beta-thalassaemia and sickle cell anaemia as paradigms of hypercoagulability

Thalassaemia and sickle cell disease (SCD) represent the most common forms of hereditary haemolytic anaemia and result from a partial or complete lack of synthesis of one of the major \u3b1- or \u3b2-globin chains of haemoglobin A or from a single amino acid mutation (\u3b26Glu\u2192Val) of the \u3b2-globin chain respectively. Although they have different pathophysiologies, patients with these conditions manifest both biochemical and clinical evidence of hypercoagulability. While the frequency of various thrombotic complications may vary in \u3b2-thalassaemia and homozygous SCD [sickle cell anaemia (SCA)], patients with both diseases manifest decreased levels of natural anticoagulant proteins, as well as increased markers of thrombin generation and platelet activation. The abnormal phospholipid membrane assymetry present in the red blood cells of \u3b2-thalassaemia and SCA patients, with resultant phosphatidylserine exposure appears to play a significant role in the aetiology of the observed hypercoagulable state. This review presents the available data on the aetiology and clinical manifestations of the coagulation and platelet activation that exist in both \u3b2-thalassaemia and SCA, as well as the potential therapeutic implications resulting from this hypercoagulability

MÖSSBAUER STUDIES OF FERRITIN-LIKE IRON IN RED BLOOD CELLS OF THALASSEMIA SICKLE-CELL ANEMIA AND HEMOGLOBIN HAMMERSMITH

De grandes quantités de fer sous forme de composés du type ferritine ont été détectées et estimées quantitativement à l'aide de la technique Mössbauer dans des globules rouges intactes de 17 patients affligés de thalassémie majeure α et β, de 2 autres affligés d'anémie et d'un autre souffrant d'instabilité de Hammersmith de l'hémoglobine. Les quantités de fer du type ferritine sont comparables à celles du fer Hb et sont particulièrement élevées dans les réticulocytes. Aucune quantité de fer du type ferritine n'a été détectée chez des patients souffrant d'anémie hémolytique auto-immune et d'anémie pernicieuse. Les hautes quantités de fer du type ferritine présentes dans les hémoglobinopathies sont probablement la conséquence d'une dénaturation intra-cellulaire du Hb suivie d'une décharge de fer excédentaire.Large amounts of ferritin-like iron were detected and quantitatively estimated, using the Mössbauer technique, in intact red blood cells of 17 patients with α and β thalassemia major, 2 with sickle-cell anemia and one with unstable hemoglobin (Hb) Hammersmith. The amounts of ferritin-like iron were comparable to those of Hb iron and were particularly large in reticulocytes. No ferritin-like iron was detected in patients with severe autoimmune hemolytic anemia and pernicious anemia. The large quantities of ferritin-like iron in hemoglobinopathies are probably a consequence of intracellular Hb denaturation and the release of excess iron

Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran

Beta-thalassaemia is a congenital haemolytic anaemia characterized by partial (intermedia, TI) or complete (major, TM) deficiency in the production of (beta)-globin chains. The primary aim of this study was to determine the prevalence of thromboembolic events in patients with (beta)-thalassaemia. To achieve this, a multiple-choice questionnaire was sent to 56 tertiary referral centres in eight countries (Lebanon, Italy, Israel, Greece, Egypt, Jordan, Saudi Arabia and Iran), requesting specific information on patients who had experienced a thromboembolic event. The study demonstrated that thromboembolic events occurred in a clinically relevant proportion (1.65%) of 8,860 thalassaemia patients (TI - 24.7% orTM - 75.3%) from the Mediterranean and Iran. Thromboembolism occurred 4.38 times more frequently in TI thanTM (p<0.001),with more venous events occurring in TI and more arterial events occurring in TM. Thrombosis in thalassaemia was also more common in females, splenectomized patients and those with profound anaemia (haemoglobin <9 g/dl). Due to the increased risk of thromboembolic events, the rationale for splenectomy should perhaps be re-assessed and the role of transfusion therapy for the prophylaxis of thrombosis, among other complications, be evaluated prospectively. (copyright) 2006 Schattauer GmbH, Stuttgart

Hepcidin and Hfe in iron overload in beta-thalassemia

Hepcidin (HAMP) negatively regulates iron absorption, degrading the iron exporter ferroportin at the level of enterocytes and macrophages. We showed that mice with beta-thalassemia intermedia (th3/+) have increased anemia and iron overload. However, their hepcidin expression is relatively low compared to their iron burden. We also showed that the iron metabolism gene Hfe is down-regulated in concert with hepcidin in th3/+ mice. These observations suggest that low hepcidin levels are responsible for abnormal iron absorption in thalassemic mice and that down-regulation of Hfe might be involved in the pathway that controls hepcidin synthesis in beta-thalassemia. Therefore, these studies suggest that increasing hepcidin and/or Hfe expression could be a strategy to reduces iron overload in these animals. The goal of this paper is to review recent findings that correlate hepcidin, Hfe, and iron metabolism in beta-thalassemia and to discuss potential novel therapeutic approaches based on these recent discoveries

Evidence for tissue iron overload in long-term hemodialysis patients and the impact of withdrawing parenteral iron.

BACKGROUND/AIMS: Erythropoiesis in long-term hemodialyzed (LTH) patients is supported by erythropoietin (rHuEpo) and intravenous (IV) iron. This treatment may end up in iron overload (IO) in major organs. We studied such patients for the parameters of IO in the serum and in major organs.METHODS: Patients were treated with rHuEpo (6-8 x 10(3) units 7 1-3/wk) and IV 100 mg ferric saccharate.RESULTS: Of 115 patients, 21 had serum ferritin (SF) > 1000 ng/mL. This group was further analyzed. Their SF and transferrin saturation (TSAT) were 2688 \ub1 1489 ng/mL and 54.2 \ub1 32.7%, respectively (vs. 125-360 ng/mL and 20-50% in normal controls). Serum hepcidin was 60.1 \ub1 29.5 nm (vs. 10.61 \ub1 6.44 nm in controls) (P < 0.001). Nineteen patients had increased malonyldialdehyde, a product of lipid peroxidation, indicating oxidative stress. T2* MRI disclosed in 19 of 21 patients moderate to severe IO in the liver and spleen, in three of eight patients in the pancreas, but in no patient in the heart. After stopping IV iron for a mean of 12 months, while continuing rHuEpo, the mean SF decreased in 11 patients to 1682 ng/mL and the mean TSAT decreased to 28%, whereas hemoglobin did not change indicating that tissue iron was utilized.CONCLUSION: High SF correlates with IO in the liver and spleen, but not in the heart