Antithrombins

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HEPARIN Heparin is a specific antithrombin agent.23 As already discussed, thrombin generation plays an intricate role in the pathogenesis of coronary artery thrombosis. Thrombin converts soluble fibrinogen to insoluble fibrin; activates coagulation factors V and VIII, which exert positive feedback on coagulation through the prothrombinase complex; and activates factor XIII, which stabilizes thrombus formation by promoting fibrin cross-linking. In addition, thrombin serves as a platelet agonist.

Unfractionated heparin consists of a mixture of molecules with molecular weights varying between 2000 and 20,000. The different-sized molecules have different effects on the coagulation system. Heparin complexes with antithrombin III, and this complex inactivates both thrombin and activated factor X. The heparin-antithrombin III complex is not effective against clot-bound thrombin. Heparin reduces the risk of AMI and death during the acute phase of unstable angina. 26 The combination therapy of aspirin and heparin reduces the short-term risk of death or myocardial infarction by 56 percent, compared with aspirin alone. 26 When heparin is used in combination with aspirin, reactivation of ischemia is prevented after cessation of the heparin infusion. 27 Thus, combination therapy with aspirin and heparin is indicated for patients with ACS not treated with fibrinolytic agents.

For patients who have been treated with aspirin and fibrinolytic therapy, the incremental value of the addition of heparin is small. The 35-day mortality rate is not improved, and the rate of major or severe bleeding is slightly increased.

Unfractionated heparin has some limitations. It has an unpredictable anticoagulant response because the bioavailability of heparin is variable. It requires careful laboratory monitoring and dose adjustment.

LOW-MOLECULAR-WEIGHT HEPARINS The low-molecular-weight heparins (LMWHs) have greater bioavailability, lower protein binding, a longer half-life, and achieve a more reliable anticoagulant effect. As a result, they can be administered in a fixed dose subcutaneously once or twice a day and achieve a stable therapeutic response without the need for monitoring anticoagulation.

Several clinical trials have compared LMWH to standard heparin regimens for treatment of ACS. The ESSENCE trial randomized 31Z1 patients with unstable angina and non-Q-wave myocardial infarction to treatment with aspirin and either subcutaneous enoxaparin (LMWH) or intravenous unfractionated heparin. 28 At 14 and 30 days, the risk of death, AMI, or recurrent angina was more than 15 percent lower in patients who received LMWH, without an increase in major bleeding complications.28 The dose of enoxaparin for treatment of ACS is 1 mg/kg body weight. The dose may change depending upon results of ongoing trials.

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