**2. Genetic risk factors**

Among the hereditary risk factors leading to a predisposition to thrombosis, antithrombin deficiency was first shown to create predisposition to thrombosis in 1965, followed by the description of protein C deficiency in 1981 and protein S in 1984. These three deficiencies represent only 15% of hereditary thrombophilias. The description of the active protein C (APC) resistance by Dahlback et al in 1993 (Dahlback, 1995) and of the factor V Leiden mutation by Bertina in 1994 (Bertina, 1999) enabled elucidation of the etiology in 20% of patients with thrombosis and in 50% of families with thrombophilia. Similarly, hyperhomocysteinemia and a mutation in the prothrombin gene were shown to cause hereditary thrombophilia in 1994 and 1996, respectively (Makris et al., 1997). In patients with genetic thrombophilia, the predisposition to thrombotic and recurrent venous thromboembolism (VTE) in the early stages of life is increased.

Risk Factor for Pulmonary Embolism 3

Antithrombin III (AT III) deficiency is among the first described thrombophilias. It is one of the most important natural protease inhibitors and a glycoprotein that is synthesized in the liver, which exhibits anticoagulant efficacy through inhibition of thrombin and the other serine proteases (factor IX a, X a, XI a, XIIa and kallikrein). Owing to these properties, it is accepted to be one of the most potent physiologic inhibitors of the fibrin formation. There are two types of antithrombin III deficiencies: type I involves reduction in the synthesis while type II involves functional inactivity. Type I AT III deficiency is characterized by both a functional and an immunological reduction in AT III. Type II AT deficiency involves variant AT III molecules (Thaler & Lechner, 1981). When the serum concentration of antithrombin III is mildly decreased, factor Xa, IXa, XIa and XIIa and thrombin cannot be inactivated, leading to thrombus formation. In addition to congenital deficiency, the antithrombin level is also decreased in cases of diffuse intravascular clotting, oral contraceptive (OC) use, and liver and kidney diseases. In antithrombin III deficiency, thrombotic events occur mostly in the mesenteric and lower extremity deep veins, leading to an increased predisposition to pulmonary embolism. A trial detected a rate of AT III deficiency at 1/600 in healthy individuals (Tait et al., 1994). In another trial, this figure was

Protein C (PC) is a glycoprotein synthesized in the liver. Its deficiency exhibits autosomal dominant or autosomal recessive inheritance. Protein C deficiency has two subtypes. Type I protein C deficiency: protein C antigen level is low due to genetic defect while the protein C activity is normal. Type II protein C deficiency involves the presence of an abnormal protein C molecule. Protein C antigen is normal while the protein C activity is low (Hoshi et al., 2007). Protein C is activated after the thrombin binds to the endothelial receptors. Activated PC binds to the factor Va and factor VIIIa and inactivates these factors, thereby inhibiting

In the general population, protein C deficiency prevalence is between 1/16000 and 36000. The fact that the protein C deficiency rate is 10% in patients with previous VTE below 40 years of age and that it increases the VTE risk 6-fold, protein C level should be investigated

Protein S is a glycoprotein that is vitamin K-dependently synthesized, exhibits an autosomal dominant inheritance and activates protein C as a cofactor. Protein S exhibits anticoagulant efficacy through both the inactivation of factor Va and factor VIIIa by Protein C that is activated as a cofactor and directly through inhibition of the interaction of prothrombin with factor Va and Xa; therefore, protein S deficiency is considered a significant risk factor for thrombosis formation (Bertina, 1999). Protein S deficiency has three subtypes. Type I protein S deficiency involves a reduction in the total protein S antigen level. The free protein S antigen level and activity is low. Type II protein S deficiency involves the presence of a functionally abnormal protein S molecule. The total and free protein S antigens are normal but the protein S activity is decreased. Type III protein S deficiency involves a normal total protein S antigen but a decreased free protein S antigen level and activity (Dykes et al., 2001). Protein S deficiency is observed at a rate of 0.03%-0.13 (Dykes et al., 2001) and 6% in

1.5% in patients diagnosed with VTE (Bauer& Rosenberg, 1991).

in all young patients with previous VTE (Folsom et al., 2002).

**2.1 Antithrombin III deficiency** 

**2.2 Protein C deficiency** 

the clot formation.

**2.3 Protein S deficiency** 


Table 1. Virchow's triad/ venous thromboembolism risk factors


Table 2. Risk factor for pulmonary embolism

Table 1. Virchow's triad/ venous thromboembolism risk factors

Genetic risk factors Acquired risk factors

Advanced age Obesity

infraction Smoking Stroke

replacement

thrombosis

Long haul air travel Immobilization Major surgery Trauma

Malignity/ Chemotherapy Central venous catheter Pregnancy/puerperality

Antiphospholipid syndrome

Congestive cardiac failure / Myocardial

The use of Oral contraceptives and hormone

Previous pulmonary emboli and deep vein

Chronic obstructive pulmonary disease (COPD) Medical Conditions requiring hospitalization

Antithrombin III deficiency Protein C deficiency Protein S deficiency

Factor V Leiden Mutation Factor II G20210A Mutation: Hyperhomocysteinemia Increase in Factor VIII Levels Congenital Dysfibrinogenemia Plasminogen deficiency Factor VII deficiency Factor XII deficiency Factor IX increase

Activated Protein C resistance and

Table 2. Risk factor for pulmonary embolism

#### **2.1 Antithrombin III deficiency**

Antithrombin III (AT III) deficiency is among the first described thrombophilias. It is one of the most important natural protease inhibitors and a glycoprotein that is synthesized in the liver, which exhibits anticoagulant efficacy through inhibition of thrombin and the other serine proteases (factor IX a, X a, XI a, XIIa and kallikrein). Owing to these properties, it is accepted to be one of the most potent physiologic inhibitors of the fibrin formation. There are two types of antithrombin III deficiencies: type I involves reduction in the synthesis while type II involves functional inactivity. Type I AT III deficiency is characterized by both a functional and an immunological reduction in AT III. Type II AT deficiency involves variant AT III molecules (Thaler & Lechner, 1981). When the serum concentration of antithrombin III is mildly decreased, factor Xa, IXa, XIa and XIIa and thrombin cannot be inactivated, leading to thrombus formation. In addition to congenital deficiency, the antithrombin level is also decreased in cases of diffuse intravascular clotting, oral contraceptive (OC) use, and liver and kidney diseases. In antithrombin III deficiency, thrombotic events occur mostly in the mesenteric and lower extremity deep veins, leading to an increased predisposition to pulmonary embolism. A trial detected a rate of AT III deficiency at 1/600 in healthy individuals (Tait et al., 1994). In another trial, this figure was 1.5% in patients diagnosed with VTE (Bauer& Rosenberg, 1991).

#### **2.2 Protein C deficiency**

Protein C (PC) is a glycoprotein synthesized in the liver. Its deficiency exhibits autosomal dominant or autosomal recessive inheritance. Protein C deficiency has two subtypes. Type I protein C deficiency: protein C antigen level is low due to genetic defect while the protein C activity is normal. Type II protein C deficiency involves the presence of an abnormal protein C molecule. Protein C antigen is normal while the protein C activity is low (Hoshi et al., 2007). Protein C is activated after the thrombin binds to the endothelial receptors. Activated PC binds to the factor Va and factor VIIIa and inactivates these factors, thereby inhibiting the clot formation.

In the general population, protein C deficiency prevalence is between 1/16000 and 36000. The fact that the protein C deficiency rate is 10% in patients with previous VTE below 40 years of age and that it increases the VTE risk 6-fold, protein C level should be investigated in all young patients with previous VTE (Folsom et al., 2002).

