Perspectives in Drug Discovery and Design, 1 (1993) 479-501
Mechanism of action of heparin and heparin-likeantithrombotics
Steven T. Olsona'* and Ingemar
"Center or Molecular Biology of Oral Diseases and Department of Biochemistry, University of Illinois at Chicago,801 S. Paulina, Chicago, IL 60612, US.A.bDepartment of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, S-751 23 Uppsala, Sweden
Received 25 January 1994Accepted 5 February 1994
Heparin; Low-molecular-weightheparin; Pentasaccharide; Antithrombin; Anticoagulant;Heparin cofactor II; Thrombin; Factor Xa; ThrombosisSUMMARYThe anticoagulant properties of the glycosaminoglycan heparin have made it an invaluable drug for theprophylaxis and treatment of thrombosis. These properties result from the ability of the polysaccharide toenhance the rate of inactivation of blood coagulation proteinases by their natural protein inhibitors, themost important of which is antithrombin. An understanding of the molecular mechanisms underlying theantithrombotic action has allowed the dissociation of the specific anticoagulant effects of heparin from othernonspecific interactions with plasma proteins, platelets and the vascular endothelium, which contribute tocertain undesirable features of heparin anticoagulant therapy. The latter include poor bioavailability aftersubcutaneous administration, rapid clearance, substantial patient-to-patient variability in the amount ofheparin that produces a therapeutic effect, and the risk of bleeding, all of which necessitate careful monitor-ing of therapy to insure safety. Such nonspecific interactions are greatly reduced in low-molecular-weightheparins, produced by enzymatic or chemical depolymerization of standard heparin, as well as in othernatural, semi-synthetic or synthetic polysaccharides or heparinoids which preferentially activate heparincofactor II, a thrombin-specific inhibitor. These derivative heparin or heparin-like substances have shownpromise of an enhanced benefit-to-risk ratio over standard heparin due to their ability to achieve the sameantithrombotic effect with less variability in the therapeutic dosage, a reduced frequency of administrationand a lowered risk of bleeding. The nonspecific effects of standard heparin appear to be virtually eliminatedwith synthetic pentasaccharides which duplicate or mimic a specific binding region in heparin for antithrom-bin. Such pentasaccharides specifically activate antithrombin to neutralize factor Xa and have lost the abilityto activate the inhibitor to neutralize thrombin, due to the requirement for both antithrombin and thrombinto bind to a single heparin chain for such activation. Nevertheless, these pentasaccharides produce anantithrombotic effect equivalent to that of standard heparin, with a predictable long-lasting action andwithout any significant risk of bleeding in a number of animal models of thrombosis. Such agents thuspromise to retain the advantages of heparin efficacy, without the disadvantages that compromise the safetyof therapy. They may indeed replace low-molecular-weight heparins and heparinoids as the next generationof heparin antithrombotics.*To whom correspondence should be addressed.0928-2866/$10.00 © 1994 ESCOM Science Publishers B.V.