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In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia

Cecilia Augustsson and Egon Persson

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  • RE: In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia
    • Mikhail V. Ovanesov, Principal Investigator CBER, US FDA
    • Other Contributors:
      • Samuel A. Woodle, ORISE Fellow
      • Alexey A. Shibeko, ORISE Fellow

    Confirmation of prior observations in new experimental systems and laboratories is a necessary element of experimental science. In agreement with our previous study in FVII-deficient plasma, Augustsson and Persson found that FVII zymogen can inhibit rFVIIa-mediated thrombin generation in FVIII-deficient plasma. Both studies employed FVII-like molecules that bind TF but cannot be activated into FVIIa (FVIIai[1] and FVIIR152A[2]) to demonstrate that FVII auto-activation can overcome zymogen inhibition. Both found that rFVIIa produces more thrombin with TF than with procoagulant lipids and platelets alone.

    Despite excellent agreement with our findings, Augustsson and Persson conclude that the lack of strong zymogen inhibition in the pharmacological range of rFVIIa disproves the role of TF and confirms that the TF-independent mode prevails. We disagree with these conclusions for the following reasons:

    1. In vitro studies show that thrombin generation is always higher when rFVIIa is tested in the presence of TF vs. absence of TF [1-3].

    2. Only the TF-dependent mechanism can explain a moderate success of bleed treatment by 2 to 35 ug/kg of plasma-derived or recombinant FVIIa [3-4] because platelets alone are apparently unable to support activity of FVIIa below 10 nM [1-3].

    3. TF-independent theory predictions failed to materialize for the rFVIIa variant NN1731, a molecule with exaggera...

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    Conflict of Interest:
    DISCLAIMER: M. V. Ovanesov, S. A. Woodle and A. M. Shibeko are employees of the US Food and Drug Administration. This paper is an informal communication and represents the authors' best judgment. These comments do not bind or obligate the US Food and Drug Administration.