Published online before print April 8, 2004, doi: 10.1161/01.ATV.0000128125.80559.9c
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© 2004 American Heart Association, Inc.
Thrombosis |
Factor XI–Dependent Reciprocal Thrombin Generation Consolidates Blood Coagulation when Tissue Factor Is Not Available
From the Cardiovascular Research Institute Maastricht (S.J.H.W., S.B., H.C.H., T.L.) and the Department of Biochemistry (T.L.), Maastricht University, Maastricht, The Netherlands.
Correspondence to Dr T. Lindhout, Department of Biochemistry, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. E-mail t.lindhout{at}bioch.unimaas.nl
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.
Methods and 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.
Our study demonstrates that thrombin initiates thrombin generation in platelet-rich plasma. Factor XI is fundamental in supporting this process that is restricted to the surface of activated platelets, implying that feedback activation of factor XI by thrombin or indirectly by factor VIIa is important in maintaining normal hemostasis as well as in mediating thrombus formation.
Key Words: factor XI • thrombin • clot formation • activated platelets • factor VIIa • collagen
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