title: Factor XIII supports platelet activation and enhances thrombus formation by matrix proteins under flow conditions.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  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.affiliation: Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull, Castle Hill Hospital, Castle Road, Cottingham, UK.
authors.forename: S G
authors.initials: SG
authors.lastname: Magwenzi
authors.forename: R A
authors.initials: RA
authors.lastname: Ajjan
authors.forename: K F
authors.initials: KF
authors.lastname: Standeven
authors.forename: L A
authors.initials: LA
authors.lastname: Parapia
authors.forename: K M
authors.initials: KM
authors.lastname: Naseem
mesh_terms: D001792:Blood Platelets / Q000166:cytology; D002448:Cell Adhesion; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005176:Factor XIII / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D039302:Integrin alphaVbeta3 / Q000502:physiology; D008856:Microscopy, Fluorescence; D015539:Platelet Activation / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology; D013927:Thrombosis / Q000503:physiopathology*
chemical_list: D016326:Extracellular Matrix Proteins; D039302:Integrin alphaVbeta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005176:Factor XIII