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Blood, 9 July 2009, Vol. 114, No. 2, pp. 452-458. Prepublished online as a Blood First Edition Paper on April 7, 2009; DOI 10.1182/blood-2009-02-203604.
THROMBOSIS AND HEMOSTASIS Factor XI contributes to thrombin generation in the absence of factor XII1 Department of Pathology, Vanderbilt University, Nashville, TN; 2 Departments of Science and Engineering and Medicine, Oregon Health and Science University, Portland; 3 Sol Sherry Thrombosis Research Center and Departments of Biochemistry and Medicine, Temple University School of Medicine, Philadelphia, PA; and 4 Department of Medicine, Vanderbilt University, Nashville, TN
During surface-initiated blood coagulation in vitro, activated factor XII (fXIIa) converts factor XI (fXI) to fXIa. Whereas fXI deficiency is associated with a hemorrhagic disorder, factor XII deficiency is not, suggesting that fXI can be activated by other mechanisms in vivo. Thrombin activates fXI, and several studies suggest that fXI promotes coagulation independent of fXII. However, a recent study failed to find evidence for fXII-independent activation of fXI in plasma. Using plasma in which fXII is either inhibited or absent, we show that fXI contributes to plasma thrombin generation when coagulation is initiated with low concentrations of tissue factor, factor Xa, or
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| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
-thrombin. The results could not be accounted for by fXIa contamination of the plasma systems. Replacing fXI with recombinant fXI that activates factor IX poorly, or fXI that is activated poorly by thrombin, reduced thrombin generation. An antibody that blocks fXIa activation of factor IX reduced thrombin generation; however, an antibody that specifically interferes with fXI activation by fXIIa did not. The results support a model in which fXI is activated by thrombin or another protease generated early in coagulation, with the resulting fXIa contributing to sustained thrombin generation through activation of factor IX. 
