Hansson Kenny M, Johansson Karin J, Wingren Cecilia, Fries Dietmar, Nelander Karin, Lövgren Ann
aDepartment of Bioscience, Cardiovascular and Metabolic Disease (CVMD), Innovative Medicines unit (iMED), AstraZeneca R&D, Mölndal, Sweden bDepartment of General and Surgical Critical Care Medicine, Innsbruck Medical University, Innsbruck, Austria cQuantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines unit (iMED), AstraZeneca R&D, Mölndal, dLeaflet Biotech Consulting, Solna, Sweden.
Blood Coagul Fibrinolysis. 2017 Apr;28(3):244-253. doi: 10.1097/MBC.0000000000000590.
: Uncontrolled bleeding remains one of the leading causes of trauma-induced death. Treatment recommendations focus on fresh frozen plasma and blood cell transfusions, whereas plasma concentrates or single coagulation factors have been studied in recent years. The effect of recombinant human prothrombin factor II (rhFII, 8 mg/kg), activated recombinant human factor VII (rhFVIIa, 300 μg/kg), plasma-derived human fibrinogen (pdhFib) (200 mg/kg), activated prothrombin complex concentrate (aPCC, 40 IU/kg), a three-factor combination intended as a minimal PCC (8 mg/kg rhFII, 640 μg/kg recombinant human factor X (rhFX), and 12 μg/kg rhFVIIa), and vehicle were investigated in a porcine model of dilutional coagulopathy with uncontrolled bleeding. Survival time and blood loss were determined up to 120 min after induction of liver injury. Rotational thromboelastometry EXTEM coagulation time and maximum clot firmness, prothrombin time, thrombin-antithrombin complex (TAT), thrombin generation (endogenous thrombin potential, ETP) were measured at baseline, after dilution, drug administration, and end of experiment. rhFII, the three-factor combination, and aPCC significantly (P < 0.01) decreased blood loss vs. vehicle and rhFII also vs. fibrinogen (P < 0.05). Survival times increased significantly for rhFII, aPCC, rhFVIIa, and pdhFib vs. vehicle (P < 0.05), and, coagulation time, maximum clot firmness, and prothrombin time improved in all groups. TAT and ETP increased transiently for rhFII and three-factor combination, whereas persistently increased for aPCC. PdhFib and rhFVIIa did not increase TAT and ETP. rhFII decreased blood loss and improved hemostatic markers and survival. In vivo, thrombin generation (TAT) and potential to form thrombin (ETP) were transiently elevated by rhFII. Addition of rhFVIIa and rhFX to rhFII did not further improve hemostatic efficacy.
失控性出血仍然是创伤导致死亡的主要原因之一。治疗建议主要集中在输注新鲜冰冻血浆和血细胞，而血浆浓缩物或单一凝血因子近年来也得到了研究。在猪稀释性凝血病伴失控性出血模型中，研究了重组人凝血酶原因子II（rhFII，8mg/kg）、活化重组人因子VII（rhFVIIa，300μg/kg）、血浆源性人纤维蛋白原（pdhFib）（200mg/kg）、活化凝血酶原复合物浓缩物（aPCC，40IU/kg）、一种旨在作为最小凝血酶原复合物的三因子组合（8mg/kg rhFII、640μg/kg重组人因子X（rhFX）和12μg/kg rhFVIIa）以及赋形剂的效果。在肝损伤诱导后长达120分钟内测定生存时间和失血量。在基线、稀释后、给药后和实验结束时测量旋转血栓弹力图EXTEM凝血时间和最大血凝块硬度、凝血酶原时间、凝血酶 - 抗凝血酶复合物（TAT）、凝血酶生成（内源性凝血酶潜力，ETP）。与赋形剂相比，rhFII、三因子组合和aPCC显著（P<0.01）减少失血量，与纤维蛋白原相比rhFII也显著减少失血量（P<0.05）。与赋形剂相比，rhFII、aPCC、rhFVIIa和pdhFib的生存时间显著增加（P<0.05），并且所有组的凝血时间、最大血凝块硬度和凝血酶原时间均有所改善。rhFII和三因子组合的TAT和ETP短暂升高，而aPCC持续升高。PdhFib和rhFVIIa未增加TAT和ETP。rhFII减少失血量，改善止血指标和生存情况。在体内，rhFII可使凝血酶生成（TAT）和形成凝血酶的潜力（ETP）短暂升高。在rhFII中添加rhFVIIa和rhFX并未进一步提高止血效果。