#### **2.3 Protein S deficiency**

Protein S is a glycoprotein that is vitamin K-dependently synthesized, exhibits an autosomal dominant inheritance and activates protein C as a cofactor. Protein S exhibits anticoagulant efficacy through both the inactivation of factor Va and factor VIIIa by Protein C that is activated as a cofactor and directly through inhibition of the interaction of prothrombin with factor Va and Xa; therefore, protein S deficiency is considered a significant risk factor for thrombosis formation (Bertina, 1999). Protein S deficiency has three subtypes. Type I protein S deficiency involves a reduction in the total protein S antigen level. The free protein S antigen level and activity is low. Type II protein S deficiency involves the presence of a functionally abnormal protein S molecule. The total and free protein S antigens are normal but the protein S activity is decreased. Type III protein S deficiency involves a normal total protein S antigen but a decreased free protein S antigen level and activity (Dykes et al., 2001). Protein S deficiency is observed at a rate of 0.03%-0.13 (Dykes et al., 2001) and 6% in

Risk Factor for Pulmonary Embolism 5

cells by causing the formation of reactive oxygen forms, such as superoxide, hydrogen peroxide and hydroxyl radicals, it causes proliferative response by affecting the smooth muscle cells and increasing collagen production, it affects the clotting system by increasing tissue factor production in the monocytes, creating acquired APC resistance and increasing the synthesis of thromboxane in the platelets (Miletich et al., 1987). Hyperhomocysteinemia is an established risk factor for VTE and is usually associated with a 2 to 4-fold increased thrombotic risk. Plasma homocysteine concentration is affected by genetic and acquired factors and thus known as the mixed risk factor (Miletich et al., 1987). Vitamin B12, vitamin B6 and folate deficiency, advanced age, chronic renal failure and malnutrition involving anti-folic drug use represent acquired factors in hyperhomocysteinemia. Gene defects in two enzymes involved in the intracellular metabolism, methyltetrahydrofolate reductase (MTHFR) and cystathionine B-synthase (CBS) result in hyperhomocysteinemia and enzyme deficiency. Various mutations have been defined in methyltetrahydrofolate reductase and CBS to date; most are rare and lead to clinical outcomes in homozygous cases only. This condition is characterized by multiple neurological deficiency, physicomotor retardation, seizures, skeletal abnormalities, lens dislocation, premature arterial disease and VTE (Weisberg et al., 1999). Methyltetrahydrofolate reductase 677 C→T is associated with highprevalence polymorphism in the general population and reduced enzyme activity in homozygous cases. Methyltetrahydrofolate reductase 1298 A→C is not considered to be

associated with hyperhomocysteinemia and not considered a thrombotic risk factor.

al., 1997).

(Kyrle et al., 2000).

**2.7 Increase in factor VIII levels** 

**2.8 Congenital dysfibrinogenemia** 

However, MTHFR results in reduced enzyme activity and increased homocysteine levels in heterozygous cases of 677 C→T (Weisberg et al., 1999). 68-bp insertion in the cystathionine B-cynthase gene (844ins68) is a common mutation in various populations. This gene change has no effect on the risk of DVT or homocysteine levels. Hyperhomocysteinemia is not defined as a genetic abnormality for VTE but as an independent risk factor (Kluijtmans et

Factor VIII is an entity with a gene localized on the 10th chromosome, which activates the factor X by forming a complex with factor IXa and phospholipids in the coagulation cascade. The increase in factor VIII is included among the thrombotic risk factors since it further increases formation of thrombin from prothrombin by factor X activation (Schambeck et al., 2004). The increased factor was detected in 3-9.4% of healthy individuals and in 11.3% of patients with VTE (Schambeck et al., 2004). A high FVIII level was reported to increase the VTE risk approximately 5-fold compared to individuals with a normal level (Schambeck et al., 2004). In addition, the factor VIII level was demonstrated to be an independent risk factor for VTE (Kraaijenhagen et al., 2000) (21) and to be correlated with the PE recurrence

The impairment in the formation of fibrin from fibrinogen secondary to the changes in the structure of fibrinogen is called dysfibrinogenemia. Dysfibrinogenemia is a dominant disease group characterized by qualitative abnormal fibrinogen formation. Various fibrinogen abnormalities are assessed within this group. Approximately 300 abnormal fibrinogen have been defined (Schorer et al., 1995). The most common structural defects are detected in fibrinopeptides and their sites of cleavage. Each dysfibrinogenemia affects

healthy individuals and families with thrombophilia (Bertina 1999). The trials performed demonstrated a 6 to 10-fold increased VTE risk in heterozygous Protein S gene carriers (Bauer& Rosenberg, 1991). As well as leading to thrombus formation in the deep (axillary, femoral etc), mesenteric, cerebral and superficial veins, it also causes PE and arterial thrombus formation. It is also one of the causes of recurrent VTE attacks. Pregnancy, OC or estrogen replacement use, nephritic syndrome, disseminated intravascular coagulation, HIV infection and liver diseases may also result in acquired protein S deficiency (Bauer& Rosenberg, 1991).

#### **2.4 Activated protein C resistance and factor V Leiden mutation**

In cases of activated partial thromboplastin time (aPTT) changes, an addition of activated Protein C to the plasma is expected to cause the prolongation of bleeding time. However, Dahlback et al detected no prolongation in some patients with VTE in 1993 (Dahlback, 1995); this phenomenon was described as the activated protein C resistance (APCR). Activated Protein C resistance is clearly associated with an increase in thrombosis incidence. The subsequent studies detected this phenotype in 20-50% of the patients with VTE (Dahlback, 1995). In many cases of hereditary APCR, aG→A transition causes translocation of the amino acids (glutamine and arginine) at 506 location in the position 1691 nucleotide as a result of the activated function of the point mutation in factor V (site of cleavage for the activated PC in the factor V molecule). This point mutation was first described in 1994 and named as Factor V Leiden (FVL), FVR Q or FV: Q (Rosendaal et al., 1995). Factor V mutation notably increases the predisposition to VTE, causes hypercoagulability and neutralizes activated PC-mediated resistance. The risk of VTE is increased 3 to 8-fold in individuals heterozygous for factor Leiden mutation; as for homozygous individuals, the increase in the thrombotic risk is 50 to 100-fold (Rosendaal et al., 1995). The incidence of factor V Leiden carriers is 1-15% in the population (Rosendaal et al., 1995). Factor V Leiden is present in 10- 50% of the cases with VTE. Factor V Leiden abnormality results from a single mutation. In APCR without factor V Leiden mutation, the VTE risk is increased (Rosendaal et al., 1995).

#### **2.5 Factor II G20210A mutation**

A new genetic factor was discovered in the etiology of VTE in 1996. The G→A transition (Factor II G20210A) of the nucleotides at 20120 location in the region of the coagulation factor II gene not undergoing 3'-translation is associated with hyperprothrombinemia. G→A transition increased the prothrombin synthesis at the level of mRNA and protein synthesis. In heterozygous carriers of this mutation, the prothrombin level is increased 1.3-fold while it is increased 1.7-fold in homozygous carriers. The increase in the plasma prothrombin level results in a predisposition to thrombosis. This mutation was detected in 1-3% of the general population and 6-18% of the patients with VTE (Poort et al. 1996). Factor II G20210A diagnosis is only established by gene analysis. It is the second most common genetic abnormality, secondary to thrombophilia. In the case of factor II G20210A, there is no increase in the risk of VTE (Miles et al., 2001).

