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Title: Cell death in platelets and megakaryocytes : implications for the maintenance of thrombostasis
Author: Clarke, Murray Charles Henry
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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We now report that thrombostasis is potentially maintained by the relative level of two opposing and different cell death programs within megakaryocytes and platelets. Firstly, platelet formation from megakaryocytes occurs by a unique, compartmentalised form of caspase-dependent apoptosis that results in the formation of multiple functional anucleate progeny. However, whilst the megakaryocyte cell body contains active caspases and displays nuclear condensation and fragmentation typical of apoptosis, the forming platelets retain functional mitochondria, do not contain active caspases, and are not phagocytosed, emphasising an atypical compartmentalised mitochondrial-independent apoptotic program. Platelet formation from megakaryocytes could be significantly augmented by ligation of the Fas death receptor, and reduced by treatment with caspase inhibitors. Secondly, we report a constitutive but caspase-independent program for the specific phagocytic clearance of intact effete platelets. Platelets aged in vitro exhibited increased expression of proapoptotic Bak and Bax, underwent diminution of function, and displayed cytoplasmic condensation and plasma membrane changes that lead to recognition by phagocyte scavenger receptors. In addition, evidence of platelets with an identical morphology was found in patients having sustained a non-Q-wave myocardial infarction. However, although platelets contained the effector caspase-3 they lacked caspase-9, a key component of the apoptosis initiator complex the apoptosome. Intriguingly, megakaryocytes contained both caspase-3 and -9, suggesting sequestration of the enzyme by the progenitors during platelet formation, again underscoring the compartmentalised death of megakaryocytes and thus explaining the inability of platelets to activate caspases during constitutive death, and hence their commitment to undergo a caspase-independent death.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available