The following article is based on a review conducted by Dr Elliot Vichinsky, published in Hematology (Am Soc Hematology Educ Program, 2007: 79-83) summarised here by TIF Medical Adviser Dr Michael Angastiniotis.

HbE is estimated to affect at least one million people around the world. Carrier frequency is highest in South East Asia, reaching as high as 60% in parts of Thailand, Laos and Cambodia. Carrier rates fall across the Indian subcontinent and southern China as the distance from South East Asia increases, to just 0.5% in Sri Lanka. However, increasing migration of populations from highly affected areas is resulting in rising prevalence in areas such as the Pacific coast of North America.

Homozygocity of HbE (HbE/E) is asymptomatic, except for the presence of target cells and microcytosis on microscopic examination; it is the compound heterozygote state with β-thalassaemia that produces clinically significant syndromes. The clinical severity of HbE/β-thalassaemia varies considerably from mild to intermediate to severe, transfusion-dependent (Winichagoon P et al, 2000).

Severity of the condition seems to be related to a number of factors, including whether the

β-thalassaemia mutation is β˚, which produces a severe clinical phenotype, or β+, which produces a milder cl inical picture. Co-inheritance of β-thalassaemia also alleviates the severity of the disease (Sripichai O et al, 2007).

The polymorphism associated with the XmnI site, linked to high HbF levels, also contributes to a milder manifestation. Other genetic modifiers may play a role, and more laboratory and clinical studies are required to fully understand the variability of these syndromes.

Many patients present with severe clinical manifestations and are treated from infancy as β-thalassaemia major patients, receiving blood transfusions and iron chelation therapy. Patients whose steady state Hb level remains constant and who are not given transfusions from early infancy are classified as patients with thalassaemia intermedia. These patients require careful follow-up to monitor any complications that may develop, including:

Thalassaemia major patients, receiving blood transfusions and iron chelation therapy. Patients whose steady state Hb level remains constant and who are not given transfusions from early infancy are classified as patients with thalassaemia intermedia. These patients require careful follow-up to monitor any complications that may develop, including:

  • Splenomegaly, which may lead to hypersplenism and a fall in Hb-levels, requiring the initiation of blood transfusion on a regular basis. Until recently this was the main indication for splenectomy, which is now known to be associated with an increased risk of thrombosis. Splenectomy favours the persistence of damaged red cells in the circulation, which are a source of negatively charged phospholipids and which increase thrombin generation. Thrombocytosis may also occur after splenectomy. Various organs are exposed to thrombi, but the lungs are particularly vulnerable.
  • A hypercoagulable state occurs in patients with thalassaemia intermedia who are not transfused but also, less frequently, in multi-transfused patients, irrespective of splenectomy. Markers of thrombin generation are increased; dysregulation of arginine metabolism with impaired nitric oxide bioavailability with effects on endothelial function has been demonstrated (Morris CR et al, 2005). One serious effect of this state is pulmonary hypertension.
  • Cardiopulmonary complications, including pulmonary hypertension and haemosiderotic cardiomyopathy, are the commonest cause of death in HbE/-thalassaemia.
  • Iron overload will occur over time, even in non-transfused patients, due to increased gastro-intestinal absorption. In HbE syndromes, the serum ferritin level is disproportionately low compared to liver iron concentration (LIC) in untransfused patients, so that in these syndromes it is important to use MRI and other techniques to monitor iron overload (Pakbaz Z and Fischer R et al, 2007). Careful monitoring is required to establish when to start chelation therapy. Cardiac, endocrine and liver complications will occur depending on the degree of iron overload.

Apart from regular blood transfusions, which may become necessary even in those with milder clinical conditions, agents elevating HbF production have been found to be helpful. The substance that has been used in practice is hydroxyurea. Responses to this treatment are variable and unpredictable, although it seems that patients homozygous for the XmnI polymorphism are more likely to respond (Koren A et al, 2008). Other substances such as decitabine and short-chain fatty acids are awaiting further trials.

References:

  • 1.Vichinsky E. HbE Syndromes. Hematology Am Soc Hematol Educ Program, 2007: 79-83
  • 2.Winichagoon P, Fucharoen S, Chen P, Wasi P. Genetic factors affecting clinical severity in beta thalassaemia syndromes. J Pediatr Hematol Oncol, 2000, 22(6): 573-80.
  • 3.Sripichai O, Munkongdee T, Kumkhaek C, Svasti S, Winichagoon P, Fucharoen S. Coinheritance of the different copy numbers of alpha-globin gene modifies severity of beta-thalassemia/Hb E disease. Ann Hematol 2007, Nov20
  • 4.Morris CR, Kuypers FA, Kato GJ et al Hemolysis associated pulmonary hypertension in thalassaemia. Ann NY Acad Sci, 2005, 1054: 481-485.
  • 5.Pakbaz Z, Fischer R, Fung E, Nielsen P, Harmatz P, Vichinsky E. Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients. Pediatr Blood Cancer. 2007 Sep; 49(3):329-32.
  • 6.Koren A, Levin C, Dgany O, Kransnov T, Elhasid R, Zalman L, Palmor H, Tamary H. Response to hydroxyurea therapy in beta-thalassemia. Am J Hematol. 2008 Jan 7

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