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¹ Department of Neurology, ² Department of Neuroradiology, ³ Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany
⁴ Department of Gynecology and Obstetrics and ⁵ Institute of Human Genetics, University of Göttingen, 37073 Göttingen, Germany
⁶ Institute for Pathology, University of Frankfurt, 60590 Frankfurt, Germany
⁷ Departments of Pathology and ⁸ Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
⁹ Rudolf Virchow Center, 97078 Würzburg, Germany

CORRESPONDENCE Thomas Renné: thomas{at}renne.net

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor–treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.

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, 02215 MA.

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