**4. Presentations of thromboembolism in beta-thalassemia**

Thromboembolism in patients with beta-thalassemia diseases could be found in both arterial and venous sites. However, venous thromboembolism is more commonly found in patients with thalassemia intermedia or NTDT, while arterial thromboembolism is more frequently seen in patients with thalassemia major or TDT [10].

### **4.1 Venous thromboembolism**

Although patients with beta-thalassemia disease are at risk of venous thromboembolism, deep vein thrombosis and pulmonary thromboembolism, the two common types of venous thromboembolism in normal population, are not generally observed. Pulmonary thromboembolism was found in lung biopsy to 41% of patients with beta-thalassemia/hemoglobin E. However, higher incidence was found in the older and splenectomized patients [27]. Simplified, revised Geneva score, based on several clinical variables, i.e., hemoptysis, old age of more than 65 years, history of venous thromboembolism, tachycardia, unilateral lower limb pain with or without deep palpation and edema, active malignancy, and surgery or fracture of lower limb within 1 month prior to the suspected symptoms and signs, has been published to use for diagnosing pulmonary thromboembolism. The more scores patients get, the higher chance of pulmonary embolism patients have [28]. Computed tomography pulmonary angiography, magnetic resonance pulmonary angiography, and ventilation/perfusion scan could be used to diagnose pulmonary thromboembolism even though conventional pulmonary angiography is the gold standard [29].

Portal vein thrombosis, which is considered as venous thrombosis of an unusual site, is more commonly reported in patients with beta-thalassemia disease [30–34] with the odds ratio of 3.5 [31]. Patients with acute portal vein thrombosis usually present with symptoms and signs of portal hypertension of bowel ischemia, i.e., abdominal pain and distension, fever, nausea/vomiting, rectal hemorrhage, and splenomegaly. If patients were not diagnosed, they might turn to sepsis-like symptoms, e.g., shock, signs of peritonitis, and even death [35]. Unlike acute portal vein thrombosis, patients with chronic portal vein thrombosis are usually asymptomatic until the presence of first symptoms and signs, i.e., upper gastrointestinal hemorrhage, splenomegaly, and ascites [35]. Doppler ultrasound, computed tomography, and magnetic resonance imaging could be used for diagnosis of portal vein thrombosis [35]. Apart from splenectomy, higher splenic weight and thalassemia

intermedia are major risk factors of portal vein thrombosis in patients with betathalassemia disease [30, 33]. Laparoscopic splenectomy was reported about the higher incidence of portal vein thrombosis even though this technique provided the better other surgical outcomes than the conventional technique [30].

#### **4.2 Arterial ischemic stroke**

Beta-thalassemia disease has been reported as a risk factor of arterial ischemic stroke since 1972 [36]. Compared to venous thromboembolism, arterial ischemic stroke is more common in patients with beta-thalassemia major [11]. Moyamoya syndrome, a cerebral vasculopathy caused by spontaneous occlusion of the arteries at the circle of Willis [37], was also reported in pediatric patients with betathalassemia disease and caused arterial ischemic stroke [38, 39]. Symptom and signs of acute ischemic stroke are based on the involved cerebral areas ranging from nonspecific symptoms, i.e., headache, nausea and vomiting, seizure, and impaired consciousness to specific neurological deficits, i.e., abnormal speech and spatial perception, hemiparesis, hemianesthesia, blurred vision, and poor coordination or walking, and cranial nerve palsies [40]. Though computed tomography of the head with or without angiography is the standard for diagnosing arterial ischemic stroke, magnetic resonance imaging of head with or without angiography could provide more details of the affected parts of the brain with higher sensitivity [40].

Moreover, the focal foci in the cerebral white matter on the magnetic resonance imaging of the brain called "silent cerebral infarction" could be found at 24–61% of patients with beta-thalassemia disease [41, 42]. However, a recent study in adult patients with beta-thalassemia disease who were asymptomatic showed that the abnormal findings on the magnetic resonance imaging of the brain were not different from the adult controls [43].

