Thalassaemia as a Hypercoagulable State


(ICAM-1), von Willebrand factor (VWF) and vascular cell adhesion molecule-1 (VCAM-1), indicates that endothelial injury or activation may be an aspect of the disease, aiding in the recruitment of white blood cells and RBCs and promoting thrombosis.23,24


Studies have


demonstrated that RBCs from TM and TI patients show increased adhesion to cultured endothelial cells (EC).25


Peripheral blood elements


Inherited thrombophilia does not play a role in the hypercoagulability of thalassaemia,26,27


low protein C and S levels have been documented.6


cardiac, hepatic or endocrine dysfunction in patients with severe iron overload may also contribute to hypercoagulability in thalassaemia.6


Clinical Implications


Epidemiological data on TEE in thalassaemia are scarce. Borgna-Pignatti et al. surveyed nine Italian paediatric thalassaemia centres, observing that 4 % of the 683 patients with TM and 9.6 % of the 52 patients with TI had experienced a TEE.28


The same group showed six years later that


1.1 % of 720 patients with TM in seven Italian centres had thrombosis.2 Cappellini et al. followed up 83 patients with TI over 10 years, 82 of whom were splenectomised and found that 29 % (24/83) experienced a venous TEE.21


After


It was found that 14 % of mortalities in the whole group were due to TEE. Age above 20 years, splenectomy, family history of TEE and previous TEE were identified as the main risk factors for thrombosis in TI. Furthermore, the study showed that 68 % of TI patients that had a TEE had an average haemoglobin level of <9 g/dl and only 33 % were receiving regular blood transfusions, whereas 94 % were splenectomised. Moreover, patients receiving aspirin therapy had a significantly lower rate of recurrent TEE.30


examining data from 8,860 patients in the Mediterranean area and Iran, Taher et al. observed that TEE occurred 4.38 times (95 % confidence interval [CI] 3.14–6.10, p<0.001) more frequently in TI than TM, with more venous events occurring in TI and more arterial events occurring in TM.30


The evidence for brain involvement in thalassaemia dates back to 1972, when 20 % of 138 TM patients in Greece were found to have neurological deficits compatible with transient ischaemic attacks (TIAs).31 Further evidence of TIAs causing neurological symptoms, such as headaches, hemiparesis and seizures, was shown in 2.2 % of patients with TM in Italy.28


than TI (28 versus 9 %, respectively),30 A more recent study on Lebanese patients The occurrence and multiplicity of Platelets


• Increased platelet aggregation


• Increased expression of activation markers • Presence of platelet morphologic abnormalities


One study directly implicated TEE as the cause of death in 2.5 % of transfusion-dependent thalassaemia patients.29


Other factors


• Cardiac dysfunction • Hepatic dysfunction • Endocrine dysfunction


Thrombophilia • No role for


prothrombotic mutations • Decreased levels of antithrombin III, protein C and protein S


• Anti-phospholipid antibodies Splenectomy


• High platelet counts and hyperactivity


• High levels of negatively charged red blood cells


Circles represent adjusted odds ratios and whiskers represent 95 % confidence intervals. Source: Reproduced from Taher et al., 20104


and Cappellini et al., 2010.5 of clinical complications.4 Thrombosis was the fifth most common


complication, affecting 14 % of the patient population. On multivariate analysis, splenectomy, age above 35 years and a serum ferritin level ≥1,000 µg/l were associated with a higher risk of thrombosis.4 Conversely, a positive history of transfusion and a haemoglobin level ≥9 g/dl were found to be protective against thrombosis (see Table 1).4 A higher occurrence of TEE with advancing age was also observed.34 In an effort to further understand the effect of splenectomy on the risk of TEE, a substudy of OPTIMAL CARE examined the characteristics of splenectomised patients with TI who developed TEE, aiming to identify high-risk patients who deserve further consideration for preventive strategies.35


Splenectomised patients with documented TEE


Although overt stroke occurs more frequently in TM it has been shown that as many as


37.5 % of patients with TI have asymptomatic brain damage on magnetic resonance imaging (MRI).31


determined that splenectomised adults with TI show a rate of silent white matter lesions as high as 60 %.32


the lesions were associated with older age (mean age of 36.1 years for lesion-positive patients versus 26.1 years for lesion-negative patients) and transfusion naivety (83.3 % of lesion-positive patients have never had a transfusion versus 25 % of lesion-negative patients).32 study from Iran followed to confirm these findings.33


(Group I, n=73) were age- and sex-matched to splenectomised patients without TEE (Group II) and non-splenectomised patients without TEE (Group III). The study determined that splenectomised TI patients who experience TEE are characterised by high nucleated RBC (≥300 x 106/l) and platelet counts (≥500 x 109/l) and are more likely to have evidence of pulmonary hypertension (PHT) and be transfusion-naive. As such, it was suggested that splenectomised TI patients at risk of developing TEE may be identified early on by these laboratory markers, presence of PHT and transfusion status.35


The study further examined how long it Another


In order to obtain much-needed clinical data concerning the optimal management of patients with TI, the Overview on practices in thalassaemia intermedia management aiming for lowering complication rates across a region of endemicity (OPTIMAL CARE) study evaluated 584 patients with TI at six comprehensive care centres (Lebanon, Italy, Iran, Egypt, United Arab Emirates and Oman) for the associations between patient and disease characteristics, treatment received and the rate


EUROPEAN ONCOLOGY & HAEMATOLOGY


took for a TEE to develop following splenectomy and found the median time to thrombosis to be eight years.35


This delay indicates that TEE in


splenectomised patients with TI is not an acute complication, but a manifestation of a chronic underlying process, further emphasising the need for a long-term treatment modality for prevention.35


Potential Preventive Strategies


Reduction of the proportion of circulating RBCs with thrombogenic potential may be achieved by introducing blood transfusions and may account for the lower rate of TEE in transfused versus non-transfused


215


but high levels of antiphospholipid antibodies and The presence of


• Expression of endothelial adhesion molecules and tissue factor on endothelial • Formation of microparticles


Nitric oxide


• Hallmark of haemolysis • ↓ (Levels leading to vasoconstriction


Red blood cells


• Formation of reactive oxygen species


• Expression of negatively charged phospholipids • Enhanced cohesiveness and aggregability


Hypercoagulability


Figure 1: Factors Contributing to Hypercoagulability in Thalassaemia


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