of the factor IX promoter results in hemophilia B. Genomics. 1992; 12(1):161-163

[36] Royle G, Van de Water NS, Berry E, Ockelford PA, Browett PJ. Haemophilia B Leyden arising de novo by point mutation in the putative factor IX promoter region. British Journal of Haematology. 1991;77(2):191-194

[37] Reitsma PH, Mandalaki T, Kasper CK, Bertina RM, Briet E. Two novel point mutations correlate with an altered developmental expression of blood coagulation factor IX (hemophilia B Leyden phenotype). Blood. 1989; 73(3):743-746

[38] Bowen DJ. Haemophilia A and haemophilia B: Molecular insights. Molecular Pathology. 2002;55(1):1-18

[39] Crossley M, Ludwig M, Stowell KM, De Vos P, Olek K, Brownlee GG. Recovery from hemophilia B Leyden: An androgen-responsive element in the factor IX promoter. Science. 1992; 257(5068):377-379

[40] Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). The New England Journal of Medicine. 2009; 361(17):1671-1675

[41] Chang J, Jin J, Lollar P, Bode W, Brandstetter H, Hamaguchi N, et al. Changing residue 338 in human factor IX from arginine to alanine causes an increase in catalytic activity. The Journal of Biological Chemistry. 1998;273(20): 12089-12094

[42] van Hylckama Vlieg A, van der Linden IK, Bertina RM, Rosendaal FR. High levels of factor IX increase the risk of venous thrombosis. Blood. 2000; 95(12):3678-3682

[43] van Minkelen R, de Visser MC, van Hylckama Vlieg A, Vos HL, Bertina RM. Sequence variants and haplotypes of the factor IX gene and the risk of venous thrombosis. Journal of Thrombosis and Haemostasis. 2008;6(9):1610-1613

[44] Bezemer ID, Bare LA, Doggen CJ, Arellano AR, Tong C, Rowland CM, et al. Gene variants associated with deep vein thrombosis. JAMA. 2008;299(11): 1306-1314

[45] Bezemer ID, Arellano AR, Tong CH, Rowland CM, Ireland HA, Bauer KA, et al. F9 Malmo, factor IX and deep vein thrombosis. Haematologica. 2009; 94(5):693-699

[46] Stanley TB, Jin DY, Lin PJ, Stafford DW. The propeptides of the vitamin Kdependent proteins possess different affinities for the vitamin K-dependent carboxylase. The Journal of Biological Chemistry. 1999;274(24):16940-16944

[47] Fusco G, Minelli A. Phenotypic plasticity in development and evolution: Facts and concepts. Philosophical Transactions of the Royal Society, B: Biological Sciences. 2010;365(1540): 547-556

[48] Chavali S, Sharma A, Tabassum R, Bharadwaj D. Sequence and structural properties of identical mutations with varying phenotypes in human coagulation factor IX. Proteins. 2008; 73(1):63-71

#### Hemophilia - Recent Advances

[49] Li T, Miller CH, Payne AB, Craig Hooper W. The CDC hemophilia B mutation project mutation list: A new online resource. Molecular Genetics & Genomic Medicine. 2013;1(4):238-245

[50] Payne AB, Miller CH, Kelly FM, Michael Soucie J, Craig Hooper W. The CDC hemophilia A mutation project (CHAMP) mutation list: A new online resource. Human Mutation. 2013;34(2): E2382-E2391

[51] Chavali S, Ghosh S, Bharadwaj D. Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. Genomics. 2009;94(6):433-437

**35**

**Chapter 3**

**Abstract**

minor surgery.

joint surgery

**1. Introduction**

patients with hemophilia is increasing annually.

tive management of patients with hemophilia.

Perioperative Management of

Major or Minor Surgery

*Atsushi Okamoto, Kenta Yamamoto, Go Eguchi,* 

Hemophilia A Using Recombinant

Factor VIII in Patients Undergoing

*Yoshitaka Kanai, Terufumi Yamaguchi and Yasuhiro Maeda*

Among the surgical treatments performed in patients with hemophilia, joint surgery for intra-articular bleeding is the most time-consuming. Previous reports describe the perioperative management of hemophiliacs undergoing coronary artery bypass grafting or of those undergoing cystectomy for treatment of hematuria. In the former study, the patient was elderly; in the latter study, the authors concluded that cystectomy in hemophiliacs is safe if monitored appropriately and that urinary diversion using the intestine should be avoided because anastomotic hemorrhaging may occur. In this study, we discuss coagulation factor replacement therapy for patient with hemophilia A undergoing major or

**Keywords:** hemophilia, hemophilia with inhibitors, perioperative management,

Due to advancements in coagulation factor preparations, hemophilia treatment has progressed from conventional bleeding replacement therapy to periodic replacement therapy. Historically, the aim has been to perform symptomatic treatment, but currently, the aim of treatment is preventive. Due to bleeding incidents that are characteristic of hemophilia, control of bleeding is particularly important for perioperative patient management. The indication for surgical treatment in patients with hemophilia includes diseases caused by bleeding related to hemophilia as well as those not related to hemophilia. The number of surgeries involving

Due to the development of hemostatic hemostasis treatments, obstacles due to bleeding in young patients are decreasing. However, surgical cases are increasing due to the trend in applying surgery to disorders, which have conventionally been treated nonsurgically and due to an increase in the number of aging patients as a result of improved life expectancy. Due to the reasons stated above, we consider that it is important to stay informed about the latest developments in the periopera-

#### **Chapter 3**

[49] Li T, Miller CH, Payne AB, Craig Hooper W. The CDC hemophilia B mutation project mutation list: A new online resource. Molecular Genetics & Genomic Medicine. 2013;1(4):238-245

Hemophilia - Recent Advances

[50] Payne AB, Miller CH, Kelly FM, Michael Soucie J, Craig Hooper W. The CDC hemophilia A mutation project (CHAMP) mutation list: A new online resource. Human Mutation. 2013;34(2):

[51] Chavali S, Ghosh S, Bharadwaj D. Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. Genomics. 2009;94(6):433-437

E2382-E2391

34

## Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients Undergoing Major or Minor Surgery

*Atsushi Okamoto, Kenta Yamamoto, Go Eguchi, Yoshitaka Kanai, Terufumi Yamaguchi and Yasuhiro Maeda*

#### **Abstract**

Among the surgical treatments performed in patients with hemophilia, joint surgery for intra-articular bleeding is the most time-consuming. Previous reports describe the perioperative management of hemophiliacs undergoing coronary artery bypass grafting or of those undergoing cystectomy for treatment of hematuria. In the former study, the patient was elderly; in the latter study, the authors concluded that cystectomy in hemophiliacs is safe if monitored appropriately and that urinary diversion using the intestine should be avoided because anastomotic hemorrhaging may occur. In this study, we discuss coagulation factor replacement therapy for patient with hemophilia A undergoing major or minor surgery.

**Keywords:** hemophilia, hemophilia with inhibitors, perioperative management, joint surgery

#### **1. Introduction**

Due to advancements in coagulation factor preparations, hemophilia treatment has progressed from conventional bleeding replacement therapy to periodic replacement therapy. Historically, the aim has been to perform symptomatic treatment, but currently, the aim of treatment is preventive. Due to bleeding incidents that are characteristic of hemophilia, control of bleeding is particularly important for perioperative patient management. The indication for surgical treatment in patients with hemophilia includes diseases caused by bleeding related to hemophilia as well as those not related to hemophilia. The number of surgeries involving patients with hemophilia is increasing annually.

Due to the development of hemostatic hemostasis treatments, obstacles due to bleeding in young patients are decreasing. However, surgical cases are increasing due to the trend in applying surgery to disorders, which have conventionally been treated nonsurgically and due to an increase in the number of aging patients as a result of improved life expectancy. Due to the reasons stated above, we consider that it is important to stay informed about the latest developments in the perioperative management of patients with hemophilia.

#### **2. Preoperative preparation**

Preoperative preparation for hemophiliac patients involves a thorough review of various aspects of the patient's condition. The first parameter to be ascertained is whether the hemophilia is of type A or type B. Following this, the severity of hemophilia needs to be confirmed. Hemophilia is classified based on the blood level of coagulation factors such as factor VIII or factor IX; the disease is characterized as severe when the blood coagulation factor level is less than 1%, moderate if it is 1–5%, and mild if the level is 5% or more. Severity of daily symptoms is generally accepted to reflect the severity of the disease. In patients receiving prophylactic replacement therapy, it is usually necessary to confirm details such as how many units are being administered and how the preparation is being self-injected. The presence of inhibitors (alloantibodies) in the blood needs to be checked as part of the preoperative preparation as well. Although it is known that patients with severe hemophilia are more likely to have developed inhibitors, genetic mutations are known to cause inhibitor formation even in cases with mild disease. Among patients who have received prior treatment, it is also important to check for HCV or HIV infections. Furthermore, if a chronic HCV infection is incident, liver cirrhosis or liver cancer may occur concomitantly, and it is thus necessary to screen patients for these conditions. The abovementioned points may be used as a checklist to evaluate the suitability of patients for surgical procedures. If the abovementioned evaluations reveal no issues, surgery may be performed as per usual protocol. Depending on the magnitude of the surgical invasion, a treatment plan may then be set up, detailing the target levels and of coagulation factors to be maintained, and the duration for which the levels need to be maintained. Regarding treatment planning, it is necessary to administer a necessary and sufficient amount of a coagulation factor preparation to prevent hemorrhagic complications. However, it should also be noted that an overdose of coagulation factor preparations can lead to a risk of thrombosis. The clearance of the coagulation factor preparation varies greatly among patients. In view of this fact, a pharmacokinetic test of factor VIII factor/factor IX preparations ideally to be used for surgery may be conducted preoperatively. Accurate pharmacokinetic profiles may be obtained by measuring coagulation factor activity before administration of the preparation, and 15 minutes, 1, 2, 4, 8, 12, and 24 hours after administration; such an evaluation allows for a proper understanding of the recovery rate and the half-life of the administered factors [1].

#### **3. Selection of coagulation factor replenishment method**

There are two main methods of administration of coagulation factor replacement therapy during surgery. The first method is a bolus administration method (BI method), which involves repeated administration of a bolus injections. The second is the continuous administration method (CI method) in which a syringe pump continuously administers coagulation factors after an initial bolus administration. Historically, the stability of the formulations used for coagulation factors has been poor; such formulations needed to be administered as soon as they were thawed. Therefore, perioperative management was predominantly performed using the BI method. In the BI method, when the coagulation factor is injected, the coagulation factor level in the blood exceeds 100% and gradually falls thereafter; when the level approaches 50%, the next bolus is administered. Bolus administration is repeated each time the blood coagulation factor level approaches 50%. The BI method has the advantage of being simple, although the associated disadvantage is that fluctuation in the coagulation

**37**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients…*

factor levels is high. Intraoperative and postoperative bleeding in recurrent invasive surgery and reoperation is also a serious issue. Recently, however, the stability of the drug and the reliability of the syringe pump have been improved significantly, and the CI method is currently the recommended method for use during major surgery. Using the CI method, the blood clotting ability of hemophilia patients without inhibitors may be restored to that of non-hemophiliac subjects, so that the indication for surgery can be adjusted to the same level as that for non-hemophiliac subjects. Scientific evidence for the effectiveness of the CI method has been accumulating, and there are many reports of surgical cases in which the CI method has been used. However, because the CI method requires specialized expertise, it is desirable to conduct this procedure under the guidance of a hemophilia specialist. The BI and the CI methods have distinct advantages and disadvantages. For routine surgical operations predicted to have less bleeding volume, selection of the BI method according to the situation of the clinical site is appropriate. There have been few systematic studies of the BI method, and hence it cannot be officially recommended. However, as mentioned above, this method has historically been used extensively for numerous types of surgical procedures. The most important advantage of the BI method is that it is a simple method. Application of this method in emergency situations should be decided based on the trough value of the coagulation factor concentration in the blood or when there is insufficient preparation time and insufficient experience with the CI method. If the staff is experienced in performing the CI method, this method may be applied in emergency situations; a provisional administration speed may be used while assuming a coagulation factor concentration of 100%. However, since the optimal administration rate varies greatly among individuals, it is better to monitor the activated partial thromboplastin time (APTT) and the coagulation factor concentration at an early stage. It is also important to check the status of syringe pumps and tubes regularly. Regardless of which method is chosen, when there is a large amount of bleeding, it is necessary not only to supplement the deficient factor but also to replenish other coagulation factors as well as healthy subjects. It is important to understand the advantages and disadvantages of the BI and the CI methods, so as to adopt the method suitable for the individual clinical

*DOI: http://dx.doi.org/10.5772/intechopen.81172*

site and as per the reference guidelines.

**administration (CI) method**

**4. Important considerations for the use of the continuous** 

Even if the target coagulation factor level is set and perioperative management with CI method is executed as planned, the coagulation factor level may not rise as expected. The reason for this may be that the coagulation factor adheres to the surface of the drip tube wall and the assumed dose is not administered. Since the formulations currently used do not include proteins such as albumin, there is a possibility that coagulation factors are lost due to being adsorbed on the tube wall surface when diluted. Therefore, in the case of the CI method, it is necessary to perform injections from the side tube as close to the patient side of the line as possible. During implementation of the CI method, the coagulation factor formulation is placed at room temperature for several hours; this implies that this protein preparation is placed in a harsh environment for an extended period, which makes it difficult to determine the dilution of the preparation and the exact amount that the patient receives. Since the amount of coagulation factor contained in one vial is large, if the preparation is intended to be administered continuously at the determined concentration, the flow rate is usually adjusted to be low, which may result in clogging of the tubes. In order to solve this problem, the use of a low-concentration

#### *Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients… DOI: http://dx.doi.org/10.5772/intechopen.81172*

factor levels is high. Intraoperative and postoperative bleeding in recurrent invasive surgery and reoperation is also a serious issue. Recently, however, the stability of the drug and the reliability of the syringe pump have been improved significantly, and the CI method is currently the recommended method for use during major surgery. Using the CI method, the blood clotting ability of hemophilia patients without inhibitors may be restored to that of non-hemophiliac subjects, so that the indication for surgery can be adjusted to the same level as that for non-hemophiliac subjects. Scientific evidence for the effectiveness of the CI method has been accumulating, and there are many reports of surgical cases in which the CI method has been used. However, because the CI method requires specialized expertise, it is desirable to conduct this procedure under the guidance of a hemophilia specialist. The BI and the CI methods have distinct advantages and disadvantages. For routine surgical operations predicted to have less bleeding volume, selection of the BI method according to the situation of the clinical site is appropriate. There have been few systematic studies of the BI method, and hence it cannot be officially recommended. However, as mentioned above, this method has historically been used extensively for numerous types of surgical procedures. The most important advantage of the BI method is that it is a simple method. Application of this method in emergency situations should be decided based on the trough value of the coagulation factor concentration in the blood or when there is insufficient preparation time and insufficient experience with the CI method. If the staff is experienced in performing the CI method, this method may be applied in emergency situations; a provisional administration speed may be used while assuming a coagulation factor concentration of 100%. However, since the optimal administration rate varies greatly among individuals, it is better to monitor the activated partial thromboplastin time (APTT) and the coagulation factor concentration at an early stage. It is also important to check the status of syringe pumps and tubes regularly. Regardless of which method is chosen, when there is a large amount of bleeding, it is necessary not only to supplement the deficient factor but also to replenish other coagulation factors as well as healthy subjects. It is important to understand the advantages and disadvantages of the BI and the CI methods, so as to adopt the method suitable for the individual clinical site and as per the reference guidelines.

#### **4. Important considerations for the use of the continuous administration (CI) method**

Even if the target coagulation factor level is set and perioperative management with CI method is executed as planned, the coagulation factor level may not rise as expected. The reason for this may be that the coagulation factor adheres to the surface of the drip tube wall and the assumed dose is not administered. Since the formulations currently used do not include proteins such as albumin, there is a possibility that coagulation factors are lost due to being adsorbed on the tube wall surface when diluted. Therefore, in the case of the CI method, it is necessary to perform injections from the side tube as close to the patient side of the line as possible. During implementation of the CI method, the coagulation factor formulation is placed at room temperature for several hours; this implies that this protein preparation is placed in a harsh environment for an extended period, which makes it difficult to determine the dilution of the preparation and the exact amount that the patient receives. Since the amount of coagulation factor contained in one vial is large, if the preparation is intended to be administered continuously at the determined concentration, the flow rate is usually adjusted to be low, which may result in clogging of the tubes. In order to solve this problem, the use of a low-concentration

*Hemophilia - Recent Advances*

**2. Preoperative preparation**

Preoperative preparation for hemophiliac patients involves a thorough review of various aspects of the patient's condition. The first parameter to be ascertained is whether the hemophilia is of type A or type B. Following this, the severity of hemophilia needs to be confirmed. Hemophilia is classified based on the blood level of coagulation factors such as factor VIII or factor IX; the disease is characterized as severe when the blood coagulation factor level is less than 1%, moderate if it is 1–5%, and mild if the level is 5% or more. Severity of daily symptoms is generally accepted to reflect the severity of the disease. In patients receiving prophylactic replacement therapy, it is usually necessary to confirm details such as how many units are being administered and how the preparation is being self-injected. The presence of inhibitors (alloantibodies) in the blood needs to be checked as part of the preoperative preparation as well. Although it is known that patients with severe hemophilia are more likely to have developed inhibitors, genetic mutations are known to cause inhibitor formation even in cases with mild disease. Among patients who have received prior treatment, it is also important to check for HCV or HIV infections. Furthermore, if a chronic HCV infection is incident, liver cirrhosis or liver cancer may occur concomitantly, and it is thus necessary to screen patients for these conditions. The abovementioned points may be used as a checklist to evaluate the suitability of patients for surgical procedures. If the abovementioned evaluations reveal no issues, surgery may be performed as per usual protocol. Depending on the magnitude of the surgical invasion, a treatment plan may then be set up, detailing the target levels and of coagulation factors to be maintained, and the duration for which the levels need to be maintained. Regarding treatment planning, it is necessary to administer a necessary and sufficient amount of a coagulation factor preparation to prevent hemorrhagic complications. However, it should also be noted that an overdose of coagulation factor preparations can lead to a risk of thrombosis. The clearance of the coagulation factor preparation varies greatly among patients. In view of this fact, a pharmacokinetic test of factor VIII factor/factor IX preparations ideally to be used for surgery may be conducted preoperatively. Accurate pharmacokinetic profiles may be obtained by measuring coagulation factor activity before administration of the preparation, and 15 minutes, 1, 2, 4, 8, 12, and 24 hours after administration; such an evaluation allows for a proper understanding

of the recovery rate and the half-life of the administered factors [1].

**3. Selection of coagulation factor replenishment method**

There are two main methods of administration of coagulation factor replacement therapy during surgery. The first method is a bolus administration method (BI method), which involves repeated administration of a bolus injections. The second is the continuous administration method (CI method) in which a syringe pump continuously administers coagulation factors after an initial bolus administration. Historically, the stability of the formulations used for coagulation factors has been poor; such formulations needed to be administered as soon as they were thawed. Therefore, perioperative management was predominantly performed using the BI method. In the BI method, when the coagulation factor is injected, the coagulation factor level in the blood exceeds 100% and gradually falls thereafter; when the level approaches 50%, the next bolus is administered. Bolus administration is repeated each time the blood coagulation factor level approaches 50%. The BI method has the advantage of being simple, although the associated disadvantage is that fluctuation in the coagulation

**36**

formulation such as that of 250 or 500 units is advised. We conclude that the CI method can be performed relatively safely by carefully selecting the appropriate formulation.

#### **5. Intraoperative and postoperative management**

Measurement of APTT and factor VIII activity is the most common measurement performed during surgery and postoperative procedures. However, in many institutions, there is delay in obtaining the results of the factor VIII activity tests after sample submission, and thus, APTT is considered to be the most useful way to monitor patient condition, especially during surgery. APTT is helpful if there is not much bleeding. However, if the coagulation factor activity other than that of factor VIII decreases, such as when significant bleeding occurs, APTT may not be normalized even if factor VIII is adequately administered. Changes in APTT are thus difficult to interpret, since APTT is affected by the magnitude of the bleeding volume and also by the degree of liver cirrhosis. However, whether the APTT is within the control level can be evaluated, unless it is extremely extended. In cases where it is not possible to obtain hemostasis either intraoperatively or after surgery despite administration of factors VIII and IX, hemophilia may be assumed as the cause, and treatment for this condition may be instituted. If coagulation factor activities other than those of factor VIII and factor IX are low as in splenectomy for cirrhosis of the liver or when the amount of bleeding is large, levels of other coagulation factors may also decrease. Therefore, when and how much fresh frozen plasma (FFP) is administered should be considered separately.

#### **6. Joint surgery**

Due to recent advancements in coagulation factor replacement therapy, it is now possible to prevent intra-articular bleeding right from infancy in children with hemophilia. It is thus possible to prevent escalation of hemophilic arthropathy in such children. On the other hand, if hemophilic synovitis has already occurred and several joints show intra-articular bleeding, arthropathy cannot be prevented, and its progress becomes an issue of concern. In joints with advanced arthropathy, degeneration cannot be avoided, even if subsequent bleeding can be completely prevented. Such degeneration of joints is a major cause of physical dysfunction in adult hemophilia patients. Hemophilic arthropathy is commonly seen in the joints of the elbows, knees, and ankles; in particular, dysfunction of lower limb joints greatly affects daily life. Orthopedic treatments for hemophilic arthropathy include measures against intra-articular bleeding, synovitis, and arthropathy. Specific orthopedic treatments are performed for treating synovitis, such as joint puncture, washing, bleeding, synovial membrane resection for the blood remaining in joints, synovial membrane resection and arthrosis, and artificial joint replacement or arthrodesis. Joint puncture and washing are useful treatment methods and are possible outpatient procedures. In the following sections, we discuss synovectomy, artificial joints, and joint fixation in more detail.

#### **7. Synovectomy**

Joints that show recurrent intra-articular bleeding on diagnostic images but do not show arthropathy are the best indications for synovial resection. There are two

**39**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients…*

major methods of synovectomy, namely, arthroscopic synovectomy (AS) and open synovectomy. Synovial restoration is a method of restoring the synovial membrane by injecting chemical substances (mainly corticosteroids and antibiotics) and radioactive isotopes into joints. Chemical synoviothesis uses chemical substances and results in severe joint pain after the injection; additionally, it is ineffective despite multiple injections to the joints. However, because it is inexpensive, it is frequently performed in developing countries. Radioactive isotope synovectomy (radioactive synoviothesis) is a treatment that can be expected to be effective with a single intra-articular injection, and it is internationally positioned as the first-line therapy for treatment of hemophilic arthritis. In this therapy modality, only beta rays with a shallow arrival depth are generated, and nuclides with a very short half-life are used. The effect of radioactive synoviothesis on genetic material and the articular cartilage have been reported by several publications, and its safety has been reviewed. However, two cases of leukemia have occurred after synovectomy using P32-labeled radionuclides [2], and in 2010, the Medical and Scientific Advisory Council (MASDAC) issued a cautionary note against the application of radioactive isotopes for synovial treatment [3]. Since arthroscopic synovectomy requires hospitalization and the use of adequate coagulation factor preparations, it is generally applied in cases where at least three cycles of radioactive synoviothesis have been ineffective. However, in Japan, arthroscopic synovectomy is the first choice of treatment. An advantage of this method is that other treatments can be added to the treatment regimen; in addition, this method also allows for the observation of the joint surface. It is recommended that arthroscopic synovectomy be performed even in early arthropathy. Invasive synovectomy is a surgical procedure which involves opening the joint capsule and observing the joint under direct vision, so that a wide expanse of the synovium can be removed in a short time. However, the degree of bleeding also increases, and administration of coagulation factor preparations may be necessary to enable installation of artificial joints. In addition, there is also a high risk of contracture after surgery, and thus, this proce-

*DOI: http://dx.doi.org/10.5772/intechopen.81172*

dure is not frequently performed.

