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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

Hansson, Kenny M.a; Pehrsson, Susannea; Johansson, Karin J.a,b; Lindblom, Annaa; Nelander, Karinc; Lövgren, Anna,d

Blood Coagulation & Fibrinolysis: June 2019 - Volume 30 - Issue 4 - p 140–148
doi: 10.1097/MBC.0000000000000812
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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.

aBioscience Cardiovascular, Early Cardiovascular, Renal and Metabolism, R&D Biopharmaceuticals, AstraZeneca, Gothenburg, AstraZeneca

bCardiology Research Unit, Sahlgrenska University Hospital

cQuantitative Systems Pharmacology, Clinical Pharmacology and Safety Sciences, R&D BioPharmaceuticals, AstraZeneca, Gothenburg

dLeaflet Biotech Consulting, Solna, Sweden

Correspondence to Kenny M. Hansson, PhD, Bioscience Cardiovascular, Early Cardiovascular, Renal and Metabolism, R&D Biopharmaceuticals, AstraZeneca, Gothenburg, Sweden. Tel: +46 31 7065371; e-mail: kenny.m.hansson@astrazeneca.com

Received 2 October, 2018

Revised 13 March, 2019

Accepted 10 April, 2019

Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.