#### **2.6 Hyperhomocysteinemia**

It is the only hereditary cause of thrombophilia that has been proven to lead to arterial and venous thrombosis. Hyperthrombosis is believed to trigger the development of thrombosis via various mechanisms; there are in vitro studies showing that it affects the endothelial

healthy individuals and families with thrombophilia (Bertina 1999). The trials performed demonstrated a 6 to 10-fold increased VTE risk in heterozygous Protein S gene carriers (Bauer& Rosenberg, 1991). As well as leading to thrombus formation in the deep (axillary, femoral etc), mesenteric, cerebral and superficial veins, it also causes PE and arterial thrombus formation. It is also one of the causes of recurrent VTE attacks. Pregnancy, OC or estrogen replacement use, nephritic syndrome, disseminated intravascular coagulation, HIV infection and liver diseases may also result in acquired protein S deficiency (Bauer&

In cases of activated partial thromboplastin time (aPTT) changes, an addition of activated Protein C to the plasma is expected to cause the prolongation of bleeding time. However, Dahlback et al detected no prolongation in some patients with VTE in 1993 (Dahlback, 1995); this phenomenon was described as the activated protein C resistance (APCR). Activated Protein C resistance is clearly associated with an increase in thrombosis incidence. The subsequent studies detected this phenotype in 20-50% of the patients with VTE (Dahlback, 1995). In many cases of hereditary APCR, aG→A transition causes translocation of the amino acids (glutamine and arginine) at 506 location in the position 1691 nucleotide as a result of the activated function of the point mutation in factor V (site of cleavage for the activated PC in the factor V molecule). This point mutation was first described in 1994 and named as Factor V Leiden (FVL), FVR Q or FV: Q (Rosendaal et al., 1995). Factor V mutation notably increases the predisposition to VTE, causes hypercoagulability and neutralizes activated PC-mediated resistance. The risk of VTE is increased 3 to 8-fold in individuals heterozygous for factor Leiden mutation; as for homozygous individuals, the increase in the thrombotic risk is 50 to 100-fold (Rosendaal et al., 1995). The incidence of factor V Leiden carriers is 1-15% in the population (Rosendaal et al., 1995). Factor V Leiden is present in 10- 50% of the cases with VTE. Factor V Leiden abnormality results from a single mutation. In APCR without factor V Leiden mutation, the VTE risk is increased (Rosendaal et al., 1995).

A new genetic factor was discovered in the etiology of VTE in 1996. The G→A transition (Factor II G20210A) of the nucleotides at 20120 location in the region of the coagulation factor II gene not undergoing 3'-translation is associated with hyperprothrombinemia. G→A transition increased the prothrombin synthesis at the level of mRNA and protein synthesis. In heterozygous carriers of this mutation, the prothrombin level is increased 1.3-fold while it is increased 1.7-fold in homozygous carriers. The increase in the plasma prothrombin level results in a predisposition to thrombosis. This mutation was detected in 1-3% of the general population and 6-18% of the patients with VTE (Poort et al. 1996). Factor II G20210A diagnosis is only established by gene analysis. It is the second most common genetic abnormality, secondary to thrombophilia. In the case of factor II G20210A, there is no

It is the only hereditary cause of thrombophilia that has been proven to lead to arterial and venous thrombosis. Hyperthrombosis is believed to trigger the development of thrombosis via various mechanisms; there are in vitro studies showing that it affects the endothelial

**2.4 Activated protein C resistance and factor V Leiden mutation** 

Rosenberg, 1991).

**2.5 Factor II G20210A mutation** 

increase in the risk of VTE (Miles et al., 2001).

**2.6 Hyperhomocysteinemia** 

cells by causing the formation of reactive oxygen forms, such as superoxide, hydrogen peroxide and hydroxyl radicals, it causes proliferative response by affecting the smooth muscle cells and increasing collagen production, it affects the clotting system by increasing tissue factor production in the monocytes, creating acquired APC resistance and increasing the synthesis of thromboxane in the platelets (Miletich et al., 1987). Hyperhomocysteinemia is an established risk factor for VTE and is usually associated with a 2 to 4-fold increased thrombotic risk. Plasma homocysteine concentration is affected by genetic and acquired factors and thus known as the mixed risk factor (Miletich et al., 1987). Vitamin B12, vitamin B6 and folate deficiency, advanced age, chronic renal failure and malnutrition involving anti-folic drug use represent acquired factors in hyperhomocysteinemia. Gene defects in two enzymes involved in the intracellular metabolism, methyltetrahydrofolate reductase (MTHFR) and cystathionine B-synthase (CBS) result in hyperhomocysteinemia and enzyme

deficiency. Various mutations have been defined in methyltetrahydrofolate reductase and CBS to date; most are rare and lead to clinical outcomes in homozygous cases only. This condition is characterized by multiple neurological deficiency, physicomotor retardation, seizures, skeletal abnormalities, lens dislocation, premature arterial disease and VTE (Weisberg et al., 1999). Methyltetrahydrofolate reductase 677 C→T is associated with highprevalence polymorphism in the general population and reduced enzyme activity in homozygous cases. Methyltetrahydrofolate reductase 1298 A→C is not considered to be associated with hyperhomocysteinemia and not considered a thrombotic risk factor.

However, MTHFR results in reduced enzyme activity and increased homocysteine levels in heterozygous cases of 677 C→T (Weisberg et al., 1999). 68-bp insertion in the cystathionine B-cynthase gene (844ins68) is a common mutation in various populations. This gene change has no effect on the risk of DVT or homocysteine levels. Hyperhomocysteinemia is not defined as a genetic abnormality for VTE but as an independent risk factor (Kluijtmans et al., 1997).

#### **2.7 Increase in factor VIII levels**

Factor VIII is an entity with a gene localized on the 10th chromosome, which activates the factor X by forming a complex with factor IXa and phospholipids in the coagulation cascade. The increase in factor VIII is included among the thrombotic risk factors since it further increases formation of thrombin from prothrombin by factor X activation (Schambeck et al., 2004). The increased factor was detected in 3-9.4% of healthy individuals and in 11.3% of patients with VTE (Schambeck et al., 2004). A high FVIII level was reported to increase the VTE risk approximately 5-fold compared to individuals with a normal level (Schambeck et al., 2004). In addition, the factor VIII level was demonstrated to be an independent risk factor for VTE (Kraaijenhagen et al., 2000) (21) and to be correlated with the PE recurrence (Kyrle et al., 2000).

#### **2.8 Congenital dysfibrinogenemia**

The impairment in the formation of fibrin from fibrinogen secondary to the changes in the structure of fibrinogen is called dysfibrinogenemia. Dysfibrinogenemia is a dominant disease group characterized by qualitative abnormal fibrinogen formation. Various fibrinogen abnormalities are assessed within this group. Approximately 300 abnormal fibrinogen have been defined (Schorer et al., 1995). The most common structural defects are detected in fibrinopeptides and their sites of cleavage. Each dysfibrinogenemia affects

Risk Factor for Pulmonary Embolism 7

patients develop VTE and myocardial infarction. While the incidence of thrombosis secondary to factor XII deficiency was not well-established, it was reported to be 8%

Factor IX plays a key role in hemostasis; it is a vitamin K–dependent glycoprotein, which is activated through the intrinsic pathway as well as the extrinsic pathway (B. Furie & BC. Furie, 1988). Factor IX, when activated by factor XIa or factor VIIa-tissue factor, converts factor X into Xa and this eventually leads to the formation of a fibrin clot. This conversion is accelerated by the presence of the nonenzymatic cofactor factor VIIIa, calcium ions, and a phospholipid membrane (van Dieijen et al., 1981). In healthy individuals, factor IX activity and antigen levels vary between 50% and 150% of that in pooled normal plasma (B. Furie & BC. Furie, 1988; van Dieijen et al., 1981). Individuals who have high levels of factor IX (>129 U/dL) have a more than 2-fold increased risk of developing a first DVT compared with individuals having low levels of factor IX. The risk of thrombosis increased with increasing plasma levels of factor IX (dose response). At factor IX levels of more than 125 U/dL, an increase of the risk can already be observed compared with the reference category (factor IX levels ≤100 U/dL). Individuals with a factor IX level over 150 U/dL have a more than 3-fold

increase in the risk of thrombosis when compared with the reference category.

The VTE incidence increases linearly with the age. Above 50 years of age, the PE incidence was detected to be higher in women. This increase is also associated with other comorbidities (cancer, myocardial infarction) that increase with age (Stein et al., 1999).

