REBOUND INCREASE IN THROMBIN GENERATION AND ACTIVITY AFTER CESSATION OF INTRAVENOUS HEPARIN IN PATIENTS WITH ACUTE CORONARY SYNDROMES

Background The abrupt cessation of heparin and other thrombin inhibito rs when used to treat acute coronary syndromes has been accompanied by a clustering of thrombotic events. It is unknown whether these events are the result of inadequate antithrombin therapy or whether they rep resent a rebound increase in thrombin activity. This study was designe d to determine whether there is a true rebound, as defined by an incre ase followed by a subsequent decrease, in thrombin activity after disc ontinuation of intravenous heparin therapy. Methods and Results Thirty -five patients with recent acute myocardial infarction or unstable ang ina who had received at least 48 hours of intravenous heparin were stu died. Patients underwent ST-segment monitoring, and blood samples for determination of thrombin generation and activity were drawn at 0, 3, 6, 10, and 24 hours after heparin discontinuation. Median aPTT was 65 seconds before heparin discontinuation. Median fibrinopeptide A increa sed from 9.5 to 16.9 ng/mL at 3 hours (P<.0004) and returned to 10.5 b y 24 hours. Prothrombin fragment 1.2 likewise transiently increased, f rom 0.34 to 0.51 nmol/L at 6 hours (P<.0002). Modified antithrombin II I decreased over time (P<.002), and activated protein C increased from 2.3 to 4.5 ng/mL at 3 hours (P<.001). Although there were no clinical thrombotic events in the first 24 hours, 4 patients had evidence of i schemia by ST-segment monitoring at a median of 12 hours after heparin discontinuation. The degree of increase in fibrinopeptide A and proth rombin fragment 1.2 was not found to be associated with baseline diagn osis, duration of heparin therapy, baseline level of antithrombin III, or activated protein C.Conclusions This study demonstrates a transien t rebound increase in thrombin activity as well as in activated protei n C upon abrupt discontinuation of intravenous heparin. Clinicians sho uld be vigilant for associated thrombotic events. Further investigatio n of the significance, mechanism, and possible prevention of this rebo und phenomenon is needed.