**8. Purpose and significance of synovectomy**

Intra-articular bleeding caused by severe hemophilia leads to severe swelling of the joints, and the mobility of the affected limb is limited due to pain. When bleeding events happen repeatedly, the synovial membrane proliferates. Treating hematomas and hemosiderin that occur in joints provides relief, but the blood vessels may re-appear on the synovial membrane; the synovial membrane assumes a villous shape and bleeds easily in such conditions. A vicious circle may be established in which synovial proliferation worsens as bleeding events occur more frequently. The joint, which shows repeated bleeding events, is called a target joint, and the ankle and knee joints in the lower limb and the elbow joint in the upper limb are commonly observed to be target joints. Chronic synovitis eventually causes articular cartilage and subchondral bone erosion and degeneration, resulting in a condition called hemophilic arthropathy. The patient does not use the affected limb either consciously or unconsciously due to pain avoidance, and the functional deterioration progresses with increasing intensity in combination with muscle weakness [4]. Synovial resection is one way to break this vicious circle. As mentioned above, synovial tissue, which shows a villous configuration, bleeds easily; however, if such tissue is surgically removed and appropriate hemostasis is maintained in conjunction with coagulation management, joints can be restored to a state in which they do not easily bleed. However, since synovial excision cannot be recommended until

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients… DOI: http://dx.doi.org/10.5772/intechopen.81172*

major methods of synovectomy, namely, arthroscopic synovectomy (AS) and open synovectomy. Synovial restoration is a method of restoring the synovial membrane by injecting chemical substances (mainly corticosteroids and antibiotics) and radioactive isotopes into joints. Chemical synoviothesis uses chemical substances and results in severe joint pain after the injection; additionally, it is ineffective despite multiple injections to the joints. However, because it is inexpensive, it is frequently performed in developing countries. Radioactive isotope synovectomy (radioactive synoviothesis) is a treatment that can be expected to be effective with a single intra-articular injection, and it is internationally positioned as the first-line therapy for treatment of hemophilic arthritis. In this therapy modality, only beta rays with a shallow arrival depth are generated, and nuclides with a very short half-life are used. The effect of radioactive synoviothesis on genetic material and the articular cartilage have been reported by several publications, and its safety has been reviewed. However, two cases of leukemia have occurred after synovectomy using P32-labeled radionuclides [2], and in 2010, the Medical and Scientific Advisory Council (MASDAC) issued a cautionary note against the application of radioactive isotopes for synovial treatment [3]. Since arthroscopic synovectomy requires hospitalization and the use of adequate coagulation factor preparations, it is generally applied in cases where at least three cycles of radioactive synoviothesis have been ineffective. However, in Japan, arthroscopic synovectomy is the first choice of treatment. An advantage of this method is that other treatments can be added to the treatment regimen; in addition, this method also allows for the observation of the joint surface. It is recommended that arthroscopic synovectomy be performed even in early arthropathy. Invasive synovectomy is a surgical procedure which involves opening the joint capsule and observing the joint under direct vision, so that a wide expanse of the synovium can be removed in a short time. However, the degree of bleeding also increases, and administration of coagulation factor preparations may be necessary to enable installation of artificial joints. In addition, there is also a high risk of contracture after surgery, and thus, this procedure is not frequently performed.

#### **8. Purpose and significance of synovectomy**

Intra-articular bleeding caused by severe hemophilia leads to severe swelling of the joints, and the mobility of the affected limb is limited due to pain. When bleeding events happen repeatedly, the synovial membrane proliferates. Treating hematomas and hemosiderin that occur in joints provides relief, but the blood vessels may re-appear on the synovial membrane; the synovial membrane assumes a villous shape and bleeds easily in such conditions. A vicious circle may be established in which synovial proliferation worsens as bleeding events occur more frequently. The joint, which shows repeated bleeding events, is called a target joint, and the ankle and knee joints in the lower limb and the elbow joint in the upper limb are commonly observed to be target joints. Chronic synovitis eventually causes articular cartilage and subchondral bone erosion and degeneration, resulting in a condition called hemophilic arthropathy. The patient does not use the affected limb either consciously or unconsciously due to pain avoidance, and the functional deterioration progresses with increasing intensity in combination with muscle weakness [4]. Synovial resection is one way to break this vicious circle. As mentioned above, synovial tissue, which shows a villous configuration, bleeds easily; however, if such tissue is surgically removed and appropriate hemostasis is maintained in conjunction with coagulation management, joints can be restored to a state in which they do not easily bleed. However, since synovial excision cannot be recommended until

*Hemophilia - Recent Advances*

formulation.

formulation such as that of 250 or 500 units is advised. We conclude that the CI method can be performed relatively safely by carefully selecting the appropriate

Measurement of APTT and factor VIII activity is the most common measurement performed during surgery and postoperative procedures. However, in many institutions, there is delay in obtaining the results of the factor VIII activity tests after sample submission, and thus, APTT is considered to be the most useful way to monitor patient condition, especially during surgery. APTT is helpful if there is not much bleeding. However, if the coagulation factor activity other than that of factor VIII decreases, such as when significant bleeding occurs, APTT may not be normalized even if factor VIII is adequately administered. Changes in APTT are thus difficult to interpret, since APTT is affected by the magnitude of the bleeding volume and also by the degree of liver cirrhosis. However, whether the APTT is within the control level can be evaluated, unless it is extremely extended. In cases where it is not possible to obtain hemostasis either intraoperatively or after surgery despite administration of factors VIII and IX, hemophilia may be assumed as the cause, and treatment for this condition may be instituted. If coagulation factor activities other than those of factor VIII and factor IX are low as in splenectomy for cirrhosis of the liver or when the amount of bleeding is large, levels of other coagulation factors may also decrease. Therefore, when and how much fresh frozen plasma (FFP) is

Due to recent advancements in coagulation factor replacement therapy, it is now possible to prevent intra-articular bleeding right from infancy in children with hemophilia. It is thus possible to prevent escalation of hemophilic arthropathy in such children. On the other hand, if hemophilic synovitis has already occurred and several joints show intra-articular bleeding, arthropathy cannot be prevented, and its progress becomes an issue of concern. In joints with advanced arthropathy, degeneration cannot be avoided, even if subsequent bleeding can be completely prevented. Such degeneration of joints is a major cause of physical dysfunction in adult hemophilia patients. Hemophilic arthropathy is commonly seen in the joints of the elbows, knees, and ankles; in particular, dysfunction of lower limb joints greatly affects daily life. Orthopedic treatments for hemophilic arthropathy include measures against intra-articular bleeding, synovitis, and arthropathy. Specific orthopedic treatments are performed for treating synovitis, such as joint puncture, washing, bleeding, synovial membrane resection for the blood remaining in joints, synovial membrane resection and arthrosis, and artificial joint replacement or arthrodesis. Joint puncture and washing are useful treatment methods and are possible outpatient procedures. In the following sections, we discuss synovectomy,

Joints that show recurrent intra-articular bleeding on diagnostic images but do not show arthropathy are the best indications for synovial resection. There are two

**5. Intraoperative and postoperative management**

administered should be considered separately.

artificial joints, and joint fixation in more detail.

**6. Joint surgery**

**38**

**7. Synovectomy**

cartilage damage is observed or compatible destroyed joint repair, there are few therapeutic options for highly advanced severe hemophilic arthropathy. Treatment in early-stage hemophilic arthropathy is aimed at providing pain relief by reducing the bleeding frequency; further, this treatment is also applied to delay the progression of arthropathy. However, since the elbow joint does not always receive a high load as compared with the joints of the lower limbs such as the knee joints, if the range of motion can be maintained with little pain or bleeding, synovial ablation is significantly beneficial. Synovial ablation is a good treatment option especially for young people with excellent bone neogenesis and tissue remodeling ability; in this patient population, remodeling may occur on the joint surface depending on the site and stage, and joint repair may also take place to some extent [5, 6].

#### **9. Surgical methods**

#### **9.1 Direct surgery**

Although different approaches exist for joint surgery, joint synovectomy under direct vision is a common orthopedic surgical procedure and requires no special techniques or instruments. However, post-surgery, synovial membrane remnants may facilitate the recurrence of intra-articular bleeding; surgical removal of the synovial membrane in the joint may also lead to joint contracture caused by postoperative scar formation. In the case of the elbow, if a thorough resection of the synovial membrane in the joint is attempted, the radial head may also have to be removed; both internal and external approaches to the joint may have to be explored. Although there are few opportunities for joint hemorrhage after surgery and hence patient activity increases, there are few things that may improve elbow flexion and extension range. Improvement of forearm restraint can be expected if radial head resection is also performed [7].

#### **9.2 Arthroscopic surgery**

Arthroscopy is a surgical procedure that allows surgical access to joints in a minimally invasive fashion and was introduced in the 1940s. Surgical procedures have benefited from advancements in hardware such as cameras, monitors, and surgical instruments. Because there is less damage to the surrounding joint tissues, arthroscopic surgery results in fewer contractures as compared to under-sight surgery. Due to the presence of critically important neural blood vessel bundles surrounding joints, a strong knowledge of anatomy and technical proficiency are required to perform this surgical procedure. However, if done well, synovial resection with arthroscopy can be as effective as or more effective than that performed under direct vision; additionally, as mentioned above, there is little contracture after surgery. Therefore, arthroscopic surgery is recommended for surgical synovectomy of the hemophilic elbow joint [8].

#### *9.2.1 Elbow arthroscopic surgery*

The elbow joint has a complicated structure in which the upper and side surfaces of the radius are in contact with the hinge joint (called the arm slider). In order to remove all proliferating synovial membranes in this joint cavity, three parts need to be approached: the anterior, posterior, and the radial parts. It is necessary to create at least two portals for inserting the arthroscope and other instruments such as a shaver. Surgery is performed after the arthroscope and other instruments have been

**41**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients…*

placed properly. Using the abovementioned portal, instruments such as a shaver and a high frequency cautery/transpiration device are employed for performing the surgery. In hemophilic arthropathy, the synovial membrane appears yellowish brown due to hemosiderin deposition caused by repetitive bleeding; the blood vessels in the synovial membrane proliferate significantly in the acute inflammatory phase and bleed easily. However, if the exposed blood vessels are cauterized intraoperatively, the surgery itself is comparable to a conventional synovectomy. It is impossible to surgically remove 100% of the synovial membrane; at the elbow joint, this membrane often grows around both side margins of the wrist joint and around the radial neck. MRI imaging of the synovial membrane is thus performed before surgery, so that a comprehensive resection of the synovium may be achieved to the extent possible. At the end of surgery, one of the portals is used to indwell a closedtype drain in the joint, and the blood in the joint is aspirated and discharged. The drain is removed at about 48–72 hours post-surgery, which is slightly longer than

**10. Perioperative hemostasis/coagulation management in synovectomy**

Coagulation factor supplementation is frequently performed before surgery, and the aim is strict hemostasis/coagulation management, so that intra-articular bleeding is prevented during the perioperative period. Synovectomy is also specifically aimed at reducing the frequency of intra-articular bleeding. Perioperative bleeding causes synovial proliferation in the joints leading to recurrent bleeding episodes; hence, it is desirable to adequately replenish coagulation factors while monitoring

Indications for artificial joint replacement include (1) late-stage arthropathy, (2) serious disruption in activities of daily living (ADL) due to arthropathy, and (3) adults (epiphyseal line is closed). The three points mentioned above are important for patient selection. For the clinical evaluation of late-stage hemophilic arthropathy, the same criteria as applied for osteoarthritis can be accepted. While effect on ADL is an important selection criterion, ADL parameters are highly subjective. Therefore, it is necessary to discuss before surgery whether the patient's desired postoperative life level can be secured. In adult hemophilia patients, it is necessary to explain that when multiple joints develop terminal arthropathy, multiple joint surgeries need to be performed. Artificial joints are usually installed in those aged 60 years or older, and at this age, re-replacement surgery may not be required. However, in some hemophilia cases, patients are forced to use a wheelchair from the age of 20 years, because of pain from arthritis. While artificial joint replacement surgery in young patients does not address the underlying arthritic condition, this surgery nevertheless becomes a necessity to improve QOL. It is important to note that performing re-replacement surgeries repeatedly is not feasible and performing artificial joint replacement may just postpone the occurrence of joint problems. However, in our opinion, living in a wheelchair in the older age may be an acceptable way of maintaining a patient's QOL, if an active lifestyle is facilitated for the patient during the young-to-mature years. For this reason, it may be better to perform artificial joint replacement even in young patients, based on the case details. The most important reason to perform artificial joint replacement is to eliminate or alleviate pain. Simultaneous synovectomy is also performed for cases with joint

*DOI: http://dx.doi.org/10.5772/intechopen.81172*

that for conventional arthroscopic surgery.

**11. Artificial joint replacement**

clotting factors and hemostatic and coagulation parameters.

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients… DOI: http://dx.doi.org/10.5772/intechopen.81172*

placed properly. Using the abovementioned portal, instruments such as a shaver and a high frequency cautery/transpiration device are employed for performing the surgery. In hemophilic arthropathy, the synovial membrane appears yellowish brown due to hemosiderin deposition caused by repetitive bleeding; the blood vessels in the synovial membrane proliferate significantly in the acute inflammatory phase and bleed easily. However, if the exposed blood vessels are cauterized intraoperatively, the surgery itself is comparable to a conventional synovectomy. It is impossible to surgically remove 100% of the synovial membrane; at the elbow joint, this membrane often grows around both side margins of the wrist joint and around the radial neck. MRI imaging of the synovial membrane is thus performed before surgery, so that a comprehensive resection of the synovium may be achieved to the extent possible. At the end of surgery, one of the portals is used to indwell a closedtype drain in the joint, and the blood in the joint is aspirated and discharged. The drain is removed at about 48–72 hours post-surgery, which is slightly longer than that for conventional arthroscopic surgery.

#### **10. Perioperative hemostasis/coagulation management in synovectomy**

Coagulation factor supplementation is frequently performed before surgery, and the aim is strict hemostasis/coagulation management, so that intra-articular bleeding is prevented during the perioperative period. Synovectomy is also specifically aimed at reducing the frequency of intra-articular bleeding. Perioperative bleeding causes synovial proliferation in the joints leading to recurrent bleeding episodes; hence, it is desirable to adequately replenish coagulation factors while monitoring clotting factors and hemostatic and coagulation parameters.

#### **11. Artificial joint replacement**

Indications for artificial joint replacement include (1) late-stage arthropathy, (2) serious disruption in activities of daily living (ADL) due to arthropathy, and (3) adults (epiphyseal line is closed). The three points mentioned above are important for patient selection. For the clinical evaluation of late-stage hemophilic arthropathy, the same criteria as applied for osteoarthritis can be accepted. While effect on ADL is an important selection criterion, ADL parameters are highly subjective. Therefore, it is necessary to discuss before surgery whether the patient's desired postoperative life level can be secured. In adult hemophilia patients, it is necessary to explain that when multiple joints develop terminal arthropathy, multiple joint surgeries need to be performed. Artificial joints are usually installed in those aged 60 years or older, and at this age, re-replacement surgery may not be required. However, in some hemophilia cases, patients are forced to use a wheelchair from the age of 20 years, because of pain from arthritis. While artificial joint replacement surgery in young patients does not address the underlying arthritic condition, this surgery nevertheless becomes a necessity to improve QOL. It is important to note that performing re-replacement surgeries repeatedly is not feasible and performing artificial joint replacement may just postpone the occurrence of joint problems. However, in our opinion, living in a wheelchair in the older age may be an acceptable way of maintaining a patient's QOL, if an active lifestyle is facilitated for the patient during the young-to-mature years. For this reason, it may be better to perform artificial joint replacement even in young patients, based on the case details. The most important reason to perform artificial joint replacement is to eliminate or alleviate pain. Simultaneous synovectomy is also performed for cases with joint

*Hemophilia - Recent Advances*

**9. Surgical methods**

radial head resection is also performed [7].

vectomy of the hemophilic elbow joint [8].

*9.2.1 Elbow arthroscopic surgery*

**9.2 Arthroscopic surgery**

**9.1 Direct surgery**

cartilage damage is observed or compatible destroyed joint repair, there are few therapeutic options for highly advanced severe hemophilic arthropathy. Treatment in early-stage hemophilic arthropathy is aimed at providing pain relief by reducing the bleeding frequency; further, this treatment is also applied to delay the progression of arthropathy. However, since the elbow joint does not always receive a high load as compared with the joints of the lower limbs such as the knee joints, if the range of motion can be maintained with little pain or bleeding, synovial ablation is significantly beneficial. Synovial ablation is a good treatment option especially for young people with excellent bone neogenesis and tissue remodeling ability; in this patient population, remodeling may occur on the joint surface depending on the site

Although different approaches exist for joint surgery, joint synovectomy under direct vision is a common orthopedic surgical procedure and requires no special techniques or instruments. However, post-surgery, synovial membrane remnants may facilitate the recurrence of intra-articular bleeding; surgical removal of the synovial membrane in the joint may also lead to joint contracture caused by postoperative scar formation. In the case of the elbow, if a thorough resection of the synovial membrane in the joint is attempted, the radial head may also have to be removed; both internal and external approaches to the joint may have to be explored. Although there are few opportunities for joint hemorrhage after surgery and hence patient activity increases, there are few things that may improve elbow flexion and extension range. Improvement of forearm restraint can be expected if

Arthroscopy is a surgical procedure that allows surgical access to joints in a minimally invasive fashion and was introduced in the 1940s. Surgical procedures have benefited from advancements in hardware such as cameras, monitors, and surgical instruments. Because there is less damage to the surrounding joint tissues, arthroscopic surgery results in fewer contractures as compared to under-sight surgery. Due to the presence of critically important neural blood vessel bundles surrounding joints, a strong knowledge of anatomy and technical proficiency are required to perform this surgical procedure. However, if done well, synovial resection with arthroscopy can be as effective as or more effective than that performed under direct vision; additionally, as mentioned above, there is little contracture after surgery. Therefore, arthroscopic surgery is recommended for surgical syno-

The elbow joint has a complicated structure in which the upper and side surfaces of the radius are in contact with the hinge joint (called the arm slider). In order to remove all proliferating synovial membranes in this joint cavity, three parts need to be approached: the anterior, posterior, and the radial parts. It is necessary to create at least two portals for inserting the arthroscope and other instruments such as a shaver. Surgery is performed after the arthroscope and other instruments have been

and stage, and joint repair may also take place to some extent [5, 6].

**40**

hemorrhage, so as to stop or reduce the number of bleeding events. On the other hand, the knee joint has been reported to show poor improvement in range of motion. For this reason, postoperative rehabilitation is important.

#### **12. Arthrodesis**

Arthrodesis involves surgically immobilizing affected joints. By sacrificing the range of motion of the joint, this procedure treats joint pain and intra-articular bleeding. This procedure is performed primarily on the ankle joint. In the natural course of hemophilic ankylosis, the joints appear stark on diagnostic images in the terminal stage. Therefore, surgery to fix joints artificially is not actively carried out, and numerous parameters are monitored while the patient is administered with symptomatic treatment. Arthrodesis has recently been reviewed as a method for treating artificial ankle joints. Although the treatment protocol varies depending on the facility, if only one side presents with terminal arthrosis, the joint function can be compensated by the other healthy side, so that joint fixation is applied. If ankle joints on both sides are candidates for artificial ankle joint replacement, this condition is an indication for artificial ankle replacement.

#### **13. Problems other than hemostasis in joint surgery**

#### **13.1 Preoperative examination and anesthesia management**

Spinal anesthesia has been conventionally contraindicated as a method of anesthesia in hemophiliac patients, and surgery has been performed with general anesthesia. The reason is that when the spinal venous plexus is damaged at the needle tip of the lumbar puncture needle, if the coagulation is insufficient, hemorrhage is prolonged and may lead to a deep hematoma; the discovery of such a hematoma is liable to be delayed due to the depth of the location. If such a hematoma occurs, there is a high risk for spinal cord injury. With modern hemostatic management methods, it is possible to maintain the levels of coagulation factors adequately while concurrently administering spinal anesthesia, and if persistent subdural anesthesia can be performed, it is effective for postoperative pain management. However, while very few institutions use spinal anesthesia during surgery in patients with hemophilia, most perform surgery with general anesthesia. There is no relevance of hemophiliac status on the choice of anesthetics. However, depending on the type of antiviral drugs used for people infected with HIV, care should be taken because some drugs inhibit the metabolism of anesthetics and increase the required dosage.

#### **13.2 Surgery in HCV- and HIV-infected patients**

Some patients who undergo orthopedic surgery (especially that of artificial knee replacement) show co-occurring HCV or HIV infections due to phytotoxicity. While a proportion of patients with successful treatments (e.g., interferon therapy) no longer have HCV infections, many patients show progression to liver cancer or liver cirrhosis due to long disease duration. In contrast, though symptomatic improvement may be achieved with the latest antiviral drugs in HIV-infected patients, a cure is not possible. Particularly with respect to hepatitis C, postoperative death cases are significantly higher among cases characterized as Child classification B, those with low ascites and albumin, and those with thrombocytopenia [9]. Confirmation of these conditions is important for surgical decisions.

**43**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients…*

**14. Latest findings due to the appearance of half-life extended drugs**

history included hemophilia A, pediatric asthma, and hypothyroidism.

Hemophilia A was diagnosed as moderate in infancy. The patient reported selfinjecting rurioctocog alfa (trade name: ADVATE®) two to three times a week for hemophilia. The final bleeding episode occurred in the left knee joint in April 2013 and required hospitalization for 3 days. Factor VIII inhibitors were not detectable in

The development of coagulation factor preparations is one of the most important factors impacting the prognosis and quality of life of patients with hemophilia. Recent advancements in extending the half-life of drugs using various mechanisms have attracted much attention. Such extended half-life formulations make it possible to reduce the frequency of self-injections even in regular prophylaxis therapy and reduce the frequency of bleeding symptoms (such as bleeding in the joints and muscles). In addition, such advancements not only extend the half-life and improve the stability of the drugs; they also impact patient burden by reducing the number of required hospital visits. Various benefits have been obtained from the use of half-life extended drugs, and this development has brought about major changes in the treatment of hemophilia. However, since half-life extended medicines are short, there is a lack of substantial evidence of the efficacy in perioperative administration regimens. Moreover, the number of cases in which these drugs have been used is too small for inclusion in case report studies. In this regard, we have experienced and reported a case of perioperative management of hemophilia A using efraloctocog alfa (ELOCTATE®) during endoscopic nasal pituitary adenomectomy for growth hormone-producing pituitary adenoma. There are no other reports of the successful use of ELOCTATE (a drug with an extended half-life) in conjunction with the BI method for a major surgery. We summarize below details of the case study [12]. A 28-year-old man was admitted to our hospital due to bulging of the glabella. He had first noticed the bulging of the glabella in 2013. He was aware of the enlargement of his fingers and the size of his shoes since August 2016, and he was now seeking medical attention. He was referred to the department of endocrinology and metabolism at our hospital with suspected acromegaly. A diagnosis of growth hormoneproducing pituitary adenoma was made by performing several tests, including a brain MRI and loading tests. Furthermore, we decided to perform endoscopic nasal pituitary adenomectomy at our department of neurosurgery. The patient clinical

Lower extremity artificial joint surgery is one of the risk factors for deep venous thrombosis (DVT), and DVT risk is of particular relevance in hemophilia patients. However, most hemophilia patients undergoing artificial joint replacement surgery are adolescents on anti-inflammatory analgesic therapy and show no other comorbidities that may influence thrombus development. Therefore, the risk of DVT occurrence due to lower extremity artificial joint surgery may be lower than that due to general lower limb prosthesis replacement surgery. However, it was reported that among asymptomatic patients, DVT was detected by lower limb ultrasonography in 10% of cases after surgery, even in patients with hemophilia [10]. A previous report has suggested that in addition to physical methods such as application of elastic stockings and intermittent pneumatic compression, anticoagulation therapy is administered at about half of the facilities where the survey was conducted [11]. Either way, even in patients with hemophilia, physicians must be alert to the development of postoperative DVT, and timely cessation of prescribed bed rest and

*DOI: http://dx.doi.org/10.5772/intechopen.81172*

early rehabilitation are important.

