Coagulation and thrombotic risk in thalassemia intermedia

As the life expectancy of β-thalassemia patients has markedly improved over the last few decades, several manifestations are increasingly 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 current clinical experience attributed to the coagulopathy in thalassemia intermedia patients is summarized. Recommendations for thrombosis prophylaxis are also discussed. 近几十年来，随着β地中海贫血患者的平均寿命得到显著提高，几种试验结果得到了进一步证实。 地中海贫血中间患者出现高发血栓栓塞症，得以识别地中海贫血高凝状态。 本文总结了当前地中海贫血中间患者的凝血病临床经验， 也讨论了血栓症预防的推荐方法。


Introduction
The term β-thalassemia intermedia (TI) was first suggested to describe patients who have a milder anemia compared to patients with β-thalassemia major (TM), and who usually present to medical attention later in childhood, and remain largely transfusion-independent.2][3] We herein review current evidence on TEE in TI patients.

Clinical experience
Borgna-Pignatti et al. surveyed nine Italian pediatric thalassemia centers, observing that 4% of the 683 patients with TM and 9.6% of the 52 patients with TI had experienced a TEE. 4 The same group showed six years later that 1.1% of 720 patients with TM in seven Italian centers had thrombosis. 5Cappellini et al. followed-up 83 patients with TI over 10 years, 82 of whom were splenectomized, and found that 29% (24/83) experienced a venous TEE. 6One study directly implicated TEE as the cause of death in 2.5% of transfusion-dependent thalassemia patients. 7After 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. 8 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 hemoglobin level of < 9 g/dl and only 33% were receiving regular blood transfusions, whereas 94% were splenectomized.Moreover, patients receiving aspirin therapy had a significantly lower rate of recurrent TEE. 8 The evidence for brain involvement in thalassemia dates back to 1972 where 20% of 138 TM patients in Greece were found to have neurological deficits compatible with transient ischemic attacks (TIAs). 9urther evidence of TIAs causing neurological symptoms, such as headaches, hemiparesis, and seizures was shown in 2.2% of patients with TM in Italy. 4Although overt stroke occurs more frequently in TM than TI (28% vs. 9%, respectively), 8 it has been shown that as many as 37.5% of patients with TI have asymptomatic brain damage on magnetic resonance imaging (MRI). 9A more recent study on Lebanese patients determined that splenectomized adults with TI show a rate of silent white matter lesions as high as 60%. 10 The occurrence and multiplicity of the lesions were associated with older age (mean age of 36.1 years for lesion positive-patients vs. 26.1 years for lesion-negative patients) and transfusion naivety (83.3% of lesionpositive patients have never had a transfusion vs. 25% of lesion-negative patients) [10].Another study from Iran followed to confirm these findings 11 In order to obtain much needed clinical data on the optimal management of patients with TI, the Overview on Practices in Thalassemia Intermedia Management Aiming for Lowering Complication rates Across a Region of Endemicity (OPTIMAL CARE) study evaluated 584 patients with TI at six comprehensive care centers (Lebanon, Italy, Iran, Egypt, United Arab Emirates, and Oman) for the associations between patient and disease characteristics, treatment received, and the rate of clinical complications. 12Thrombosis was the 5 th most common complication, affecting 14% of the patient population.On multivariate analysis, splenectomy, age above 35 years, and a serum ferritin level ≥ 1000 μg/l were associated with a higher risk for thrombosis. 12Conversely, a positive history of transfusion and a hemoglobin level ≥ 9 g/dl were found to be protective against thrombosis 12 (Table 2).A higher occurrence of TEE with advancing age was also observed. 13 sub-study of the OPTIMAL CARE examined the characteristics of splenectomized patients with TI who develop TEE aiming to identify high-risk patients who deserve further consideration for preventive strategies.14 Splenectomized patients with documented TEE (Group I, n = 73) were age-and sex-matched to splenectomized patients without TEE (Group II) and non-splenectomized patients without TEE (Group III).The study determined that splenectomized TI patients who experience TEE are characterized by high nucleated RBC (≥ 300 x 10 6 /l) and platelet counts (≥ 500 x 10 9 /l), are more likely to have evidence of pulmonary hypertension (PHT), and be transfusion naive.As such, it was suggested that splenectomized TI patients at risk of developing TEE may be identified early on by these laboratory markers, presence of PHT, and transfusion status.14 The study further examined how long it took for a TEE to develop following splenectomy and found the median time to thrombosis to be 8 years.14 This delay indicates that TEE in splenectomized patients with TI is not an acute complication, but a manifestation of a chronic underlying process, further emphasizing the need for a long-term treatment modality for prevention.14