The risk of PE by obesity is correlated with the body mass index. While the relative risk of pulmonary embolism is 1.7 for those with a body mass index of 25-28.9 kg/m², it is increased 3.2-fold for those with a BMI ≥29 (Goldhaber et al., 1997). Obesity is correlated with VTE, particularly in women. It was reported to be an independent risk factor in women with a body mass index ≥ 29. However, there are controversial study results on this subject

Air travel is a risk factor for PE. In a trial by Lapostolle et al, severe pulmonary embolism was detected in 56 of 135.29 million passengers from 14 countries. The assessment of the results revealed a rate of 1.5 in one million cases in those flying more than 5000 km and a rate of 4.8 in one million cases in those flying more than 10000 km, leading to the reported result that PE risk was correlated with flight distance. Conditions that lead to hemoconcentration during air travel, such as dehydration, lower oxygen pressure and foot

Immobility is a condition that is most commonly observed in PE, which may concomitantly exist with other risk factors (Stein et al., 1999). Long-term absence of mobilization results in

swelling are believed to induce venous stasis (Lapostolle et al., 2001).

approximately (Goodnough et al., 1983).

**2.12 Factor IX increase** 

**3. Acquired risk factors** 

**3.1 Advanced age** 

(Goldhaber et al., 1997).

**3.3 Long haul air travel** 

**3.4 Immobilization** 

**3.2 Obesity** 

thrombin time and clotting in a different way. While some dysfibrinogenemias do not have the effect of bleeding or thrombosis, some may cause abnormal bleeding and even thrombosis (Schorer et al., 1995).

#### **2.9 Plasminogen deficiency**

Plasminogen (plg) plays an important role in intravascular and extravascular brinolysis, wound healing, cell migration, tissue remodeling, angiogenesis, and embryogenesis (Castellino & Ploplis, 2005).

Plasminogen deficiency shows an autosomal dominant inheritance.

Plasminogen deficiency is classified into two groups: one is type I deficiency characterized by the parallel reduction of both activity and antigen, and the other is dysplasminogenemia (type II) characterized by reduced activity with a normal antigen level (Schuster et al., 2001).

Hypoplasminogenemia (type I plg deciency): No signicantly increased risk of deep venous thrombosis. In hypoplasminogenemia, or type I plg deciency, the level of immunoreactive plg is reduced in parallel with its functional activity. The specic plg activity is normal.

Some further case reports and family studies had originally suggested that heterozygous hypoplasminogenemia might be a risk factor for venous thrombosis (Leebeek et al., 1989). The relationship between hypoplasminogenemia and venous thrombosis has more recently been called into question, mainly based on two lines of evidence. Dysplasminogenemia (type II plg deciency): in dysplasminogenemia, or type II plg deciency, the level of immunoreactive plg is normal (or only slightly reduced), whereas the specic functional plg activity is markedly reduced because of abnormalities in the variant plg molecule (Robbins, 1990).

#### **2.10 Factor VII deficiency**

Inherited factor VII (FVII) deciency is the most widespread of the rare inherited bleeding disorders, with an estimated prevalence of 1 in 400 000 Caucasians (Mariani et al., 2005). It is characterized by a wide heterogeneity as regards clinical, biological and genetic parameters. Clinical features are extremely variable, ranging from mild cutaneo-mucosal bleeding to lethal cerebral haemorrhages, and are poorly correlated with residual FVII coagulant activity (FVII:C). Moreover, several patients remain asymptomatic (Aynaoğlu et al., 2010), even under conditions of high haemorrhagic challenge. Notably, in some rare cases, patients have a history of arterial (Escoffre et al., 1995) or venous (Mariani & Bernardi, 2009) thromboses. The mechanisms accounting for the association of FVII deciencies with thrombosis remain unclear. FVII deciency is characterized by a wide heterogeneity, even amongst those patients presenting with rare thrombotic events. In a few case reports, thrombosis can occur in "usual" sites, such as the deep veins of the lower limbs or pulmonary embolism, or in atypical sites, such as the sinus veins (Lietz et al., 2005). The rst series of FVII deciency associated with thrombosis included seven cases of venous thrombosis, localized primarily in typical sites (lower limbs and pulmonary embolism) (Mariani et al., 2005).

#### **2.11 Factor XII deficiency**

Severe FXII deficiency (FXII activity <1%) shows an autosomal recessive inheritance and patients are detected to have a prolonged aPTZ time. Despite this prolongation in the active partial thromboplastin time, patients do not have bleeding diathesis. In contrast, these patients develop VTE and myocardial infarction. While the incidence of thrombosis secondary to factor XII deficiency was not well-established, it was reported to be 8% approximately (Goodnough et al., 1983).

#### **2.12 Factor IX increase**

6 Pulmonary Embolism

thrombin time and clotting in a different way. While some dysfibrinogenemias do not have the effect of bleeding or thrombosis, some may cause abnormal bleeding and even

Plasminogen (plg) plays an important role in intravascular and extravascular brinolysis, wound healing, cell migration, tissue remodeling, angiogenesis, and embryogenesis

Plasminogen deficiency is classified into two groups: one is type I deficiency characterized by the parallel reduction of both activity and antigen, and the other is dysplasminogenemia (type II) characterized by reduced activity with a normal antigen level (Schuster et al., 2001). Hypoplasminogenemia (type I plg deciency): No signicantly increased risk of deep venous thrombosis. In hypoplasminogenemia, or type I plg deciency, the level of immunoreactive plg is reduced in parallel with its functional activity. The specic plg

Some further case reports and family studies had originally suggested that heterozygous hypoplasminogenemia might be a risk factor for venous thrombosis (Leebeek et al., 1989). The relationship between hypoplasminogenemia and venous thrombosis has more recently been called into question, mainly based on two lines of evidence. Dysplasminogenemia (type II plg deciency): in dysplasminogenemia, or type II plg deciency, the level of immunoreactive plg is normal (or only slightly reduced), whereas the specic functional plg activity is markedly reduced because of abnormalities in the variant plg molecule

Inherited factor VII (FVII) deciency is the most widespread of the rare inherited bleeding disorders, with an estimated prevalence of 1 in 400 000 Caucasians (Mariani et al., 2005). It is characterized by a wide heterogeneity as regards clinical, biological and genetic parameters. Clinical features are extremely variable, ranging from mild cutaneo-mucosal bleeding to lethal cerebral haemorrhages, and are poorly correlated with residual FVII coagulant activity (FVII:C). Moreover, several patients remain asymptomatic (Aynaoğlu et al., 2010), even under conditions of high haemorrhagic challenge. Notably, in some rare cases, patients have a history of arterial (Escoffre et al., 1995) or venous (Mariani & Bernardi, 2009) thromboses. The mechanisms accounting for the association of FVII deciencies with thrombosis remain unclear. FVII deciency is characterized by a wide heterogeneity, even amongst those patients presenting with rare thrombotic events. In a few case reports, thrombosis can occur in "usual" sites, such as the deep veins of the lower limbs or pulmonary embolism, or in atypical sites, such as the sinus veins (Lietz et al., 2005). The rst series of FVII deciency associated with thrombosis included seven cases of venous thrombosis, localized primarily in typical sites

Severe FXII deficiency (FXII activity <1%) shows an autosomal recessive inheritance and patients are detected to have a prolonged aPTZ time. Despite this prolongation in the active partial thromboplastin time, patients do not have bleeding diathesis. In contrast, these

Plasminogen deficiency shows an autosomal dominant inheritance.

(lower limbs and pulmonary embolism) (Mariani et al., 2005).

thrombosis (Schorer et al., 1995).

**2.9 Plasminogen deficiency** 

(Castellino & Ploplis, 2005).

activity is normal.

(Robbins, 1990).

