Factor XIII (FXIII) stabilizes thrombi against fibrinolysis by cross-linking α2-antiplasmin (α2AP) to fibrin. Cellular FXIII (FXIII-A) is abundant in platelets, but the extracellular functions of this pool are unclear, as it is not released by classical secretion mechanisms. We examined the function of platelet FXIII-A using Chandler model thrombi formed from FXIII-depleted plasma. Platelets stabilized FXIII-depleted thrombi in a transglutaminase-dependent manner. FXIII-A activity on activated platelets was unstable and was rapidly lost over 1 h. Inhibiting platelet activation abrogated the ability of platelets to stabilize thrombi. Incorporation of a neutralizing antibody to α2AP into FXIII-depleted thrombi revealed that the stabilizing effect of platelet FXIII-A on lysis was α2AP-dependent. Platelet FXIII-A activity and antigen were associated with the cytoplasm and membrane fraction of unstimulated platelets and these fractions were functional in stabilizing FXIII-depleted thrombi against lysis. Fluorescence confocal microscopy and flow cytometry revealed exposure of FXIII-A on activated membranes with maximal signal detected with thrombin and collagen stimulation. FXIII-A was evident in protruding 'caps' on the surface of phosphatidylserine-positive platelets. Our data show a functional role for platelet FXIII-A through exposure on the activated platelet membrane where it exerts antifibrinolytic function through cross-linking α2AP to fibrin.
Bibliographical noteCopyright © 2014 American Society of Hematology.
The study was supported by grants FS/11/2/28579 (N.J.M. & A.S.L) and PG/11/1/28461 (N.J.M & C.S.W) from the British Heart Foundation and the University of Aberdeen Development Trust (N.J.M & J.L.M). N.A.B held a Leverhulme Trust Emeritus Fellowship. We are grateful to Dr Janne Koikkalainen for performing the Western blot for TG2 in platelets. We thank the Medical Statistics Team, the Microscopy and Histology Core Facility and the Iain Fraser Cytometry Centre at the University of Aberdeen for excellent advice and use of the facilities and the Scottish National Blood Transfusion Service for outdated platelets.
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- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Personal Chair
- School of Medicine, Medical Sciences & Nutrition, Cardiometabolic Disease
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cardiovascular and Diabetes Centre
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences