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Study of patients with suspected platelet-based bleeding disorders: a search for patients with a defect in the P2Y12 ADP receptor

By Ban Behnam Dawood


Mild platelet-based bleeding disorders are among the most complex bleeding disorders to understand, due to the absence of a ‘gold standard’ test for diagnosis and the significant overlap with the bleeding phenotype observed in healthy individuals. The work in this thesis is focussed on patients with a clinically diagnosed mild platelet disorder for which no acquired cause was identified by the referring expert clinician. ADP and thromboxane A2 (TxA2) are key secondary mediators of platelet aggregation and function in synergy to facilitate robust platelet activation in the event of vascular damage. Less than ten function-disrupting inherited gene defects in the ADP P2Y12 receptor and only one in the platelet TxA2 receptor have been reported, with none in the UK. Over a period of nearly 4 years, patients with a diagnosis of platelet dysfunction made at UK Comprehensive Haemophilia Care Centres were investigated using platelet aggregation and secretion assays alongside controls and reference curves to nine platelet agonists to exhibit an abnormal bleeding phenotype in response to different platelet agonists, focusing in searching on P2Y12 receptor defects. In addition, the P2Y12 ADP receptor from 140 subjects diagnosed with mild type 1 von Willebrand Disease (VWD) from the EU MCMDM-1VWD study was sequenced in view of the similarity in bleeding phenotype of patients with type 1 VWD and mild platelet disorders and the fact that both conditions show incomplete penetrance consistent with a multifactorial basis for each disorder. The sequencing was performed by Dr Martina Daly in Sheffield. The work in this thesis has led to the identification / characterisation of a patient who is homozygous for an early missense mutation in the P2Y12 ADP receptor and two patients with heterozygous point mutations in the P2Y12 ADP receptor (who also has type 1VWD) and in the TxA2 receptor. In addition, I studied platelet aggregation and secretion, along with a number of more specialised assays, in nearly 80 other patients during the course of the thesis and have subdivided these on the basis of the observed defect. Interestingly, in nearly one third of the patients, a platelet defect was not found

Topics: RD Surgery, RC Internal medicine
Year: 2010
OAI identifier: oai:etheses.bham.ac.uk:1519

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