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J. Biol. Chem., Vol. 280, Issue 50, 41352-41359, December 16, 2005

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Thrombin-activable Factor X Re-establishes an Intrinsic Amplification in Tenase-deficient Plasmas^*

From the INSERM U428, Faculté de Pharmacie, Université Paris V, 75270 Paris, France

Classical hemophilia results from a defect of the intrinsic tenase complex, the main factor X (FX) activator. Binding of factor VIIa to tissue factor triggers coagulation, but little amplification of thrombin production occurs. Handling of hemophilia by injection of the deficient or missing (thus foreign) factor often causes immunological complications. Several strategies have been designed to bypass intrinsic tenase complex, but none induce true auto-amplification of thrombin production. In an attempt to re-establish a cyclic amplification of prothrombin activation in the absence of tenase, we prepared a chimera of FX having fibrinopeptide A for the activation domain (FX_FpA). We reasoned that cascade initiation would produce traces of thrombin that would activate FX_FpA (contrary to its normal homologue). Given that the activation domain of FX is released upon activation, thrombin cleavage would produce authentic FXa that would produce more thrombin, which in turn would activate more chimeras. FX_FpA was indeed activable by thrombin, albeit at a relatively low rate (5 x 10³ M^-1 s^-1). Nevertheless, FX_FpA allowed in vitro amplification of thrombin production, and 100 nM efficiently corrected thrombin generation in tenase-deficient plasmas. A decisive advantage of FX_FpA could be that the artificial cascade is self-regulating: FX_FpA had little influence on the clotting time of normal plasma, yet corrected that of tenase deficiency. Another advantage could be the half-life of FX_FpA in blood; FX has a half-life of about 30 h (less than 3 h for FVIIa). It is also reasonable to expect little or no immunogenicity, because FX and fibrinopeptide A both circulate normally in the blood of hemophiliacs.

Received for publication, July 19, 2005 , and in revised form, September 20, 2005.

^* This work was supported by the Institut National de la Santé et de la Recherche Médicale of France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Joseph Stokes Research Inst., Children's Hospital of Philadelphia, PA 19104.

² To whom correspondence should be addressed: INSERM U428, Université Paris V, Faculté de Pharmacie, 4 Av. de l'Observatoire 75270 Paris Cedex 06, France. Tel.: 33-1-5373-9828; Fax: 33-1-4407-1772; E-mail: lebonnie{at}infobiogen.fr.

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