**2.10 Factor VII deficiency** 

**2.11 Factor XII deficiency** 

Factor IX plays a key role in hemostasis; it is a vitamin K–dependent glycoprotein, which is activated through the intrinsic pathway as well as the extrinsic pathway (B. Furie & BC. Furie, 1988). Factor IX, when activated by factor XIa or factor VIIa-tissue factor, converts factor X into Xa and this eventually leads to the formation of a fibrin clot. This conversion is accelerated by the presence of the nonenzymatic cofactor factor VIIIa, calcium ions, and a phospholipid membrane (van Dieijen et al., 1981). In healthy individuals, factor IX activity and antigen levels vary between 50% and 150% of that in pooled normal plasma (B. Furie & BC. Furie, 1988; van Dieijen et al., 1981). Individuals who have high levels of factor IX (>129 U/dL) have a more than 2-fold increased risk of developing a first DVT compared with individuals having low levels of factor IX. The risk of thrombosis increased with increasing plasma levels of factor IX (dose response). At factor IX levels of more than 125 U/dL, an increase of the risk can already be observed compared with the reference category (factor IX levels ≤100 U/dL). Individuals with a factor IX level over 150 U/dL have a more than 3-fold increase in the risk of thrombosis when compared with the reference category.

### **3. Acquired risk factors**

#### **3.1 Advanced age**

The VTE incidence increases linearly with the age. Above 50 years of age, the PE incidence was detected to be higher in women. This increase is also associated with other comorbidities (cancer, myocardial infarction) that increase with age (Stein et al., 1999).

#### **3.2 Obesity**

The risk of PE by obesity is correlated with the body mass index. While the relative risk of pulmonary embolism is 1.7 for those with a body mass index of 25-28.9 kg/m², it is increased 3.2-fold for those with a BMI ≥29 (Goldhaber et al., 1997). Obesity is correlated with VTE, particularly in women. It was reported to be an independent risk factor in women with a body mass index ≥ 29. However, there are controversial study results on this subject (Goldhaber et al., 1997).

#### **3.3 Long haul air travel**

Air travel is a risk factor for PE. In a trial by Lapostolle et al, severe pulmonary embolism was detected in 56 of 135.29 million passengers from 14 countries. The assessment of the results revealed a rate of 1.5 in one million cases in those flying more than 5000 km and a rate of 4.8 in one million cases in those flying more than 10000 km, leading to the reported result that PE risk was correlated with flight distance. Conditions that lead to hemoconcentration during air travel, such as dehydration, lower oxygen pressure and foot swelling are believed to induce venous stasis (Lapostolle et al., 2001).

#### **3.4 Immobilization**

Immobility is a condition that is most commonly observed in PE, which may concomitantly exist with other risk factors (Stein et al., 1999). Long-term absence of mobilization results in

Risk Factor for Pulmonary Embolism 9

2. Smoking is associated with a higher plasma concentration of fibrinogen (Yanbaeva et

Most patients with acute ischemic stroke or intracranial hemorrhage survive the initial event. Early in-hospital mortality has been attributed not only to swelling of the brain and enlargement of hematoma but also to aspiration pneumonitis, sepsis, and severe heart disease (Brandstater et al., 1992). Pulmonary embolism after a stroke has received some attention, but the incidence is considered small. The incidence of clinical PE reported in the absence of heparin prophylaxis varies considerably, depending on the methodology of the studies. In the International Stroke Trial, the incidence was 0.8% at 2 weeks (International Stroke Trial Collaborative Group [ISTCG], 1997). Similarly, in a retrospective study of 607 patients who had acute stroke, PE was reported in 1% during the period of hospitalization (Davenport et al., 1996). However, prospective studies that focused specifically on venous thromboembolic complications reported incidences of clinically apparent PE of 10% to 13% (excluding pulmonary emboli identified in autopsy that were asymptomatic during life) (Warlow et al., 1972). In a retrospective study of 363 patients who did not receive heparin prophylaxis and entered a rehabilitation unit four weeks after stroke, 4% developed PE (confirmed by VQ scanning) on average 11 days after entering the unit (Subbarao & Smith, 1984). Only one small study has prospectively screened for PE by using VQ scintigraphy. Dickmann et al (Dickmann et al., 1988) studied a group of 23 patients 10 days after hemorrhagic stroke and found evidence of PE in 39%, though the proportion with symptoms was not stated. Autopsy studies show that half of the patients who die in hospital after the first 48 hours post stroke have evidence of PE, (McCarthy & Turner, 1986) which suggests that pulmonary emboli are often subclinical and/or unrecognized after stroke.

Cancer patients have a higher risk of complications and recurrence compared to patients without cancer. This risk is more marked especially in the pancreas, pulmonary disease, gastrointestinal system and mucinous carcinoma patients (Er & Zacharski 2006). Different mechanisms were proposed for the development of thrombotic predisposition in cancer patients. Development of procoagulant activity by the tumor products, coagulatory macrophage activation, endothelial cell injury and platelet activation secondary to interaction with the tumor cells are among these mechanisms. Some malignities (pancreas, colon, lungs and promyelocytic leukemias) systemically result in activation of the clotting system, leading to thrombotic complications. In cancer patients, the serum concentrations of the clotting factors, such as factors V, VIII, VII and fibrinogen are increased. Again, in these patients, local or systemic coagulation may occur secondary to vascular wall injury and factor X is activated (Falanga & Zacharski, 2005). The chemotherapeutical agents used for DVT after chemotherapy are significantly involved in this process due to the endothelial injury occurring in the vein to which these agents are administered (Nightingale et al., 1997).

Jugular, subclavian and femoral venous catheters lead to vascular injury and represent a focus for thrombus formation. Although less common, these patients may develop

3. Smoking is associated with reduced fibrinolysis (Lee & Lip, 2003; Yarnell et al., 2000). 4. Smoking is associated with inflammation (Yanbaeva et al., 2007; Yarnell et al., 2000). 5. Smoking increases the viscosity of the blood (Yanbaeva et al., 2007; Lee & Lip, 2003).

al., 2007; Lee & Lip, 2003).

**3.10 Malignity/chemotherapy** 

**3.11 Central venous catheter** 

**3.9 Stroke** 

a weakening of the muscles that provide an upward flow of the blood in the leg veins. The blood accumulates backwards; thus, among the activated platelets and clotting factors, thrombin in particular accumulates locally, leading to the formation of thrombus. Even if for a short time, for example one week, in the postoperative period, immobilization increases the risk of VTE (Stein et al., 1999).

#### **3.5 Major surgery**

Surgical intervention is one of the most significant acquired risk factors that cause PE. The decreased mobility during the operation, hypercoagulation secondary to local trauma and endothelial injury, the prothrombotic process that may be caused by the general anesthesia administered increase the risk of PE (Rosendaal, 1999). The presence of operation history within a 45-90 day period increases the risk of thromboembolism 6 to 22-fold (Rosendaal, 1999); 25% of these emboli occur after discharge from the hospital (Huber et al., 1992). Surgeries of the hip, knees, and the abdominopelvic region represent the most risky operations for venous thromboembolism development (Huber et al., 1992).

#### **3.6 Trauma**

Trauma is also a risk factor for PE development; the localization of the trauma is very important with respect to venous thrombus development (Geerts et al., 1996). VTE occurs in 50% of chest or abdomen traumas, 54% of head traumas and 62% of spinal cord injuries, and 69% of lower extremity orthopedic traumas (Geerts et al., 1996). The incidence of venous thromboembolism increases proportionally with time after the traumatic event. While the rate of PE confirmed by autopsy was 3.3% in those who survived less than 24 hours after trauma, this rate was 5.5% in those who survived up to seven days. PE was reported at a rate of 18.6% in individuals who survived longer (Geerts et al., 1996). Patients over 45, a requirement of more than three days bed rest, a previous history of VTE, fractures of the lower extremity, pelvis, spine, the development of coma and plegia, a requirement for blood transfusion and surgery further increase the risk of DVT and PE, therefore, effective and safe prophylactic anticoagulant treatment is recommended in traumatic patients unless contraindicated (Shackford et al., 1990).

#### **3.7 Congestive cardiac failure/myocardial infraction**

The presence of congestive cardiac failure or arrhythmia underlying heart disease further increases the risk of PE. In cardiac failure, the risk of mortality from PE is increased due to decreased cardiopulmonary reserve (Anderson & Spencer, 2003). The increase of factor VIII, fibrinogen and fibrinolysis in the acute phase following acute myocardial infarction leads to PE (Anderson & Spencer, 2003). Nearly all of the PEs occurring in acute myocardial infarction result from deep vein thrombosis in the lower extremity. Very rarely, they result from mural thrombi occurring in the infraction site in the right ventricle (Anderson & Spencer, 2003).

