INTRODUCTION: The recommended duration of post-operative Low-Molecular-Weight-Heparins (LMWHs) thromboprophylaxis in Total-Hip-Replacement (THR) and Total-Knee-Replacement (TKR) surgery is controversial. Our aim is to study the thrombin generation (TG) modifications induced by surgery and to evaluate the effect of LMWH on TG during and after the recommended duration.PATIENTS/METHODS: Thirty-one patients received 4000IU anti-Xa/day of enoxaparin, 8-hours post-operatively (15 THR for 30-days and 16 TKR for 15-days). TG assay sensitive to enoxaparin was performed, pre-operatively (D0), 7-hours post-surgery (D1), 8-days post-surgery (D8), and 2-days after thromboprophylaxis withdrawal (D32 and D17), evaluating: lag-time, endogenous thrombin potential (ETP), peak amount of generated thrombin (Peak), time-to-Peak (tt-Peak), and the Mean-Rate-Index [MRI=Peak/(tt-Peak-lag-time)].RESULTS: TKR surgery decreased lag-time and tt-Peak and increased MRI on D1 vs D0 (p<0.05). In contrast, THR did not significantly modify TG. Enoxaparin effectively reduced thrombin generation in both groups. Thromboprophylaxis withdrawal resulted in rebound increase of TG in the TKR patients (ETP, Peak & MRI significantly increased on D17 vs D0; p<0.05, and vs. D1; p<0.05) but not in THR patients. Variability in the response to enoxaparin was observed among patients of the same group.CONCLUSIONS: TKR surgery is more thrombogenic than THR surgery. In THR patients TG was efficiently inhibited by 30-day thromboprophylaxis, whereas, in TKR patients treated for 15-days TG was not effectively inhibited. Individual variability of the response to enoxaparin was observed in both groups revealing some form of biological resistance to enoxaparin. TG assay may represent the breakthrough step to efficient antithrombotic strategy in clinical settings with high thrombotic risk.