Computational analysis of intersubject variability and thrombin generation in dilutional coagulopathy

BACKGROUND: Blood dilutionis a frequent complication of massive transfusion during trauma and surgery. This article investigates the quantitative effects of blood plasma dilutionon thrombingeneration in the context of intersubjectvariability. STUDY DESIGN AND METHODS: A thoroughly validated computational model was used to simulate thrombingeneration curves for 472 healthy subjects in the Leiden Thrombophilia Study. Individual thrombincurves were calculated for undiluted blood and for different dilutionscenarios. For every such curve, five standard quantitative parameters of thrombingeneration were calculated and analyzed. RESULTS: Thrombingeneration parameters in diluted blood plasmadisplayed significant intersubjectvariability (with a coefficient of variation up to approx. 28%). Nevertheless, dilutionaleffects in the majority (or all) of the subjects in the study group were characterized by persistent patterns. In particular, the largest dilutioninduced change typically occurred in the maximum slope (MS) of the thrombincurve, followed by a change in thrombinpeak height (PH), whereas the smallest change often occurred in the area under the curve. The identified patterns demonstrated considerable robustness to variations in dilutionscenario and tissue factorconcentration. CONCLUSION: Dilutionaleffects on thrombingeneration 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 dilutionindicators 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.