A B Hirsh and Levine Heparin

HE IMPETUS for the development of low molecular T weight heparins (LMWHs) as potential antithrombotic agents came from two observations in the mid 1970s and early 1980s. The first was the finding that LMWH fractions prepared from standard commercial grade heparin (SH) progressively lose their ability to prolong the activated partial thromboplastin time (APT") while retaining their ability to inhibit activated factor X (factor Xa).'.' The second was the observation that, for an equivalent antithrombotic effect, LMWHs produce less bleeding in experimental models than SH.-"8 Since then considerable progress has been made. The mechanism for the difference between the anticoagulant profiles of LMWHs and SH has been elucidatedY-is and studies of platelet function"-'"." and vascular permeability'" have provided plausible explanations for the reduced experimental bleeding observed with LMWHs. Important differences between LMWHs and SH have been found in their plasma recovery (bioavailability) at low doses,21,22 in their pharmacokinetic^^^^^' and in the variability of their anticoagulant response to fixed doses.28 A number of LMWHs have been developed commercially and have been shown to be safe and effective for the prevention and treatment of venous thromboembolism, and at least five different LMWHs are licensed for clinical use in Europe. Large multicenter trials have been completed in Canada and the United States, but as yet LMWHs are not approved for routine clinical use in North America. In this report, we review the anticoagulant, antithrombotic, hemorrhagic, pharmacokinetic, and clinical effects of LMWHs and, where appropriate, compare and contrast the properties of the LMWHs with SH. binding s e q ~ e n c e ~ " ~ ~ * Only about one third of the SH molecules contain the unique pentasaccharide sequence, and its distribution along the heparin chain appears to be r a n d ~ m . ~ , ~ ' ~ ~ ' T h e major anticoagulant effect of SH is through its interaction with ATIII."-46 This interaction produces a conformational change in ATII147-4y and so markedly accelerates the ability of ATIII to inactivate the coagulation enzymes thrombin (Ha), factor Xa, and factor IXa.34 Of these enzymes, thrombin is most sensitive to inhibition by heparin, both because ATIII inhibits thrombin more rapidly than factor Xa'41n+s' and because factor Xa is protected from inhibition by the ATIII/heparin when it is bound to phospholipid in the prothrombinase c o m p l e ~ . ~ ~ ~ ~ Heparin potentiates the inactivation of thrombin by serving as a template to which both ATIII and thrombin bind to form a ternary complex.34~45~46~s6~s' In contrast, the accelerated inactivation of factor Xa by hepariniATII1 does not require ternary complex formation but is achieved solely through heparin binding to AT111.29~"*37~39~58 Heparin molecules with fewer than 18 saccharides (MW < 5,400) are unable to bind thrombin and AT111 simultaneously and, therefore, are unable to accelerate the inactivation of thrombin by ATIII, but retain their ability to catalyze the inhibition of factor Xa by ATIII'",'','' (Fig 1 and Table 1). The anticoagulant activity of SH is also mediated by a second plasma cofactor, heparin cofactor I1 (HCII)." This anticoagulant effect is specific for thrombin, does not require the unique ATIII-binding pentasaccharide, and requires a minimum chain length of 24 monosaccharide units (MW 7,200).6n-63 LMWHs are fragments of commercial grade SH produced by either chemical or enzymatic dep~lymerization.~~ Depolymerization of heparin invariably leads to partial loss