Defective thrombus formation in mice lacking coagulation factor XII.
Blood coagulation is thought to be initiated by plasma protease factor VIIa in complex with the membrane protein tissue factor. In contrast, coagulation factor XII (FXII)-mediated fibrin formation is not believed to play an important role for coagulation in vivo. We used FXII-deficient mice to study the contributions of FXII to thrombus formation in vivo. Intravital fluorescence microscopy and blood flow measurements in three distinct arterial beds revealed a severe defect in the formation and stabilization of platelet-rich occlusive thrombi. Although FXII-deficient mice do not experience spontaneous or excessive injury-related bleeding, they are protected against collagen- and epinephrine-induced thromboembolism. Infusion of human FXII into FXII-null mice restored injury-induced thrombus formation. These unexpected findings change the long-standing concept that the FXII-induced intrinsic coagulation pathway is not important for clotting in vivo. The results establish FXII as essential for thrombus formation, and identify FXII as a novel target for antithrombotic therapy.
Renné
Thomas
T
Institute of Clinical Biochemistry and Pathobiochemistry, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg, 97078 Würzburg, Germany. thomas@renne.net
Pozgajová
Miroslava
M
Grüner
Sabine
S
Schuh
Kai
K
Pauer
Hans-Ulrich
HU
Burfeind
Peter
P
Gailani
David
D
Nieswandt
Bernhard
B
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D003094:Collagen / Q000008:administration & dosage; D004837:Epinephrine / Q000008:administration & dosage; D015942:Factor VIIa / Q000378:metabolism; D005175:Factor XII Deficiency / Q000235:genetics / Q000378:metabolism*; D015956:Factor XIIa / Q000235:genetics / Q000378:metabolism*; D006470:Hemorrhage / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D013923:Thromboembolism / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
D014662:Vasoconstrictor Agents; D003094:Collagen; D015942:Factor VIIa; D015956:Factor XIIa; D004837:Epinephrine