Prevention and Management
Reduction of the proportion of circulating RBCs with thrombogenic potential may be attained by introducing blood transfusions, and may justify the lower rate of TEE in transfused vs. non-transfused patients in previous studies. 8,10,12,14 Assuch, transfusion therapy may be worthwhile to prevent the occurrence of TEE and other complications 1 in TI patients for whom current practice does not necessarily recommend transfusions.Rather than enforcing the regular transfusion regimens implemented in TM, blood transfusion, if initiated in patients with TI will should be individually tailored to meet patient needs.Although introduction of blood transfusions will increase the rate of iron accumulation, effective methods of iron chelation are now available, and the benefits of transfusion therapy may greatly outweigh the cost and inconvenience of iron chelation therapy. 15This approach requires prospective evaluation.
Since splenectomy is a major contributor to TEE in patients with thalassemia, 16 reassessment of the procedure and appropriate risk benefit-evaluation prior to any attempt at splenectomy is called for.This is also essential in line with recent evidence on high rates of other clinical complications after splenectomy, 12 alongside the well-known increased susceptibility to infection. 17he literature lacks proper evidence on the role of antiplatelet or anticoagulant agents in the management of thalassemia. 3The lower recurrence rate of TEE in TI patients, who took aspirin after their first TEE, when compared to those who did not, suggests a potential role for aspirin. 8Moreover, the association of higher platelet counts with TEE in patients with TI further suggests a role for aspirin in this patient population. 14  Fetal hemoglobin inducing agents like decitabine and hydroxycarbamide were also shown to lower plasma markers of thrombin generation. 2 Hydroxycarbamide may modulate hypercoagulability in several ways, it may reduce phospholipid expression on the surface of RBCs and platelets, and decrease RBC adhesion to thrombospondin, a thrombin sensitive protein. 2 It may also decrease leukocyte count, particularly monocytes expressing transcription factor, in addition to being a nitric oxide donor. 18t is recommended that each patient be assessed individually and assigned a personalized thrombotic risk based on intrinsic and extrinsic factors.High nucleated RBC and platelet counts, evidence of PHT, and transfusion naivety can be used as indicators of TEE for splenectomized patients with TI and could be practical in the clinical setting. 14uch a risk-assessment model would be valuable in identifying highrisk patients and targeting them for further testing.Several diagnostic tests are being explored to help identify patients at risk, with promising preliminary results. 19he hypercoagulable state in TI is due to multiple elements, a combination of which is often the drive behind a clinical TEE.Splenectomy and transfusion naivety are increasingly highlighted as important factors for TEE.An individualized approach is recommended to establish an optimal strategy for preventing the occurrence of this complication of TI.

Thalassemia
Reports 2011; volume 1(s2):e15 N o n -c o m m e r c i a l u s e o n l y

Table 1 .
Factors contributing to hypercoagulability in thalassemia intermedia. 1 Factor Mechanisms Red blood cells • Formation of reactive oxygen species • Expression of negatively charged phospholipids • Enhanced cohesiveness and aggregability Platelets • Increased platelet aggregation • Increased expression of activation markers • Presence of platelet morphologic abnormalities Peripheral blood elements • Expression of endothelial adhesion molecules and tissue factor on endothelial cells • Formation of microparticles Splenectomy • High platelet counts and hyperactivity • High levels of negatively charged red blood cells Nitric oxide • Decreased levels leading to vasoconstriction Thrombophilia • Decreased levels of antithrombin III, protein C and protein S • Anti-phospholipid antibodies • No role for prothrombotic mutations Other factors • Cardiac dysfunction • Hepatic dysfunction • Endocrine dysfunction