**13.3 Prevention of deep venous thrombosis (DVT)**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients… DOI: http://dx.doi.org/10.5772/intechopen.81172*

#### **13.3 Prevention of deep venous thrombosis (DVT)**

*Hemophilia - Recent Advances*

**12. Arthrodesis**

hemorrhage, so as to stop or reduce the number of bleeding events. On the other hand, the knee joint has been reported to show poor improvement in range of

Arthrodesis involves surgically immobilizing affected joints. By sacrificing the range of motion of the joint, this procedure treats joint pain and intra-articular bleeding. This procedure is performed primarily on the ankle joint. In the natural course of hemophilic ankylosis, the joints appear stark on diagnostic images in the terminal stage. Therefore, surgery to fix joints artificially is not actively carried out, and numerous parameters are monitored while the patient is administered with symptomatic treatment. Arthrodesis has recently been reviewed as a method for treating artificial ankle joints. Although the treatment protocol varies depending on the facility, if only one side presents with terminal arthrosis, the joint function can be compensated by the other healthy side, so that joint fixation is applied. If ankle joints on both sides are candidates for artificial ankle joint replacement, this condi-

Spinal anesthesia has been conventionally contraindicated as a method of anesthesia in hemophiliac patients, and surgery has been performed with general anesthesia. The reason is that when the spinal venous plexus is damaged at the needle tip of the lumbar puncture needle, if the coagulation is insufficient, hemorrhage is prolonged and may lead to a deep hematoma; the discovery of such a hematoma is liable to be delayed due to the depth of the location. If such a hematoma occurs, there is a high risk for spinal cord injury. With modern hemostatic management methods, it is possible to maintain the levels of coagulation factors adequately while concurrently administering spinal anesthesia, and if persistent subdural anesthesia can be performed, it is effective for postoperative pain management. However, while very few institutions use spinal anesthesia during surgery in patients with hemophilia, most perform surgery with general anesthesia. There is no relevance of hemophiliac status on the choice of anesthetics. However, depending on the type of antiviral drugs used for people infected with HIV, care should be taken because some drugs inhibit the metabolism of anesthetics and increase the required dosage.

Some patients who undergo orthopedic surgery (especially that of artificial knee replacement) show co-occurring HCV or HIV infections due to phytotoxicity. While a proportion of patients with successful treatments (e.g., interferon therapy) no longer have HCV infections, many patients show progression to liver cancer or liver cirrhosis due to long disease duration. In contrast, though symptomatic improvement may be achieved with the latest antiviral drugs in HIV-infected patients, a cure is not possible. Particularly with respect to hepatitis C, postoperative death cases are significantly higher among cases characterized as Child classification B, those with low ascites and albumin, and those with thrombocytopenia [9].

Confirmation of these conditions is important for surgical decisions.

motion. For this reason, postoperative rehabilitation is important.

tion is an indication for artificial ankle replacement.

**13.2 Surgery in HCV- and HIV-infected patients**

**13. Problems other than hemostasis in joint surgery**

**13.1 Preoperative examination and anesthesia management**

**42**

Lower extremity artificial joint surgery is one of the risk factors for deep venous thrombosis (DVT), and DVT risk is of particular relevance in hemophilia patients. However, most hemophilia patients undergoing artificial joint replacement surgery are adolescents on anti-inflammatory analgesic therapy and show no other comorbidities that may influence thrombus development. Therefore, the risk of DVT occurrence due to lower extremity artificial joint surgery may be lower than that due to general lower limb prosthesis replacement surgery. However, it was reported that among asymptomatic patients, DVT was detected by lower limb ultrasonography in 10% of cases after surgery, even in patients with hemophilia [10]. A previous report has suggested that in addition to physical methods such as application of elastic stockings and intermittent pneumatic compression, anticoagulation therapy is administered at about half of the facilities where the survey was conducted [11]. Either way, even in patients with hemophilia, physicians must be alert to the development of postoperative DVT, and timely cessation of prescribed bed rest and early rehabilitation are important.

#### **14. Latest findings due to the appearance of half-life extended drugs**

The development of coagulation factor preparations is one of the most important factors impacting the prognosis and quality of life of patients with hemophilia. Recent advancements in extending the half-life of drugs using various mechanisms have attracted much attention. Such extended half-life formulations make it possible to reduce the frequency of self-injections even in regular prophylaxis therapy and reduce the frequency of bleeding symptoms (such as bleeding in the joints and muscles). In addition, such advancements not only extend the half-life and improve the stability of the drugs; they also impact patient burden by reducing the number of required hospital visits. Various benefits have been obtained from the use of half-life extended drugs, and this development has brought about major changes in the treatment of hemophilia. However, since half-life extended medicines are short, there is a lack of substantial evidence of the efficacy in perioperative administration regimens. Moreover, the number of cases in which these drugs have been used is too small for inclusion in case report studies. In this regard, we have experienced and reported a case of perioperative management of hemophilia A using efraloctocog alfa (ELOCTATE®) during endoscopic nasal pituitary adenomectomy for growth hormone-producing pituitary adenoma. There are no other reports of the successful use of ELOCTATE (a drug with an extended half-life) in conjunction with the BI method for a major surgery. We summarize below details of the case study [12]. A 28-year-old man was admitted to our hospital due to bulging of the glabella. He had first noticed the bulging of the glabella in 2013. He was aware of the enlargement of his fingers and the size of his shoes since August 2016, and he was now seeking medical attention. He was referred to the department of endocrinology and metabolism at our hospital with suspected acromegaly. A diagnosis of growth hormoneproducing pituitary adenoma was made by performing several tests, including a brain MRI and loading tests. Furthermore, we decided to perform endoscopic nasal pituitary adenomectomy at our department of neurosurgery. The patient clinical history included hemophilia A, pediatric asthma, and hypothyroidism.

Hemophilia A was diagnosed as moderate in infancy. The patient reported selfinjecting rurioctocog alfa (trade name: ADVATE®) two to three times a week for hemophilia. The final bleeding episode occurred in the left knee joint in April 2013 and required hospitalization for 3 days. Factor VIII inhibitors were not detectable in the patient's blood. We prepared a regimen for administration of rFVIIIFc in accordance with guidelines for hemostasis treatment for hemophilia patients without inhibitors (Revision 2013, published by the Japanese society of Thrombosis and Hemostasis). At our hospital, the results of factor VIII activity cannot be obtained promptly, so in the perioperative period, we monitored APTT in lieu of factor VIII levels in sera. From day 2 onward, we injected rFVIIIFc intravenously at 2 PM daily and measured APTT and factor VIII activity at 6 AM the following morning (16 hours after intravenous injection). A blood test was conducted to measure APTT and factor VIII activity at 6 AM on surgery day. On the day of the surgery, 4000 IU of rFVIIIFc were intravenously injected at 8 AM (1 hour before leaving the ward for the surgery), and APTT and factor VIII activity were measured again after 15 minutes of intravenous injection (because peak levels of rFVIIIFc in the blood are achieved approximately 15 minutes after intravenous injection). APTT at this time was assumed to be a function primarily of factor VIII activity and was used as the most important index in perioperative control. The surgery began at 10:14 AM and ended at 1:39 PM (3 hours and 25 minutes). The surgery performed was an endoscopic nasal pituitary adenomectomy. The volume of bleeding during the surgery was 150 ml and was in close agreement with the expected volume of bleeding. Prior to surgery, a risk of bleeding from the nasal mucosa was suspected; however, only two mild nasal bleeding events were confirmed and were resolved adequately. The patient was discharged on day 13, on schedule. Thus, perioperative management using drugs with an extended half-life can be applied to control hemostasis/coagulation at the perioperative stage using the BI method even for major surgery, as in the case described above. The advantage of perioperative management by the BI method using half-life extended drugs is that these drugs need to be administered through intravenous injection only once a day, and such a treatment protocol is easy to perform at a hospital. Furthermore, the BI method is also economical as it reduces the amount and thus the cost of the drug, as compared with the CI method using the existing coagulation factor preparations. For perioperative management using extended half-life drugs, we consider that further case studies are necessary to prepare dosing regimens. However, such drugs have the potential to impact not only periodic replacement therapy but also perioperative management in hemophilia patients. For the reasons stated above, we feel that the extended half-life drugs have the potential to significantly impact hemophilia treatment.

#### **15. Possibility of subcutaneously injectable coagulation factor preparations**

Another recent advancement in hemophilia drugs is the development of a subcutaneously injectable formulation, which overcomes the need for intravenous injection. The common name of this drug is emicizumab, and the trade name is HEMLIBRA®. The efficacy of emicizumab is characterized as "suppression of bleeding tendency in congenital factor VIII-deficient patients positive for inhibitors against factor VIII." As with other factor VIII drugs and bypass medicines, there are no indications for administration during perioperative period or during sudden bleeding events, and increase in blood emicizumab levels is disallowed. Currently, this drug has been formulated as an intravenous injection and is being used for sudden bleeding events or during surgery in patients who undergo prophylactic replacement therapy with subcutaneous coagulation factor preparations. In the future, it is expected that this drug will also be recommended for use in hemophilia patients who are negative for factor VIII inhibitors. However, currently, this drug is being administered only to patients positive for factor VIII inhibitors. Phase III clinical trials of

**45**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients…*

the use of emicizumab in surgical cases have been conducted, but the subjects have been limited to those positive for factor VIII inhibitors. Literature evidence of the use of emicizumab during surgery in patients without inhibitors is lacking, and thus comparative assessments cannot be made. There is also no evidence regarding the use of this drug during time of surgery in patients with inhibitors as well. As described above, there is little evidence to support the efficacy of emicizumab administration

Inhibitors are anti-factor VIII or anti-factor IX allogeneic antibodies generated against factor VIII and factor IX in pharmaceutical preparations as a result of replacement therapy with coagulation factor preparations. When an inhibitor generates, it binds to factor VIII and factor IX, resulting in structural and functional abnormalities. Furthermore, as the clearance is increased by the formation of the antigen-antibody complex, the hemostatic effect of replacement therapy drastically decreases/disappears [13]. Hemostasis therapy is roughly divided into neutralization therapy and bypass hemostasis therapy. And it is chosen mainly based on the severity of bleeding symptoms, the potency and reactivity of the inhibitor, and past

Inhibitors are measured by Bethesda method [14] based on coagulation single step method. The amount of antibody that inactivates factor VIII or factor IX contained in 1 ml of normal plasma by 50% is defined as 1 Bethesda Unit/ml (BU/ml). Normally, >0.6 BU/ml is judged to be positive for inhibitors. In particular, the Nijmegen method is recommended for measurements around 1 BU/ml [15]. Inhibitor titers are defined as high titer ≧ 5 BU/ml and low titer <5 BU/ml. A high responder (HR) is defined as a case in which an inhibitor of ≧5 BU/ml in the Factor VIII/IX Subcommittee of the International Conference on Thrombosis and Hemostasis. And it is recommended that <5 BU/ml case be defined as low responder (LR) [16]. Inhibitor titers may jump sharply 5–7 days after preparation administration. This is called an anamnestic response. The Japan Society of Thrombosis and Hemostasis Academic Standardization Committee Hemophilia Subcommittee advocates an algorithm for selecting therapeutic prepara-

The first choice of low titer (<5 BU/ml) inhibitor holding LR with no anamnestic

response in the past is a continuation of replacement therapy [17]. To obtain a definite hemostatic effect, add the necessary formulation for inhibitor neutralization and target hemostatic level. The neutralization amount (unit) is theoretically calculated as 40 × weight (kg) × {[100 hematocrit value (%)]/100} × inhibitor titer (BU/ml). Depending on the inactivation pattern of the anti-factor VIII or anti-IX factor activity of the inhibitor, it may not necessarily rise as expected. Therefore, monitoring of coagulation factor activity is desired. Bypass hemostasis therapy

tions depending on the potency of the inhibitor and either HR or LR.

**17.1 Selection criteria for replacement therapy and dosage**

*DOI: http://dx.doi.org/10.5772/intechopen.81172*

**16.1 Outline**

medical history.

**16.2 Inhibitor phenotype**

**17. Replacement therapy**

in perioperative period, and further studies are indicated.

**16. Treatment of hemophiliac patients with inhibitors**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients… DOI: http://dx.doi.org/10.5772/intechopen.81172*

the use of emicizumab in surgical cases have been conducted, but the subjects have been limited to those positive for factor VIII inhibitors. Literature evidence of the use of emicizumab during surgery in patients without inhibitors is lacking, and thus comparative assessments cannot be made. There is also no evidence regarding the use of this drug during time of surgery in patients with inhibitors as well. As described above, there is little evidence to support the efficacy of emicizumab administration in perioperative period, and further studies are indicated.

#### **16. Treatment of hemophiliac patients with inhibitors**

#### **16.1 Outline**

*Hemophilia - Recent Advances*

the patient's blood. We prepared a regimen for administration of rFVIIIFc in accordance with guidelines for hemostasis treatment for hemophilia patients without inhibitors (Revision 2013, published by the Japanese society of Thrombosis and Hemostasis). At our hospital, the results of factor VIII activity cannot be obtained promptly, so in the perioperative period, we monitored APTT in lieu of factor VIII levels in sera. From day 2 onward, we injected rFVIIIFc intravenously at 2 PM daily and measured APTT and factor VIII activity at 6 AM the following morning (16 hours after intravenous injection). A blood test was conducted to measure APTT and factor VIII activity at 6 AM on surgery day. On the day of the surgery, 4000 IU of rFVIIIFc were intravenously injected at 8 AM (1 hour before leaving the ward for the surgery), and APTT and factor VIII activity were measured again after 15 minutes of intravenous injection (because peak levels of rFVIIIFc in the blood are achieved approximately 15 minutes after intravenous injection). APTT at this time was assumed to be a function primarily of factor VIII activity and was used as the most important index in perioperative control. The surgery began at 10:14 AM and ended at 1:39 PM (3 hours and 25 minutes). The surgery performed was an endoscopic nasal pituitary adenomectomy. The volume of bleeding during the surgery was 150 ml and was in close agreement with the expected volume of bleeding. Prior to surgery, a risk of bleeding from the nasal mucosa was suspected; however, only two mild nasal bleeding events were confirmed and were resolved adequately. The patient was discharged on day 13, on schedule. Thus, perioperative management using drugs with an extended half-life can be applied to control hemostasis/coagulation at the perioperative stage using the BI method even for major surgery, as in the case described above. The advantage of perioperative management by the BI method using half-life extended drugs is that these drugs need to be administered through intravenous injection only once a day, and such a treatment protocol is easy to perform at a hospital. Furthermore, the BI method is also economical as it reduces the amount and thus the cost of the drug, as compared with the CI method using the existing coagulation factor preparations. For perioperative management using extended half-life drugs, we consider that further case studies are necessary to prepare dosing regimens. However, such drugs have the potential to impact not only periodic replacement therapy but also perioperative management in hemophilia patients. For the reasons stated above, we feel that the extended half-life drugs have

the potential to significantly impact hemophilia treatment.

**15. Possibility of subcutaneously injectable coagulation factor** 

Another recent advancement in hemophilia drugs is the development of a subcutaneously injectable formulation, which overcomes the need for intravenous injection. The common name of this drug is emicizumab, and the trade name is HEMLIBRA®. The efficacy of emicizumab is characterized as "suppression of bleeding tendency in congenital factor VIII-deficient patients positive for inhibitors against factor VIII." As with other factor VIII drugs and bypass medicines, there are no indications for administration during perioperative period or during sudden bleeding events, and increase in blood emicizumab levels is disallowed. Currently, this drug has been formulated as an intravenous injection and is being used for sudden bleeding events or during surgery in patients who undergo prophylactic replacement therapy with subcutaneous coagulation factor preparations. In the future, it is expected that this drug will also be recommended for use in hemophilia patients who are negative for factor VIII inhibitors. However, currently, this drug is being administered only to patients positive for factor VIII inhibitors. Phase III clinical trials of

**44**

**preparations**

Inhibitors are anti-factor VIII or anti-factor IX allogeneic antibodies generated against factor VIII and factor IX in pharmaceutical preparations as a result of replacement therapy with coagulation factor preparations. When an inhibitor generates, it binds to factor VIII and factor IX, resulting in structural and functional abnormalities. Furthermore, as the clearance is increased by the formation of the antigen-antibody complex, the hemostatic effect of replacement therapy drastically decreases/disappears [13]. Hemostasis therapy is roughly divided into neutralization therapy and bypass hemostasis therapy. And it is chosen mainly based on the severity of bleeding symptoms, the potency and reactivity of the inhibitor, and past medical history.

#### **16.2 Inhibitor phenotype**

Inhibitors are measured by Bethesda method [14] based on coagulation single step method. The amount of antibody that inactivates factor VIII or factor IX contained in 1 ml of normal plasma by 50% is defined as 1 Bethesda Unit/ml (BU/ml). Normally, >0.6 BU/ml is judged to be positive for inhibitors. In particular, the Nijmegen method is recommended for measurements around 1 BU/ml [15]. Inhibitor titers are defined as high titer ≧ 5 BU/ml and low titer <5 BU/ml. A high responder (HR) is defined as a case in which an inhibitor of ≧5 BU/ml in the Factor VIII/IX Subcommittee of the International Conference on Thrombosis and Hemostasis. And it is recommended that <5 BU/ml case be defined as low responder (LR) [16]. Inhibitor titers may jump sharply 5–7 days after preparation administration. This is called an anamnestic response. The Japan Society of Thrombosis and Hemostasis Academic Standardization Committee Hemophilia Subcommittee advocates an algorithm for selecting therapeutic preparations depending on the potency of the inhibitor and either HR or LR.

#### **17. Replacement therapy**

#### **17.1 Selection criteria for replacement therapy and dosage**

The first choice of low titer (<5 BU/ml) inhibitor holding LR with no anamnestic response in the past is a continuation of replacement therapy [17]. To obtain a definite hemostatic effect, add the necessary formulation for inhibitor neutralization and target hemostatic level. The neutralization amount (unit) is theoretically calculated as 40 × weight (kg) × {[100 hematocrit value (%)]/100} × inhibitor titer (BU/ml). Depending on the inactivation pattern of the anti-factor VIII or anti-IX factor activity of the inhibitor, it may not necessarily rise as expected. Therefore, monitoring of coagulation factor activity is desired. Bypass hemostasis therapy

described later is the first choice for HR types that have elevated ≧ 5 BU/ml in the past even at <5 BU/ml, but in case of severe bleeding symptoms or major surgery, replacement therapy is selected. However, in the case of HR, it is practical to plan a hemostasis therapy after the reaction, taking into consideration the appearance of previous immune response after 5–7 days after administration. Usually change to bypass hemostasis therapy. Even when the inhibitor titer is 5–10 BU/ml, it is possible to carry out neutralization therapy with high volumes of Factor VIII and Factor IX preparation at severe bleeding and major surgery.

#### **17.2 Selection of replacement therapy preparation**

There are three types of factor VIII (FVIII) preparations that can be used in Japan. They are plasma-derived factor VIII formulation, genetically modified factor VIII, and plasma-derived factor VIII (FVIII)/von Willebrand factor (VWF) complex preparation. There are two types of factor IX preparation that can be used: plasma-derived preparations and recombinant preparations. In some hemophilia A inhibitor cases, it is known that the hemostatic effect of the FIII/VWF preparation exceeds that of the factor VIII preparation. It is clarified that this inhibitor is an antibody which recognizes the factor VIII light chain and suppresses FVIII/VWF binding, and reactivity to FVIII is decreased by the presence of VWF [18].

#### **17.3 Method of administration of preparation**

Normally, factor VIII preparation and factor IX preparation are administered in bolus, but continuous administration is also selected at severe bleeding and hemostatic management of major operation. There are no standards for dose administration in inhibitor cases. If the inhibitor is completely neutralized by the initial bolus administration, the coagulation factor activity can theoretically be maintained in the administration example similar to the cases without inhibitor. In practice, however, higher doses are often required.

#### **18. Bypass hemostatic therapy**

According to the guidelines published by the Japan Thrombosis Hemorrhagic Society, the first choice when the inhibitor titer ≧ 5 BU/ml is bypass hemostasis therapy except severe bleeding symptoms and hemostasis management during major surgery [17]. Traditionally, activated prothrombin complex concentrates (aPCC) or prothrombin complex concentrates (PCC) were the main body of bypass hemostasis therapy, but bypass hemostasis therapy has greatly advanced after the introduction of genetically modified active factor VII factor formulation (rFVIIa). Sales of PCC preparations adapted for inhibitors have been discontinued. Currently available bypass preparations are three, aPCC (FEIBA®), rFVIIa (NovoSeven®), and blood coagulation factor X factor-activated factor VII (Byclot®).

#### **18.1 Bypass hemostatic therapy preparation**

*18.1.1 Activated prothrombin complex concentrates (aPCC)*

#### *18.1.1.1 Hemostasis management during surgery by aPCC*

Conventionally, it was extremely difficult for a variety of reasons to perform hemostasis management at the time of surgery of HR inhibitor cases with

**47**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients…*

inhibitors of high titer by only aPCC. The main reasons are the uncertainty of the hemostatic effect, expensive medical expenses, thrombosis, and fear of onset of disseminated intravascular coagulation syndrome (DIC), and furthermore, the evidence is low. Many of the cases used aPCC in combination after neutralization therapy with factor VIII and factor IX preparations. However, in conjunction with the increase in patients undergoing surgery by rFVIIa, reports on practical cases with only aPCC have been increasing in recent years. According to a multicenter retrospective study by Negrier et al., aPCC was used for 19 small surgical procedures [19]. The most frequent cases were joint puncture (10 cases), the number of doses was two to six times, and the administration days were in the range of 2–4 days, both of which were effective. The dose was 78–160 units/kg/day. Four cases were used for tooth extraction, three cases were administered twice, one case was administered six times, and the administration period was, respectively, 1 day and 3 days. Four cases were performed in major surgery. The breakdown was knee joint synovectomy, knee arthroplasty, skin muscle formation, and prostatectomy. The dose and duration of aPCC during major surgery differ depending on the operation name. The dose is 120–210 units/kg/day and the administration period is 5–21 days. The dosing regimen after surgical treatment such as subcutaneously implanted central intravenous catheterization procedure ranged from 50 to 74 units/kg one to two times/day; dosing days ranged from 1 to 6 days [20]. In Japan, since aPCC had limitation of use (inhibitor potency ≥10 BU/ml, within 3 days of administration), experience of using aPCC in major surgery is small. Since these restrictions have been removed since 2008, surgical therapy using aPCC in Japan could be considered. The number of cases is still small internationally, and it is necessary to standardize on the aPCC administration regimen at the

A fragment of factor VIII is detected in aPCC. Therefore, there are cases in which inhibitor titers are increased by repeated administration of aPCC. This is because aPCC contains the light chain fragment of factor VIII, and it is common in inhibitors of the light chain recognition type in particular [21]. Therefore, in cases that the inhibitor titer does not decrease and the high value is sustained, it is necessary to pay attention to the anamnestic response caused by aPCC. Incidentally, even in cases with this history of reaction, there are cases in which they subsequently decline as a result. In the report of Negrier et al., anamnestic response was seen in 31.5% of the patients, but of which 64.7% had

rFVIIa is being used not only for small surgical operations but also for moderate or more surgical operations. Lusher et al. collected results on 103 surgical operations totaling 21 cases of major operation, 57 cases of small operation, and 25 cases of suturing relation [22]. According to the report, effective cases were 81, 86 and 92%, respectively, indicating that major surgery is also possible with hemostasis management by rFVIIa. Even in Japan, there are no restrictions on insurance medical treatment, so we have used more experience than aPCC and the number of cases such as large orthopedic surgery including artificial joint replacement surgery is increasing. Schrarer et al. recommended that 90 μg/kg every 2–3 days for 1–2 days, in large

*DOI: http://dx.doi.org/10.5772/intechopen.81172*

time of surgery in the future.

gradually decreased [19].

