Recombinant Prothrombin Therapy for Hemorrhage

不受控制的出血仍然是创伤性死亡的主要原因之一。目前的治疗建议集中在新鲜冷冻血浆和血细胞输注，这似乎并不有效。在过去的几年里，凝血酶原复合物中心被越来越多地用于治疗血管相关性凝血病，其有效但会诱导弥散性血管内凝血。最近的动物实验表明，不同于凝血酶原复合物中心，来自CHO细胞的重组人凝血酶原（因子II）作为单一疗法有效地减少失血量，提高存活率，而不引起血栓栓塞。然而，CHO细胞不足以进行具有成本效益和功能性的生产。我们的初步研究表明，HEK293是一个高度偏好的宿主，能够实现高表达水平和足够的翻译后修饰。我们建议优化从HEK293细胞生产人重组凝血酶原，并在猪稀释凝血模型中比较凝血酶原复合物浓缩物的有效性和安全性。

Uncontrolled bleeding remains one of the leading causes of trauma-induced death. Current treatment recommendations focus on fresh frozen plasma and blood cell transfusions which do not seem to be effective. Over the last few years, these is increasing use of prothrombin complex cencentrate to treat hemorrhage-associated coagulapathy which is effective but induces disseminated intravascular coagulation. Recent animal studies demonstarte that different from prothrombin complex cencentrate, recombinant human prothrombin (factor II) from CHO cells as monotherapy effectively reduced blood loss and improved survival without causing thromboembolism. However, CHO cell is not adequate for cost-effective and functional production. Our preliminary sudies indicate that HEK293 is a highly prefered host that enables high expression level and adequate post-translational modifications. We propose to optimize the production of human recombinant prothrombin from HEK293 cells and compare the efficacy and safety with prothrombin complex concentrate in a porcine model of dilutional coagulapthy.