Therapeutic correction of thrombin generation in dilution-induced coagulopathy

Abstract

Prothrombin complex concentrates (PCCs), which contain different coagulation proteins, are attractive alternatives to the standard methods to treat dilution-induced (and, generally, traumatic) coagulopathy. We investigated the ability of a novel PCC composition to restore normal thrombin generation in diluted blood. The performance of the proposed PCC composition (coagulation factors [F] II, IX, and X and the anticoagulant antithrombin), designated PCC-AT, was compared with that of FVIIa and PCC-FVII, which is the PCC composition containing FII, FVII, FIX, and FX (main components of most PCCs). We used a thoroughly validated computational model to simulate thrombin generation in normal and diluted blood for 472 healthy subjects in the control group of the Leiden Thrombophilia Study. For every simulated thrombin curve, we calculated and analyzed five standard thrombin generation parameters. The three therapeutic agents (FVIIa, PCC-FVII, and PCC-AT) caused statistically significant changes in each of the five thrombin generation parameters in diluted blood. Factor VIIa tended to primarily impact clotting time, thrombin peak time, and maximum slope of the thrombin curve, whereas in the case of PCC-FVII, thrombin peak height and the area under the thrombin curve were affected particularly strongly. As a result, these two therapeutics tended to push those respective parameters outside their normal ranges. PCC-AT significantly outperformed both FVIIa and PCC-FVII in its ability to normalize individual thrombin generation parameters in diluted blood. Furthermore, PCC-AT could simultaneously restore all five thrombin generation parameters to their normal levels in every subject in the study group. Our computational results suggest that PCC-AT may demonstrate a superior ability to restore normal thrombin generation compared with FVIIa and PCC-FVII.