*18.1.2.1 Hemostasis management during surgery by rFVIIa*

*18.1.2 rFVIIa*

*18.1.1.2 Anamnestic response by aPCC*

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients… DOI: http://dx.doi.org/10.5772/intechopen.81172*

inhibitors of high titer by only aPCC. The main reasons are the uncertainty of the hemostatic effect, expensive medical expenses, thrombosis, and fear of onset of disseminated intravascular coagulation syndrome (DIC), and furthermore, the evidence is low. Many of the cases used aPCC in combination after neutralization therapy with factor VIII and factor IX preparations. However, in conjunction with the increase in patients undergoing surgery by rFVIIa, reports on practical cases with only aPCC have been increasing in recent years. According to a multicenter retrospective study by Negrier et al., aPCC was used for 19 small surgical procedures [19]. The most frequent cases were joint puncture (10 cases), the number of doses was two to six times, and the administration days were in the range of 2–4 days, both of which were effective. The dose was 78–160 units/kg/day. Four cases were used for tooth extraction, three cases were administered twice, one case was administered six times, and the administration period was, respectively, 1 day and 3 days. Four cases were performed in major surgery. The breakdown was knee joint synovectomy, knee arthroplasty, skin muscle formation, and prostatectomy. The dose and duration of aPCC during major surgery differ depending on the operation name. The dose is 120–210 units/kg/day and the administration period is 5–21 days. The dosing regimen after surgical treatment such as subcutaneously implanted central intravenous catheterization procedure ranged from 50 to 74 units/kg one to two times/day; dosing days ranged from 1 to 6 days [20]. In Japan, since aPCC had limitation of use (inhibitor potency ≥10 BU/ml, within 3 days of administration), experience of using aPCC in major surgery is small. Since these restrictions have been removed since 2008, surgical therapy using aPCC in Japan could be considered. The number of cases is still small internationally, and it is necessary to standardize on the aPCC administration regimen at the time of surgery in the future.

#### *18.1.1.2 Anamnestic response by aPCC*

A fragment of factor VIII is detected in aPCC. Therefore, there are cases in which inhibitor titers are increased by repeated administration of aPCC. This is because aPCC contains the light chain fragment of factor VIII, and it is common in inhibitors of the light chain recognition type in particular [21]. Therefore, in cases that the inhibitor titer does not decrease and the high value is sustained, it is necessary to pay attention to the anamnestic response caused by aPCC. Incidentally, even in cases with this history of reaction, there are cases in which they subsequently decline as a result. In the report of Negrier et al., anamnestic response was seen in 31.5% of the patients, but of which 64.7% had gradually decreased [19].

#### *18.1.2 rFVIIa*

*Hemophilia - Recent Advances*

described later is the first choice for HR types that have elevated ≧ 5 BU/ml in the past even at <5 BU/ml, but in case of severe bleeding symptoms or major surgery, replacement therapy is selected. However, in the case of HR, it is practical to plan a hemostasis therapy after the reaction, taking into consideration the appearance of previous immune response after 5–7 days after administration. Usually change to bypass hemostasis therapy. Even when the inhibitor titer is 5–10 BU/ml, it is possible to carry out neutralization therapy with high volumes of Factor VIII and Factor

There are three types of factor VIII (FVIII) preparations that can be used in Japan. They are plasma-derived factor VIII formulation, genetically modified factor VIII, and plasma-derived factor VIII (FVIII)/von Willebrand factor (VWF) complex preparation. There are two types of factor IX preparation that can be used: plasma-derived preparations and recombinant preparations. In some hemophilia A inhibitor cases, it is known that the hemostatic effect of the FIII/VWF preparation exceeds that of the factor VIII preparation. It is clarified that this inhibitor is an antibody which recognizes the factor VIII light chain and suppresses FVIII/VWF binding, and reactivity to FVIII is decreased by the presence of VWF [18].

Normally, factor VIII preparation and factor IX preparation are administered in bolus, but continuous administration is also selected at severe bleeding and hemostatic management of major operation. There are no standards for dose administration in inhibitor cases. If the inhibitor is completely neutralized by the initial bolus administration, the coagulation factor activity can theoretically be maintained in the administration example similar to the cases without inhibitor. In practice,

According to the guidelines published by the Japan Thrombosis Hemorrhagic Society, the first choice when the inhibitor titer ≧ 5 BU/ml is bypass hemostasis therapy except severe bleeding symptoms and hemostasis management during major surgery [17]. Traditionally, activated prothrombin complex concentrates (aPCC) or prothrombin complex concentrates (PCC) were the main body of bypass hemostasis therapy, but bypass hemostasis therapy has greatly advanced after the introduction of genetically modified active factor VII factor formulation (rFVIIa). Sales of PCC preparations adapted for inhibitors have been discontinued. Currently available bypass preparations are three, aPCC (FEIBA®), rFVIIa (NovoSeven®),

and blood coagulation factor X factor-activated factor VII (Byclot®).

Conventionally, it was extremely difficult for a variety of reasons to perform hemostasis management at the time of surgery of HR inhibitor cases with

IX preparation at severe bleeding and major surgery.

**17.2 Selection of replacement therapy preparation**

**17.3 Method of administration of preparation**

however, higher doses are often required.

**18.1 Bypass hemostatic therapy preparation**

*18.1.1 Activated prothrombin complex concentrates (aPCC)*

*18.1.1.1 Hemostasis management during surgery by aPCC*

**18. Bypass hemostatic therapy**

**46**

#### *18.1.2.1 Hemostasis management during surgery by rFVIIa*

rFVIIa is being used not only for small surgical operations but also for moderate or more surgical operations. Lusher et al. collected results on 103 surgical operations totaling 21 cases of major operation, 57 cases of small operation, and 25 cases of suturing relation [22]. According to the report, effective cases were 81, 86 and 92%, respectively, indicating that major surgery is also possible with hemostasis management by rFVIIa. Even in Japan, there are no restrictions on insurance medical treatment, so we have used more experience than aPCC and the number of cases such as large orthopedic surgery including artificial joint replacement surgery is increasing. Schrarer et al. recommended that 90 μg/kg every 2–3 days for 1–2 days, in large

surgery, and, in small surgery, the same amount of administration every 2–4 hours, every 6–7 days and every 6–8 hours 2 weeks [23]. Rodriguez et al. collected 108 cases of orthopedic surgical cases with inhibitor and reported the usefulness of rFVIIa [24]. Eighty cases of orthopedic surgical cases were collected over the period from 2000 to 2006. The initial dose was 120 μg/kg and thereafter administration of 90 μg/ kg every 2 hours or 50 μg/kg/hour in continuous administration. Obergfell et al. reported that this regimen is useful [25]. In Japan's guidelines, as in the case of severe bleeding hemostasis therapy, administration is performed every 2 hours for 1–2 days at the time of major operation. Thereafter, they recommend a regimen that gradually extends the dosing interval, for example, every 3, 4, 8, and 12 hours [17]. Because of its short half-life and the fact that thrombin burst is caused by high concentration of FVIIa is considered to be the basis of hemostatic effect, bolus administration is recommended in principle for administration of rFVIIa. However, there are increasing reports that sustained administration therapy is useful, especially when frequent administration is required as in surgical operation [26, 27]. In general administration method, continuous administration is started at 14–16.5 μg/kg/hour after the initial bolus administration of 90–120 μg/kg. Thereafter, the factor VII activity (FVII:C) is administered so as to maintain at least 10 units/ml. However, Ludlam et al. recently encouraged maintaining the trough level of FVII:C at 30 units/ml at a dose of 50 μg/ kg/h during major surgery [28].

#### *18.1.3 Mixture of plasma-derived factor VIIa and factor X (MC710)*

MC710 is a plasma-derived new bypass hemostatic therapeutic agent developed in Japan, because the effect of FVIIa is enhanced and sustained due to the coexistence of FX (FVIIa:FX = 1:10). According to pharmacodynamic analysis by coagulation waveform analysis conducted in Phase I study, activated partial thromboplastin time (APTT), maximum solidification rate, and maximum coagulation acceleration peaked 10 minutes after MC 710 administration. And it was before administration level 12 hours after administration. Although the enhancing effect of MC710 was not concentration dependent, it was higher than 120 μg/kg of rFVIIa or 50/75 U/kg of aPCC at dose>80 μg/kg [29]. Furthermore, in Phase II clinical trials, efficacy and safety were examined at two doses of 60 μg/kg and 120 μg/kg in patients with inhibitors of six cases. The hemostasis effect was effective and remarkable 8 hours after administration in total nine bleeding episodes. There were no side effects attributable to the formulation [30].

#### **19. Selection of bypass hemostatic therapy preparation**

Both current bypass treatment formulations, aPCC and rFVIIa, have been clarified for efficacy in hemostatic therapy for acute bleeding and surgical treatment. However, as to selection of both formulations, it is necessary to comprehensively select the presence/absence of anamnestic response in the past, the risk of thrombosis, and past hemostatic effect. It was revealed that the hemostasis effect between a single dose of aPCC (75–100 Units/kg) and two doses of rFVIIa (90–120 μg/kg) is equivalent to the hemorrhage of the joint [31]. Interestingly, however, cases were found in which there was a difference in hemostatic effect among the preparations. Even in the same case, the difference in the hemostatic effect between both preparations suggests that it is necessary to change to multiple drugs when the first choice preparation is ineffective [32]. For the selection of preparations at the time of surgery, it has been reported that preparations are added ex vivo to the patient's plasma

**49**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients…*

prior to surgery and the hemostatic effect is judged by rotation thromboelastometry

Regarding the effectiveness of ITI therapy, the only statistically proven factor is the potency of the inhibitor at the beginning of ITI. Therefore, the lower the inhibitor titer, the higher the success rate. Recent international clinical studies of ITI also target <10 BU/ml patients [34]. As a rule, rFVIIa is the first choice in cases where

Some patients with hemophilia B with some inhibitors have allergic symptoms for the preparation containing factor IX. Allergic symptoms are often severe and may present anaphylaxis. The essence of allergic symptoms is anti-IX factor IgG (immunoglobulin G), which is said to be particularly IgG1 antibody [35]. The aPCC preparation contains factor IX. Patients who are allergic to factor IX preparation may have similar symptoms to aPCC. For such cases, it is also possible to desensitize by administering a preparation containing factor IX in small amounts [36]. In general, however, the first choice in cases with allergic history is rFVIIa and MC710.

Here we summarize the various options available for the perioperative management of patients with hemophilia and also discuss joint surgery, which is an important aspect of treatment of patients with hemophilia. Unlike healthy subjects, patients with hemophilia require special perioperative management. We hope that this manuscript will help in formulating better treatment of patients with hemo-

We would like to thank Mr. Satoshi Shinmura (pharmacist at Bioverativ Japan) and Mr. Yoichi Hirose (medical representative at Chugai Pharmaceutical Co., Ltd.) who helped with the collection of the thesis and advised on the latest developments

I would like to thank the coauthors who supported the writing of this chapter

*DOI: http://dx.doi.org/10.5772/intechopen.81172*

**20. Bypass hemostatic therapy in special case**

anamnestic response occurs with aPCC administration.

**20.2 Cases with a history of allergic symptoms**

**20.1 Cases before immune tolerance induction (ITI therapy)**

(ROTEM) before operation [33].

**21. Conclusion**

philia in the future.

in the field.

**Acknowledgements**

**Conflict of interest**

and advised me.

We do not have conflicts of interest to disclose.

**Notes/thanks/other declarations**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients… DOI: http://dx.doi.org/10.5772/intechopen.81172*

prior to surgery and the hemostatic effect is judged by rotation thromboelastometry (ROTEM) before operation [33].

#### **20. Bypass hemostatic therapy in special case**

#### **20.1 Cases before immune tolerance induction (ITI therapy)**

Regarding the effectiveness of ITI therapy, the only statistically proven factor is the potency of the inhibitor at the beginning of ITI. Therefore, the lower the inhibitor titer, the higher the success rate. Recent international clinical studies of ITI also target <10 BU/ml patients [34]. As a rule, rFVIIa is the first choice in cases where anamnestic response occurs with aPCC administration.

#### **20.2 Cases with a history of allergic symptoms**

Some patients with hemophilia B with some inhibitors have allergic symptoms for the preparation containing factor IX. Allergic symptoms are often severe and may present anaphylaxis. The essence of allergic symptoms is anti-IX factor IgG (immunoglobulin G), which is said to be particularly IgG1 antibody [35]. The aPCC preparation contains factor IX. Patients who are allergic to factor IX preparation may have similar symptoms to aPCC. For such cases, it is also possible to desensitize by administering a preparation containing factor IX in small amounts [36]. In general, however, the first choice in cases with allergic history is rFVIIa and MC710.

#### **21. Conclusion**

*Hemophilia - Recent Advances*

kg/h during major surgery [28].

able to the formulation [30].

*18.1.3 Mixture of plasma-derived factor VIIa and factor X (MC710)*

**19. Selection of bypass hemostatic therapy preparation**

MC710 is a plasma-derived new bypass hemostatic therapeutic agent developed in Japan, because the effect of FVIIa is enhanced and sustained due to the coexistence of FX (FVIIa:FX = 1:10). According to pharmacodynamic analysis by coagulation waveform analysis conducted in Phase I study, activated partial thromboplastin time (APTT), maximum solidification rate, and maximum coagulation acceleration peaked 10 minutes after MC 710 administration. And it was before administration level 12 hours after administration. Although the enhancing effect of MC710 was not concentration dependent, it was higher than 120 μg/kg of rFVIIa or 50/75 U/kg of aPCC at dose>80 μg/kg [29]. Furthermore, in Phase II clinical trials, efficacy and safety were examined at two doses of 60 μg/kg and 120 μg/kg in patients with inhibitors of six cases. The hemostasis effect was effective and remarkable 8 hours after administration in total nine bleeding episodes. There were no side effects attribut-

Both current bypass treatment formulations, aPCC and rFVIIa, have been clarified for efficacy in hemostatic therapy for acute bleeding and surgical treatment. However, as to selection of both formulations, it is necessary to comprehensively select the presence/absence of anamnestic response in the past, the risk of thrombosis, and past hemostatic effect. It was revealed that the hemostasis effect between a single dose of aPCC (75–100 Units/kg) and two doses of rFVIIa (90–120 μg/kg) is equivalent to the hemorrhage of the joint [31]. Interestingly, however, cases were found in which there was a difference in hemostatic effect among the preparations. Even in the same case, the difference in the hemostatic effect between both preparations suggests that it is necessary to change to multiple drugs when the first choice preparation is ineffective [32]. For the selection of preparations at the time of surgery, it has been reported that preparations are added ex vivo to the patient's plasma

surgery, and, in small surgery, the same amount of administration every 2–4 hours, every 6–7 days and every 6–8 hours 2 weeks [23]. Rodriguez et al. collected 108 cases of orthopedic surgical cases with inhibitor and reported the usefulness of rFVIIa [24]. Eighty cases of orthopedic surgical cases were collected over the period from 2000 to 2006. The initial dose was 120 μg/kg and thereafter administration of 90 μg/ kg every 2 hours or 50 μg/kg/hour in continuous administration. Obergfell et al. reported that this regimen is useful [25]. In Japan's guidelines, as in the case of severe bleeding hemostasis therapy, administration is performed every 2 hours for 1–2 days at the time of major operation. Thereafter, they recommend a regimen that gradually extends the dosing interval, for example, every 3, 4, 8, and 12 hours [17]. Because of its short half-life and the fact that thrombin burst is caused by high concentration of FVIIa is considered to be the basis of hemostatic effect, bolus administration is recommended in principle for administration of rFVIIa. However, there are increasing reports that sustained administration therapy is useful, especially when frequent administration is required as in surgical operation [26, 27]. In general administration method, continuous administration is started at 14–16.5 μg/kg/hour after the initial bolus administration of 90–120 μg/kg. Thereafter, the factor VII activity (FVII:C) is administered so as to maintain at least 10 units/ml. However, Ludlam et al. recently encouraged maintaining the trough level of FVII:C at 30 units/ml at a dose of 50 μg/

**48**

Here we summarize the various options available for the perioperative management of patients with hemophilia and also discuss joint surgery, which is an important aspect of treatment of patients with hemophilia. Unlike healthy subjects, patients with hemophilia require special perioperative management. We hope that this manuscript will help in formulating better treatment of patients with hemophilia in the future.

#### **Acknowledgements**

We would like to thank Mr. Satoshi Shinmura (pharmacist at Bioverativ Japan) and Mr. Yoichi Hirose (medical representative at Chugai Pharmaceutical Co., Ltd.) who helped with the collection of the thesis and advised on the latest developments in the field.

#### **Conflict of interest**

We do not have conflicts of interest to disclose.

#### **Notes/thanks/other declarations**

I would like to thank the coauthors who supported the writing of this chapter and advised me.

*Hemophilia - Recent Advances*

### **Author details**

Atsushi Okamoto, Kenta Yamamoto, Go Eguchi, Yoshitaka Kanai, Terufumi Yamaguchi and Yasuhiro Maeda\* Department of Hematology, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan

\*Address all correspondence to: ymaeda@ommc-hp.jp

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**51**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients…*

single-Centre experience. Haemophilia.

thromboembolic disease in patients with haemophilia. Thrombosis Research.

[12] Okamoto A, Yamamoto K, Eguchi G, et al. Perioperative management of haemophilia A using recombinant factor VIII Fc fusion protein in a patient undergoing endoscopic nasal pituitary adenomectomy for a growth hormone-producing pituitary adenoma. Haemophilia. 2017;**6**:e525-e527. DOI:

[13] Shima M. Characterization of factor VIII inhibitors. International Journal of

Hematology. 2006;**83**:109-118

[14] Kasper CK, Aledort L, Aronson D, et al. Proceedings: A more uniform measurement of factor VIII inhibitors. Thrombosis et Diathesis Haemorrhagica. 1975;**34**:612

[15] Verbruggen B, Novakova I, Wessels H, et al. The Nijmegen modification of the Bethesda assay for factor VIII; C inhibitors: Improved specificity and reliability. Thrombosis and Haemostasis.

[16] White GC 2nd, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the international society on thrombosis and haemostasis. Thrombosis

and Haemostasis. 2001;**85**:560

[10] Hermans C, Hammer F, Lobet S, et al. Subclinical deep venous thrombosis observed in 10% of hemophilic patients undergoing major orthopedic surgery. Journal of Thrombosis and Haemostasis.

2013;**19**:951-955

2010;**8**:1138-1140

10.1111/hae.13347

1995;**73**:247-251

[11] Hermans C. Venous

2012;**130**(Suppl 1):S50-S52

*DOI: http://dx.doi.org/10.5772/intechopen.81172*

[1] Amano K. Hemostasis Management of the Latest Haemophilia. Tokyo: Medical Plactice 24 Bunkodo; 2007.

[2] Dunn AL, Manco-Johnson M, Busch MT, et al. Leukemia and P32 radionuclide synovectomy for hemophilic arthropathy. Journal of Thrombosis and Haemostasis.

[3] Medical and Scientific Advisory Council: MASAC Recommendation #194. 2010. Available from: http://www. hemophilia.org/NHFWeb/MainPgs/ MainNHF.aspx?menuid=156&conten

[4] Taketani H. Orthopedic treatment for haemophilic arthropathy. Blood

[5] Tanaka Y, Shinohara Y, Narikawa K, et al. Arthroscopic synovectomies combined with reduced weight-bearing using patella tendonbearing braces were very effective for progressed haemophilic ankle arthropathy in three paediatric patients. Haemophilia. 2009;**15**:833-836

[6] Shimada K, Takedani H, Inoue K, et al. Arthroscopic synovectomy of the elbow covered with rFVIIa in a Haemophilia B juvenile with inhibitor. Haemophilia. 2012;**18**:e414-e416

[7] Lofqvist T, Nilsson IM, Petersson C. Orthopaedic surgery in hemophilia. Clinical Orthopaedics and Related Research. 1996;**332**:232-241

[8] Journeycake JM, Miller KL, Anderson AM, et al. Arthroscopic synovectomy in children and adolescents with hemophilia. Journal of Pediatric

Hematology/Oncology. 2003;**25**:726-731

[9] Hirose J, Takedani H, Koibuchi T. The risk of elective orthopaedic surgery for haemophilia patients:Japanese

Frontier. 2006;**16**:1797-1804

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*Hemophilia - Recent Advances*

**50**

**Author details**

Center, Osaka, Japan

provided the original work is properly cited.

Terufumi Yamaguchi and Yasuhiro Maeda\*

\*Address all correspondence to: ymaeda@ommc-hp.jp

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Hematology, National Hospital Organization Osaka Minami Medical

Atsushi Okamoto, Kenta Yamamoto, Go Eguchi, Yoshitaka Kanai,

[1] Amano K. Hemostasis Management of the Latest Haemophilia. Tokyo: Medical Plactice 24 Bunkodo; 2007. pp. 2165-2170

[2] Dunn AL, Manco-Johnson M, Busch MT, et al. Leukemia and P32 radionuclide synovectomy for hemophilic arthropathy. Journal of Thrombosis and Haemostasis. 2005;**3**:1541-1542

[3] Medical and Scientific Advisory Council: MASAC Recommendation #194. 2010. Available from: http://www. hemophilia.org/NHFWeb/MainPgs/ MainNHF.aspx?menuid=156&conten tid=335

[4] Taketani H. Orthopedic treatment for haemophilic arthropathy. Blood Frontier. 2006;**16**:1797-1804

[5] Tanaka Y, Shinohara Y, Narikawa K, et al. Arthroscopic synovectomies combined with reduced weight-bearing using patella tendonbearing braces were very effective for progressed haemophilic ankle arthropathy in three paediatric patients. Haemophilia. 2009;**15**:833-836

[6] Shimada K, Takedani H, Inoue K, et al. Arthroscopic synovectomy of the elbow covered with rFVIIa in a Haemophilia B juvenile with inhibitor. Haemophilia. 2012;**18**:e414-e416

[7] Lofqvist T, Nilsson IM, Petersson C. Orthopaedic surgery in hemophilia. Clinical Orthopaedics and Related Research. 1996;**332**:232-241

[8] Journeycake JM, Miller KL, Anderson AM, et al. Arthroscopic synovectomy in children and adolescents with hemophilia. Journal of Pediatric Hematology/Oncology. 2003;**25**:726-731

[9] Hirose J, Takedani H, Koibuchi T. The risk of elective orthopaedic surgery for haemophilia patients:Japanese

single-Centre experience. Haemophilia. 2013;**19**:951-955

[10] Hermans C, Hammer F, Lobet S, et al. Subclinical deep venous thrombosis observed in 10% of hemophilic patients undergoing major orthopedic surgery. Journal of Thrombosis and Haemostasis. 2010;**8**:1138-1140

[11] Hermans C. Venous thromboembolic disease in patients with haemophilia. Thrombosis Research. 2012;**130**(Suppl 1):S50-S52

[12] Okamoto A, Yamamoto K, Eguchi G, et al. Perioperative management of haemophilia A using recombinant factor VIII Fc fusion protein in a patient undergoing endoscopic nasal pituitary adenomectomy for a growth hormone-producing pituitary adenoma. Haemophilia. 2017;**6**:e525-e527. DOI: 10.1111/hae.13347

[13] Shima M. Characterization of factor VIII inhibitors. International Journal of Hematology. 2006;**83**:109-118

[14] Kasper CK, Aledort L, Aronson D, et al. Proceedings: A more uniform measurement of factor VIII inhibitors. Thrombosis et Diathesis Haemorrhagica. 1975;**34**:612

[15] Verbruggen B, Novakova I, Wessels H, et al. The Nijmegen modification of the Bethesda assay for factor VIII; C inhibitors: Improved specificity and reliability. Thrombosis and Haemostasis. 1995;**73**:247-251

[16] White GC 2nd, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the international society on thrombosis and haemostasis. Thrombosis and Haemostasis. 2001;**85**:560

#### *Hemophilia - Recent Advances*

[17] Sakai M, Taki M, Ieko M, et al. Guidelines for hemostasis treatment for congenital hemophilia patients with inhibitors 2013 revised edition. Japanese Journal of Thrombosis and Hemostasis. 2013;**19**:520-539

[18] Inoue T, Shima M, Takeyama M, et al. Higher recovery of factor VIII(FVIII) with intermediate FVIII/ von Willebrand factor concentrate than with recombinant FVIII in a haemophilia A patient with an inhibitor. Haemophilia. 2006;**12**:110-113

[19] Negrier C, Goudemand J, Sultan Y, et al. Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. French FEIBA Study Group. Factor eight bypassing activity. Thrombosis and Haemostasis. 1997;**77**:1113-1119

[20] Kraut EH, Aledort LM, Arkin S, et al. Surgical interventions in a cohort of patients with haemophilia A and inhibitors: An experiential retrospective chart review. Haemophilia. 2007;**13**:508-517

[21] Yoshioka A, Kamisue S, Tanaka I, et al. Anamnestic response following infusion of prothrombin complex concentrates (PCC) and activated prothrombin complex concentrates (aPCC) in hamophilia A patients with inhibitors. Blood Coagulation and Fibrinolysis. 1991;**2**:51-58

[22] Lusher JM, Roberts HR, Davignon G, et al. A randomized, doubleblind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. rFVIIa Study Group. Haemophilia. 1998;**4**:790-798

[23] Scharrer I. Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VIII deficiency. Haemophilia. 1999;**5**:253-259

[24] Rodrigues-Merchan EC, Jd WJ, Wallny T, et al. Elective orthopedic surgery for hemophilia patients with inhibitors: New opportunities. Seminars in Hematology. 2004;**41**(1 Suppl):109-116

[25] Obergfell A, Auvinen MK, Mathew P. Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopedic surgery: A review of the literature. Haemophilia. 2008;**14**:233-241

[26] Schulman S, Bech Jensen M, Varon D, et al. Feasibility of using recombinant factor VIIa in continuous infusion. Thrombosis and Haemostasis. 1996;**75**:32-36

[27] Mauser-Bunschoten EP, Koopman MM, Goede-Bolder AD, et al. Efficacy of recombinant factor VIIa administered by continuous infusion to haemophilia patients with inhibitors. Haemophilia. 2002;**8**:649-656

[28] Ludlam CA, Smith MP, Morfini M, et al. A prospective study of recombinant activated factor VII administered by continuous infusion to inhibitor patients undergoing elective major orthopaedic surgery: A pharmacokinetic and efficacy evaluation. British Journal of Haematology. 2003;**120**:808-813

[29] Shirahata A, Fukutake K, Mimaya J, et al. Results of clot waveform analysis and thrombin generation test for a plasma-derived factor VIIa and X mixture (MC710) in haemophilia patients with inhibitors—Phase I trial; 2nd report. Haemophilia. 2013;**19**:330-337

[30] Shirahata A, Fukutake K, Takamatsu J, et al. A phase II clinical trial of a mixture of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors: Haemostatic efficacy, safety and pharmacokinetics/pharmacodynamics. Haemophilia. 2013;**19**:853-860

**53**

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients…*

*DOI: http://dx.doi.org/10.5772/intechopen.81172*

[31] Astermark J, Donfield SM, DiMichele DM, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: The FEIBA NovoSeven Comparative (FENOC) study. Blood.

