To understand complications associated with β-thalassemia, it is imperative not only to be familiar with the underlying pathophysiology but also to consider how the pathophysiology is influenced by conventional therapies such as splenectomy, transfusions, and iron chelation (Figure 2). These therapies become embedded in the patient’s clinical profile, and their use, or lack thereof, determines which complications are likely to be observed throughout the disease course.

Ineffective erythropoiesis and peripheral hemolysis lead to a state of chronic anemia that can cause growth and developmental delay, typical anemia-related symptoms such as fatigue, and leg ulcers and can promote organ failure in adolescents and young adults. An independent effect of anemia on psychological well-being has also been reported.

Ineffective erythropoiesis leads to marrow expansion and associated bone changes, pain, and deformity, which account for characteristic features of β-thalassemia such as craniofacial protrusions. Compensatory extramedullary foci that can undergo hematopoiesis also become activated, including the spleen and liver (hepatosplenomegaly) and other tissues in the body, where they can grow into extramedullary hematopoietic pseudotumors; if they emerge in areas such as the paraspinal canal or chest, these pseudotumors can cause serious compression and may require emergency management.

Peripheral hemolysis in β-thalassemia causes red cells to express prothrombotic markers on their surface, leading to a hypercoagulable state, which is further promoted by platelet activation, microparticles, and other coagulation anomalies. Clinically, these disorders can be manifested as venous and arterial thrombosis, pulmonary hypertension, and cerebrovascular events, including silent infarcts, which increase with aging.

Figure 2:
Caption: Pathophysiological and Clinical Manifestations of β-Thalassemia.
Description: The circled numbers and letters link complications with causal risk factors.

Beta (β)-thalassemia is characterized by a hypercoagulable state and an increased risk of thrombosis, which can result in significant morbidity and mortality. The coagulation pattern and determinants of thrombosis in patients with β-thalassemia remain largely unknown. The aim of this study was to evaluate the whole blood thromboelastometry (TEM) profile of β-thalassemic children by ROTEM(®). ROTEM(®) assays (INTEM, EXTEM) and traditional coagulation parameters (platelet count, prothrombin time, activated partial thromboplastin time, and fibrinogen) were performed on blood samples from 17 subjects with β-thalassemia and 19 non-thalassemic controls. Maximum clot firmness (MCF) was significantly higher in subjects with β-thalassemia than in controls on EXTEM and INTEM analysis (p < 0.001 and p < 0.001, respectively). Of the patients with β-thalassemia, MCF was higher and clot formation time was shorter in splenectomized subjects than in non-splenectomized subjects on EXTEM and INTEM (p = 0.026, p = 0.002, p < 0.001, p < 0.001, respectively). TEM profiles in β-thalassemic children were more hypercoagulable compared with controls. Larger prospective studies are needed to evaluate the relevance of the association between ROTEM(®) profile and thromboembolic events in patients with β-thalassemia.

Thromboembolic complications are not uncommon in thalassemia. Previous studies suggest increased platelet aggregation and a potential role of pathological changes in the red blood cell (RBC) lipid membrane, induced by oxidative stress. In the present study, platelet adhesion and the effect of thalassemic RBC on platelet adhesion under flow conditions were evaluated, using the Cone and Plate (let) Analyzer(CPA). Twenty-two beta-thalassemia patients and 22 blood type-matched healthy controls were studied. An increased platelet adhesion (% surface coverage, SC), was observed in patients as compared to controls (p < 0.05). When platelet count and haematocrit were normalized by autologous reconstitution, a significant increase in platelet aggregation (average size, AS) was observed (p < 0.05). Increased platelet adhesion (SC and AS), was demonstrated in six patients with a history of thrombosis as compared to 16 patients without any history of thrombosis (p < or = 0.007) and in 17 splenectomized patients as compared to five non-splenectomized patients (p = 0.003). In reconstitution studies, thalassemic RBC mixed with normal platelet-rich plasma significantly increased platelet adhesion compared to normal RBC (SC p < 0.03, AS p < 0.02). Thalassemic platelets reconstituted with normal RBC, had increased aggregation (AS, p < 0.004) in comparison with normal platelets. The results indicate that increased platelet adhesion in beta-thalassemia is induced by both platelets and RBC. Increased platelet adhesion correlated with clinical thrombotic events and thus may suggest a mechanism of thrombosis in thalassemic patients. The potential application of the CPA in identifying thalassemic patients with high risk for thrombosis should be studied prospectively in a larger cohort of patients.

As the life expectancy of beta-thalassemia patients has markedly improved over the last decade, several new complications are being recognized. The presence of a high incidence of thromboembolic events, mainly in thalassemia intermedia patients, has led to the identification of a hypercoagulable state in thalassemia. In this review, the molecular and cellular mechanisms leading to hypercoagulability in thalassemia are highlighted, and the current clinical experience is summarized. Recommendations for thrombosis prophylaxis are also discussed.

Beta (β)-thalassemia is characterized by a hypercoagulable state and an increased risk of thrombosis, which can result in significant morbidity and mortality. The molecular and cellular mechanisms contributing to hypercoagulability are diverse and include chronic platelet activation, alteration of red blood cell membranes, abnormal expression of adhesion molecules on vascular endothelial cells, and dysregulation of hemostasis. Regular transfusions decrease the risk of thrombosis, whereas splenectomy significantly increases the risk. Splenectomized adults with non-transfusion-dependent thalassemia are also at high risk for ischemic brain damage. Strategies to lower the risk of thrombosis should be considered, including transfusion therapy to raise hemoglobin levels and avoidance or delay of splenectomy.

Venous thromboembolic events, such as pulmonary embolism, deep venous thrombosis, and portal vein thrombosis, have been observed in adult thalassemia patients, mainly in beta-thalassemia intermedia. The clinical findings are consistent with the observation of several alterations that indicate a state of activation of the hemostatic mechanisms in thalassemias. These alterations have usually been related to high platelet counts due to splenectomy and/or liver dysfunction. In a retrospective study of a large cohort of adults with thalassemia, we found a larger prevalence of venous thromboembolic events in transfusion-independent patients with thalassemia intermedia (29%) than in regularly transfused patients with thalassemia major (2%); moreover, the higher prevalence occurred particularly in splenectomized thalassemia intermedia patients. More recently, a multicenter study involving 56 tertiary referral centers in 7 countries was planned to assess the magnitude of thrombotic risk in thalassemia patients. The total number of patients who had thrombotic events was 146 (1.65%) out of 8860, with a prevalence of 0.9% in thalassemia major and 4% in thalassemia intermedia. The highest prevalence was confirmed in splenectomized patients. The observation that thrombotic events are more frequent in beta-thalassemia patients who are not receiving regular transfusions (thalassemia intermedia or thalassemia major patients in less developed countries with limited transfusion resources) or in thalassemic patients who have undergone splenectomy strongly supports the procoagulant activity of circulating damaged red blood cells.

Thalassemia, an inherited hemolytic disorder, is associated with a high incidence of thrombosis. The major mechanisms underlying thromboembolism (TE) are an abnormal red blood cell surface, platelet activation and endothelial cell activation. A higher risk of TE is found in splenectomized patients due to thrombocytosis and increased abnormal RBCs in the circulation. Regular RBC transfusions can reduce the proportion of abnormal RBCs and suppress erythropoiesis. Regular transfusion may also reduce levels of circulating coagulation markers and reduce elevated pulmonary artery pressure. To prevent thromboembolic events, aspirin is now recommended for splenectomized patients with thrombocytosis.