#### **3.8 Smoking**

Smoking may increase the risk of VTE through a number of mechanisms:

1. Smoking is a well established, potent risk factor for a number of diseases, including cancer and cardiovascular diseases (stroke and coronary heart diseases); these, in turn, are associated with an increased risk of VTE. Therefore, smoking might be associated with the risk of provoked VTE.


#### **3.9 Stroke**

8 Pulmonary Embolism

a weakening of the muscles that provide an upward flow of the blood in the leg veins. The blood accumulates backwards; thus, among the activated platelets and clotting factors, thrombin in particular accumulates locally, leading to the formation of thrombus. Even if for a short time, for example one week, in the postoperative period, immobilization increases

Surgical intervention is one of the most significant acquired risk factors that cause PE. The decreased mobility during the operation, hypercoagulation secondary to local trauma and endothelial injury, the prothrombotic process that may be caused by the general anesthesia administered increase the risk of PE (Rosendaal, 1999). The presence of operation history within a 45-90 day period increases the risk of thromboembolism 6 to 22-fold (Rosendaal, 1999); 25% of these emboli occur after discharge from the hospital (Huber et al., 1992). Surgeries of the hip, knees, and the abdominopelvic region represent the most risky

Trauma is also a risk factor for PE development; the localization of the trauma is very important with respect to venous thrombus development (Geerts et al., 1996). VTE occurs in 50% of chest or abdomen traumas, 54% of head traumas and 62% of spinal cord injuries, and 69% of lower extremity orthopedic traumas (Geerts et al., 1996). The incidence of venous thromboembolism increases proportionally with time after the traumatic event. While the rate of PE confirmed by autopsy was 3.3% in those who survived less than 24 hours after trauma, this rate was 5.5% in those who survived up to seven days. PE was reported at a rate of 18.6% in individuals who survived longer (Geerts et al., 1996). Patients over 45, a requirement of more than three days bed rest, a previous history of VTE, fractures of the lower extremity, pelvis, spine, the development of coma and plegia, a requirement for blood transfusion and surgery further increase the risk of DVT and PE, therefore, effective and safe prophylactic anticoagulant treatment is recommended in traumatic patients unless

The presence of congestive cardiac failure or arrhythmia underlying heart disease further increases the risk of PE. In cardiac failure, the risk of mortality from PE is increased due to decreased cardiopulmonary reserve (Anderson & Spencer, 2003). The increase of factor VIII, fibrinogen and fibrinolysis in the acute phase following acute myocardial infarction leads to PE (Anderson & Spencer, 2003). Nearly all of the PEs occurring in acute myocardial infarction result from deep vein thrombosis in the lower extremity. Very rarely, they result from mural thrombi occurring in the infraction site in the right ventricle (Anderson &

1. Smoking is a well established, potent risk factor for a number of diseases, including cancer and cardiovascular diseases (stroke and coronary heart diseases); these, in turn, are associated with an increased risk of VTE. Therefore, smoking might be associated

operations for venous thromboembolism development (Huber et al., 1992).

the risk of VTE (Stein et al., 1999).

contraindicated (Shackford et al., 1990).

with the risk of provoked VTE.

**3.7 Congestive cardiac failure/myocardial infraction** 

Smoking may increase the risk of VTE through a number of mechanisms:

**3.5 Major surgery** 

**3.6 Trauma** 

Spencer, 2003).

**3.8 Smoking** 

Most patients with acute ischemic stroke or intracranial hemorrhage survive the initial event. Early in-hospital mortality has been attributed not only to swelling of the brain and enlargement of hematoma but also to aspiration pneumonitis, sepsis, and severe heart disease (Brandstater et al., 1992). Pulmonary embolism after a stroke has received some attention, but the incidence is considered small. The incidence of clinical PE reported in the absence of heparin prophylaxis varies considerably, depending on the methodology of the studies. In the International Stroke Trial, the incidence was 0.8% at 2 weeks (International Stroke Trial Collaborative Group [ISTCG], 1997). Similarly, in a retrospective study of 607 patients who had acute stroke, PE was reported in 1% during the period of hospitalization (Davenport et al., 1996). However, prospective studies that focused specifically on venous thromboembolic complications reported incidences of clinically apparent PE of 10% to 13% (excluding pulmonary emboli identified in autopsy that were asymptomatic during life) (Warlow et al., 1972). In a retrospective study of 363 patients who did not receive heparin prophylaxis and entered a rehabilitation unit four weeks after stroke, 4% developed PE (confirmed by VQ scanning) on average 11 days after entering the unit (Subbarao & Smith, 1984). Only one small study has prospectively screened for PE by using VQ scintigraphy. Dickmann et al (Dickmann et al., 1988) studied a group of 23 patients 10 days after hemorrhagic stroke and found evidence of PE in 39%, though the proportion with symptoms was not stated. Autopsy studies show that half of the patients who die in hospital after the first 48 hours post stroke have evidence of PE, (McCarthy & Turner, 1986) which suggests that pulmonary emboli are often subclinical and/or unrecognized after stroke.

#### **3.10 Malignity/chemotherapy**

Cancer patients have a higher risk of complications and recurrence compared to patients without cancer. This risk is more marked especially in the pancreas, pulmonary disease, gastrointestinal system and mucinous carcinoma patients (Er & Zacharski 2006). Different mechanisms were proposed for the development of thrombotic predisposition in cancer patients. Development of procoagulant activity by the tumor products, coagulatory macrophage activation, endothelial cell injury and platelet activation secondary to interaction with the tumor cells are among these mechanisms. Some malignities (pancreas, colon, lungs and promyelocytic leukemias) systemically result in activation of the clotting system, leading to thrombotic complications. In cancer patients, the serum concentrations of the clotting factors, such as factors V, VIII, VII and fibrinogen are increased. Again, in these patients, local or systemic coagulation may occur secondary to vascular wall injury and factor X is activated (Falanga & Zacharski, 2005). The chemotherapeutical agents used for DVT after chemotherapy are significantly involved in this process due to the endothelial injury occurring in the vein to which these agents are administered (Nightingale et al., 1997).

#### **3.11 Central venous catheter**

Jugular, subclavian and femoral venous catheters lead to vascular injury and represent a focus for thrombus formation. Although less common, these patients may develop

Risk Factor for Pulmonary Embolism 11

of recurrence within 5 years after the first DVT is 21.5% (Hansson et al., 2000). Jeffrey et al (Jeffrey et al., 1992) detected the PE recurrence as 8.3% and reported that recurrence occurred mostly within the first week of treatment. In addition, mortality was 45% in these

Antiphospholipid syndrome (APS) characterized by arterial and venous thrombosis predisposition, repeated miscarriage and the presence of antiphospholipid antibodies is one of the leading causes of acquired thrombophilia. While the pathogenesis of the syndrome is not elucidated clearly, the negatively charged phospholipids and the phospholipid antibodies developing against the phospholipid protein complexes (lupus anticoagulant-LA and anticardiolipin antibodies-AKLA) are believed to be responsible for clinical manifestations. In AFS, the most important factor affecting mortality and morbidity is thromboembolic complications. Thromboses can both involve the arterial and the venous system and may be observed in each tissue and organ. The recurring tendency of the thromboses and the high risk of consecutive thrombotic complications involving the same system (for example, recurrent arterial thrombosis in a case with previous arterial thrombosis) are interesting. Approximately 2/3 of the cases develop venous thromboembolism and 1/3 develop arterial thrombosis. In venous thrombosis, DVT and PE rank first while ischemic cerebral attack ranks first in arterial thrombosis followed by myocardial infarction and digital thromboses. Thrombosis in abnormal regions is common in antiphospholipid syndrome (thrombosis in upper extremity veins, intra abdominal veins