[32] Hayashi T, Tanaka I, Shima M, et al. Unresponsiveness to factor VIII inhibitor bypassing agents during Haemostatic treatment for life-threatening massive bleeding in a patient with haemophilia A and a high responding inhibitor. Haemophilia.

[33] Furukawa S, Nogami K, Ogiwara K, et al. Systematic monitoring of hemostatic management in hemophilia

DM. International immnne tolerance study: The principal results of the international immune tolerance study: A randomized dose comparison. Blood.

[35] Sawamoto Y, Shima M, Yamamoto M, et al. Measurement of anti-factor IX IgG subclasses in haemophilia B patients who developed inhibitors with episodes of allergic reactions to factor IX concentrates. Thrombosis Research.

[36] Shibata M, Shima M, Misu H, et al. Management of haemophilia B inhibitor patients with anaphylactic reactions to FIX concentrates. Haemophilia.

A patients with inhibitor in the perioperative period using rotational thromboelastometry. Journal of Thrombosis and Haemostasis.

2007;**109**:546-551

2004;**10**:397-400

2015;**13**:1279-1284

2012;**119**:1335-1344

1996;**83**:279-286

2003;**9**:269-271

[34] Hay CR, Dimichele

*Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients… DOI: http://dx.doi.org/10.5772/intechopen.81172*

[31] Astermark J, Donfield SM, DiMichele DM, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: The FEIBA NovoSeven Comparative (FENOC) study. Blood. 2007;**109**:546-551

[32] Hayashi T, Tanaka I, Shima M, et al. Unresponsiveness to factor VIII inhibitor bypassing agents during Haemostatic treatment for life-threatening massive bleeding in a patient with haemophilia A and a high responding inhibitor. Haemophilia. 2004;**10**:397-400

[33] Furukawa S, Nogami K, Ogiwara K, et al. Systematic monitoring of hemostatic management in hemophilia A patients with inhibitor in the perioperative period using rotational thromboelastometry. Journal of Thrombosis and Haemostasis. 2015;**13**:1279-1284

[34] Hay CR, Dimichele DM. International immnne tolerance study: The principal results of the international immune tolerance study: A randomized dose comparison. Blood. 2012;**119**:1335-1344

[35] Sawamoto Y, Shima M, Yamamoto M, et al. Measurement of anti-factor IX IgG subclasses in haemophilia B patients who developed inhibitors with episodes of allergic reactions to factor IX concentrates. Thrombosis Research. 1996;**83**:279-286

[36] Shibata M, Shima M, Misu H, et al. Management of haemophilia B inhibitor patients with anaphylactic reactions to FIX concentrates. Haemophilia. 2003;**9**:269-271

**52**

*Hemophilia - Recent Advances*

2013;**19**:520-539

[17] Sakai M, Taki M, Ieko M, et al. Guidelines for hemostasis treatment for congenital hemophilia patients with inhibitors 2013 revised edition. Japanese Journal of Thrombosis and Hemostasis.

[24] Rodrigues-Merchan EC, Jd WJ, Wallny T, et al. Elective orthopedic surgery for hemophilia patients with inhibitors: New opportunities. Seminars in Hematology. 2004;**41**(1

[25] Obergfell A, Auvinen MK, Mathew P. Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopedic surgery: A review of the literature. Haemophilia.

[26] Schulman S, Bech Jensen M, Varon D, et al. Feasibility of using recombinant factor VIIa in continuous infusion. Thrombosis and Haemostasis.

[27] Mauser-Bunschoten EP, Koopman MM, Goede-Bolder AD, et al. Efficacy of recombinant factor VIIa administered by continuous infusion to haemophilia patients with inhibitors. Haemophilia.

[28] Ludlam CA, Smith MP, Morfini M, et al. A prospective study of recombinant activated factor VII administered by continuous infusion to inhibitor patients undergoing elective major orthopaedic surgery: A pharmacokinetic and efficacy evaluation. British Journal of Haematology. 2003;**120**:808-813

[29] Shirahata A, Fukutake K, Mimaya J, et al. Results of clot waveform analysis and thrombin generation test for a plasma-derived factor VIIa and X mixture (MC710) in haemophilia patients with inhibitors—Phase I trial; 2nd report. Haemophilia. 2013;**19**:330-337

[30] Shirahata A, Fukutake K, Takamatsu J, et al. A phase II clinical trial of a mixture of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors: Haemostatic efficacy, safety and pharmacokinetics/pharmacodynamics.

Haemophilia. 2013;**19**:853-860

Suppl):109-116

2008;**14**:233-241

1996;**75**:32-36

2002;**8**:649-656

[18] Inoue T, Shima M, Takeyama M, et al. Higher recovery of factor VIII(FVIII) with intermediate FVIII/ von Willebrand factor concentrate than with recombinant FVIII in a haemophilia A patient with an inhibitor.

Haemophilia. 2006;**12**:110-113

[19] Negrier C, Goudemand J, Sultan Y, et al. Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. French FEIBA Study Group. Factor eight bypassing activity. Thrombosis and Haemostasis. 1997;**77**:1113-1119

[20] Kraut EH, Aledort LM, Arkin S, et al. Surgical interventions in a cohort of patients with haemophilia A and inhibitors: An experiential

2007;**13**:508-517

Fibrinolysis. 1991;**2**:51-58

retrospective chart review. Haemophilia.

[21] Yoshioka A, Kamisue S, Tanaka I, et al. Anamnestic response following infusion of prothrombin complex concentrates (PCC) and activated prothrombin complex concentrates (aPCC) in hamophilia A patients with inhibitors. Blood Coagulation and

[22] Lusher JM, Roberts HR, Davignon G, et al. A randomized, doubleblind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. rFVIIa Study Group. Haemophilia. 1998;**4**:790-798

[23] Scharrer I. Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VIII deficiency. Haemophilia. 1999;**5**:253-259

**55**

**Chapter 4**

**Abstract**

ing disorders.

postpartum

**1. Introduction**

to 1:1–3 million in the general population [1, 2].

*and Hilda Luna-Záizar*

Clinical Issues in Women with

*Ana-Rebeca Jaloma-Cruz, Isaura-Araceli González-Ramos,* 

Various inherited bleeding disorders deserve careful medical management due to their implications in women's health. In both hemophilia A and B, almost exclusively, males are affected while carrier females are generally asymptomatic. Nevertheless, carriers may present important bleeding tendencies, which can eventually constitute a serious threat to life, especially after surgery or postpartum. In addition, in rare but significant cases, some genetic mechanisms have been found to cause hemophilia in females. Aside from von Willebrand disease, which is the most widespread and better described hemorrhagic condition in women, platelet disorders and some rare clotting deficiencies cause a wide variety of mucocutaneous bleedings, menorrhagia, or postpartum bleeding, hence constituting an important health risk. A review of the genetic and pathophysiological aspects as well as main clinical complications of all these conditions will allow for preventive practices aimed at improving the quality of life of women with bleed-

**Keywords:** symptomatic carriers and women with hemophilia, von Willebrand disease, platelet disorders, rare bleeding disorders, bleedings in pregnancy and

Inherited bleeding disorders are a group of deficiencies including the decreased function or number of platelets (thrombocytopenia) and clotting factor deficiencies, mainly von Willebrand disease (VWD), hemophilia A (HA), and hemophilia B (HB), as well as rare bleeding disorders (RBDs) such as deficiencies of factors (F) I (fibrinogen), II, FV, combined FV-FVIII, FVII, FX, FXI, and FXIII and congenital deficiency of vitamin K-dependent factors and plasminogen activator inhibitor (PAI-1). Mostly autosomal recessive, together they have a prevalence of 1:500,000

Although all these entities cause bleeding tendencies in the affected males or females, there are relevant clinical issues related to obstetric and gynecological

Menorrhagia or the more precise term of heavy menstrual bleeding (HMB) recommended by the International Federation of Gynecology and Obstetrics (FIGO)

conditions that require special considerations in their management [1].

Inherited Bleeding Disorders

*Diana Ornelas-Ricardo, Clara-Ibet Juárez-Vázquez* 

#### **Chapter 4**

## Clinical Issues in Women with Inherited Bleeding Disorders

*Ana-Rebeca Jaloma-Cruz, Isaura-Araceli González-Ramos, Diana Ornelas-Ricardo, Clara-Ibet Juárez-Vázquez and Hilda Luna-Záizar*

#### **Abstract**

Various inherited bleeding disorders deserve careful medical management due to their implications in women's health. In both hemophilia A and B, almost exclusively, males are affected while carrier females are generally asymptomatic. Nevertheless, carriers may present important bleeding tendencies, which can eventually constitute a serious threat to life, especially after surgery or postpartum. In addition, in rare but significant cases, some genetic mechanisms have been found to cause hemophilia in females. Aside from von Willebrand disease, which is the most widespread and better described hemorrhagic condition in women, platelet disorders and some rare clotting deficiencies cause a wide variety of mucocutaneous bleedings, menorrhagia, or postpartum bleeding, hence constituting an important health risk. A review of the genetic and pathophysiological aspects as well as main clinical complications of all these conditions will allow for preventive practices aimed at improving the quality of life of women with bleeding disorders.

**Keywords:** symptomatic carriers and women with hemophilia, von Willebrand disease, platelet disorders, rare bleeding disorders, bleedings in pregnancy and postpartum

#### **1. Introduction**

Inherited bleeding disorders are a group of deficiencies including the decreased function or number of platelets (thrombocytopenia) and clotting factor deficiencies, mainly von Willebrand disease (VWD), hemophilia A (HA), and hemophilia B (HB), as well as rare bleeding disorders (RBDs) such as deficiencies of factors (F) I (fibrinogen), II, FV, combined FV-FVIII, FVII, FX, FXI, and FXIII and congenital deficiency of vitamin K-dependent factors and plasminogen activator inhibitor (PAI-1). Mostly autosomal recessive, together they have a prevalence of 1:500,000 to 1:1–3 million in the general population [1, 2].

Although all these entities cause bleeding tendencies in the affected males or females, there are relevant clinical issues related to obstetric and gynecological conditions that require special considerations in their management [1].

Menorrhagia or the more precise term of heavy menstrual bleeding (HMB) recommended by the International Federation of Gynecology and Obstetrics (FIGO)

is the most common symptom in women with bleeding disorders and is defined as bleeding that lasts more than 7 days or results in the loss of more than 80 mL of blood per menstrual cycle [1, 3]. In terms of women's quality of life, HMB is defined as "the excessive menstrual blood loss which interferes with the woman's physical, emotional, social and material quality of life, and can occur alone or in combination with other symptoms; HMB is typically associated with a symptom complex, including variable pelvic pain and somatic symptoms" [3].

The FIGO also classifies the dysfunctional uterine bleeding disorders and identifies impaired hemostasis as one of the three recognized causes [3]. More than 70% of women with VWD present HMB and they are five times more likely to suffer from this complication than women without the condition. As for platelet disorders, the prevalence of HMB is 51% in women with Bernard-Soulier syndrome and 98% in women with Glanzmann thrombasthenia. HMB is present in 59% of women with FXI deficiency, in 57% of hemophilia carriers, and in 35–70% of women with other rare factor deficiencies [1].

In addition to HMB, women with bleeding disorders frequently suffer from large clots and flooding during their menstruation as well as bleeds after their menstrual period, conditions that may seriously affect their quality of life. Since 1990, Higham et al. proposed a pictorial blood assessment chart (PBAC) that was based on a validation study against the alkaline hematin method for blood measurement, which is known to be very accurate and reproducible but not practical in routine clinical use [4]. A score greater than 100, based on the number of used tampons or towels and the points assigned according to the estimated blood soaking, represents a very good prediction and considers a menstrual blood loss of more than 80 mL as positive HMB. The passage of clots and flooding episodes are also registered and considered for the score [1, 4].

HMB can be considered a significant symptom of a bleeding disorder, especially when it is present at menarche. The hematological evaluation of women with HMB should take into account the personal and familial bleeding history of epistaxis, easy bruising bleeding in the oral cavity, prolonged bleeding following dental extraction, unexpected post-surgical bleeding, hemorrhage requiring transfusion, and postpartum hemorrhage, especially after 24 h [1]. In patients with at least 2–3 symptoms, additional screening and confirmatory tests for VWD, platelet function, coagulation times, and clotting factor levels are mandatory [1].

Concerning the management of pregnancy and postpartum, women suspected of having a bleeding disorder or being a carrier of hemophilia should undergo diagnostic testing before getting pregnant in order to receive appropriate preconception counseling and early pregnancy management. This information allows for consideration of the available reproductive choices and options for prenatal diagnosis such as planning for pregnancy and establishing the best management in terms of hemostatic treatment and for the support of the pregnancy [1]. After the delivery, the elevated coagulation factor returns to the pre-pregnancy levels; therefore, the main risk of bleeding is after miscarriage or delivery. Postpartum hemorrhage (PPH) is a major cause of maternal morbidity and mortality, especially in developing countries or rural regions. PPH accounts for an estimated 140,000 maternal deaths each year worldwide and many women suffer from long-term debilitating consequences of the resultant anemia. Even if the most common causes of PPH are uterine atony, retained placenta, or genital tract trauma, coagulation disorders are also recognized causes of such complication [1].

In the next sections, we summarize clinical generalities, genetic aspects, impact on women's health, recommended treatment, and medical management of common inherited bleeding disorders.

**57**

*Clinical Issues in Women with Inherited Bleeding Disorders*

Hemophilia is an X-linked disease due to mutations in the genes *F8* and *F9* (causing HA and HB, respectively) and subsequent deficiency of the clotting factors VIII (FVIII) and IX (FIX). HA affects 1/5000–10,000 males and HB 1/30,000 males. Both factors act in the same step of the coagulation mechanism and, when any of them is deficient, a diminished thrombin generation ensues. The symptoms have an inverse correlation with the plasmatic activity of the deficient factor, and the diagnosis and severity classification are based on the residual factor level [5].

Due to its recessive X-linked inheritance, males are mostly affected while the heterozygous female carriers are usually asymptomatic. Although some carriers have various bleeding manifestations and can even express severe (FVIII/FIX <0.01 U mL-1) or moderate (FVIII/FIX 0.01–0.05 U mL-1) phenotypes, their specific clini-

Hemophilia female carriers may be affected by hemorrhagic manifestations due to different genetic conditions: both mutated alleles with homozygous or compound heterozygous mutations in *F8* or *F9* genes, hemizygosity in 45,X (Turner syndrome) patients with a mutated X chromosome, or extremely skewed X-chromosome inactivation pattern (X-IP) in carriers who have inactivated the wild-type allele and thereby have a highly decreased amount of the concerned factor and express the symptoms of the disease [7]. The molecular genetic analysis is essential in elucidating the mechanisms underlying the bleeding phenotype in females with hemophilia [8–10].

In accordance with international estimations, there are 3–5 potential female carriers for each male with hemophilia, but not every carrier knows her genetic status. According to the study of Bernard, only 38% of the potential carriers have been screened about their carrier/non-carrier status. He analyzed 408 potential carriers and reported that only a limited fraction of them received information from a hemophilia specialist about their status and underwent coagulation factor analysis; the remaining large fraction failed to accomplish the screening due to lack of communication within the family and unawareness of the inheritance mode [11]. If women do not realize the possibility of being carriers, all their symptoms can be overlapped with normal women and those with VWD or qualitative platelet disorders [7]; so, all possible or potential carriers must be screened and should be

Different studies have shown the increased tendency of bleeding in hemophilia carriers compared to healthy females. Olsson et al. described the bleeding symptoms in 126 hemophilia carriers in contrast to 90 non-hemophilia carriers; the hemorrhagic tendency was normal in 82 carriers (65%) and in all but two women in the control group (98%). They reported that there was no difference in bleeding symptoms between carriers from hemophiliac families and carriers with sporadic mutations. The proportion of carriers and controls reporting bleeding symptoms was different with statistically significant results (p < 0.001), **Table 1** [13].

Paroskie compared 44 HA carriers with 43 healthy women and found a significant (p < 0.05) increase in clinical features as shown in **Table 2** [5]. Contrary to

cal manifestations and genetic data have hardly been described [6].

advised about care and surveillance regarding bleeding tendencies [12].

*DOI: http://dx.doi.org/10.5772/intechopen.82119*

**2. Symptomatic hemophilia carriers**

**2.1 Generalities**

**2.2 Genetic aspects**

**2.3 Clinical features**

#### **2. Symptomatic hemophilia carriers**

#### **2.1 Generalities**

*Hemophilia - Recent Advances*

rare factor deficiencies [1].

considered for the score [1, 4].

causes of such complication [1].

inherited bleeding disorders.

is the most common symptom in women with bleeding disorders and is defined as bleeding that lasts more than 7 days or results in the loss of more than 80 mL of blood per menstrual cycle [1, 3]. In terms of women's quality of life, HMB is defined as "the excessive menstrual blood loss which interferes with the woman's physical, emotional, social and material quality of life, and can occur alone or in combination with other symptoms; HMB is typically associated with a symptom complex,

The FIGO also classifies the dysfunctional uterine bleeding disorders and identifies impaired hemostasis as one of the three recognized causes [3]. More than 70% of women with VWD present HMB and they are five times more likely to suffer from this complication than women without the condition. As for platelet disorders, the prevalence of HMB is 51% in women with Bernard-Soulier syndrome and 98% in women with Glanzmann thrombasthenia. HMB is present in 59% of women with FXI deficiency, in 57% of hemophilia carriers, and in 35–70% of women with other

In addition to HMB, women with bleeding disorders frequently suffer from large

HMB can be considered a significant symptom of a bleeding disorder, especially when it is present at menarche. The hematological evaluation of women with HMB should take into account the personal and familial bleeding history of epistaxis, easy bruising bleeding in the oral cavity, prolonged bleeding following dental extraction, unexpected post-surgical bleeding, hemorrhage requiring transfusion, and postpartum hemorrhage, especially after 24 h [1]. In patients with at least 2–3 symptoms, additional screening and confirmatory tests for VWD, platelet function,

Concerning the management of pregnancy and postpartum, women suspected of

In the next sections, we summarize clinical generalities, genetic aspects, impact on women's health, recommended treatment, and medical management of common

having a bleeding disorder or being a carrier of hemophilia should undergo diagnostic testing before getting pregnant in order to receive appropriate preconception counseling and early pregnancy management. This information allows for consideration of the available reproductive choices and options for prenatal diagnosis such as planning for pregnancy and establishing the best management in terms of hemostatic treatment and for the support of the pregnancy [1]. After the delivery, the elevated coagulation factor returns to the pre-pregnancy levels; therefore, the main risk of bleeding is after miscarriage or delivery. Postpartum hemorrhage (PPH) is a major cause of maternal morbidity and mortality, especially in developing countries or rural regions. PPH accounts for an estimated 140,000 maternal deaths each year worldwide and many women suffer from long-term debilitating consequences of the resultant anemia. Even if the most common causes of PPH are uterine atony, retained placenta, or genital tract trauma, coagulation disorders are also recognized

coagulation times, and clotting factor levels are mandatory [1].

clots and flooding during their menstruation as well as bleeds after their menstrual period, conditions that may seriously affect their quality of life. Since 1990, Higham et al. proposed a pictorial blood assessment chart (PBAC) that was based on a validation study against the alkaline hematin method for blood measurement, which is known to be very accurate and reproducible but not practical in routine clinical use [4]. A score greater than 100, based on the number of used tampons or towels and the points assigned according to the estimated blood soaking, represents a very good prediction and considers a menstrual blood loss of more than 80 mL as positive HMB. The passage of clots and flooding episodes are also registered and

including variable pelvic pain and somatic symptoms" [3].

**56**

Hemophilia is an X-linked disease due to mutations in the genes *F8* and *F9* (causing HA and HB, respectively) and subsequent deficiency of the clotting factors VIII (FVIII) and IX (FIX). HA affects 1/5000–10,000 males and HB 1/30,000 males. Both factors act in the same step of the coagulation mechanism and, when any of them is deficient, a diminished thrombin generation ensues. The symptoms have an inverse correlation with the plasmatic activity of the deficient factor, and the diagnosis and severity classification are based on the residual factor level [5].

#### **2.2 Genetic aspects**

Due to its recessive X-linked inheritance, males are mostly affected while the heterozygous female carriers are usually asymptomatic. Although some carriers have various bleeding manifestations and can even express severe (FVIII/FIX <0.01 U mL-1) or moderate (FVIII/FIX 0.01–0.05 U mL-1) phenotypes, their specific clinical manifestations and genetic data have hardly been described [6].

Hemophilia female carriers may be affected by hemorrhagic manifestations due to different genetic conditions: both mutated alleles with homozygous or compound heterozygous mutations in *F8* or *F9* genes, hemizygosity in 45,X (Turner syndrome) patients with a mutated X chromosome, or extremely skewed X-chromosome inactivation pattern (X-IP) in carriers who have inactivated the wild-type allele and thereby have a highly decreased amount of the concerned factor and express the symptoms of the disease [7]. The molecular genetic analysis is essential in elucidating the mechanisms underlying the bleeding phenotype in females with hemophilia [8–10].

