Recombinant human prothrombin (MEDI8111) combined with fibrinogen dose-dependently improved survival time and reduced blood loss in a porcine model of dilutional coagulopathy with uncontrolled bleeding.

: Uncontrolled bleeding due to trauma and coagulopathy is an area with high unmet medical need and high mortality rate. Treatment recommendations focus on transfusion of blood components while optimal therapy to improve coagulation remains to be established. The haemostatic effect of 2, 4 and 8 mg/kg recombinant prothrombin (MEDI8111) co-administered with 100 mg/kg fibrinogen (n = 7-8) was investigated in a porcine model of dilutional coagulopathy with uncontrolled bleeding. Vehicle (n = 11), fibrinogen alone (100  mg/kg , n = 15) were included as controls. Dilutional coagulopathy was induced by replacing ∼75% of the blood volume with hydroxyethyl starch and a standardized liver incision was made followed by intravenous administration of study compounds. Survival time and blood loss were determined up to 120 min after liver incision. Rotational thromboelastometry (ROTEM EXTEM), prothrombin time (PT), thrombin--antithrombin complex and thrombin generation were measured at baseline, after dilution and 10, 40, 80 and 120 min after compound administration. Administration of MEDI8111+fibrinogen improved haemostasis, decreased blood loss and dose-dependently improved survival time compared to fibrinogen. All pigs receiving a dose of 8 mg/kg MEDI8111+fibrinogen, which restored normal prothrombin concentration, survived to the end of the experiment with close to normal haemostasis as measured by PT and ROTEM EXTEM CT. Administration of fibrinogen and MEDI8111 was sufficient to improve survival time and haemostasis in severely coagulopathic pigs. The dose-dependent haemostatic improvement observed with MEDI8111 administration suggests that prothrombin concentration was rate limiting for coagulation.

Prothrombin time is predictive of low plasma prothrombin concentration and clinical outcome in patients with trauma hemorrhage: analyses of prospective observational cohort studies.

BACKGROUND: Fibrinogen and prothrombin have been suggested to become rate limiting in trauma associated coagulopathy. Administration of fibrinogen is now recommended, however, the importance of prothrombin to patient outcome is unknown. METHODS: We have utilized two trauma patient databases (database 1 n = 358 and database 2 n = 331) to investigate the relationship of plasma prothrombin concentration on clinical outcome and coagulation status. Database 1 has been used to assess the relationship of plasma prothrombin to administered packed red blood cells (PRBC), clinical outcome and coagulation biomarkers (Prothrombin Time (PT), ROTEM EXTEM Coagulation Time (CT) and Maximum Clot Firmness (MCF)). ROC analyses have been performed to investigate the ability of admission coagulation biomarkers to predict low prothrombin concentration (database 1), massive transfusion and 24 h mortality (database 1 and 2). The importance of prothrombin was further investigated in vitro by PT and ROTEM assays in the presence of a prothrombin neutralizing monoclonal antibody and following step-wise dilution. RESULTS: Patients who survived the first 24 h had higher admission prothrombin levels compared to those who died (94 vs.67 IU/dL). Patients with lower transfusion requirements within the first 24 h (≤10 units of PRBCs) also had higher admission prothrombin levels compared to patients with massive transfusion demands (>10 units of PRBCs) (95 vs.62 IU/dL). Admission PT, in comparison to admission ROTEM EXTEM CT and MCF, was found to be a better predictor of prothrombin concentration <60 IU/dL (AUC 0.94 in database 1), of massive transfusion (AUC 0.92 and 0.81 in database 1 and 2 respectively) and 24 h mortality (AUC 0.90 and 0.78 in database 1 and 2, respectively). In vitro experiments supported a critical role for prothrombin in coagulation and demonstrated that PT and ROTEM EXTEM CT are sensitive methods to measure low prothrombin concentration. DISCUSSION: Our analyses suggest that prothrombin concentration at admission is predictive of mortality and transfusion and indicates that prothrombin and fibrinogen are rate limiting in coagulopathy. CONCLUSIONS: Admission PT is predictive of low prothrombin concentration and clinical outcome. PT could therefore be used as a surrogate for prothrombin concentration and further evaluation of point-of-care devices for faster PT analysis is warranted.

Recombinant human prothrombin reduced blood loss in a porcine model of dilutional coagulopathy with uncontrolled bleeding.

: 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.