#### **4.3 Diagnosis**

Making a diagnosis of thromboembolism in patients with beta-thalassemia does not differ from diagnosing this condition in normal population which is usually based on the imaging of the suspected area of thromboembolism, e.g., computed tomography with angiography of the brain in a patient who is suspicious for having an arterial ischemic stroke. Several studies have demonstrated derangement of proteins hemostatic system in patients with beta-thalassemia diseases including increased platelet aggregation and coagulation proteins (factor VIII and von Willebrand factor) and decreased natural anticoagulants (protein C, protein S, and antithrombin) [24, 25] which encourage hypercoagulable state [44]. Besides diagnosing a symptomatic patient, the novel investigations, i.e., thrombin generation assay and rotatory thromboelastometry (ROTEM®), are able to demonstrate patients with hypercoagulable state in patients with beta-thalassemia disease who are at risk of developing thromboembolism [45, 46]. In addition, yearly monitoring of thrombin generation markers, e.g., D-dimer and thrombin-antithrombin (TAT) complex, is recommended by TIF in patients with thalassemia who are splenectomized [47].

#### **5. Treatment**

1.Regular RBC transfusion is recommended to treat patients with betathalassemia disease, particularly NTDT, who are at risk of thromboembolism or have developed thromboembolic events by keeping hemoglobin level higher

**113**

*Thromboembolism in Beta-Thalassemia Disease DOI: http://dx.doi.org/10.5772/intechopen.89313*

platelets in the circulation [49, 50].

are prone to have thromboembolism [12, 22, 48].

than 9 g/dL [3] to correct hypercoagulable state as transfusion naïve patients

2.Hematopoietic stem cell transplantation (HSCT) has been reported as the management that could normalize the abnormal hemostatic derangement in patients with beta-thalassemia disease by increasing natural anticoagulant proteins and decreasing microparticles and RBC-expressing PS and activating

3.Antithrombotic agents in patients with beta-thalassemia disease who have thromboembolism are recommended as per the standard local or international

ASA 2–5 mg/kg/day is the mainstream management for the prevention and treatment of thromboembolism in patients in beta-thalassemia especially in splenectomized patients who have platelet count higher than 500,000/mm3

However, ASA resistance has been reported in patients with thalassemia who were splenectomized, and increase dose of ASA could overcome this resistance [51].

4.Hydroxyurea, a hemoglobin F stimulating agent, was reported about the favorable effects not only increased hemoglobin F, hemoglobin level and improved the clinical symptoms of beta-thalassemia disease but also decreased hypercoagulable state due to the diminished exposure of PS on RBC membrane [54, 55]. Moreover, Iqbal et al. recently reported the change of metabolites, i.e., glycerol, triethanolamine, linoleic acid, palmitic acid, and stearic acid to the healthy pattern of metabolic pathway in pediatric patients with beta-

Since patients with beta-thalassemia disease are at risk of thromboembolism as the same as other medical inpatients, the current approach is to stratify patients with the optimal risk assessment model (RAM) by using the available approaches, e.g., Padua Prediction Score and the Caprini Risk Assessment Model, to guide thromboprophylaxis [57]. However, the systematic review showed that there was not any specific risk assessment model which was superior to the others [58]. Moreover, thalassemia-specific risk assessment model for thromboprophylaxis may need to be developed due to distinctive pathophysiology of thromboembolism in

In conclusion, the hypercoagulable state in beta-thalassemia disease is the result of several risk factors, a combination of which is often the drive behind a clinical thromboembolism. Splenectomy and transfusion naivety are increasingly

thalassemia disease after treating with hydroxyurea [56].

patients with beta-thalassemia disease.

b.Anticoagulants consist of conventional anticoagulants, i.e., unfractionated heparin, low-molecular-weight heparin, vitamin K antagonist (VKA), and direct oral anticoagulants (DOAC) including direct oral anti-activated factor X (Xa), e.g., rivaroxaban, and direct oral antithrombin (IIa), i.e. dabigratan. Those medications are used to treat thromboembolism in patients with beta-thalassemia disease. Unlike sickle cell disease, the evidences of using DOAC in patients with thalassemia disease who develop thromboembolism are limited [52]. However, the recent study showed that using rivaroxaban in patients with hemoglobinopathies including thalassemia was effective and did not increase risk of bleeding or thrombosis [53].

[3].

guidelines to treat patients with thromboembolism [3, 12].

a.Anti-platelets: acetyl salicylic acid (ASA)

*Beta Thalassemia*

**4.2 Arterial ischemic stroke**

ent from the adult controls [43].

**4.3 Diagnosis**

splenectomized [47].

