Factor XI–Dependent Reciprocal Thrombin Generation Consolidates Blood Coagulation when Tissue Factor Is Not Available

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 24; no. 6; pp. 1138 - 1142
• Main Authors: Wielders, Simone J.H, Béguin, Suzette, Hemker, H Coenraad, Lindhout, Theo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.06.2004; Hagerstown, MD Lippincott
• Subjects: Adult; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood Coagulation; Blood Platelets - drug effects; Blood Platelets - metabolism; Cardiology. Vascular system; Collagen - pharmacology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Enzyme Activation; Factor VIIa - pharmacology; Factor VIII - physiology; Factor XI - physiology; Factor XI Deficiency - blood; Feedback, Physiological; Hemophilia A - blood; Humans; Lipoproteins - pharmacology; Medical sciences; Plasma; Thrombin - biosynthesis; Thrombin - pharmacology; Thrombin - physiology; Blood coagulation; clot formation; Serine endopeptidases; Enzyme; factor VIIa; Glycoprotein; Tissue factor; Cardiovascular disease; Thrombin; Clot; Vascular disease; Peptidases; Factor XI; Platelet; activated platelets; Collagen; Atherosclerosis; Hydrolases; Coagulation factor
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000128125.80559.9c

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.