In accordance with international estimations, there are 3–5 potential female carriers for each male with hemophilia, but not every carrier knows her genetic status. According to the study of Bernard, only 38% of the potential carriers have been screened about their carrier/non-carrier status. He analyzed 408 potential carriers and reported that only a limited fraction of them received information from a hemophilia specialist about their status and underwent coagulation factor analysis; the remaining large fraction failed to accomplish the screening due to lack of communication within the family and unawareness of the inheritance mode [11].

If women do not realize the possibility of being carriers, all their symptoms can be overlapped with normal women and those with VWD or qualitative platelet disorders [7]; so, all possible or potential carriers must be screened and should be advised about care and surveillance regarding bleeding tendencies [12].

#### **2.3 Clinical features**

Different studies have shown the increased tendency of bleeding in hemophilia carriers compared to healthy females. Olsson et al. described the bleeding symptoms in 126 hemophilia carriers in contrast to 90 non-hemophilia carriers; the hemorrhagic tendency was normal in 82 carriers (65%) and in all but two women in the control group (98%). They reported that there was no difference in bleeding symptoms between carriers from hemophiliac families and carriers with sporadic mutations. The proportion of carriers and controls reporting bleeding symptoms was different with statistically significant results (p < 0.001), **Table 1** [13].

Paroskie compared 44 HA carriers with 43 healthy women and found a significant (p < 0.05) increase in clinical features as shown in **Table 2** [5]. Contrary to


#### **Table 1.**

*Bleeding symptoms in hemophilia carriers and normal women.*


#### **Table 2.**

*Clinical traits related to hemorrhages in hemophilia carriers and normal women.*

what would be expected, laboratory results do not always correlate with the clinical picture. A comparison of FVIII:C/FIX:C levels, hemoglobin, platelets, and fibrinogen between symptomatic hemophilia carriers and asymptomatic carriers did not reveal significant differences, yet a subgroup of carriers with factor levels within the lower normal range exhibited increased blood symptoms [14].

Srivaths et al. compared the bleeding complications in adolescents and adults and found that anemia and gynecologic procedures/surgeries were less frequent in adolescents likely because of an early detection [15]. On the other hand, in the case of HB due to Hemophilia B Leyden mutation (c.-22T>C) in the promotor of *F9* gene, there is a physiological mechanism that tends to normalize the FIX plasma levels according to age, which is mainly mediated by growth hormones rather than androgens that may ameliorate the bleeding symptoms in patients and female carriers [16].

#### **2.4 Impact on women's health**

The time between the start of bleeding symptoms and the diagnosis of a FVIII/FIX deficiency is often prolonged. Di Michele et al. reported that the mean period of diagnosis for hemophilia carriers with severe FVIII/FIX deficiency was 8.5 months compared to 2 months for similarly affected males; but if the deficiency was moderate, the diagnosis was delayed for 48 months compared to 4 months for similarly affected men [6].

The most common symptom, HMB, can have a significant impact on quality of life, missed days at work/school, iron deficiency anemia, need for hospitalization or blood transfusions, and higher costs in medical care [7]. Delayed diagnosis situates affected women at risk for co-morbidity and even mortality depending on the

**59**

*Clinical Issues in Women with Inherited Bleeding Disorders*

clinical context; this is why the carrier status and the percentage of clotting factor should be determined, and a proper genetic counseling should be offered [15].

Dose, intervals, and duration for treatment depend on the clinical situation, effectiveness, and laboratory test results [7]. The treatment may include tranexamic acid, oral contraceptive pills (in some HMB), or factor VIII/IX [7, 15]. Hemostatic plans for hemophilia carriers with severe or mild FVIII/FIX deficiency should be noticed among primary care physicians and specialists in gynecology/obstetrics, hematology, orthopedics, clinical genetics, etc. Although each patient requires a personalized management, here we describe general guidelines for the treatment of

Adolescents and women with HMB often respond well to standard therapies such as combined oral contraception pills, progestin-only pills, intrauterine devices, or antifibrinolytics such as aminocaproic acid or tranexamic acid. These therapies are warranted as the two key mechanisms in HMB are excessive local fibrinolytic

The management of a hemophilia carrier should be coordinated among the hematologist, obstetrician, and anesthetist. During pregnancy, plasma levels of von Willebrand factor (VWF) and FVIII may rise sufficiently to permit safe hemostasis without exogenous hemostatic support, but they should be re-examined at 32–34 weeks of pregnancy; if the levels are less than 50% and more particularly less than 30% of the reference ranges, DDAVP or FVIII concentrates may be used. In pregnancy, FIX levels do not rise [17]. The use of DDAVP in symptomatic carriers of FVIII deficiency is controversial because the prescriber's information advises that the drug is contraindicated with lactation and recommends precaution during pregnancy. This drug has been used in the first and second trimester in 27 symptomatic carriers without adverse events [18]. Moreover, symptomatic carriers with factor levels less than 50% should receive a recombinant factor to prevent bleeding at delivery or spinal anesthesia [19]. Determination of fetal sex and prenatal hemophilia testing in any at-risk pregnancy are essential for planning the safe delivery of

DDAVP is also indicated for HA patients with factor VIII coagulant activity levels greater than 5%. Intravenous dose is 0.3 μg/kg IV over 15–30 minutes (for pre-op, 30 minutes before the procedure). Intranasal administration is indicated for patients with FVIII levels >5% at a dose of 50 μg (if the patient's weight is <50 kg) or

Management of females represents a special challenge due to the risk of menorrhagia or postpartum bleeding, the large proportion (almost 40%) of unaware hemophilia carriers, and the medical inexperience of hemophilia in women.

The successful management in symptomatic hemophilia carriers requires the coordination of hematology, obstetrics/gynecology, orthopedics, and the coagulation laboratory as well as a complete education of the hemophilia carriers with

300 μg (if weight ≥ 50 kg) 2 h before any surgical procedure [20].

**2.6 Recommended integral management**

*DOI: http://dx.doi.org/10.5772/intechopen.82119*

the main hemorrhagic disorders in women:

mechanisms and inhibition of platelet function [7].

**2.5 Treatment**

*2.5.1 HMB*

*2.5.2 During pregnancy*

an affected female.

clinical context; this is why the carrier status and the percentage of clotting factor should be determined, and a proper genetic counseling should be offered [15].

#### **2.5 Treatment**

*Hemophilia - Recent Advances*

*Taken from information reported by Olsson et al. [13].*

*Bleeding symptoms in hemophilia carriers and normal women.*

what would be expected, laboratory results do not always correlate with the clinical picture. A comparison of FVIII:C/FIX:C levels, hemoglobin, platelets, and fibrinogen between symptomatic hemophilia carriers and asymptomatic carriers did not reveal significant differences, yet a subgroup of carriers with factor levels within the

**Clinical features Carriers (%) Controls (%)** Heavy menstrual bleeding 70 5 Cutaneous bruising 65 40 Oral cavity bleeding 50 25 Post-surgical bleeding 48 9 Hematomas 35 8 Postpartum bleeding 30 8 Hemarthrosis 18 0

**Clinical features Carriers (%) Controls (%)** Menorrhagia 37 16 Bleeding from minor wounds 32 0 Surgery 32 7.2 Tooth extraction 30 0 Nosebleed 24 4.4 Cutaneous bleeding 17 1.1

Srivaths et al. compared the bleeding complications in adolescents and adults and found that anemia and gynecologic procedures/surgeries were less frequent in adolescents likely because of an early detection [15]. On the other hand, in the case of HB due to Hemophilia B Leyden mutation (c.-22T>C) in the promotor of *F9* gene, there is a physiological mechanism that tends to normalize the FIX plasma levels according to age, which is mainly mediated by growth hormones rather than androgens that may ameliorate the bleeding symptoms in patients and female

The time between the start of bleeding symptoms and the diagnosis of a FVIII/FIX deficiency is often prolonged. Di Michele et al. reported that the mean period of diagnosis for hemophilia carriers with severe FVIII/FIX deficiency was 8.5 months compared to 2 months for similarly affected males; but if the deficiency was moderate, the diagnosis was delayed for 48 months compared to 4 months for

The most common symptom, HMB, can have a significant impact on quality of life, missed days at work/school, iron deficiency anemia, need for hospitalization or blood transfusions, and higher costs in medical care [7]. Delayed diagnosis situates affected women at risk for co-morbidity and even mortality depending on the

lower normal range exhibited increased blood symptoms [14].

*Clinical traits related to hemorrhages in hemophilia carriers and normal women.*

**58**

carriers [16].

**Table 2.**

**Table 1.**

**2.4 Impact on women's health**

*Taken from the study of Paroskie [5].*

similarly affected men [6].

Dose, intervals, and duration for treatment depend on the clinical situation, effectiveness, and laboratory test results [7]. The treatment may include tranexamic acid, oral contraceptive pills (in some HMB), or factor VIII/IX [7, 15]. Hemostatic plans for hemophilia carriers with severe or mild FVIII/FIX deficiency should be noticed among primary care physicians and specialists in gynecology/obstetrics, hematology, orthopedics, clinical genetics, etc. Although each patient requires a personalized management, here we describe general guidelines for the treatment of the main hemorrhagic disorders in women:

#### *2.5.1 HMB*

Adolescents and women with HMB often respond well to standard therapies such as combined oral contraception pills, progestin-only pills, intrauterine devices, or antifibrinolytics such as aminocaproic acid or tranexamic acid. These therapies are warranted as the two key mechanisms in HMB are excessive local fibrinolytic mechanisms and inhibition of platelet function [7].

#### *2.5.2 During pregnancy*

The management of a hemophilia carrier should be coordinated among the hematologist, obstetrician, and anesthetist. During pregnancy, plasma levels of von Willebrand factor (VWF) and FVIII may rise sufficiently to permit safe hemostasis without exogenous hemostatic support, but they should be re-examined at 32–34 weeks of pregnancy; if the levels are less than 50% and more particularly less than 30% of the reference ranges, DDAVP or FVIII concentrates may be used. In pregnancy, FIX levels do not rise [17]. The use of DDAVP in symptomatic carriers of FVIII deficiency is controversial because the prescriber's information advises that the drug is contraindicated with lactation and recommends precaution during pregnancy. This drug has been used in the first and second trimester in 27 symptomatic carriers without adverse events [18]. Moreover, symptomatic carriers with factor levels less than 50% should receive a recombinant factor to prevent bleeding at delivery or spinal anesthesia [19]. Determination of fetal sex and prenatal hemophilia testing in any at-risk pregnancy are essential for planning the safe delivery of an affected female.

DDAVP is also indicated for HA patients with factor VIII coagulant activity levels greater than 5%. Intravenous dose is 0.3 μg/kg IV over 15–30 minutes (for pre-op, 30 minutes before the procedure). Intranasal administration is indicated for patients with FVIII levels >5% at a dose of 50 μg (if the patient's weight is <50 kg) or 300 μg (if weight ≥ 50 kg) 2 h before any surgical procedure [20].

#### **2.6 Recommended integral management**

Management of females represents a special challenge due to the risk of menorrhagia or postpartum bleeding, the large proportion (almost 40%) of unaware hemophilia carriers, and the medical inexperience of hemophilia in women.

The successful management in symptomatic hemophilia carriers requires the coordination of hematology, obstetrics/gynecology, orthopedics, and the coagulation laboratory as well as a complete education of the hemophilia carriers with

the aim of providing them the best available information on the risk of bleeding, genetic implications in the offspring, reproductive options, and antenatal management of the affected offspring and mother [19].

#### **3. von Willebrand disease in women**

#### **3.1 Generalities**

VWD is the most common inherited bleeding disorder with a worldwide prevalence of 1% [21], associated with mucocutaneous and postoperative bleeding that is caused by a qualitative or quantitative defect of the VWF [22], a glycoprotein that participates in primary and secondary hemostasis via platelet adhesion at the site of the endothelial injury and platelet aggregation with the formation of the platelet plug, not to mention its role in transporting and stabilizing the FVIII [23].

VWD does not present sex, ethnic, or geographic predilection; however, the number of symptomatic women is greater than that of men in most populations (ratio 2:1) due to menstrual and delivery bleeding disorders [24]. The International Society on Thrombosis and Hemostasis (ISTH) recognizes six types of VWD [25] depending on the amount and functional activity of VWF. There can be a partial or total quantitative defect (type 1 and 3) or a qualitative defect (type 2) [26]. Moreover, type 2 VWD is subdivided into 4 variants (2A, 2B, 2M, and 2N) based on the details of the patient's phenotype [27].

#### **3.2 Genetic aspects**

The *VWF* gene, also known as *VWD*, is located at 12p13.3 and has a length of 178 kilobases (kb), and its 52 exons are transcribed into a 9 kb mRNA that encodes a pre-pro-VWF protein of 2813 amino acids whose different domains interact with other proteins and perform specific functions [28]. The expression of the *VWF* gene is limited to endothelial cells and megakaryocytes [29]. Different mutations cause quantitative (VWD types 1 and 3) or qualitative (type 2) defects in the VWF protein. VWD mostly has an autosomal dominant inheritance; only types 3 and 2N (in some cases type 2A) are inherited in an autosomal recessive manner [22].

#### **3.3 Clinical features**

Clinical manifestations of VWD could arise only when a hemostatic challenge occurs and include the following main symptoms:


**61**

**Figure 1.**

*pregnancy.*

*Clinical Issues in Women with Inherited Bleeding Disorders*

• Gastrointestinal bleeding, particularly in patients with type 2A VWD.

• Patients with type 3 and type 2N VWD may have hemarthroses due to a low level

HMB occurs in approximately 80% of cases and is associated with significant co-morbidity, namely iron deficiency anemia, stress, and reduction in the quality of life affecting daily activities; in addition, it entails higher costs in medical care [31]. There is evidence that women with VWD have higher rates of postpartum hemorrhage and transfusions at the time of delivery compared to healthy women [32]. Under normal conditions, postpartum hemorrhage is controlled due to the progressive increased activity of VWF and FVIII during pregnancy that reaches its maximum level at the time of delivery and subsequently decreases to a baseline level in approximately 1 month [32]. In VWD patients, the amount, functional activity, and behavior of VWF vary according to the disease's type and FVIII concentration **Figure 1** [33]. Although the function of the placenta may be impaired, there are inconsistent results about the risk of abortion in women with VWD [34].

Under normal conditions, a doubling of the levels of FVIII and VWF (VWF: Ag)

Because VWD is the most common cause of HMB, appropriate tests (measurement of VWF: Ag and VWF: RCo) should be performed to establish an accurate

*Behavioral patterns of VWF and FVIII under normal conditions and in different VWD subtypes during* 

and functional activity of the VWF (VWF: RCo) can be observed. Patients with severe VWD type 1 (increased clearance) do not show a significant increase in levels of VWF and FVIII. On the other hand, in type 1 there is a progressive increase in VWF levels; however, it is not as high as in normal conditions. In type 2A, the functional activity of VWF remains low due to the absence of high molecular weight multimers, and in type 2M the ratio of VWF: Ag/VWF: RCo is affected due to the low increase in VWF: RCo. In type 2N, FVIII remains reduced due to the

inability of the VWF to bind to FVIII. Taken from Castaman [33].

diagnosis and the specific treatment for the disease [35].

*DOI: http://dx.doi.org/10.5772/intechopen.82119*

of FVIII [30].

**3.5 Treatment**

**3.4 Impact on women's health**


#### **3.4 Impact on women's health**

*Hemophilia - Recent Advances*

**3.1 Generalities**

**3.2 Genetic aspects**

**3.3 Clinical features**

ment of the affected offspring and mother [19].

**3. von Willebrand disease in women**

the details of the patient's phenotype [27].

autosomal recessive manner [22].

occurs and include the following main symptoms:

• Excessive mucocutaneous bleeding.

• Hematoma with minimal trauma.

• Recurrent and prolonged epistaxis.

• Gingival hemorrhage.

ing after delivery.

the aim of providing them the best available information on the risk of bleeding, genetic implications in the offspring, reproductive options, and antenatal manage-

VWD is the most common inherited bleeding disorder with a worldwide prevalence of 1% [21], associated with mucocutaneous and postoperative bleeding that is caused by a qualitative or quantitative defect of the VWF [22], a glycoprotein that participates in primary and secondary hemostasis via platelet adhesion at the site of the endothelial injury and platelet aggregation with the formation of the platelet

VWD does not present sex, ethnic, or geographic predilection; however, the number of symptomatic women is greater than that of men in most populations (ratio 2:1) due to menstrual and delivery bleeding disorders [24]. The International Society on Thrombosis and Hemostasis (ISTH) recognizes six types of VWD [25] depending on the amount and functional activity of VWF. There can be a partial or total quantitative defect (type 1 and 3) or a qualitative defect (type 2) [26]. Moreover, type 2 VWD is subdivided into 4 variants (2A, 2B, 2M, and 2N) based on

The *VWF* gene, also known as *VWD*, is located at 12p13.3 and has a length of 178 kilobases (kb), and its 52 exons are transcribed into a 9 kb mRNA that encodes a pre-pro-VWF protein of 2813 amino acids whose different domains interact with other proteins and perform specific functions [28]. The expression of the *VWF* gene is limited to endothelial cells and megakaryocytes [29]. Different mutations cause quantitative (VWD types 1 and 3) or qualitative (type 2) defects in the VWF protein. VWD mostly has an autosomal dominant inheritance; only types 3 and 2N (in some cases type 2A) are inherited in an

Clinical manifestations of VWD could arise only when a hemostatic challenge

• Prolonged bleeding after some dental procedure, surgery, or trauma.

• HMB (the most common symptom in women) or prolonged or excessive bleed-

plug, not to mention its role in transporting and stabilizing the FVIII [23].

**60**

HMB occurs in approximately 80% of cases and is associated with significant co-morbidity, namely iron deficiency anemia, stress, and reduction in the quality of life affecting daily activities; in addition, it entails higher costs in medical care [31]. There is evidence that women with VWD have higher rates of postpartum hemorrhage and transfusions at the time of delivery compared to healthy women [32].

Under normal conditions, postpartum hemorrhage is controlled due to the progressive increased activity of VWF and FVIII during pregnancy that reaches its maximum level at the time of delivery and subsequently decreases to a baseline level in approximately 1 month [32]. In VWD patients, the amount, functional activity, and behavior of VWF vary according to the disease's type and FVIII concentration **Figure 1** [33]. Although the function of the placenta may be impaired, there are inconsistent results about the risk of abortion in women with VWD [34].

Under normal conditions, a doubling of the levels of FVIII and VWF (VWF: Ag) and functional activity of the VWF (VWF: RCo) can be observed. Patients with severe VWD type 1 (increased clearance) do not show a significant increase in levels of VWF and FVIII. On the other hand, in type 1 there is a progressive increase in VWF levels; however, it is not as high as in normal conditions. In type 2A, the functional activity of VWF remains low due to the absence of high molecular weight multimers, and in type 2M the ratio of VWF: Ag/VWF: RCo is affected due to the low increase in VWF: RCo. In type 2N, FVIII remains reduced due to the inability of the VWF to bind to FVIII. Taken from Castaman [33].

#### **3.5 Treatment**

Because VWD is the most common cause of HMB, appropriate tests (measurement of VWF: Ag and VWF: RCo) should be performed to establish an accurate diagnosis and the specific treatment for the disease [35].

#### **Figure 1.**

*Behavioral patterns of VWF and FVIII under normal conditions and in different VWD subtypes during pregnancy.*

The treatment focuses on two central aspects: increasing the concentration of functional VWF available for hemostasis and providing complementary therapies to stabilize it [36]. DDAVP is administered intravenously or intranasally to increase plasmatic VWF through the release of endogenous VWF stored in Weibel-Palade bodies of endothelial cells. DDAVP is used in hemostatic challenges such as dental extractions and moderate nosebleeds or menorrhagia [36]. The administration of recombinant VWF is recommended in patients who do not respond to DDAVP or that require sustained levels of VWF in severe hemostatic challenges such as trauma and surgery [36]. Additional therapies include antifibrinolytic agents, aminocaproic acid, and tranexamic acid, which are recommended in mild to moderate bleedings. They are often used as adjunctive therapy in addition to concentrates of DDAVP or VWF in surgery or delivery [36].

#### **3.6 Recommended integral management**

Management in women presents a special challenge due to HMB and possible complications during pregnancy [37]. The successful management of pregnancy involves the coordination of obstetrics, anesthesia, and the coagulation laboratory that monitors levels of VWF: RCo and FVIII:C [37].

#### **4. Platelet disorders**

#### **4.1 Idiopathic thrombocytopenic purpura (ITP)**

#### *4.1.1 Generalities*

Idiopathic thrombocytopenic purpura or immune thrombocytopenia (ITP) is the most common acquired blood disorder. In this disease, autoantibodies against platelets render them susceptible to rapid clearance from the circulation [38–40]. Although the mechanism of origin of these antibodies is unknown, they belong to the gamma-globulin fraction expressed on platelet membranes and destroy the platelets [41–43] via their interaction with certain surface glycoproteins (GPs) identified as GP IIb-IIIa, GP Ib, and GP V [43]. The GP IIb-IIIa complex is the antigenic target in most patients. Platelets with antibodies are removed by splenic macrophages; however, their reactivation can lead to ineffective thrombopoiesis [40].

#### *4.1.2 Genetic aspects*

A positive family history is suggestive of hereditary thrombocytopenia. In addition to a presumptive autosomal dominant ITP, it has been found that the receptor for the Fc region of complexed immunoglobulin gamma (*FCGR2C*) predisposes to the disease [44, 45]. Several of their polymorphisms are related to the development of immunological reactions, but their contribution as a cause of ITP is still uncertain [46].

#### *4.1.3 Clinical features*

ITP can be acute or chronic and is characterized by (1) thrombocytopenia <150 × 109 L<sup>−</sup><sup>1</sup> without other identifiable cause, (2) purpuric rash, and (3) normal function of bone marrow. Its approximate incidence is 3 to 8 per 100,000 children per year [43]. Acute ITP is frequent in children aged <10 years who have low platelet counts (usually 20,000 to 30 × 109 L<sup>−</sup><sup>1</sup> ). The onset of signs and symptoms is often

**63**

*Clinical Issues in Women with Inherited Bleeding Disorders*

preceded by a viral illness. Chronic ITP affects mainly adolescents with platelet

more likely to exhibit an underlying autoimmune disorder. Yet, the disease may be

According to duration, ITP can be (1) newly diagnosed (<3 months), (2) persistent (between 3 and 6 months), or (3) chronic (>12 months). The clinical presentation can be (1) severe, patients with relevant bleeding, or requiring additional interventions or increased drug dose, or (2) refractory, severe clinical manifestations after splenectomy.

Typical clinical presentation affects apparently healthy individuals; begins with easy bruising and purpuric rash [40]; and evolves to nasal, gingival, gastrointestinal tract, vaginal, urinary tract, retina, or conjunctivae bleedings. Bone marrow smears show normal or increased megakaryocytes, whereas plasma thrombopoietin levels

About 7% of pregnancies or 1-10 in 10,000 pregnant women are diagnosed

[48, 49]. Only near 30% requires treatment and support from a multidisciplinary team [39, 50]. Recommended first-line therapy is intravenous immunoglobulin or corticosteroids, which have similar efficacy for platelet count increase. The latter may have mild toxicity for the mother and fetus, but usual adverse effects include

The pharmacologic management of acute ITP continues being controversial, because in approximately 80% of patients the disease is self-limited and disappears in the first 6 months after diagnosis without medication. For the 20% of patients who progress to the chronic type [43], prednisone at a standard dose of 1 mg/kg/day for 2–4 weeks is the first choice drug [39]. Yet, a randomized clinical trial has shown that it is better to use high-dose pulsed dexamethasone (40 mg/ day for 4 days) than standard prednisone therapy in adult patients with immune

Integral management of a patient with ITP is based on support measures (reduce physical activity, wear protective head-gear, adapt protective padding to the crib, avoid medications that affect platelets, and keep a constant evaluation and dental care) sometimes complemented with pharmacological and surgical treatment [43].

