Prothrombin time, expressed as international normalized ratio (INR) and activated partial thromboplastin time (aPTT), are standard methods of monitoring coumadin and heparin administration. Prothrombin activation fragment (F1.2) is an index of in vivo thrombin generation. We hypothesized that F1.2 would provide a better surrogate of thromboembolism risk than standard coagulation assays during ventricular assist device (VAD) support. INR, PTT and F1.2 were analyzed in 31 patients after implantation of a left-sided VAD daily during hospitalization and weekly after discharge. Thromboembolic events (TE) were defined by evidence of neurological injury revealed by plasma levels of S-100beta. The relationships between F1.2, INR for patients on coumadin and aPTT for patients on heparin were evaluated from 1250 observations of blood samples. S-100beta was positively correlated with F1.2, but not with INR and aPTT. Correlation between S-100beta and F1.2 is significantly higher than with the other two markers (P<0.0001). Higher values of aPTT and INR were not associated with TE. Compared to conventional coagulation assays, the F1.2 level provides a single endpoint that is a more accurate predictor of TE after VAD implantation. Further trials that incorporate the F1.2 marker into anticoagulation algorithms may help reduce adverse events in this high-risk population.