Rebound thrombin generation after heparin therapy in unstable angina: A randomized comparison between unfractionated and low-molecular-weight heparin

Objectives This study compared rebound coagulation in patients with acute coronary syndrome patients after discontinuation of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Background Up to a quarter of patients hospitalized for unstable angina experience recurrent ischemia after discontinuation of UFH or LMWH therapy, which may be the result of rebound coagulation activation and subsequent thrombosis. It is unknown whether UFH and LMWH differ in this respect. Methods We randomized 71 patients admitted with unstable angina to intravenous UFH or subcutaneous LMWH (dalteparin) and measured plasma markers of coagulation before, during, and after treatment. Results A complete series of measurements was obtained in 59 patients. Plasma prothrombin fragment 1+2 (F1+2) levels decreased in both groups during treatment. After loss of therapeutic plasma drug levels, F1+2 increased (within 3 h) to a maximum level at 12 to 24 h that was higher than before or during treatment in both groups (p < 0.0001). In both groups, F1+2 levels remained higher than pretreatment up to 24 h after discontinuation. Similarly, thrombin-antithrombin (TAT) levels exceeded treatment and pretreatment levels, at a slower rate after dalteparin than after UFH. However, after dalteparin a higher peak value of TAT was observed. Conclusions Rebound coagulation activation occurs within hours after discontinuation of both UFH and dalteparin. With both drugs, thrombin generation is significantly greater after treatment than before or during treatment. A longer duration or weaning of treatment, or continuation with another anticoagulant treatment, may reduce rebound coagulation activation and ischemic events.