title: Thrombin-mediated activation of endogenous factor XI in plasma in the presence of physiological glycosaminoglycans occurs only with high concentrations of thrombin.
abstract: The variable bleeding tendency associated with a genetic deficiency of factor XI (FXI) and the lack of bleeding disorders in individuals with a genetic deficiency of factor XII (FXII) suggest an alternative mechanism for FXI activation in vivo. Recently, thrombin has been shown to activate FXI. However, in plasma this activation has been shown to occur only with exogenous FXI and a non-physiological cofactor (sulphatides), and the occurrence of this reaction in a plasma environment has been questioned. Using recently developed sensitive assays for FXIa-inhibitor complexes we found thrombin-mediated and FXII-dependent activation of endogenous FXI in plasma in the presence of heparan sulphate, heparin, dermatan sulphate or dextran sulphate. Using heparan sulphate, which is present in the human vascular system, activation of about 1-2% of plasma FXI was observed, however, only after addition of very high amounts (500 nmol/l) of human alpha-thrombin to FXII-deficient plasma (at a 1 to 4 final dilution). We conclude that endogenous FXI in plasma can be activated by thrombin in the presence of various glycosaminoglycans, including the physiological compounds heparan sulphate and dermatan sulphate, but only at very high concentrations of thrombin, corresponding to 100% prothrombin activation in undiluted plasma.
authors.affiliation: Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, University of Amsterdam, The Netherlands.
authors.forename: W A
authors.initials: WA
authors.lastname: Wuillemin
authors.forename: K
authors.initials: K
authors.lastname: Mertens
authors.forename: H
authors.initials: H
authors.lastname: ten Cate
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects*; D003871:Dermatan Sulfate / Q000494:pharmacology; D016264:Dextran Sulfate / Q000494:pharmacology; D005172:Factor XI / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D013917:Thrombin / Q000494:pharmacology*
chemical_list: D006025:Glycosaminoglycans; D003871:Dermatan Sulfate; D006493:Heparin; D005172:Factor XI; D016264:Dextran Sulfate; D013917:Thrombin