Bernard-Soulier syndrome (BSS) results from a deficiency of platelet glycoprotein protein Ib (GPIb), which mediates the initial interaction of platelets

L-1. Females are affected more frequently than males and are

L-1 measured on 2 occasions with more

L-1 of platelet counts are at increased risk for

L-1 of platelet count) generally in the first trimester

L-1 and a greater than twofold

*DOI: http://dx.doi.org/10.5772/intechopen.82119*

Platelet counts define two types: (1) ≥100×109

are decreased. Patients with 10-20×109

intracranial hemorrhage (ICH) [43].

*4.1.4 Impact on women's health*

with gestational ITP (<150×109

*4.1.5 Treatment*

thrombocytopenia [51].

*4.1.6 Recommended integral management*

Patients require consulting a hematologist.

**4.2 Bernard-Soulier syndrome**

*4.2.1 Generalities*

than 7 days between each sampling and (2) ≥30×109

weight gain, hyperglycemia, and hypertension [39].

increase in platelet count measured on 2 occasions >7 days apart [47].

counts of 20-70×109

asymptomatic [43].

preceded by a viral illness. Chronic ITP affects mainly adolescents with platelet counts of 20-70×109 L-1. Females are affected more frequently than males and are more likely to exhibit an underlying autoimmune disorder. Yet, the disease may be asymptomatic [43].

According to duration, ITP can be (1) newly diagnosed (<3 months), (2) persistent (between 3 and 6 months), or (3) chronic (>12 months). The clinical presentation can be (1) severe, patients with relevant bleeding, or requiring additional interventions or increased drug dose, or (2) refractory, severe clinical manifestations after splenectomy. Platelet counts define two types: (1) ≥100×109 L-1 measured on 2 occasions with more than 7 days between each sampling and (2) ≥30×109 L-1 and a greater than twofold increase in platelet count measured on 2 occasions >7 days apart [47].

Typical clinical presentation affects apparently healthy individuals; begins with easy bruising and purpuric rash [40]; and evolves to nasal, gingival, gastrointestinal tract, vaginal, urinary tract, retina, or conjunctivae bleedings. Bone marrow smears show normal or increased megakaryocytes, whereas plasma thrombopoietin levels are decreased. Patients with 10-20×109 L-1 of platelet counts are at increased risk for intracranial hemorrhage (ICH) [43].

#### *4.1.4 Impact on women's health*

About 7% of pregnancies or 1-10 in 10,000 pregnant women are diagnosed with gestational ITP (<150×109 L-1 of platelet count) generally in the first trimester [48, 49]. Only near 30% requires treatment and support from a multidisciplinary team [39, 50]. Recommended first-line therapy is intravenous immunoglobulin or corticosteroids, which have similar efficacy for platelet count increase. The latter may have mild toxicity for the mother and fetus, but usual adverse effects include weight gain, hyperglycemia, and hypertension [39].

#### *4.1.5 Treatment*

*Hemophilia - Recent Advances*

DDAVP or VWF in surgery or delivery [36].

**3.6 Recommended integral management**

**4. Platelet disorders**

ineffective thrombopoiesis [40].

*4.1.2 Genetic aspects*

*4.1.3 Clinical features*

L<sup>−</sup><sup>1</sup>

counts (usually 20,000 to 30 × 109

<150 × 109

*4.1.1 Generalities*

that monitors levels of VWF: RCo and FVIII:C [37].

**4.1 Idiopathic thrombocytopenic purpura (ITP)**

The treatment focuses on two central aspects: increasing the concentration of functional VWF available for hemostasis and providing complementary therapies to stabilize it [36]. DDAVP is administered intravenously or intranasally to increase plasmatic VWF through the release of endogenous VWF stored in Weibel-Palade bodies of endothelial cells. DDAVP is used in hemostatic challenges such as dental extractions and moderate nosebleeds or menorrhagia [36]. The administration of recombinant VWF is recommended in patients who do not respond to DDAVP or that require sustained levels of VWF in severe hemostatic challenges such as trauma and surgery [36]. Additional therapies include antifibrinolytic agents, aminocaproic acid, and tranexamic acid, which are recommended in mild to moderate bleedings. They are often used as adjunctive therapy in addition to concentrates of

Management in women presents a special challenge due to HMB and possible complications during pregnancy [37]. The successful management of pregnancy involves the coordination of obstetrics, anesthesia, and the coagulation laboratory

Idiopathic thrombocytopenic purpura or immune thrombocytopenia (ITP) is the most common acquired blood disorder. In this disease, autoantibodies against platelets render them susceptible to rapid clearance from the circulation [38–40]. Although the mechanism of origin of these antibodies is unknown, they belong to the gamma-globulin fraction expressed on platelet membranes and destroy the platelets [41–43] via their interaction with certain surface glycoproteins (GPs) identified as GP IIb-IIIa, GP Ib, and GP V [43]. The GP IIb-IIIa complex is the antigenic target in most patients. Platelets with antibodies are removed by splenic macrophages; however, their reactivation can lead to

A positive family history is suggestive of hereditary thrombocytopenia. In addition to a presumptive autosomal dominant ITP, it has been found that the receptor for the Fc region of complexed immunoglobulin gamma (*FCGR2C*) predisposes to the disease [44, 45]. Several of their polymorphisms are related to the development of immunological reactions, but their contribution as a cause of ITP is still uncertain [46].

ITP can be acute or chronic and is characterized by (1) thrombocytopenia

function of bone marrow. Its approximate incidence is 3 to 8 per 100,000 children per year [43]. Acute ITP is frequent in children aged <10 years who have low platelet

L<sup>−</sup><sup>1</sup>

without other identifiable cause, (2) purpuric rash, and (3) normal

). The onset of signs and symptoms is often

**62**

The pharmacologic management of acute ITP continues being controversial, because in approximately 80% of patients the disease is self-limited and disappears in the first 6 months after diagnosis without medication. For the 20% of patients who progress to the chronic type [43], prednisone at a standard dose of 1 mg/kg/day for 2–4 weeks is the first choice drug [39]. Yet, a randomized clinical trial has shown that it is better to use high-dose pulsed dexamethasone (40 mg/ day for 4 days) than standard prednisone therapy in adult patients with immune thrombocytopenia [51].

#### *4.1.6 Recommended integral management*

Integral management of a patient with ITP is based on support measures (reduce physical activity, wear protective head-gear, adapt protective padding to the crib, avoid medications that affect platelets, and keep a constant evaluation and dental care) sometimes complemented with pharmacological and surgical treatment [43]. Patients require consulting a hematologist.

#### **4.2 Bernard-Soulier syndrome**

#### *4.2.1 Generalities*

Bernard-Soulier syndrome (BSS) results from a deficiency of platelet glycoprotein protein Ib (GPIb), which mediates the initial interaction of platelets

#### *Hemophilia - Recent Advances*

with the subendothelial components via the von Willebrand protein. It is a rare but severe bleeding disorder in which platelets do not aggregate in response to ristocetin. Platelets from BSS patients lack a major surface membrane glycoprotein complex called GPIb-IX-V that functions as a receptor for VWF and whose absence causes giant platelets [52]. This complex is the initial contact for adhesion of platelets in damaged vessels, mediates the interaction with VWF (GPIb-IX-V/ VWF), and interacts with the platelet cytoskeleton [52, 53]. The GPIb-IX-V complex comprises GPIbα, GPIbβ, GPIX, and GPV proteins whose assemblage forms the receptor [54].

#### *4.2.2 Genetic aspects*

BSS usually results from autosomal recessive mutations in *GP1BA, GP1BB*, and *GP9* genes that code for 3/4 proteins of the GPIb-IX-V complex (mutations in the 4th gene involved, *GP5*, are unreported) [52, 54]. Compound heterozygous patients outnumber homozygous patients. Only a few cases result from autosomal dominant mutations [55]. Although BSS carriers are usually asymptomatic with normal platelet counts, sometimes they show slightly enlarged platelets, slightly decreased GPIb-IX-V complex expression, and/or a moderately reduced ristocetin response [55, 56].

#### *4.2.3 Clinical and hematological features*

Clinical presentation of BSS is characterized by epistaxis, gingival and cutaneous bleeding, hemorrhages post trauma, prolonged skin bleeding time, thrombocytopenia, and large platelets. Patients often suffer from mucocutaneous bleedings of different severity [54]. In females, it can be associated with severe menorrhagia [52]. Typically, platelet counts are low, and the platelets are so large (often the size of red blood cells) that they may be missed on blood counts because most automatic counters do not count them as platelets [40]. The clinical laboratory assessment of GPIb-IX-V/VWF interaction with platelets reveals impaired platelet agglutination after stimulation with ristocetin [52, 54, 57].

#### *4.2.4 Impact on women's health*

Some women with BSS require oral contraceptive treatment for menorrhagia and even platelet transfusions in cases of severe bleeding [57]. Generally, pregnancies of patients with BSS are not complicated [58]. However, if during the delivery the patient presents severe bleeding, platelet transfusions or hysterectomy can be performed to control it [59].

#### *4.2.5 Treatment*

Usually, platelet transfusions are effective as BSS treatment; the inconvenience is the alloantibody development against GpIb [56]. Transfusions must be used only for severe bleeding and emergencies [40]. Also, the use of DDAVP, epsilonaminocaproic acid (EACA), and recombinant factor VIIa (rVIIa) has been approved as an effective therapy for some patients [56].

#### *4.2.6 Recommended integral management*

BSS care is generally based on support measures only, inclusive for dental care. Actually, most patients do not require medication. The use of antiplatelet treatment must be avoided, and a hematologist should be consulted for its prescription [60].

**65**

*Clinical Issues in Women with Inherited Bleeding Disorders*

platelet count, morphology, and size are normal [56]*.*

Glanzmann thrombasthenia (GT) is a rare dysfunction of the platelet integrin receptor CD41 (GPIIb/IIIa complex) that prevents the formation of aggregates in response to many agents, except for ristocetin [40, 56]. There are two GT types according to the functionality of the GP IIb/IIIa complex; type I is caused by the total absence of the GP IIb/IIIa complex and exhibits a more severe phenotype; type II is usually milder because some of the GP IIb/IIIa complexes are functional [40].

GT is an autosomal recessive disorder due to diverse mutations of the multi-subunit

Clinical manifestations are variable in severity and frequency and depend on the genotype. Bleeding symptoms are present in patients homozygous or compound heterozygous for GPIIb/IIIa mutations [67]. As a minimum symptom, the patients have lifelong mucosal bleeding [56]*.* The bleeding (epistaxis, gingival hemorrhage, and menorrhagia) can be frequent, severe, and sometimes fatal [62, 68]. Severe epistaxis is common, mainly in childhood. Some patients only had bruising. Less commonly, gastrointestinal bleeding and hematuria have been observed [69]. The

The transfusion history of red cell and/or platelet is frequent. Affected women

The standard treatment for continuous bleeding has been platelet transfusions, especially for patients refractory to local measures and/or antifibrinolytic drugs [70]. However, the efficacy of platelet transfusion is limited by alloantibodies against platelets [56]*.* Several authors of clinical trials recommend the use of rFVIIa in the management of intractable epistaxis. It has been documented that this agent is effective in the management of bleeding or during surgeries at doses from 120 to

GT is a hemorrhagic lifelong disorder that requires integral support measures. Most patients have a history of transfusions indicated for severe bleeding [40, 67]. Fortunately, the prognosis of patients is good due to supportive care, and the disease has limited effect on their daily lives [69]. Dental and hematological advice

are at risk of severe HMB and bleeding during pregnancy and delivery [69].

GpIIb/IIIa complex [56, 61–63]. The carriers or heterozygotes are asymptomatic, although they show a 50% reduction in the number of GpIIb/IIIa molecules [56]*. ITGA2B* and *ITGB3* genes code for proteins GPIIb and GPIIIa, respectively, and both are located at 17q21 [64]. GT is frequent in regions where consanguineous marriages

*DOI: http://dx.doi.org/10.5772/intechopen.82119*

**4.3 Glanzmann thrombasthenia**

*4.3.1 Generalities*

*4.3.2 Genetic aspects*

are common [65, 66].

*4.3.3 Clinical features*

*4.3.4 Impact on women's health*

*4.3.5 Treatment*

300 μg/kg [71, 72].

is recommended.

*4.3.6 Recommended integral management*

#### **4.3 Glanzmann thrombasthenia**

#### *4.3.1 Generalities*

*Hemophilia - Recent Advances*

forms the receptor [54].

*4.2.3 Clinical and hematological features*

after stimulation with ristocetin [52, 54, 57].

as an effective therapy for some patients [56].

*4.2.6 Recommended integral management*

*4.2.4 Impact on women's health*

performed to control it [59].

*4.2.5 Treatment*

*4.2.2 Genetic aspects*

with the subendothelial components via the von Willebrand protein. It is a rare but severe bleeding disorder in which platelets do not aggregate in response to ristocetin. Platelets from BSS patients lack a major surface membrane glycoprotein complex called GPIb-IX-V that functions as a receptor for VWF and whose absence causes giant platelets [52]. This complex is the initial contact for adhesion of platelets in damaged vessels, mediates the interaction with VWF (GPIb-IX-V/ VWF), and interacts with the platelet cytoskeleton [52, 53]. The GPIb-IX-V complex comprises GPIbα, GPIbβ, GPIX, and GPV proteins whose assemblage

BSS usually results from autosomal recessive mutations in *GP1BA, GP1BB*, and *GP9* genes that code for 3/4 proteins of the GPIb-IX-V complex (mutations in the 4th gene involved, *GP5*, are unreported) [52, 54]. Compound heterozygous patients outnumber homozygous patients. Only a few cases result from autosomal dominant mutations [55]. Although BSS carriers are usually asymptomatic with normal platelet counts, sometimes they show slightly enlarged platelets, slightly decreased GPIb-IX-V

Clinical presentation of BSS is characterized by epistaxis, gingival and cutaneous bleeding, hemorrhages post trauma, prolonged skin bleeding time, thrombocytopenia, and large platelets. Patients often suffer from mucocutaneous bleedings of different severity [54]. In females, it can be associated with severe menorrhagia [52]. Typically, platelet counts are low, and the platelets are so large (often the size of red blood cells) that they may be missed on blood counts because most automatic counters do not count them as platelets [40]. The clinical laboratory assessment of GPIb-IX-V/VWF interaction with platelets reveals impaired platelet agglutination

Some women with BSS require oral contraceptive treatment for menorrhagia and even platelet transfusions in cases of severe bleeding [57]. Generally, pregnancies of patients with BSS are not complicated [58]. However, if during the delivery the patient presents severe bleeding, platelet transfusions or hysterectomy can be

Usually, platelet transfusions are effective as BSS treatment; the inconvenience is the alloantibody development against GpIb [56]. Transfusions must be used only for severe bleeding and emergencies [40]. Also, the use of DDAVP, epsilonaminocaproic acid (EACA), and recombinant factor VIIa (rVIIa) has been approved

BSS care is generally based on support measures only, inclusive for dental care. Actually, most patients do not require medication. The use of antiplatelet treatment must be avoided, and a hematologist should be consulted for its prescription [60].

complex expression, and/or a moderately reduced ristocetin response [55, 56].

**64**

Glanzmann thrombasthenia (GT) is a rare dysfunction of the platelet integrin receptor CD41 (GPIIb/IIIa complex) that prevents the formation of aggregates in response to many agents, except for ristocetin [40, 56]. There are two GT types according to the functionality of the GP IIb/IIIa complex; type I is caused by the total absence of the GP IIb/IIIa complex and exhibits a more severe phenotype; type II is usually milder because some of the GP IIb/IIIa complexes are functional [40].

#### *4.3.2 Genetic aspects*

GT is an autosomal recessive disorder due to diverse mutations of the multi-subunit GpIIb/IIIa complex [56, 61–63]. The carriers or heterozygotes are asymptomatic, although they show a 50% reduction in the number of GpIIb/IIIa molecules [56]*. ITGA2B* and *ITGB3* genes code for proteins GPIIb and GPIIIa, respectively, and both are located at 17q21 [64]. GT is frequent in regions where consanguineous marriages are common [65, 66].

#### *4.3.3 Clinical features*

Clinical manifestations are variable in severity and frequency and depend on the genotype. Bleeding symptoms are present in patients homozygous or compound heterozygous for GPIIb/IIIa mutations [67]. As a minimum symptom, the patients have lifelong mucosal bleeding [56]*.* The bleeding (epistaxis, gingival hemorrhage, and menorrhagia) can be frequent, severe, and sometimes fatal [62, 68]. Severe epistaxis is common, mainly in childhood. Some patients only had bruising. Less commonly, gastrointestinal bleeding and hematuria have been observed [69]. The platelet count, morphology, and size are normal [56]*.*

#### *4.3.4 Impact on women's health*

The transfusion history of red cell and/or platelet is frequent. Affected women are at risk of severe HMB and bleeding during pregnancy and delivery [69].

#### *4.3.5 Treatment*

The standard treatment for continuous bleeding has been platelet transfusions, especially for patients refractory to local measures and/or antifibrinolytic drugs [70]. However, the efficacy of platelet transfusion is limited by alloantibodies against platelets [56]*.* Several authors of clinical trials recommend the use of rFVIIa in the management of intractable epistaxis. It has been documented that this agent is effective in the management of bleeding or during surgeries at doses from 120 to 300 μg/kg [71, 72].

#### *4.3.6 Recommended integral management*

GT is a hemorrhagic lifelong disorder that requires integral support measures. Most patients have a history of transfusions indicated for severe bleeding [40, 67]. Fortunately, the prognosis of patients is good due to supportive care, and the disease has limited effect on their daily lives [69]. Dental and hematological advice is recommended.

### **5. Rare bleeding disorders (RBDs) in pregnancy and postpartum**

#### **5.1 Generalities**

RBDs account for 3–5% of all inherited coagulation conditions and are characterized by a wide variability of bleeding symptoms that range from mild to severe in individuals affected by the same disorder. Most commonly, mucocutaneous bleeding and post-surgery hemorrhage are observed. Affected women usually suffer from menorrhagia, spontaneous abortion, and bleeding after delivery [73]. Although most RBDs are autosomal recessive traits, some cases of FXI deficiency and hypo- and dysfibrinogenemia are autosomal dominant. According to the epidemiological data of the World Federation of Hemophilia (WFH) and European Network of the Rare Bleeding Disorders (EN-RBDs), the prevalence of each deficiency among the total affected population is as follows: FVII (39%), FXI (26%), Fibrinogen, FV and FX (8–9%), FXIII (6%), combined FV + FVIII (3%), and FII (1%) [73].

Medical management and treatment of the RBSs are suboptimal because of their very low frequency. As a result, affected individuals received delayed diagnosis, incomplete laboratory testing, and limited treatment options. Standardization of coagulation assays, global clotting assays, and genomic sequencing promises to improve the diagnosis of RBDs, but there is still a long gap to overcome [1]. **Table 3** shows a general scope of the physiological characteristics, symptoms, and impact of the RBDs.


**67**

*Clinical Issues in Women with Inherited Bleeding Disorders*

**Bleeding symptoms**

spontaneous CNS hemorrhages, miscarriages, and abnormal scarring

Mucosal tract and postoperative

Umbilical cord, CNS hemorrhages, and postoperative (children may show skeletal abnormalities)

*Clinical symptoms and laboratory/molecular diagnosis in rare bleeding disorders (RBDs).*

**Laboratory diagnosis**

APTT normal, PT normal, TT normal specific FXIII assay

> APTT**↑**, PT**↑**, TT normal

APTT**↑**, PT**↑↑**, TT normal

**Prevalence Gene** 

1: 2,000,000 *F13A1*

1: 1,000,000 *LMAN1*

<50 families *GGCX* (2p12)

**(chromosome)**

(6p24-p25) *F13B* (1q31-q32.1)

(18q21.3-q22) *MCFD2* (2p21-p16.3)

> *VKORC1* (16p11.2)

**5.2 RBDs in pregnancy, delivery, and puerperium**

clinical complications [74].

(FXIII) [1].

pregnancy [75].

**6. Conclusion**

Women with RBDs require especial medical treatment and care. In addition to common bleeding symptoms, they may also experience gynecological bleeding and are at increased risk of hemorrhagic ovarian cysts, endometriosis, and endometrial hyperplasia polyps and fibroids. Pregnancy and childbirth in women with RBDs are real clinical challenges; miscarriages, bleeding during pregnancy, and postpartum hemorrhage are frequent and may represent severe

*CNS, central nervous system; APTT, activated partial thromboplastin time; PT, prothrombin time. Taken from* 

There has been a higher risk of diverse obstetric complications reported in women with RBDs; miscarriage and placental abruption resulting in fetal loss or preterm delivery are rather common in women deficient in fibrinogen or factor XIII

To resolve the clinical complications of women with RBDs, it is important to consider the behavior of the clotting factors in normal conditions and their tendency to increase during pregnancy that has been attributed to the increase of estrogen concentrations, especially in the third trimester (fibrinogen, FVII, FVIII, FX, FXII, FXIII, and VWF). Other factors (FII, V, IX, and XIII) increase slightly or remain unchanged while FXI is the only factor that decreases during

Inherited bleeding disorders may seriously impact the women's quality of life through their detrimental effects on academic, professional, and social life. Longlasting HMB causes iron deficiency anemia with consequences on physical and mental well-being. Medical care for women with bleeding disorders is lacking in many countries and there may be cultural taboos and obstacles preventing women

*DOI: http://dx.doi.org/10.5772/intechopen.82119*

**level (μg/mL)**

> each factor

> each factor

F XIII 10–20 Umbilical cord,

**Deficiency Plasma** 

FV + FVIII As for

VKCFD As for

*Castaman and Linari [73].*

**Table 3.**


*Clinical Issues in Women with Inherited Bleeding Disorders DOI: http://dx.doi.org/10.5772/intechopen.82119*

#### **Table 3.**

*Castaman and Linari [73].*

*Hemophilia - Recent Advances*

**5.1 Generalities**

and FII (1%) [73].

**Deficiency Plasma** 

**level (μg/mL)**

Fibrinogen 1500–4000 Umbilical cord,

*F II* 100 Umbilical cord,

F V 10 Mucosal tract and

F VII 0.13–1.0 Mucosal tract,

F X 10 Umbilical cord,

F XI 3–6 Oral cavity, post-

**5. Rare bleeding disorders (RBDs) in pregnancy and postpartum**

RBDs account for 3–5% of all inherited coagulation conditions and are characterized by a wide variability of bleeding symptoms that range from mild to severe in individuals affected by the same disorder. Most commonly, mucocutaneous bleeding and post-surgery hemorrhage are observed. Affected women usually suffer from menorrhagia, spontaneous abortion, and bleeding after delivery [73]. Although most RBDs are autosomal recessive traits, some cases of FXI deficiency and hypo- and dysfibrinogenemia are autosomal dominant. According to the epidemiological data of the World Federation of Hemophilia (WFH) and European Network of the Rare Bleeding Disorders (EN-RBDs), the prevalence of each deficiency among the total affected population is as follows: FVII (39%), FXI (26%), Fibrinogen, FV and FX (8–9%), FXIII (6%), combined FV + FVIII (3%),

Medical management and treatment of the RBSs are suboptimal because of their

**Laboratory diagnosis**

*Afibrinogenemia:* APTT**↑↑**, PT**↑↑**, TT**↑↑**, *dyshypofibrinogenemia*: APTT**↑**, PT**↑↑**, TT**↑↑**

> APTT**↑↑**, PT**↑** TT normal

APTT**↑**, PT**↑**, TT normal

APTT normal, PT**↑**, TT normal

APTT**↑**, PT**↑**, TT normal

APTT**↑**, **↑**T, PT normal, TT normal **Prevalence Gene** 

1:1,000,000 *FGA, FGB,*

1:2,000,000 *F2* (11p11-q12)

1: 1,000,000 *F5* (1q24.2)

1: 500,000 *F7* (13q34)

1: 1,000,000 *F10* (13q34)

1: 1,000,000 *F11* (4q35.2)

**(chromosome)**

and *FGG* (4q28)

very low frequency. As a result, affected individuals received delayed diagnosis, incomplete laboratory testing, and limited treatment options. Standardization of coagulation assays, global clotting assays, and genomic sequencing promises to improve the diagnosis of RBDs, but there is still a long gap to overcome [1]. **Table 3** shows a general

scope of the physiological characteristics, symptoms, and impact of the RBDs.

