A zymogen-like factor Xa variant corrects the coagulation defect in hemophilia |
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Authors: | Ivanciu Lacramioara Toso Raffaella Margaritis Paris Pavani Giulia Kim Haein Schlachterman Alexander Liu Jian-Hua Clerin Valerie Pittman Debra D Rose-Miranda Rosalind Shields Kathleen M Erbe David V Tobin James F Arruda Valder R Camire Rodney M |
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Institution: | Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. |
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Abstract: | Effective therapies are needed to control excessive bleeding in a range of clinical conditions. We improve hemostasis in vivo using a conformationally pliant variant of coagulation factor Xa (FXa(I16L)) rendered partially inactive by a defect in the transition from zymogen to active protease. Using mouse models of hemophilia, we show that FXa(I16L) has a longer half-life than wild-type FXa and does not cause excessive activation of coagulation. Once clotting mechanisms are activated to produce its cofactor FVa, FXa(I16L) is driven to the protease state and restores hemostasis in hemophilic animals upon vascular injury. Moreover, using human or murine analogs, we show that FXa(I16L) is more efficacious than FVIIa, which is used to treat bleeding in hemophilia inhibitor patients. FXa(I16L) may provide an effective strategy to enhance blood clot formation and act as a rapid pan-hemostatic agent for the treatment of bleeding conditions. |
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