title: Factor XI-dependent reciprocal thrombin generation consolidates blood coagulation when tissue factor is not available.
abstract: OBJECTIVE
  Feedback activation of factor XI by thrombin is a likely alternative for tissue factor-dependent propagation of thrombus formation. However, the hypothesis that thrombin can initiate and propagate its formation in a factor XI-dependent and platelet-dependent manner has not been tested in a plasma milieu.
  
  
  RESULTS
  We investigated thrombin generation in recalcified platelet-rich plasma activated with varying amounts of thrombin or factor VIIa. Thrombin initiates and propagates dose-dependently thrombin generation only when platelets and plasma factor XI are present. Incubation of thrombin-activated platelets with a tissue factor neutralizing antibody had no effect on thrombin formation, indicating that platelet-associated tissue factor, if present at all, is not involved. In the absence of factor VIII, thrombin could not initiate its own formation, whereas factor VIIa-induced thrombin generation was reduced. Collagen strongly stimulated both thrombin-initiated and factor VIIa-initiated thrombin generation.
  
  
  CONCLUSIONS
  These findings support the notion that platelet-localized feedback activation of factor XI by thrombin plays an important role in maintaining normal hemostasis as well as in sustaining thrombus formation when the TF pathway is inhibited by tissue factor pathway inhibitor.
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Simone J H
authors.initials: SJ
authors.lastname: Wielders
authors.forename: Suzette
authors.initials: S
authors.lastname: Béguin
authors.forename: H Coenraad
authors.initials: HC
authors.lastname: Hemker
authors.forename: Theo
authors.initials: T
authors.lastname: Lindhout
mesh_terms: D000328:Adult; D001777:Blood Coagulation; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004789:Enzyme Activation; D005169:Factor VIII / Q000502:physiology; D015942:Factor VIIa / Q000494:pharmacology; D005172:Factor XI / Q000502:physiology*; D005173:Factor XI Deficiency / Q000097:blood; D025461:Feedback, Physiological; D006467:Hemophilia A / Q000097:blood; D006801:Humans; D008074:Lipoproteins / Q000494:pharmacology; D010949:Plasma; D013917:Thrombin / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*
chemical_list: D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D005169:Factor VIII; D003094:Collagen; D005172:Factor XI; D015942:Factor VIIa; D013917:Thrombin