title: Functional factor XIII-A is exposed on the stimulated platelet surface.
abstract: 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 because 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 hour. Inhibiting platelet activation abrogated the ability of platelets to stabilize thrombi. Incorporating 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 by cross-linking α2AP to fibrin.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Joanne L
authors.identifier: http://orcid.org/0000-0001-8762-4542
authors.initials: JL
authors.lastname: Mitchell
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Ausra S
authors.initials: AS
authors.lastname: Lionikiene
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Fraser
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Claire S
authors.identifier: http://orcid.org/0000-0001-8127-6102
authors.initials: CS
authors.lastname: Whyte
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Nuala A
authors.initials: NA
authors.lastname: Booth
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Nicola J
authors.identifier: http://orcid.org/0000-0002-7452-0813
authors.initials: NJ
authors.lastname: Mutch
mesh_terms: D000933:Antifibrinolytic Agents / Q000737:chemistry; D001777:Blood Coagulation / Q000502:physiology; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003094:Collagen / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D026122:Factor XIIIa / Q000502:physiology*; D005337:Fibrin / Q000737:chemistry; D005342:Fibrinolysis; D005434:Flow Cytometry; D006801:Humans; D018613:Microscopy, Confocal; D015539:Platelet Activation; D013917:Thrombin / Q000737:chemistry; D013927:Thrombosis / Q000473:pathology; D011503:Transglutaminases / Q000737:chemistry; D000979:alpha-2-Antiplasmin / Q000737:chemistry
chemical_list: D000933:Antifibrinolytic Agents; D003432:Cross-Linking Reagents; D000979:alpha-2-Antiplasmin; D005337:Fibrin; D003094:Collagen; D026122:Factor XIIIa; D011503:Transglutaminases; D013917:Thrombin