BACKGROUND: Activated coagulation factor XIII (FXIIIa) is a transglutaminase that crosslinks fibrin at sites of vascular injury. FXIIIa also associates with blood platelets, although its role in platelet function is unclear and requires clarification. OBJECTIVES: To evaluate the ability of FXIIIa to support platelet adhesion and spreading under conditions of physiologic flow, and to identify the underpinning receptors and signaling events. METHODS AND RESULTS: Platelet adhesion to immobilized FXIIIa was measured by fluorescence microscopy, and signaling events were characterized by immunoblotting. Immobilized FXIIIa supported platelet adhesion and spreading under static conditions through mechanisms that were dually and differentially dependent on integrins α(IIb)β(3) and α(v)β(3). Platelet adhesion was independent of FXIIIa transglutaminase or protein disulfide isomerase activity. Moreover, adhesion was abolished by antibodies that prevented interaction with FXIIIa, but maintained when potential interactions with fibrinogen were blocked. Platelet adhesion to FXIIIa was reduced significantly by either the specific α(IIb)β(3) antagonist tirofiban or the selective α(v)β(3)-blocking antibody LM609, and abolished when they were used in combination. Importantly, platelet adhesion was preserved under venous and arterial flow conditions in which both integrins played essential roles. In contrast, FXIIIa stimulated the formation of filopodia and lamellipodia in adherent platelets that was mediated exclusively by α(IIb)β(3) and eliminated by the Src-family inhibitor 4-amino-5-(4-methylphenyl-7-(t-butyl)pyrazolo(3,4-d)pyrimidine, indicating a tyrosine kinase-dependent mechanism. Crucially, under conditions of arterial shear, FXIIIa accentuated platelet recruitment by von Willebrand factor and collagen. CONCLUSIONS: Our data demonstrate a potential role for FXIIIa in supporting platelet adhesion at sites of vascular damage, particularly in association with other thrombogenic matrix proteins.
BACKGROUND: Activated coagulation factor XIII (FXIIIa) is a transglutaminase that crosslinks fibrin at sites of vascular injury. FXIIIa also associates with blood platelets, although its role in platelet function is unclear and requires clarification. OBJECTIVES: To evaluate the ability of FXIIIa to support platelet adhesion and spreading under conditions of physiologic flow, and to identify the underpinning receptors and signaling events. METHODS AND RESULTS: Platelet adhesion to immobilized FXIIIa was measured by fluorescence microscopy, and signaling events were characterized by immunoblotting. Immobilized FXIIIa supported platelet adhesion and spreading under static conditions through mechanisms that were dually and differentially dependent on integrins α(IIb)β(3) and α(v)β(3). Platelet adhesion was independent of FXIIIa transglutaminase or protein disulfide isomerase activity. Moreover, adhesion was abolished by antibodies that prevented interaction with FXIIIa, but maintained when potential interactions with fibrinogen were blocked. Platelet adhesion to FXIIIa was reduced significantly by either the specific α(IIb)β(3) antagonist tirofiban or the selective α(v)β(3)-blocking antibody LM609, and abolished when they were used in combination. Importantly, platelet adhesion was preserved under venous and arterial flow conditions in which both integrins played essential roles. In contrast, FXIIIa stimulated the formation of filopodia and lamellipodia in adherent platelets that was mediated exclusively by α(IIb)β(3) and eliminated by the Src-family inhibitor 4-amino-5-(4-methylphenyl-7-(t-butyl)pyrazolo(3,4-d)pyrimidine, indicating a tyrosine kinase-dependent mechanism. Crucially, under conditions of arterial shear, FXIIIa accentuated platelet recruitment by von Willebrand factor and collagen. CONCLUSIONS: Our data demonstrate a potential role for FXIIIa in supporting platelet adhesion at sites of vascular damage, particularly in association with other thrombogenic matrix proteins.
Authors: Prajeeda M Nair; Shaunak G Pandya; Shatha F Dallo; Kristin M Reddoch; Robbie K Montgomery; Heather F Pidcoke; Andrew P Cap; Anand K Ramasubramanian Journal: Br J Haematol Date: 2017-06-04 Impact factor: 6.998
Authors: Claire S Whyte; Frauke Swieringa; Tom G Mastenbroek; Ausra S Lionikiene; Marcus D Lancé; Paola E J van der Meijden; Johan W M Heemskerk; Nicola J Mutch Journal: Blood Date: 2015-02-23 Impact factor: 22.113
Authors: Rolf P Kreutz; Abbas Bitar; Janelle Owens; Zeruesenay Desta; Jeffrey A Breall; Elisabeth von der Lohe; Anjan Sinha; Matteo Vatta; Perry Nystrom; Yan Jin; David A Flockhart Journal: J Thromb Thrombolysis Date: 2014-10 Impact factor: 2.300