Genetic polymorphisms, platelet activation and plasma homocysteine concentrations in atherothrombotic stroke

Meiklejohn, David J. (2000) Genetic polymorphisms, platelet activation and plasma homocysteine concentrations in atherothrombotic stroke. MD thesis, University of Glasgow.

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Atherothrombotic stroke arises following rupture of an atheromatous plaque, and occlusion occurs directly due to thrombosis in small arteries, or indirectly by embolisation if a large vessel plaque ruptures. Three risk factors that are claimed to influence these process were investigated. The influence of platelet activation and genetic polymorphisms of platelet membrane glycoproteins on the risk of thrombotic stroke was assessed. Following plaque rupture, platelets have a pivotal role in arterial thrombus formation, and platelet membrane glycoproteins (GP) IIIa (the fibrinogen receptor) and Ib (which binds von Willebrand factor) are crucial in this process. The lb allele of the HPA 1a/1b GPIIIa polymorphism and the 2b allele of the HPA 2a/2b GPIb polymorphism are claimed to be risk factors for stroke and myocardial infarction (MI), but reports are conflicting and consistent functional evidence of enhanced thrombogenicity is lacking. Increased factor VII activity (VIIc) has been claimed to be a risk factor for MI and stroke, but the data are conflicting. VIIc is dependent on both environmental and genetic influences, and recently two polymorphisms of the factor VII gene associated with lower VIIc have been claimed to be protective against MI. A raised plasma homocysteine concentration has been proposed as a cause for atherosclerosis. However the role of homocysteine in stroke aetiology remains controversial, since prospective studies have reported a weaker association than those conducted retrospectively. Furthermore there are few reports of plasma homocysteine concentrations both before and after the event. The following studies were conducted to address these issues: An investigation of the effect of HPA la/lb genotype on platelet fibrinogen binding by whole blood flow cytometry in healthy subjects. The effect of the lb allele on platelet fibrinogen binding was investigated in healthy subjects by whole blood flow cytometry. 35 platelet or plasma donors (34 HPA 1a/1b and one HPA 1b/1b) possessing the lb allele were compared with 35 donors homozygous for the la allele. There was no allele dependent difference in the percentage of platelets binding fibrinogen at baseline (p=0.14, Mann Whitney U test) or following stimulation with ADP (p=0.72, Student's t-test). An paradoxical increase in the density of fibrinogen binding sites was observed in la platelets after ADP stimulation (p=0.05, Mann Whitney U test), 1b platelets tended to exhibit greater activation as assessed by the percentage of platelets expressing P-Selectin, but this did not reach statistical significance (p=0.08, Mann-Whitney U test). These data do not identify a functional mechanism by which the 1b allele might mediate an increased risk of arterial thrombosis. (Abstract shortened by ProQuest.).

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Professor Mike Greaves.
Keywords: Medicine, genetics.
Subjects: R Medicine > R Medicine (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences
Date of Award: 2000
Depositing User: Enlighten Team
Unique ID: glathesis:2000-73681
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jun 2019 08:56
Last Modified: 14 Jul 2022 10:43
Thesis DOI: 10.5525/gla.thesis.73681
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