Thalassaemia
Thalassaemia as a Hypercoagulable State Maria D Cappellini,1
Khaled M Musallam2 and Ali T Taher3
1. Professor of Medicine, Department of Internal Medicine, Fondazione IRCCS “Ca’ Granda” Ospedale Policlinico, University of Milan; 2. Clinical Research Fellow; 3. Professor of Medicine, Department of Internal Medicine, Hematology–Oncology Division, American University of Beirut Medical Center
Abstract
Although the life expectancy of thalassaemia patients has markedly improved over the last few decades, patients still suffer from many complications of this congenital disease. The presence of a high incidence of thromboembolic events, mainly in thalassaemia intermedia, has led to the identification of a hypercoagulable state in these patients. In this article, the molecular and cellular mechanisms leading to hypercoagulability in thalassaemia are highlighted, with a special focus on thalassaemia intermedia, being the type with the highest incidence of thrombotic events as compared with other types of thalassaemia. Clinical experience and available clues regarding optimal management are also discussed.
Keywords Thalassaemia, hypercoagulability, thromboembolism, stroke, splenectomy, transfusion
Disclosure: The authors have no conflicts of interest to declare. Received: 6 April 2011 Accepted: 23 May 2011 Citation: European Oncology & Haematology, 2011;7(3):214–6 Correspondence: Maria Domenica Cappellini, Professor of Medicine, Department of Internal Medicine, Fondazione IRCSS “Ca’ Granda” Ospedale Policlinico, Università di Milano, Via Francesco Sforza 35, 20122 Milano, Italy. E:
maria.cappellini@
unimi.it
The term β-thalassaemia intermedia (TI) was first suggested to describe patients who have milder anaemia compared with patients with TM and who usually present to medical attention later in childhood and remain largely transfusion-independent. However, recent evidence suggests that the diagnosis of TI carries higher morbidity than previously recognised, especially in the transfusion-independent patient, where the mechanism of disease remains largely unbalanced.3 Three main factors highlight the pathophysiology of TI: ineffective erythropoiesis, chronic anaemia/haemolysis, and iron overload secondary to increased intestinal absorption.3
Phenotypic diversity within the β-thalassaemia syndromes has traditionally received considerable interest, with several molecular and environmental modifiers of disease severity so far described.1 Patients with transfusion-dependent β-thalassaemia major (TM) suffer the most severe form and show the highest mortality rates.1 Nevertheless, the introduction of safe transfusion practices and effective iron chelation therapy continues to improve patient survival, allowing for several clinical complications to have time to manifest.2
The
extreme diversity in phenotypic expression within the diagnosis of TI itself led to a wide variation in observed clinical complications and management practices.3,4
Among the medical complications of
TI that were found to occur at high rates, even more frequently than in patients with TM, are thromboembolic events (TEE).5
Here, we
review current evidence on TEE in thalassaemia patients, with special emphasis on TI.
Pathophysiology
Hypercoagulability in patients with thalassaemia has been attributed to several factors (see Figure 1).5,6 factors that leads to TEE.
214 It is often a combination of these
It is widely accepted that patients with thalassaemia have chronically activated platelets and enhanced platelet aggregation,7
as confirmed
by the increased expression of CD62P (P-selectin) and CD63, markers of in vivo platelet activation.8,9 have high platelet counts,10,11 enhanced consumption.12
Splenectomised thalassaemia patients but with a shorter lifespan due to It has also been shown that splenectomised
TM and non-splenectomised TI patients have four to 10 times higher levels of metabolites of prostacyclin (PGI2) and thromboxane A2, both markers of haemostatic activity, than controls. However, no significant difference was found between TM and TI patients.13
Furthermore, the oxidation of globin subunits in thalassaemia erythroid cells leads to the formation of haemichromes14
which precipitate,
instigating haem disintegration and the eventual release of toxic non-transferrin-bound iron species.15
The free iron in turn catalyses the
formation of reactive oxygen species, leading to oxidation of membrane proteins and formation of red-cell ‘senescence’ antigens such as phosphatidylserine,16
which cause the thalassaemic red blood cells
(RBCs) to become rigid and deformed and to aggregate, resulting in premature cell removal.17
phospholipids increase thrombin generation,18,19
Thalassaemic RBCs with negatively charged as evidenced by
studies using annexin V, a protein with high affinity and specificity for anionic phospholipids.19
higher number of these negatively charged RBCs and in turn show higher thrombin generation.20,21
thromboembolic events in TI is under investigation.
The presence of other peripheral blood elements in thalassaemia patients, such as E-selectin (ELAM-1), intercellular adhesion molecule-1
© TOUCH BRIEFINGS 2011 TI patients were also found to have higher levels
of procoagulant microparticles of RBC, leukocytic and endothelial origins compared with controls;22
the contribution of these fragments to Splenectomised patients have a substantially
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