title: Stimulation of thrombin- and plasmin-mediated activation of thrombin-activatable fibrinolysis inhibitor by anionic molecules.
abstract: BACKGROUND
  Thrombin-activatable fibrinolysis inhibitor (TAFI) is a proenzyme that, once activated, attenuates fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin. TAFI can be activated by thrombin or plasmin via a cleavage at Arg92 that removes the activation peptide from the enzyme, TAFIa. Thrombomodulin enhances thrombin-mediated TAFI activation and glycosaminoglycans enhance plasmin-mediated TAFI activation. The aim of this study was to investigate whether there are other anionic molecules that function as a cofactor for thrombin- or plasmin-mediated TAFI activation.
  
  
  METHODS
  TAFI activation by thrombin or plasmin was studied in the presence of physiological anionic molecules (polyphosphate, heparin, hyaluronan, DNA and dermatan sulfate) and the non-physiological sodium dodecyl sulfate (SDS). Additionally, the effect of these molecules on TAFIa stability and on thrombin-mediated protein C activation was determined.
  
  
  RESULTS
  Unfractioned heparin, calcium-saturated polyphosphate with an average chain length of 100 monomers (Ca-PolyP100) and SDS significantly enhanced TAFI activation by thrombin and plasmin. Dermatan sulfate and polyphosphates with sodium as counter ion (Na-PolyP700, Na-PolyP100 and Na-PolyP70) enhanced plasmin-mediated but not thrombin-mediated TAFI activation. Additionally, unfractioned heparin, Ca-PolyP100 and SDS enhanced thrombin-mediated protein C activation. The different nature of anionic molecules capable of enhancing TAFI and protein C activation suggests a general mechanism.
  
  
  CONCLUSIONS
  Several anionic molecules function as (potent) cofactors for thrombin- and plasmin-mediated TAFI activation and thrombin-mediated protein C activation. This may imply that thrombin and plasmin activity is regulated in the vasculature by more cofactors than currently appreciated.
authors: Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Tom
authors: T
authors: Plug
authors: Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands.
authors: Joost C M
authors: JC
authors: Meijers
mesh_terms: D000838:Anions; D005341:Fibrinolysin / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D011486:Protein C / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism*
chemical_list: D000838:Anions; D011486:Protein C; D013917:Thrombin; D005341:Fibrinolysin
keywords: Carboxypeptidase B2; Plasmin; Protein C; Thrombin; Thrombin-activatable fibrinolysis inhibitor (TAFI)