Abstract
Low molecular weight heparins (LMWH) are replacing unfractionated heparin (UH) as safe and effective agents for the prevention and treatment of thromboembolism. Although LMWH offer many advantages over UH, usage is less clearly defined in certain special populations, including renal dysfunction, obesity and pregnancy. This article will briefly review the pharmacology of LMWH and discuss usage in these special populations.
UH is a large molecule consisting of a heterogeneous mixture of sulfated polysaccharide chains. 1 Low molecular weight heparins (LMWH) are produced by fragmenting the unfractionated heparin (UH) into a mixture of shorter chains with a molecular size approximately one third that of UH.
Both UH and LMWH produce their antithrombotic effect by activating antithrombin III, which in turn has inhibitory effects on factors IIa (thrombin) and Xa. 1-3 However, the major difference in the mechanisms of LMWH and UH are the relative degrees to which these two factors are inhibited. UH is a strong inhibitor of both factor IIa and factor Xa. In contrast, LMWH are primarily factor Xa inhibitors with relatively little anti-IIa activity. These differences result directly from the shorter chain lengths of LMWH, which limit the ability to bind factor IIa.
In the clinical setting, LMWH have several advantages over UH. LMWH have better bioavailability, two-to-fourfold longer half-lives and dose-independent elimination. 2 Unlike UH, LMWH are not extensively bound to plasma proteins, including platelet factor 4, histidine-rich glycoprotein, fibronectin, vitronectin, and vonWillebrand factor. 2 When administered in standard doses, LMWH do not alter platelet aggregation, fibrinolysis or global clotting tests. Thus, monitoring of coagulation tests such as the prothrombin time, activated partial thromboplastin time, or thrombin time is not required with LMWH. 2,3 As a result of these pharmacokinetic differences, standard doses of LMWH administered once or twice daily produce predictable antithrombotic responses in most patients. Finally, use of LMWH may facilitate outpatient treatment, which in turn may reduce patient costs.
The potential adverse effects of LMWH are similar to UH and include bleeding, thrombocytopenia, elevated liver enzymes, skin reactions and osteoporosis. 1,3 In comparative trials, bleeding complications with LMWH have consistently been found to be equivalent to or less than those of UH. A potentially dangerous form of heparin-induced thrombocytopenia (HIT), which is associated with antibody formation and an increased risk of thrombosis, may occur with either UH or LMWH, but the incidence appears to be significantly lower with LMWH. Nonetheless, in patients with a history of antibody-positive HIT, LMWH should be avoided. Like UH, prolonged use (eg, more than 6 months) of LMWH has been associated with reductions in bone density and fractures, although the overall risk appears to be lower. Local skin reactions may occur with either UH or LMWH when given by the subcutaneous route.
Three LMWH approved by the Food and Drug Administration (FDA) are dalteparin, enoxaparin, and tinzaparin. 4 (A fourth LMWH, ardeparin, is approved by the FDA only for deep vein thrombosis prophylaxis). Both dalteparin and enoxaparin are approved for prophylaxis or treatment of a variety of venous and arterial thromboembolic disorders. Tinzaparin is approved only for the treatment of deep venous thrombosis. Because of differences in the relative anti-Xa/IIa activity among various LMWH, these agents are not considered therapeutically equivalent and cannot be used interchangeably.
Practice guidelines of the American College of Chest Physicians (ACCP) support the use of LMWH as an alternative to UH for both prevention and treatment of venous thromboembolism (VTE). 5,6 These recommendations are based on strong clinical trial evidence demonstrating equivalent or superior efficacy and safety of LMWH as compared with UH in various medical and surgical patient populations. The ACCP guidelines also recommend LMWH as an alternative to UH for patients with acute coronary syndromes (ACS). 7 The 2002 practice guidelines of the American Heart Association and American College of Cardiology (AHA/ACC) recommend LMWH and specifically enoxaparin as the heparin of choice for patients with unstable angina or non-ST-segment elevation myocardial infarction, including those undergoing catheterization and possible percutaneous coronary interventions. 8 LMWH is preferred over UH unless coronary artery bypass graft surgery is planned within 24 hours. For ACS patients, enoxaparin is the LMWH of choice based on studies demonstrating superior outcomes as compared with those of UH, tinzaparin, or dalteparin. 9-11