Roles of coagulation factor XIII in the functions of blood platelets

Magwenzi, Simbarashe G.

Medicine
January 2011

Thesis or dissertation


Rights
© 2011 Simbarashe G Magwenzi. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.
Abstract

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.

Publisher
Hull York Medical School, The University of Hull
Qualification level
Doctoral
Qualification name
PhD
Language
English
Extent
Filesize: 21 MB
Identifier
hull:5785
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