The Journal of Experimental Medicine
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Published online 11 July 2005 doi:10.1084/jem.20050664
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 2, 271-281
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ARTICLE

 Defective thrombus formation in mice lacking coagulation factor XII

Thomas Renné1, Miroslava Pozgajová2, Sabine Grüner2, Kai Schuh1, Hans-Ulrich Pauer3, Peter Burfeind4, David Gailani5,6, and Bernhard Nieswandt1,2

1 Institute of Clinical Biochemistry and Pathobiochemistry, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg, 97078 Würzburg, Germany
2 Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg, 97078 Würzburg, Germany
3 Department of Gynecology and Obstetrics, University of Göttingen, 37073 Göttingen, Germany
4 Institute of Human Genetics, University of Göttingen, 37073 Göttingen, Germany
5 Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232
6 Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232

CORRESPONDENCE Bernhard Nieswandt: bernhard.nieswandt{at}virchow.uni-wuerzburg.de OR Thomas Renné: thomas{at}renne.net

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.

Abbreviations used: aPTT, activated partial thromboplastin time; FXII, coagulation factor XII; PFP, platelet-free plasma; PRP, platelet-rich plasma; PS, phosphatidylserine; TF, tissue factor.

H.-U. Pauer's present address is Center for Hemostasis and Thrombosis Research, Vascular Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215.


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