Computational analysis of intersubject variability and thrombin generation in dilutional coagulopathy

Abstract

Blood dilution is a frequent complication of massive transfusion during trauma and surgery. This article investigates the quantitative effects of blood plasma dilution on thrombin generation in the context of intersubject variability. A thoroughly validated computational model was used to simulate thrombin generation curves for 472 healthy subjects in the Leiden Thrombophilia Study. Individual thrombin curves were calculated for undiluted blood and for different dilution scenarios. For every such curve, five standard quantitative parameters of thrombin generation were calculated and analyzed. Thrombin generation parameters in diluted blood plasma displayed significant intersubject variability (with a coefficient of variation up to approx. 28%). Nevertheless, dilutional effects in the majority (or all) of the subjects in the study group were characterized by persistent patterns. In particular, the largest dilution-induced change typically occurred in the maximum slope (MS) of the thrombin curve, followed by a change in thrombin peak height (PH), whereas the smallest change often occurred in the area under the curve. The identified patterns demonstrated considerable robustness to variations in dilution scenario and tissue factor concentration. Dilutional effects on thrombin generation in a human population can be predicted from trends identified for the "average" subject and then refined by performing an analysis of actual subjects in the study group. The MS and PH are dilution indicators that are both sensitive and reliable across a large subject group and could potentially be used as disease markers in the diagnosis of coagulopathic conditions.