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Blood coagulation factor XII—a neglected player in stroke pathophysiology

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Abstract

Ischemic stroke is a devastating disease which, in most cases, is caused by thrombotic occlusion of brain arteries. The molecular mechanisms involved in microvascular thrombus formation during focal cerebral ischemia are not well understood. As a consequence, the current antithrombotic drugs used to treat acute stroke or prevent stroke recurrence either show limited efficacy or put patients at risk for serious bleeding complications. The serine protease blood coagulation factor XII (FXII) initiates the intrinsic pathway of coagulation which, together with the extrinsic pathway, culminates in the formation of fibrin. A physiological function of FXII in clot formation and hemostasis in vivo has been questioned for more than 50 years. This was mainly due to the fact that hereditary FXII deficiency does not induce any bleeding phenotype in humans. However, recent studies in transgenic mice challenged this concept by demonstrating that FXII deficiency prevents pathological thrombus formation, but does not affect regular hemostasis. These findings entailed investigations in relevant disease models of thromboembolism including ischemic stroke. The present review summarizes the pathophysiological role of FXII in experimental cerebral ischemia and highlights novel therapeutic strategies based on FXII inhibition.

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Acknowledgments

Parts of the work summarized in this review were supported by the German Research Council (Deutsche Forschungsgemeinschaft SFB 688, TP B1 to BN, GS and TP A13 to CK), by CSL Behring GmbH, Marburg, Germany. MP holds a postdoctoral fellowship granted by the Medical Faculty of the University of Heidelberg, Germany.

Conflict of interest

CK, BN, and GS hold or have applied for patents to prevent or treat thromboembolic diseases including stroke with novel antithrombotics. CK receives financial support for research projects from CSL Behring GmbH, Marburg, Germany. MP and MB did not declare any conflicts of interest.

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Authors and Affiliations

  1. Department of Neuroradiology, Heidelberg University Hospital, INF 400, 69120, Heidelberg, Germany

    Mirko Pham & Martin Bendszus

  2. Department of Neurology, University Clinics of Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany

    Guido Stoll & Christoph Kleinschnitz

  3. Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany

    Bernhard Nieswandt

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  1. Mirko Pham
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Correspondence to Mirko Pham or Christoph Kleinschnitz.

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Pham, M., Stoll, G., Nieswandt, B. et al. Blood coagulation factor XII—a neglected player in stroke pathophysiology. J Mol Med 90, 119–126 (2012). https://doi.org/10.1007/s00109-011-0812-9

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