Selective factor VIII activation by the tissue factor–factor VIIa–factor Xa complex

Yuichi Kamikubo, G. Loredana Mendolicchio, Antonella Zampolli, Patrizia Marchese, Andrea S. Rothmeier, Jennifer Nagrampa Orje, Andrew J. Gale, Sriram Krishnaswamy, András Gruber, Henrik Østergaard, Lars C. Petersen, Wolfram Ruf and Zaverio M. Ruggeri

Key Points

  • A coagulation initiating pathway is revealed in which the TF-FVIIa-nascent FXa complex activates FVIII apart from thrombin feedback.

  • Direct activation of the intrinsic pathway by TF may preserve hemostasis under anticoagulant therapy targeting thrombin amplification.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


Safe and effective antithrombotic therapy requires understanding of mechanisms that contribute to pathological thrombosis but have a lesser impact on hemostasis. We found that the extrinsic tissue factor (TF) coagulation initiation complex can selectively activate the antihemophilic cofactor, FVIII, triggering the hemostatic intrinsic coagulation pathway independently of thrombin feedback loops. In a mouse model with a relatively mild thrombogenic lesion, TF-dependent FVIII activation sets the threshold for thrombus formation through contact phase-generated FIXa. In vitro, FXa stably associated with TF-FVIIa activates FVIII, but not FV. Moreover, nascent FXa product of TF-FVIIa can transiently escape the slow kinetics of Kunitz-type inhibition by TF pathway inhibitor and preferentially activates FVIII over FV. Thus, TF synergistically primes FIXa-dependent thrombin generation independently of cofactor activation by thrombin. Accordingly, FVIIa mutants deficient in direct TF-dependent thrombin generation, but preserving FVIIIa generation by nascent FXa, can support intrinsic pathway coagulation. In ex vivo flowing blood, a TF-FVIIa mutant complex with impaired free FXa generation but activating both FVIII and FIX supports efficient FVIII-dependent thrombus formation. Thus, a previously unrecognized TF-initiated pathway directly yielding FVIIIa-FIXa intrinsic tenase complex may be prohemostatic before further coagulation amplification by thrombin-dependent feedback loops enhances the risk of thrombosis.

  • Submitted February 6, 2017.
  • Accepted July 6, 2017.
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