**3. Pathophysiology**

The pathophysiology of thromboembolism in beta-thalassemia disease is the combinations of abnormalities in several parts of hemostatic system including [9, 12]:


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

more than 300/mm3

**4.1 Venous thromboembolism**

when the platelet count is higher than 600,000/mm3

after splenectomy [22].

thrombophilic risk factors causing thromboembolism [12, 26].

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

found in beta-thalassemic patients who TDT for 42% [23].

6.Organ dysfunction resulting from hemochromatosis particularly cardiac

7.Thrombophilia, i.e., natural anticoagulant deficiencies, leads to hypercoagulable state. Deficiencies of protein C and protein S, the natural anticoagulant proteins, have been reported as a risk factor of thromboembolism in patients with beta-thalassemia disease [12, 24, 25]. In addition, increased incidence of antiphospholipid antibodies, i.e., lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein 1, is commonly found in patients with beta-thalassemia disease. Those antibodies are considered as strong

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].

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

hemochromatosis causes cardiomyopathy and cardiac arrhythmia [12] which is

and the NRBCs count is

*Beta Thalassemia*

this complication.

**3. Pathophysiology**

endothelial cells [9].

increased thrombin generation [15].

increased activation of hemostatic system [17–19].

in chronic pulmonary thromboembolism [12, 20].

alpha- and beta-thalassemia diseases [4].

**2. Incidence**

have been increasingly published recently. Understanding the pathophysiology of thromboembolism in thalassemia diseases is the key for the management to prevent

The incidence of thromboembolism in patients with thalassemia diseases is between 1.7 and 9.2% [4, 10, 11]; therefore, the incidence of thromboembolism in patients with thalassemia diseases is approximately 10 times higher than normal population [6]. The incidence is 4.4 times more prevalent in patients with NTDT than ones with TDT [10]. However, this complication could be seen in both patients

The pathophysiology of thromboembolism in beta-thalassemia disease is the combinations of abnormalities in several parts of hemostatic system including [9, 12]:

2.Increased number of circulating activated and aggregated platelets which are especially found in splenectomized patients [13, 14]. The activated and aggregated platelets of splenectomized patients with thalassemia usually have shorter platelet lifespan [14], higher response to several agonists, i.e., adenosine diphosphate (ADP), epinephrine, and collagen [15], and more elevated level of plasma beta-thromboglobulin [16] than the platelets of normal population. All findings reflect hyperaggregation of platelets which result in

3.Increased endothelial activation caused by the activation of monocytes and granulocytes leads to endothelial injury and increased level of endothelial adhesion proteins and tissue factor contributing to hypercoaguable state. Moreover, the elevation of endothelial cell, platelet and white blood cell (WBC) and RBC microparticles, which are the shedded fragments containing high PS with the size of 0.1–2 μm from activated and apoptotic cells, leads to

4.Decreased nitric oxide (NO), secondary to hemolysis caused by the decreased level of arginine leads to pulmonary vasoconstriction and subsequently results

5.Rise of platelet count and nucleated RBCs (NRBCs) after splenectomy which was firstly reported in 1966 [21]. This phenomenon is a strong associated factor of thromboembolism in patients with thalassemia disease particularly

1.Exposure of phosphatidylserine (PS) to external membrane of abnormal RBCs called "flip-flop phenomenon" which is caused by the decrease of normal asymmetrical dissemination of RBC membrane phospholipids [9]. In addition, free iron secondary to hemochromatosis induces lipid oxidation and elevates the level of membrane-bounded hemichromes and immunoglobulin causing alteration of the structures of spectrin and band 3 protein of RBC membrane and consequently resulting in aggregation and adhesion of abnormal RBCs to

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when the platelet count is higher than 600,000/mm3 and the NRBCs count is more than 300/mm3 after splenectomy [22].