**Bleeding symptoms**

hemarthrosis, mucosal tract, menorrhagia, first trimester abortion, CNS Venous, and arterial thromboembolism are reported

hemarthrosis, and mucosal tract

postoperative

hemarthrosis, hematomas, and neonatal CNS hemorrage

hemarthrosis, hematomas, and CNS hemorrhages

traumatic, and postoperative

**66**

*Clinical symptoms and laboratory/molecular diagnosis in rare bleeding disorders (RBDs).*

#### **5.2 RBDs in pregnancy, delivery, and puerperium**

Women with RBDs require especial medical treatment and care. In addition to common bleeding symptoms, they may also experience gynecological bleeding and are at increased risk of hemorrhagic ovarian cysts, endometriosis, and endometrial hyperplasia polyps and fibroids. Pregnancy and childbirth in women with RBDs are real clinical challenges; miscarriages, bleeding during pregnancy, and postpartum hemorrhage are frequent and may represent severe clinical complications [74].

There has been a higher risk of diverse obstetric complications reported in women with RBDs; miscarriage and placental abruption resulting in fetal loss or preterm delivery are rather common in women deficient in fibrinogen or factor XIII (FXIII) [1].

To resolve the clinical complications of women with RBDs, it is important to consider the behavior of the clotting factors in normal conditions and their tendency to increase during pregnancy that has been attributed to the increase of estrogen concentrations, especially in the third trimester (fibrinogen, FVII, FVIII, FX, FXII, FXIII, and VWF). Other factors (FII, V, IX, and XIII) increase slightly or remain unchanged while FXI is the only factor that decreases during pregnancy [75].

#### **6. Conclusion**

Inherited bleeding disorders may seriously impact the women's quality of life through their detrimental effects on academic, professional, and social life. Longlasting HMB causes iron deficiency anemia with consequences on physical and mental well-being. Medical care for women with bleeding disorders is lacking in many countries and there may be cultural taboos and obstacles preventing women

#### *Hemophilia - Recent Advances*

from seeking help, specifically for menstrual problems, which may lead to marital disharmony and possibly fertility problems. Caregivers are often unaware about bleeding disorders in women, and therefore, even when women do seek help, the diagnosis is often neglected and appropriated treatment is not provided. In addition, bleeding disorders in women have negative consequences on the nutrition and well-being of their children. Early identification of young girls and women with HMB for managing their menstruation and iron deficiency is crucial in improving women's health in general [1].

### **Acknowledgements**

We are grateful to Dr. Horacio Rivera for his valuable suggestions in the edition of the document. We dedicate this work to the Federación de Hemofilia de la República Mexicana, A.C., and we deeply appreciate their financial support for the publication.

### **Conflict of interest**

All the authors declare that there is no conflict of interest regarding their contribution to this chapter.


**69**

**Author details**

Ana-Rebeca Jaloma-Cruz1

Diana Ornelas-Ricardo3

provided the original work is properly cited.

Social Security, Guadalajara, Jalisco, Mexico

University of Guadalajara, Guadalajara, Jalisco, Mexico

University of Guadalajara, Guadalajara, Jalisco, Mexico

\*Address all correspondence to: arjaloma@gmail.com

*Clinical Issues in Women with Inherited Bleeding Disorders*

VWF:Ag antigen test of the VWF used to measure the amount of VWF VWF:RCo a ristocetin cofactor test used to measure functional activity of the

*DOI: http://dx.doi.org/10.5772/intechopen.82119*

VWD von Willebrand disease VWF von Willebrand factor

VWF

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

4 Department of Chemistry, University Center of Exact Sciences and Engineering,

\*, Isaura-Araceli González-Ramos2

1 Genetics Division, Biomedical Research Center of Occident, Mexican Institute of

, Clara-Ibet Juárez-Vázquez<sup>2</sup>

2 Genetics Department, Institute of Biological Sciences, Medicine Faculty, Autonomous University of Guadalajara, Guadalajara, Jalisco, Mexico

3 PhD Program on Human Genetics, University Center of Health Sciences,

,

and Hilda Luna-Záizar4

#### **Appendices and nomenclature**

*Clinical Issues in Women with Inherited Bleeding Disorders DOI: http://dx.doi.org/10.5772/intechopen.82119*

*Hemophilia - Recent Advances*

women's health in general [1].

**Acknowledgements**

**Conflict of interest**

bution to this chapter.

**Appendices and nomenclature**

FXIII factor XIII protein *F8* factor 8 gene *F9* factor 9 gene

HA hemophilia A HB hemophilia B

Kb Kilobases

BSS Bernard-Soulier syndrome

desmopressin EACA epsilon-aminocaproic acid

FIX:C factor IX procoagulant activity FVIII:C factor VIII procoagulant activity

GPIb platelet glycoprotein protein Ib GPs platelet surface glycoproteins GT Glanzmann thrombasthenia

HMB heavy menstrual bleeding ICH Intracranial hemorrhage

thrombocytopenia IVIg Intravenous immunoglobulin

PAI-1 plasminogen activator inhibitor PBAC pictorial blood assessment chart

PPH postpartum hemorrhage RBDs rare bleeding disorders rVIIa recombinant factor VIIa

publication.

from seeking help, specifically for menstrual problems, which may lead to marital disharmony and possibly fertility problems. Caregivers are often unaware about bleeding disorders in women, and therefore, even when women do seek help, the diagnosis is often neglected and appropriated treatment is not provided. In addition, bleeding disorders in women have negative consequences on the nutrition and well-being of their children. Early identification of young girls and women with HMB for managing their menstruation and iron deficiency is crucial in improving

We are grateful to Dr. Horacio Rivera for his valuable suggestions in the edition of the document. We dedicate this work to the Federación de Hemofilia de la República Mexicana, A.C., and we deeply appreciate their financial support for the

All the authors declare that there is no conflict of interest regarding their contri-

DDAVP 1-deamino-8-D-arginine vasopressin, denominated as

ISTH International Society on Thrombosis and Hemostasis ITP idiopathic thrombocytopenic purpura or immune

FCGRC2 receptor for the Fc region of complexed immunoglobulin gamma FIGO The International Federation of Gynecology and Obstetrics

**68**


### **Author details**

Ana-Rebeca Jaloma-Cruz1 \*, Isaura-Araceli González-Ramos2 , Diana Ornelas-Ricardo3 , Clara-Ibet Juárez-Vázquez<sup>2</sup> and Hilda Luna-Záizar4

1 Genetics Division, Biomedical Research Center of Occident, Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico

2 Genetics Department, Institute of Biological Sciences, Medicine Faculty, Autonomous University of Guadalajara, Guadalajara, Jalisco, Mexico

3 PhD Program on Human Genetics, University Center of Health Sciences, University of Guadalajara, Guadalajara, Jalisco, Mexico

4 Department of Chemistry, University Center of Exact Sciences and Engineering, University of Guadalajara, Guadalajara, Jalisco, Mexico

\*Address all correspondence to: arjaloma@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[27] Nichols WL, Hultin MB, James AH. von Willebrand disease (VWD): Evidence based diagnosis management guidelines, the National Heart, Lung and Blood Institute (NHLBI), expert Panel report (USA). Haemophilia. 2008;**14**:171-232. DOI: 10.1111/j.1365-2516.2007.01643.x

[28] VWF von Willebrand factor [*Homo sapiens* (human)]—Gene—NCBI [Internet]. 2018. Available from: https:// www.ncbi.nlm.nih.gov/gene/7450 [Accessed: July 10, 2018]

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[10] Olsson A, Ljung R, Hellgren M. Phenotype and genotype comparisons in carriers of haemophilia A. Haemophilia.

2016;**22**:e235-e237. DOI: 10.1111/

[12] Lavaut K. Importancia del diagnóstico de portadoras en familias con antecedentes de hemofilia. Revista Cubana de Hematologia e Inmunología y Hemoterapia. 2014;**30**:108-113. ISBN

[13] Olsson A, Hellgren M, Berntorp E. Association between bleeding tendency and healthrelated quality of life in carriers of moderate and severe haemophilia. Haemophilia. 2015;**21**:742-746. DOI:

[14] Olsson A, Hellgren M, Berntorp E. Clotting factor level is not a good predictor of bleeding in carriers of haemophilia A and B. Blood Coagulation & Fibrinolysis. 2014;**25**:471-475. DOI: 10.1097/ MBC.0000000000000083

[15] Srivaths LV, Zhang QC, Byams VR. Differences in bleeding phenotype and provider interventions in postmenarchal adolescents when compared to adult women with bleeding disorders and

heavy menstrual bleeding.

10.1111/hae.13330

Haemophilia. 2018;**24**:63-69. DOI:

10.1111/hae.12796

[11] Bernard W, Lambert C, Henrard S. Screening of haemophilia carriers in moderate and severe haemophilia A and B: Prevalence and determinants. Haemophilia. 2018;**24**:e142-e144. DOI:

pjms.333.12496

hae.12928

10.1111/hae.13468

0864-0289

[2] Hermans C, Kulkarni R. Women with bleeding disorders. Hemophilia. 2018;**24**:29-36. DOI: 10.1111/hae.13502

[3] Fraser IS, Critchley HOD, Broder M.

[4] Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. British Journal of Obstetrics and Gynaecology. 1990;**97**:734-739. DOI: 10.1111/j.1471-

[5] Paroskie A, Gailani D, DeBraun MR. A cross-sectional study of bleeding phenotype in haemophilia A carriers. British Journal of Haematology. 2015;**170**:223-228. DOI: 10.1111/

[6] Di Michele DM, Gibb C, Lefkowitz JM. Severe and moderate haemophilia A and B in US females. Haemophilia. 2014;**20**:e136-e143. DOI: 10.1111/

[7] Staber J, Croteau SE, Davis J. The spectrum of bleeding in women and girls with haemophilia B. Haemophilia.

[8] Pavlova A, Brondke H, Müsebeck J. Molecular mechanisms underlying hemophilia A phenotype in seven females. Journal of Thrombosis and Haemostasis. 2009;**7**:976-982. DOI: 10.1111/j.1538-7836.2009.03346.x

2018;**24**:180-185. DOI: 10.1111/

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10.1055/s-0031-1287662

0528.1990.tb16249.x

bjh.13423

hae.12364

hae.13376

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[37] Neff AT, Sidonio RF Jr. Management of VWD. Hematology. American Society of Hematology. Education Program. 2014;**2014**:536-541. DOI: 10.1182/ asheducation 2014.1.536

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[39] Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood. 2017;**129**:2829-2835. DOI: 10.1182/ blood-2017-03-754119

[40] Medscape Drug Reference. Platelet Disorders Overview of Platelet Disorders [Internet]. 2017. Available from: https://emedicine.medscape. com/article/201722-overview#showall [Accessed: July 24, 2018]

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[44] Breunis WB, van Mirre E, Bruin M. Copy number variation of the activating *FCGR2C* gene predisposes to idiopathic thrombocytopenic purpura. Blood. 2008;**111**:1029-1038. DOI: 10.1182/ blood-2007-03-079913

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from the monoallelic Ala156Val mutation of GPIb alpha (Bolzano mutation). Haematologica. 2012;**97**:82-88. DOI: 10.3324/haematol.2011.050682

[56] Handin RI. Inherited platelet disorders. Hematology American Society of Hematology Education Program. 2005;**1**:396-402. DOI: 10.1182/

[57] Savoia A, Pastore A, De Rocco D. Clinical and genetic aspects Bernard-Soulier syndrome: Searching for genotype/phenotype correlations. Haematologica. 2011;**96**:417-423. DOI:

10.3324/haematol.2010.032631

1714677

PMID: 2915873

July 24, 2018]

PMID: 12083483

12163005

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[60] Medscape Drug Reference. Bernard-

Management [Internet]. 2016. Available from: https://emedicine.medscape.com/ article/954877-treatment [Accessed:

[61] D'Andrea G, Colaizzo D, Vecchione G. Glanzmann's thrombasthenia: Identification of 19 new mutations in 30 patients. Thrombosis and Haemostasis. 2002;**87**:1034-1042.

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[51] Matschke J, Müller-Beissenhirtz H, Novotny J. A randomized trial of daily prednisone versus pulsed dexamethasone in treatmentnaïve adult patients with immune thrombocytopenia: EIS 2002 Study. Acta Haematologica. 2016;**136**:101-107.

[52] Lopez JA, Andrews RK, Afshar-Kharghan V. Bernard-Soulier syndrome. Blood. 1998;**91**:4397-4418. PMID:

[53] Andrews R, Berndt M, Lopez J. The glycoprotein Ib-IX-V complex. In: Michelson AD, editor. Platelets. 2nd ed. San Diego, CA: Academic Press; 2006.

[54] Li R, Emsley J. The organizing principle of the platelet glycoprotein Ib-IX-V complex. Journal of Thrombosis and Haemostasis. 2013;**11**:605-614. DOI:

[55] Noris P, Perrotta S, Bottega R. Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived

[48] Kelton JG. Idiopathic thrombocytopenic purpura complicating pregnancy. Blood Reviews. 2002;**16**:43-46. DOI: 10.1054/

blre.2001.0181

10636060

blood-2002-10-3317

DOI: 10.1159/000445420

9616133

pp. 145-164

10.1111/jth.12144

*Clinical Issues in Women with Inherited Bleeding Disorders DOI: http://dx.doi.org/10.5772/intechopen.82119*

[48] Kelton JG. Idiopathic thrombocytopenic purpura complicating pregnancy. Blood Reviews. 2002;**16**:43-46. DOI: 10.1054/ blre.2001.0181

*Hemophilia - Recent Advances*

[32] James AH, Konkle BA, Kouides P. Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis. Haemophilia. 2015;**21**: 81-87. DOI: 10.1111/hae.12568

Disorders [Internet]. 2017. Available from: https://emedicine.medscape. com/article/201722-overview#showall

[Accessed: July 24, 2018]

PMID: 2187937

PMID:13359508

PMID: 10702324

blood-2007-03-079913

[Accessed: July 24, 2018]

July 25, 2018]

[41] Harrington WJ, Minnich V,

Hollingsworth JW. Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura. Journal of Laboratory and Clinical Medicine. 1951;**115**:636-645.

[42] Arimura G, Harrington WJ, Minnich V. The autoimmune thrombocytopenias. Progress in Hematology. 1956;**1**:166-192.

[43] Chu YW, Korb J, Sakamoto KM. Idiopathic thrombocytopenic purpura. Pediatrics in Review. 2000;**21**:95-104.

[44] Breunis WB, van Mirre E, Bruin M. Copy number variation of the activating *FCGR2C* gene predisposes to idiopathic thrombocytopenic purpura. Blood. 2008;**111**:1029-1038. DOI: 10.1182/

[45] Online Mendelian Inheritance in Man (OMIM). Thrombocytopenic purpura autoimmune (OMIM 188030) [Internet]. 2009. Available from:

https://www.omim.org/entry/188030#9

[46] U.S. National Library of Medicine. Genetics Home Reference. Immune thrombocytopenia [Internet]. 2018. Available from: https://ghr. nlm.nih.gov/condition/immunethrombocytopenia#genes [Accessed:

[47] Rodeghiero F, Stasi R, Gernsheimer T.

Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: Report from an international working group. Blood. 2009;**113**:2386-2393. DOI: 10.1182/

blood-2008-07-162503

[33] Castaman G. Changes of von Willebrand Factor during Pregnancy in Women with and without von Willebrand Disease. Mediterranean Journal of Hematology and Infectious Diseases. 2013;**5**:2013052. DOI: 10.4084/MJHID.2013.052

[34] Skeith L, Rydz N, O'Beirne M. Pregnancy loss in women with von Willebrand disease: A single-center pilot study. Blood Coagulation & Fibrinolysis. 2017;**28**:393-397. DOI: 10.1097/MBC.0000000000000620

[35] Lee C, Kadir A, Kouides P. Women with von Willebrand disease. In: Federici A, Lee C, editors. von Willebrand Disease: Basic and Clinical Aspects. 1st ed. Chichester: Wiley; 2011. pp. 174-185

[36] Ng CJ, Paola D, von Willebrand Disease J. Diagnostic strategies and treatment options. Pediatric Clinics of North America. 2018;**65**:527-541. DOI:

[37] Neff AT, Sidonio RF Jr. Management of VWD. Hematology. American Society of Hematology. Education Program. 2014;**2014**:536-541. DOI: 10.1182/

[38] Ahn YS, Horstman LL. Idiopathic

[39] Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood. 2017;**129**:2829-2835. DOI: 10.1182/

[40] Medscape Drug Reference.

Platelet Disorders Overview of Platelet

10.1016/j.pcl.2018.02.004

asheducation 2014.1.536

blood-2017-03-754119

thrombocytopenic purpura: Pathophysiology and management. International Journal of Hematology. 2002;**76**:123-131. PMID: 12430912

**72**

[49] American College of Obstetricians and Gynecologists. ACOG practice bulletin: Thrombocytopenia in pregnancy. Number 6, September 1999. Clinical management guidelines for obstetrician-gynecologists. International Journal of Gynecology & Obstetrics. 1999;**67**:117-128. PMID: 10636060

[50] Webert KE, Mittal R, Sigouin C. A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood. 2003;**102**:4306-4311. DOI: 10.1182/ blood-2002-10-3317

[51] Matschke J, Müller-Beissenhirtz H, Novotny J. A randomized trial of daily prednisone versus pulsed dexamethasone in treatmentnaïve adult patients with immune thrombocytopenia: EIS 2002 Study. Acta Haematologica. 2016;**136**:101-107. DOI: 10.1159/000445420

[52] Lopez JA, Andrews RK, Afshar-Kharghan V. Bernard-Soulier syndrome. Blood. 1998;**91**:4397-4418. PMID: 9616133

[53] Andrews R, Berndt M, Lopez J. The glycoprotein Ib-IX-V complex. In: Michelson AD, editor. Platelets. 2nd ed. San Diego, CA: Academic Press; 2006. pp. 145-164

[54] Li R, Emsley J. The organizing principle of the platelet glycoprotein Ib-IX-V complex. Journal of Thrombosis and Haemostasis. 2013;**11**:605-614. DOI: 10.1111/jth.12144

[55] Noris P, Perrotta S, Bottega R. Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived

from the monoallelic Ala156Val mutation of GPIb alpha (Bolzano mutation). Haematologica. 2012;**97**:82-88. DOI: 10.3324/haematol.2011.050682

[56] Handin RI. Inherited platelet disorders. Hematology American Society of Hematology Education Program. 2005;**1**:396-402. DOI: 10.1182/ asheducation-2005.1.396

[57] Savoia A, Pastore A, De Rocco D. Clinical and genetic aspects Bernard-Soulier syndrome: Searching for genotype/phenotype correlations. Haematologica. 2011;**96**:417-423. DOI: 10.3324/haematol.2010.032631

[58] Peng TC, Kickler TS, Bell WR. Obstetric complications in a patient with Bernard-Soulier syndrome. American Journal of Obstetrics and Gynecology. 1991;**165**:425-426. PMID: 1714677

[59] Peaceman AM, Katz AR, Laville M. Bernard-Soulier syndrome complicating pregnancy: A case report. Obstetrics and Gynecology. 1989;**73**:457-459. PMID: 2915873

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[64] Rosenberg N, Yatuv R, Sobolev V. Major mutations in calf-1 and calf-2 domains of glycoprotein IIb in patients with Glanzmann thrombasthenia enable GPIIb/IIIa complex formation, but impair its transport from the endoplasmic reticulum to the Golgi apparatus. Blood. 2003;**101**:4808-4815. DOI: 10.1182/blood-2002-08-2452

[65] Newman PJ, Seligsohn U, Lyman S. The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. Proceedings of the National Academy of Sciences of the United States of America. 1991;**88**:3160-3164. PMID: 2014236

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[74] Palla R, Peyvandy F, Shapiro AD. Rare bleeding disorders: Diagnosis and treatment. Review Series. Blood. 2015;**125**:2052-2061. DOI: 10.1182/ blood-2014-08-532820

[75] Hellgren M. Hemostasis during normal pregnancy and puerperium. Seminars in Thrombosis and Hemostasis. 2003;**29**:125-130. DOI: 10.1159/000217305

*Hemophilia - Recent Advances*

Platelets. 2002;**13**:387-393. DOI: 10.1080/0953710021000024394

[64] Rosenberg N, Yatuv R, Sobolev V. Major mutations in calf-1 and calf-2 domains of glycoprotein IIb in patients with Glanzmann thrombasthenia enable GPIIb/IIIa complex formation, but impair its transport from the endoplasmic reticulum to the Golgi apparatus. Blood. 2003;**101**:4808-4815. DOI: 10.1182/blood-2002-08-2452

agents. Seminars in Hematology. 2006;**43**:S33-S536. DOI: 10.1053/j. seminhematol.2005.11.009

[71] Valentino LA. Use of rFVIIa in 4 children with Glanzmann thromboasthenia. Journal of Pediatric Hematology/Oncology. 2006;**28**:653-658. DOI: 10.1097/01.

mph.0000212993.49188.73

[72] Franchini M. The use of recombinant activated factor VII in platelet disorders: A critical review of the literature. Blood Transfusion. 2009;**7**:24-28. DOI:

[73] Castaman G, Linari S. Diagnosis and treatment of von Willebrand disease and rare bleeding disorders. Journal of Clinical Medicine. 2017;**6**:1-18. DOI:

[74] Palla R, Peyvandy F, Shapiro AD. Rare bleeding disorders: Diagnosis and treatment. Review Series. Blood. 2015;**125**:2052-2061. DOI: 10.1182/

[75] Hellgren M. Hemostasis during normal pregnancy and puerperium. Seminars in Thrombosis and Hemostasis. 2003;**29**:125-130. DOI:

10.2450/2008.0015-08

10.3390/jcm6040045

blood-2014-08-532820

10.1159/000217305

[65] Newman PJ, Seligsohn U, Lyman S.

Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. Proceedings of the National Academy of Sciences of the United States of America. 1991;**88**:3160-3164. PMID:

[66] Toogeh G, Sharifian R, Lak M. Presentation and pattern of symptoms in 382 patients with Glanzmann thrombasthenia in Iran. American Journal of Hematology. 2004;**77**: 198-199. DOI: 10.1002/ajh.20159

[67] Franchini M, Favaloro EJ, Lippi G. Glanzmann thrombasthenia: An update. Clinica Chimica Acta. 2010;**411**:1-6. DOI: 10.1016/j.cca.2009.10.016

[68] Nurden AT, George JN. Inherited abnormalities of the platelet membrane: Glanzmann thrombasthenia, Bernard-Soulier syndrome, and other disorders. In: Hemostasis and Thrombosis, Basic Principles and Clinical Practice. 6th ed. Philadelphia: Lippincott, Williams &

Wilkins; 2005. pp. 987-1010

[69] Nurden AT. Glanzmann thrombasthenia. Orphanet Journal of Rare Diseases. 2006;**6, 1**:10. DOI:

[70] Poon MC, Zotz R, Di Minno G. Glanzmann's thrombasthenia treatment: A prospective observational registry on the use of recombinant human activated

factor VII and other hemostatic

10.1186/1750-1172-1-10

The molecular genetic basis of

2014236

**74**

### *Edited by Pankaj Abrol*

The book Hemophilia - Recent Advances covers various rapid advances being made in this field. The authors have produced state-of-the art chapters. Over some decades, management of hemophilia has progressed from episode based to prophylaxis. It has moved from plasma and cryoprecipitate to new generations of recombinant coagulation factors. Efforts have been made to cover recent advances in the field. The intricacies of genotype and phenotype of hemophilia are explained. Management with recombinant factors has added to problems like inhibitors, which require more skillful handling. Perioperative management of hemophilia is also explained. Every chapter of this book is peer reviewed and evidence based. The information provided in this book makes the readers well informed and more inquisitive, thereby raising new issues, innovation, and research.

Published in London, UK © 2019 IntechOpen © StMax89 / iStock

Hemophilia - Recent Advances

Hemophilia

Recent Advances

*Edited by Pankaj Abrol*