The Incidence of Thromboembolic Events among 8860 Patients with Thalassemia Major and Intermedia in the Mediterranean Area and Iran.
Authors: Taher Ali , Mehio Ghassan , Bignamini Daniela , Kattamis Antonios , Rachmilewitz Eliezer , Cappellini Maria 
Published: October 2019

Abstract
Thalassemia is a congenital hemolytic disorder caused by a partial or complete deficiency of globin chain synthesis. It is well recognized that patients with thalassemia major (TM) are at a higher risk of developing clinical and/or sub-clinical thrombotic events, particularly splenectomized thalassemia intermedia (TI) patients.
The aim of this study is to assess the magnitude of this problem and whether there is a rationale to consider preventive treatment. A questionnaire was sent to 56 tertiary referral centers in 7 countries in the Mediterranean area and in Iran. It included multiple choice questions such as: type of thalassemia, occurrence of thrombotic events, frequency of blood transfusions, average pre-transfusion hemoglobin (Hb) levels, presence of pulmonary hypertension, medications, thrombophilia profile, recurrence of thrombosis, presence of pulmonary hypertension, and outcome of the thrombotic events.
The number of patients treated for thalassemia was 8860 (6670 TM, 2190 TI). The number of patients reported to have a thrombotic event was 1.75%, 0.9% with TM and 4% with TI. Forty five per cent of the patients were males, and 55% were females. The mean age at which thrombosis occurred (+/− standard deviation) was 30+/−13 years. The thrombotic event was diagnosed clinically and radiologically in 63% of cases, clinically in 27% and only radiologically in 10%. We found a significant difference (p=0.009) in the site of thrombosis, with 57% being venous, 40% arterial, and 3% both arterial and venous. The incidence of stroke was 18%, pulmonary embolism (PE) 13%, deep vein thrombosis (DVT) 32%, both PE and DVT 0.7%, superficial thrombophlebitis 4.7%, and portal vein thrombosis 16% (p=0.071). The outcome of thrombotic events was fatal in 14% of cases. Recurrence of thrombosis occured in 32% of cases. Out of the 85 TI patients , 94% were splenectomized, 68% had an average pre-transfusion Hb level < 9 gm/dl, and 33% were maintained on regular blood transfusions. Recurrence of thrombosis in TI patients was higher when the average pre-transfusion Hb level was less than 9 gm/dl (19 patients) compared to a Hb ≥ to 9 gm/dl (5 patients) (p=0.118). Moreover, recurrence of thrombosis was also found to be higher among patients with an average pre-transfusion Hb level < 9 gm/dl who were not regularly transfused (11 patients) compared with those who were regularly transfused (8 patients) (p=0.805).
TI patients maintained on Aspirin had lower incidence of stroke, DVT, PE, superficial thrombophlebitis, and portal vein thrombosis.
Finally, 15 TI patients had pulmonary hypertension that was associated in half of them with PE and/or DVT. All these patients were splenectomized and 10 had an average pre-transfusion Hb level <9 gm/dl. Several factors could be responsible for thromboembolic phenomena in thalassemia icluding age, splenectomy, ineffective erythropoiesis, changes in the RBC lipid membrane resulting from oxidative stress etc. All these variables are under evaluation in order to define preventive guidelines.
A multicenter clinical trial is indicated in order to evaluate possible prophylactic treatment with platelet anti-aggregates and antioxidants in prevention of thromboembolic events particularly in splenectomized patients with TI.