COPD is a major health burden worldwide. It is the fourth-leading cause of mortality, accounting for > 3 million deaths annually; and by 2020, COPD will be the third-leading cause of death, trailing only ischemic heart disease and stroke. Most COPD-related deaths occur during periods of exacerbation (Sapey & Stockley, 2006). Previous studies (Sidney et al., 2005) estimate that 50 to 70% of all COPD exacerbations are precipitated by an infectious process, while 10% are due to environmental pollution. Up to 30% of exacerbations are caused by an unknown etiology Sapey & Stockley, 2006). Exacerbations are characterized by increase in cough and dyspnea. A study (Sidney et al., 2005) suggests that patients with COPD have approximately twice the risk of PE and other venous thromboembolic events (VTE) than those without COPD. Since thromboembolic events can lead to cough and dyspnea (just like infectious events), PE may be another common cause of COPD exacerbations (Tapson, 2008). However, dissimilar to infectious etiologies, which are effectively treated by antimicrobials and systemic corticosteroids, thromboembolic diseases require anticoagulant therapy and significant delays in treatment are associated with poor outcomes (Hull et al., 1997). Owing to multiple perfusion and ventilation abnormalities frequently observed in COPD lungs (even in the absence of VTE), noninvasive diagnosis of PE using imaging modalities was a significant challenge until quite recently. With the advent of contrast-enhanced (multidetector) CT, it is now possible to reliably diagnose PE in COPD subjects with minimal discomfort or risk to the patients. The primary purpose of this review was to determine the reported prevalence of PE in patients with COPD who required

patients.

**3.15 Antiphospholipid syndrome** 

and the veins inside the head) (Hanly, 2003).

hospitalization for their disease.

**3.16 Chronic Obstructive Pulmonary Disease (COPD)** 

symptomatic PE caused by the catheter-associated upper extremity thrombi (Haire & Lieberman 1992). In approximately 10-20% of the cases with pulmonary emboli, the emboli results from the thrombus in the site of the superior vena cava. Recently, upper extremity venous thrombus has been commonly known to occur as a result of invasive diagnostic and therapeutical procedures (intravascular catheter and intravenous chemotherapeutical agents) (Haire & Lieberman 1992).

#### **3.12 Pregnancy/puerperality**

Compared to the age-matched individuals, the risk of VTE is 5-fold higher in pregnant women. While 75% of the deep vein thrombi occur in the pre-delivery period, 66% of the PEs develop after the delivery. The risk is 20-fold higher in the postpartum period relative to the antepartum period (Kovacevich et al., 2000; Greer, 2003). Venous stasis secondary to dilated uterus in pregnancy, hormonal venous atonia, increased levels of thrombin and various clotting factors (fibrinopeptide A), increased platelet activation, decreased acquired protein S, antithrombin deficiency, the decreased APC response due to factor VIII increase are the risk factors. There are no trials using objective diagnostic techniques to show that cesarean section involves an additional thrombotic risk relative to normal delivery. The risk of a thrombotic event is higher in patients who are on mandatory bed rest due to premature action or preterm premature membrane rupture (Kovacevich et al., 2000). Since oral anticoagulation is risky for the fetus, low-molecule weight heparin treatment with a lower osteoporosis risk relative to the conventional heparin that will be maintained at least until puerperality appears to be an appropriate choice (Greer, 2003).

#### **3.13 The use of oral contraceptives and hormone replacement**

Oral contraceptive (OC) use was shown to increase the risk of PE approximately 3-7-fold. Oral contraceptives result in PE by increasing the levels of coagulation factors, such as prothrombin, factor VII, factor VIII, factor X and fibrinogen, and decreasing the levels of the coagulation factors, such as antithrombin III and protein S (Spitzer et al., 1996). Compared to the persons who are not on oral contraceptives, the risk was detected to be 3.4 for lowestrogen levonorgestrel and 7.3 and 10.2 for the 3rd generation progesterone desogestrel and gestodene (World Health organization [WHO], 1995). Third generation OC use increases the VTE risk particularly in Factor V Leiden mutation carriers and those with a positive familial history (Bloemenkamp et al., 1995). In women, hormone replacement therapy used in the postmenopausal period is reported to be a risk factor for PE (Cushman et al., 2004). This risk is higher in patients with coronary artery disease. The risk is higher at the start of treatment and disappears upon discontinuation of the hormone replacement therapy. The mechanism involved in the increase of thrombosis by estrogen alone or in combination with progesterone is not known. However, recent trials report that OCs cause a reduction in the sensitivity to activated protein C irrespective of the type of drug used and that this reduction is higher with 3rd generation monophasic OCs relative to 2nd generation drugs (Rosing et al., 1997).

#### **3.14 Previous pulmonary emboli and deep vein thrombosis**

Hospitalized patients with a history of pulmonary emboli have a significant risk of recurrence. More than 50% of patients with a history of venous thromboembolism undergoing surgery develop postoperative DVT if no prophylaxis is administered. The rate

symptomatic PE caused by the catheter-associated upper extremity thrombi (Haire & Lieberman 1992). In approximately 10-20% of the cases with pulmonary emboli, the emboli results from the thrombus in the site of the superior vena cava. Recently, upper extremity venous thrombus has been commonly known to occur as a result of invasive diagnostic and therapeutical procedures (intravascular catheter and intravenous chemotherapeutical

Compared to the age-matched individuals, the risk of VTE is 5-fold higher in pregnant women. While 75% of the deep vein thrombi occur in the pre-delivery period, 66% of the PEs develop after the delivery. The risk is 20-fold higher in the postpartum period relative to the antepartum period (Kovacevich et al., 2000; Greer, 2003). Venous stasis secondary to dilated uterus in pregnancy, hormonal venous atonia, increased levels of thrombin and various clotting factors (fibrinopeptide A), increased platelet activation, decreased acquired protein S, antithrombin deficiency, the decreased APC response due to factor VIII increase are the risk factors. There are no trials using objective diagnostic techniques to show that cesarean section involves an additional thrombotic risk relative to normal delivery. The risk of a thrombotic event is higher in patients who are on mandatory bed rest due to premature action or preterm premature membrane rupture (Kovacevich et al., 2000). Since oral anticoagulation is risky for the fetus, low-molecule weight heparin treatment with a lower osteoporosis risk relative to the conventional heparin that will be maintained at least until

Oral contraceptive (OC) use was shown to increase the risk of PE approximately 3-7-fold. Oral contraceptives result in PE by increasing the levels of coagulation factors, such as prothrombin, factor VII, factor VIII, factor X and fibrinogen, and decreasing the levels of the coagulation factors, such as antithrombin III and protein S (Spitzer et al., 1996). Compared to the persons who are not on oral contraceptives, the risk was detected to be 3.4 for lowestrogen levonorgestrel and 7.3 and 10.2 for the 3rd generation progesterone desogestrel and gestodene (World Health organization [WHO], 1995). Third generation OC use increases the VTE risk particularly in Factor V Leiden mutation carriers and those with a positive familial history (Bloemenkamp et al., 1995). In women, hormone replacement therapy used in the postmenopausal period is reported to be a risk factor for PE (Cushman et al., 2004). This risk is higher in patients with coronary artery disease. The risk is higher at the start of treatment and disappears upon discontinuation of the hormone replacement therapy. The mechanism involved in the increase of thrombosis by estrogen alone or in combination with progesterone is not known. However, recent trials report that OCs cause a reduction in the sensitivity to activated protein C irrespective of the type of drug used and that this reduction is higher with 3rd generation monophasic OCs relative to 2nd generation drugs

Hospitalized patients with a history of pulmonary emboli have a significant risk of recurrence. More than 50% of patients with a history of venous thromboembolism undergoing surgery develop postoperative DVT if no prophylaxis is administered. The rate

puerperality appears to be an appropriate choice (Greer, 2003).

**3.13 The use of oral contraceptives and hormone replacement** 

**3.14 Previous pulmonary emboli and deep vein thrombosis** 

agents) (Haire & Lieberman 1992).

