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Title: Roles of coagulation factor XIII in the functions of blood platelets
Author: Magwenzi, Simbarashe G.
ISNI:       0000 0004 2705 8392
Awarding Body: University of Hull
Current Institution: University of Hull
Date of Award: 2011
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Activated blood coagulation factor XIII (FXIIIa) is a transglutaminase that stabilises fibrin clots and associates with platelets. In the present study, the role of factor XIII (FXIII) in modulating physiological platelet functional responses including adhesion, signal transduction and spreading were examined. Under static conditions, platelets adhered to surface-immobilised plasma-purified and recombinant human FXIII leading to the formation of filopodia and lamellipodia. Adhesion to FXIIIa was mediated through integrin-dependent mechanisms, since it was abolished by treatment with RGDS. Moreover, platelet adhesion to FXIIIa was reduced partially, but significantly by either the specific integrin dnbPs antagonist tirofiban or the selective avp3-blocking antibody LM609, and abolished when used in combination. However, spreading was exclusively mediated by OubPs since it was ablated by tirofiban, but unaffected by LM609. Importantly, FXIIIa-mediated platelet accrual was preserved under venous and arterial flow conditions where both integrins played essential roles. Under these conditions, platelet adhesion to immobilised activated FXIII (FXIIIa) was apparent at a shear rate of 300s"1, significantly reduced at 800s"1, but absent above 1000s"1. These platelet-FXIII interactions occurred independently of FXIII transglutaminase and protein disulfide isomerase activities. However, platelet adhesion and spreading were abolished by the Src family inhibitor PP1 indicating a tyrosine kinase-dependent mechanism. Consistent with this, FXIIIa stimulated tyrosine-phosphorylation of several proteins including Syk, SLP-76 and PLCv2 but not LAT, in adherent platelets. FXIIIa immobilised rapidly on collagen, and enhanced collagen-induced thrombus formation at a shear rate of 800s"1 . When co-immobilised with fibrinogen and vWF, the coagulation factor also accentuated platelet accrual by these key platelet adhesive proteins also at arterial shear. These data provide evidence that FXIIIa supports platelet adhesion under flow and potentiates the thrombogenic effects of established platelet ligands, suggesting a novel role for FXIIIa in enhancing platelet-dependent haemostasis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine