Persistent thrombin generation during heparin therapy in patients with acute coronary syndromes

Intravenous heparin, a fundamental therapy in the treatment of patients with acute coronary syndromes, acts by inhibiting thrombin and activated factors X, IX, XI, and XII. It has also been demonstrated that heparin reduces plasma fibrinopeptide A, a marker of thrombin activity, but it is unknown whether it decreases prothrombin fragment 1+2, an indirect marker of thrombin generation. We measured the plasma levels of prothrombin fragment 1+2, fibrinopeptide A, and antithrombin III in 64 consecutive patients with unstable angina or myocardial infarction receiving intravenous heparin. Blood samples were obtained at baseline (before any treatment) and then at 90 minutes and 24 and 48 hours after the administration of an intravenous bolus of heparin (5000 IU) followed by a continuous infusion of 1000 IU per hour to maintain activated partial thromboplastin time at more than double its baseline levels. In comparison with baseline, there was a significant decrease in fibrinopeptide A at 90 minutes and at 24 and 48 hours (baseline, 2.3 nmol/L; 90 minutes, 1.15 nmol/L; 24 hours, 1.4 nmol/L; 48 hours, 1.2 nmol/L; P<.0001) but no change in prothrombin fragment 1+2 levels (baseline, 1.27 nmol/L; 90 minutes, 1.3 nmol/L; 24 hours, 1.33 nmol/L; 48 hours, 1.29 nmol/L; P=NS). Antithrombin III activity decreased at 24 and 48 hours (baseline, 108%; 24 hours, 97%; 48 hours, 95%; P<.0001). Hence, in patients with acute coronary syndromes, intravenous heparin at a dose reaching an activated partial thromboplastin time that adequately suppresses thrombin activity does not suppress increased thrombin generation.