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An investigation into the regulation of haemostasis in sickle cell disease and beta thalassaemia

McDonald, Sally Jean; (2003) An investigation into the regulation of haemostasis in sickle cell disease and beta thalassaemia. Masters thesis (M.Phil), UCL (University College London). Green open access

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Sickle cell disease (SCD) and β thalassaemia (β thal) are congenital blood disorders caused by abnormal or inadequate haemoglobin synthesis respectively. These pathological conditions are characterised by the production of abnormal red blood cells (RBCs) that have a shortened life-span as well as abnormal biological, biochemical and adhesive properties. Chronic RBC haemolysis and anaemia, as well as repetitive episodes of RBC sickling and vasocclusion in SCD, may result in delayed growth and development, susceptibility to infection and progressive organ failure. Blood coagulation properties also appear to be affected as some patients experience thrombotic complications, which can be associated with significant morbidity and/or mortality. I embarked on this study because a well controlled, comprehensive investigation of the haemostatic (blood clotting) system had not been undertaken in these patients. I examined aspects of haemostasis in SCD and β thal, paying particular attention to abnormalities that predispose individuals to a heightened risk of venous thrombosis while addressing issues that had complicated previously published work: my subjects were free of acute clinical complications; they were compared to control groups of similar ethnicity; their genotype and transfusion status was taken into account and liver function was assessed. Haemostatic variables of interest were initially examined in healthy Black (n = 28) and Caucasian (n = 33) subjects with HbAA genotypes. Levels of each variable were compared and reference ranges were independently established within the two ethnic groups. Mild variation was noted for some variables; significant differences included higher prothrombin fragment 1+2 levels in Caucasians, but longer APTTs and higher thrombin:antithrombin complexes, prothrombin and soluble E-selectin levels in Blacks. 44 SCD (HbSC or HbSS) and 41 p thal (intermedia or major) patients were investigated and compared to the Black and Caucasian control groups respectively. Haemostasis was altered in SCD: thrombin generation was increased, plasma levels of clotting factors, physiological inhibitors and other proteins were reduced and fibrin deposition was increased. Certain haemostatic variables were more significantly altered in HbSS compared to HbSC, which may reflect greater preservation of hepatic function and less RBC damage in HbSC, however the extent of abnormal thrombin generation was similar in the two genotypes. Mild activation of the endothelium was evident in untransfused HbSS patients and was strongly associated with inflammation. Patients with p thal intermedia were untransfused and showed broadly similar abnormalities tountransfused HbSS patients, including excessive thrombin generation and endothelial cell activation; abnormalities tended to be milder in β thal major (Thai Maj) patients, who were transfusion-dependent. Altered plasma levels of coagulation system proteins in SCD and β thal represent a chronic, consumptive coagulopathy that is probably exacerbated by mildly impaired hepatic synthesis. There was no evidence of gross liver disease in this cohort, although some hepatic dysfunction could not be entirely excluded, particularly in patients with substantial iron overload. (Abstract shortened by UMI.)

Type: Thesis (Masters)
Qualification: M.Phil
Title: An investigation into the regulation of haemostasis in sickle cell disease and beta thalassaemia
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; Thalassemia
URI: https://discovery.ucl.ac.uk/id/eprint/10106542
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