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Current massive transfusion guidelines are derived from washout equations that may not apply to bleeding trauma patients. Our aim was to analyze these guidelines using a computer simulation.A combined hemodilution and hemodynamic model of an exsanguinating patient was developed to calculate the changes in prothrombin time (PT), fibrinogen, and platelets with bleeding. The model was calibrated to data from 44 patients. Time intervals to subhemostatic values of each coagulation test were calculated for a range of replacement options.Prolongation of PT is the sentinel event of dilutional coagulopathy and occurs early in the operation. The key to preventing coagulopathy is plasma infusion before PT becomes subhemostatic. The optimal replacement ratios were 2:3 for plasma and 8:10 for platelets. Concurrent transfusion of plasma with blood is another effective strategy for minimizing coagulopathy.Existing protocols underestimate the dilution of clotting factors in severely bleeding patients. The model presents an innovative approach to optimizing component replacement in exsanguinating hemorrhage.