title: Recombinant human prothrombin reduced blood loss in a porcine model of dilutional coagulopathy with uncontrolled bleeding.
abstract: : 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.
authors.affiliation: 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.
authors.forename: Kenny M
authors.initials: KM
authors.lastname: Hansson
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Johansson
authors.forename: Cecilia
authors.initials: C
authors.lastname: Wingren
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fries
authors.forename: Karin
authors.initials: K
authors.lastname: Nelander
authors.forename: Ann
authors.initials: A
authors.lastname: Lövgren
mesh_terms: D000818:Animals; D001778:Blood Coagulation Disorders / Q000097:blood*; D001780:Blood Coagulation Tests / Q000379:methods*; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000097:blood*; D006490:Hemostatics / Q000494:pharmacology*; D006801:Humans; D011516:Prothrombin / Q000378:metabolism*; D013552:Swine
chemical_list: D006490:Hemostatics; D011516:Prothrombin