Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety.

H eparin is the anticoagulant of choice when a rapid anticoagulant effect is required because its onset of action is immediate when administered by intravenous injection. Heparin is administered in low doses when used for primary prophylaxis and high doses when used therapeutically to prevent recurrent thrombosis. Its use is almost always limited to an in-hospital setting because it must be administered parenterally. When heparin is given in therapeutic doses, its anticoagulant effect must be monitored and the dosage must be adjusted frequently. When long-term anticoagulant therapy is indicated, in-hospital heparin administration is usually followed by treatment with oral anticoagulants. A period of overlap of approximately four days should be used, during which time both anticoagulants are given in combination. Long-term out-of-hospital heparin treatment is used when anticoagulant therapy is indicated in pregnancy and in the rare patient who has development of recurrent venous thromboembolism while being treated with appropriate doses of oral anticoagulants. Heparin is effective and indicated for the prevention of venous thromboembolism (level I) (see "Prevention of Venous Thromboembolism" by Clagett et al in this issue), for the treatment of venous thromboembolism (level I) for the early treatment of patients with unstable angina (level I) and acute myocardial infarction (level I) in patients who have cardiac surgery under cardiac bypass (level I) (new chapter), who have vascular surgery (level 111), and in selected patients with disseminated intravascular thrombosis (level III). In this chapter, the mechanism of action of heparin, its pharmacokinetics, anticoagulant effects, and laboratory monitoring will be reviewed. The clinical use of heparin will be summarized briefly since this is discussed in detail in other chapters. In addition, the potential of a new class of heparins, the low molecular weight heparins (LMWHs) will be discussed and their biophysical, pharmacokinetics, antithrombotic, and hemorrhagic properties will be compared with standard heparin. STRUCTURE A N D MECHANISM OF ACTION OF HEPARIN Heparin is a glycosaminoglycan (GAG) composed of chains of alternating residues of D-glucosamine and a uronic acid.' Its major anticoagulant effect is accounted for by a unique pentasaccharide with a high affinity binding sequence to ant i thrombin 111 (ATIII).2-1L The unique sequence is present in only one third of heparin m01ecules.l~~" The anticoagulant effect of heparin is mediated largely through its interaction with ATIII;I4-l7 this produces a conformational change in ATIIIIH-m and so markedly accelerates its ability to inactivate the coagulation enzymes thrombin (factor IIa), factor Xa, and factor IXa.Wf these three enzymes, thrombin is the most sensitive to inhibition by heparin/ATIII .3.21-25 Heparin catalyzes the inactivation of thrombin by ATIII by acting as a template to which both the enzyme and inhibitor bind to form a ternary comp l e ~ . ~ . ~ ~ ' ~ . ~ ~ ~ " In contrast, the inactivation of factor Xa by ATIIVheparin complex is achieved by binding of the enzyme to ATIII only and does not require ternary complex formation. 1*3.6.7.g.W Heparin molecules that contain fewer than 18 saccharides are unable to bind thrombin and ATIII simultanbbusly and, therefore, are unable to accelerate the inactivation of thrombin by ATIII, but retain their ability to catalyze the inhibition of factor Xa by ATIIIn.28J" (Fig 1). Heparin also catalyzes the inactivation of thrombin by a second plasma cofactor, heparin cofactor I1 (HCII).=I This second anticoagulant effect of heparin is specific for thrombin, it does not require the unique ATIII-binding pentasaccharide, and it is achieved only at very high doses of h e ~ a r i n . ~ ~ ~ ~ Heparin is heterogeneous w& respect to molecular size, anticoagulant activity, and pharmacokinetic properties. The molecular weight of heparin ranges from 5,000 to 30,000 with a mean molecular weight of 15,000 (approximately 50 monosaccharide chains).The anticoagulant activity of heparin is heterogeneous because of the following: (1) only one third of the heparin molecules administered to patients have anti-