Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Nat Biotechnol. 2011 Oct 23;29(11):1028-33. doi: 10.1038/nbt.1995.
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.
需要有效的治疗方法来控制多种临床情况下的过度出血。我们使用凝血因子 Xa（FXa（I16L））的构象柔韧变体来改善体内止血，该变体通过在酶原到活性蛋白酶的转变过程中的缺陷而部分失活。使用血友病的小鼠模型，我们表明 FXa（I16L）的半衰期比野生型 FXa 长，并且不会引起凝血过度激活。一旦凝血机制被激活以产生其辅因子 FVa，FXa（I16L）就会被驱动到蛋白酶状态，并在血管损伤后恢复血友病动物的止血功能。此外，使用人或鼠类似物，我们表明 FXa（I16L）比用于治疗血友病抑制剂患者出血的 FVIIa 更有效。FXa（I16L）可能提供一种有效的策略来增强血栓形成，并作为治疗出血情况的快速全面止血剂。