**5. Treatment**

intermedia are major risk factors of portal vein thrombosis in patients with betathalassemia disease [30, 33]. Laparoscopic splenectomy was reported about the higher incidence of portal vein thrombosis even though this technique provided the

Beta-thalassemia disease has been reported as a risk factor of arterial ischemic stroke since 1972 [36]. Compared to venous thromboembolism, arterial ischemic stroke is more common in patients with beta-thalassemia major [11]. Moyamoya syndrome, a cerebral vasculopathy caused by spontaneous occlusion of the arteries at the circle of Willis [37], was also reported in pediatric patients with betathalassemia disease and caused arterial ischemic stroke [38, 39]. Symptom and signs of acute ischemic stroke are based on the involved cerebral areas ranging from nonspecific symptoms, i.e., headache, nausea and vomiting, seizure, and impaired consciousness to specific neurological deficits, i.e., abnormal speech and spatial perception, hemiparesis, hemianesthesia, blurred vision, and poor coordination or walking, and cranial nerve palsies [40]. Though computed tomography of the head with or without angiography is the standard for diagnosing arterial ischemic stroke, magnetic resonance imaging of head with or without angiography could provide more details of the affected parts of the brain with higher sensitivity [40].

Moreover, the focal foci in the cerebral white matter on the magnetic resonance imaging of the brain called "silent cerebral infarction" could be found at 24–61% of patients with beta-thalassemia disease [41, 42]. However, a recent study in adult patients with beta-thalassemia disease who were asymptomatic showed that the abnormal findings on the magnetic resonance imaging of the brain were not differ-

Making a diagnosis of thromboembolism in patients with beta-thalassemia does not differ from diagnosing this condition in normal population which is usually based on the imaging of the suspected area of thromboembolism, e.g., computed tomography with angiography of the brain in a patient who is suspicious for having an arterial ischemic stroke. Several studies have demonstrated derangement of proteins hemostatic system in patients with beta-thalassemia diseases including increased platelet aggregation and coagulation proteins (factor VIII and von Willebrand factor) and decreased natural anticoagulants (protein C, protein S, and antithrombin) [24, 25] which encourage hypercoagulable state [44]. Besides diagnosing a symptomatic patient, the novel investigations, i.e., thrombin generation assay and rotatory thromboelastometry (ROTEM®), are able to demonstrate patients with hypercoagulable state in patients with beta-thalassemia disease who are at risk of developing thromboembolism [45, 46]. In addition, yearly monitoring of thrombin generation markers, e.g., D-dimer and thrombin-antithrombin (TAT) complex, is recommended by TIF in patients with thalassemia who are

1.Regular RBC transfusion is recommended to treat patients with beta-

thalassemia disease, particularly NTDT, who are at risk of thromboembolism or have developed thromboembolic events by keeping hemoglobin level higher

better other surgical outcomes than the conventional technique [30].

**112**

than 9 g/dL [3] to correct hypercoagulable state as transfusion naïve patients are prone to have thromboembolism [12, 22, 48].

	- a.Anti-platelets: acetyl salicylic acid (ASA)

ASA 2–5 mg/kg/day is the mainstream management for the prevention and treatment of thromboembolism in patients in beta-thalassemia especially in splenectomized patients who have platelet count higher than 500,000/mm3 [3]. However, ASA resistance has been reported in patients with thalassemia who were splenectomized, and increase dose of ASA could overcome this resistance [51].


Since patients with beta-thalassemia disease are at risk of thromboembolism as the same as other medical inpatients, the current approach is to stratify patients with the optimal risk assessment model (RAM) by using the available approaches, e.g., Padua Prediction Score and the Caprini Risk Assessment Model, to guide thromboprophylaxis [57]. However, the systematic review showed that there was not any specific risk assessment model which was superior to the others [58]. Moreover, thalassemia-specific risk assessment model for thromboprophylaxis may need to be developed due to distinctive pathophysiology of thromboembolism in patients with beta-thalassemia disease.

In conclusion, the hypercoagulable state in beta-thalassemia disease is the result of several risk factors, a combination of which is often the drive behind a clinical thromboembolism. Splenectomy and transfusion naivety are increasingly highlighted as important risk factors for thromboembolism, especially in patients with NTDT. An individualized approach is recommended to establish an optimal strategy for preventing the occurrence of this complication in patients with betathalassemia disease.