**3.12 Pregnancy/puerperality** 

(Rosing et al., 1997).

of recurrence within 5 years after the first DVT is 21.5% (Hansson et al., 2000). Jeffrey et al (Jeffrey et al., 1992) detected the PE recurrence as 8.3% and reported that recurrence occurred mostly within the first week of treatment. In addition, mortality was 45% in these

#### **3.15 Antiphospholipid syndrome**

patients.

Antiphospholipid syndrome (APS) characterized by arterial and venous thrombosis predisposition, repeated miscarriage and the presence of antiphospholipid antibodies is one of the leading causes of acquired thrombophilia. While the pathogenesis of the syndrome is not elucidated clearly, the negatively charged phospholipids and the phospholipid antibodies developing against the phospholipid protein complexes (lupus anticoagulant-LA and anticardiolipin antibodies-AKLA) are believed to be responsible for clinical manifestations. In AFS, the most important factor affecting mortality and morbidity is thromboembolic complications. Thromboses can both involve the arterial and the venous system and may be observed in each tissue and organ. The recurring tendency of the thromboses and the high risk of consecutive thrombotic complications involving the same system (for example, recurrent arterial thrombosis in a case with previous arterial thrombosis) are interesting. Approximately 2/3 of the cases develop venous thromboembolism and 1/3 develop arterial thrombosis. In venous thrombosis, DVT and PE rank first while ischemic cerebral attack ranks first in arterial thrombosis followed by myocardial infarction and digital thromboses. Thrombosis in abnormal regions is common in antiphospholipid syndrome (thrombosis in upper extremity veins, intra abdominal veins and the veins inside the head) (Hanly, 2003).

#### **3.16 Chronic Obstructive Pulmonary Disease (COPD)**

COPD is a major health burden worldwide. It is the fourth-leading cause of mortality, accounting for > 3 million deaths annually; and by 2020, COPD will be the third-leading cause of death, trailing only ischemic heart disease and stroke. Most COPD-related deaths occur during periods of exacerbation (Sapey & Stockley, 2006). Previous studies (Sidney et al., 2005) estimate that 50 to 70% of all COPD exacerbations are precipitated by an infectious process, while 10% are due to environmental pollution. Up to 30% of exacerbations are caused by an unknown etiology Sapey & Stockley, 2006). Exacerbations are characterized by increase in cough and dyspnea. A study (Sidney et al., 2005) suggests that patients with COPD have approximately twice the risk of PE and other venous thromboembolic events (VTE) than those without COPD. Since thromboembolic events can lead to cough and dyspnea (just like infectious events), PE may be another common cause of COPD exacerbations (Tapson, 2008). However, dissimilar to infectious etiologies, which are effectively treated by antimicrobials and systemic corticosteroids, thromboembolic diseases require anticoagulant therapy and significant delays in treatment are associated with poor outcomes (Hull et al., 1997). Owing to multiple perfusion and ventilation abnormalities frequently observed in COPD lungs (even in the absence of VTE), noninvasive diagnosis of PE using imaging modalities was a significant challenge until quite recently. With the advent of contrast-enhanced (multidetector) CT, it is now possible to reliably diagnose PE in COPD subjects with minimal discomfort or risk to the patients. The primary purpose of this review was to determine the reported prevalence of PE in patients with COPD who required hospitalization for their disease.

Risk Factor for Pulmonary Embolism 13

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Dahlback, B. (1995). Inherited Thrombophilia: resistance to activated protein C as a

Davenport, RJ., Dennis, MS., Wellwood, I.,& Warlow, CP. (1996). Complications after acute

Dickmann, U., Voth, E., Schicha, H., Henze, T., Prange, H., & Emrich, D. (1988). Heparin

Dykes, AC., Walker, ID., McMahon, AD., Islam, SI., & Tait RC. (2001). A study of protein S

Er, O., & Zacharski, L. (2006). Management of cancer-associated venous thrombosis. *Vasc* 

Escoffre, M, Zini, JM., Schliamser, L., Mazoyer, E., Soria, C., Tobelem, G., & Dupuy, E.(1995).

Falanga, A., & Zacharski, L. (2005). Deep vein thrombosis in cancer: the scale of the problem

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#### **3.17 Medical conditions requiring hospitalization**

The incidence of thromboembolic diseases in inpatients is reported to be different depending on the type of disease. While the risk is reported to be 3% in patients without risk factors, it is reported to be 50% in patients with previous VTE. Massive PEs account for 4-8% of inpatient mortality (Rubinstein et al., 1988). The VTE risk is higher in patients with neurological and cardiac diseases during hospitalization compared to other patient groups (Nicolaides et al., 2001). There are certain diseases that have been proven to increase the risk of venous thromboembolism complications; these include SLE, inflammatory intestinal diseases, nephritic syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative diseases, Behcet's disease, Cushing syndrome and sickle cell syndrome. The number of DVT cases is larger in these diseases relative to the general population.

#### **4. References**


The incidence of thromboembolic diseases in inpatients is reported to be different depending on the type of disease. While the risk is reported to be 3% in patients without risk factors, it is reported to be 50% in patients with previous VTE. Massive PEs account for 4-8% of inpatient mortality (Rubinstein et al., 1988). The VTE risk is higher in patients with neurological and cardiac diseases during hospitalization compared to other patient groups (Nicolaides et al., 2001). There are certain diseases that have been proven to increase the risk of venous thromboembolism complications; these include SLE, inflammatory intestinal diseases, nephritic syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative diseases, Behcet's disease, Cushing syndrome and sickle cell syndrome. The number of DVT

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**1. Introduction** 

threatening one causing cardiogenic shock.

cardiopulmonary status of the patient.

pulmonary resistance, the highly compliant RV dilates acutely.

**2** 

*Singapore* 

**Risk Stratification of Patients** 

Calvin Woon-Loong Chin *National Heart Center Singapore* 

**with Acute Pulmonary Embolism** 

Acute pulmonary embolism (PE) is an under-diagnosed but potentially fatal condition. This condition presents with a wide clinical spectrum, from asymptomatic small PE to life-

Depending on the estimated risk of an adverse outcome, treatment with thrombolysis or embolectomy may be indicated in high-risk individuals. Conversely, early hospital discharge or even home treatment with anti-coagulation may be considered in low risk PE. Thus, a systematic approach to risk stratification is essential in guiding the management of patients diagnosed with acute PE. Evidence-based prognostic tools such as clinical scores, echocardiography, computed tomography scans, and cardiac biomarkers will be discussed.

Anatomically massive PE has been defined as having more than 50% obstruction of the pulmonary vasculature or the occlusion of two or more lobar arteries (Urokinase Pulmonary Embolism Study Group, 1970). In a unique situation, a large embolus may lodge at the bifurcation of the main pulmonary artery, i.e. saddle embolus. Although it was once regarded as a severe form of PE, a saddle PE shares a similar clinical course with a non-saddle PE, and low in-hospital mortality (Pruszczyk et al., 2003; Kaczyńska et al., 2005; Ryu et al., 2007). An anatomically massive PE in a patient with adequate cardiopulmonary reserve and a submassive PE in a patient with poor reserve may manifest similar hemodynamic outcomes. The hemodynamic response to an acute PE depends not only the size of the embolus and the degree of pulmonary vasculature obstruction, but also on the physiologic reaction to the neurohumoral factors released and the underlying

Normally, the RV faces low resistance as it empties into a low-pressure system of the pulmonary vasculature. In acute PE, both mechanical obstruction and hypoxic vasoconstriction increase pulmonary vascular resistance, and this initiates a series of hemodynamic derangements leading to RV dysfunction (Figure 1). The release of humoral factors, such as serotonin from platelets, thrombin from plasma and histamine from tissue also contribute to pulmonary artery vasoconstriction. As a consequence of the elevated

Initially, compensatory maintenance of cardiac output is achieved by catecholamine-driven tachycardia and vasoconstriction. The left atrial contraction also contributes more than usual to

**2. Hemodynamic consequences of acute pulmonary embolism** 

