Comparative Efficacy of Different Low-Molecular-Weight Heparins (LMWHs) and Drug Interactions with LMWH: Implications for Management of Vascular Disorders

ABSTRACT

The low-molecular-weight heparins (LMWHs) are more efficacious and safer than unfractionated heparin (UFH) in the prevention and treatment of venous thrombosis and to a certain extent in the treatment of acute ischemic syndromes. Because of their predictable pharmacokinetics and bioavailability after subcutaneous administration, LMWHs can be more convenient for outpatient use than UFH. Differences in the manufacturing process of LMWHs result in significant structural and molecular weight differences; thus, LMWHs have individual biochemical and pharmacological profiles and are not interchangeable on the basis of either mass or anti-Xa activity. Using thromboelastograph (TEG) and platelet aggregometry, this investigation compared the in vitro efficacy among various LMWHs and examined the interactions between LMWHs and platelet glycoprotein (GP) IIb/IIIa antagonists. TEG was used to determine the ability of platelet and fibrin interactions to augment blood clots, an effect measured under conditions of maximal platelet activation during clot formation accelerated by recombinant human tissue factor (TF). The comparative efficacy of LMWHs on different mediator-induced clot retraction in human blood was assessed by TEG, which demonstrated the potency of different LMWHs to inhibit various mediator-induced clot formations under shear. Tinzaparin was relatively more effective in inhibiting TF-, lipopolysaccharide-, factor (f) Xa-, and thrombin-induced clot formation under shear. Under these conditions, platelets significantly enhance clot strength (eightfold vs. platelet-free fibrin clots). LMWHs appear to have broader efficacy than other anticoagulants. Abciximab and roxifiban further inhibited clot strength by affecting the transmission of platelet contractile force to fibrin by platelet GPIIb/IIIa receptors. Subtherapeutic doses of tinzaparin combined with abciximab or roxifiban resulted in a distinct synergy that improved anticoagulant and antiplatelet efficacy mediated by TF, fXa, or thrombin. As these data suggest, the combination of low-dose tinzaparin with low-dose GPIIb/IIIa antagonists (abciximab, roxifiban) may be efficacious in the prevention and treatment of various thromboembolic disorders.

Low-molecular-weight heparin - platelet GPIIb/IIIa antagonists - tinzaparin - Thromboelastograph^℗ - tissue factor - platelet aggregation

REFERENCES

• 1 Mousa S A, Bennett J S. Platelets in health and disease: Platelet GPIIb-IIIa structure and function: Recent advances in antiplatelet therapy.  Drugs of the Future . 1996;  21 1141-1154
• 2 Mousa S A. Antiplatelet therapies: From aspirin to GPIIb/IIIa-receptor antagonists and beyond.  Drug Discovery Today . 1999;  4 552-561
• 3 Ashby B, Daniel J L, Smith J B. Mechanisms of platelet activation and inhibition. In: Page CP, ed. The Platelet in Health and Disease Oxford, UK: Blackwell Science 1991: 1-26
• 4 Pytela R, Pierschbacher M D, Ginsberg M H, Plow E F, Ruoslahti E. Platelet membrane glycoprotein IIb/IIIa: Member of a family of Arg-Gly-Asp-specific adhesion receptors.  Science . 1986;  231 1559-1562
• 5 Phillips D R, Charo I F, Scarborough R M. GPIIb-IIIa: The responsive integrin.  Cell . 1991;  65 359-362
• 6 The EPIC Investigation. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty.  N Engl J Med . 1994;  330 956-961
• 7 Mousa S A, Topol E J. Novel antiplatelet therapies: Recent advances in the development of platelet GPIIb/IIIa receptor antagonists. In: Holmes DR, Serruys PW, eds. Current Review of Interventional Cardiology, 3rd ed Philadelphia: Current Science 1997: 114-129
• 8 Coller B S, Folts J D, Scudder L E, Smith S R. Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model.  Blood . 1986;  68 783-786
• 9 Tcheng J E. Platelet glycoprotein IIb/IIIa integrin blockade: Recent clinical trials in interventional cardiology.  Thromb Haemost . 1997;  78 205-209
• 10 Peerlinck K, De Lepeleire I, Goldberg M. MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man.  Circulation . 1993;  88(4 pt 1) 1512-1517
• 11 Tcheng J E, Harrington R A, Kottke-Marchant K. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrelin in elective coronary intervention.  Circulation . 1995;  91 2151-2157
• 12 Mousa S A, Forsythe M, Lorelli W. Novel nonpeptide antiplatelet glycoprotein IIb/IIIa receptor antagonist, DMP754: Receptor binding affinity and specificity.  Coron Artery Dis . 1996;  7 767-774
• 13 Narjes H, Weisenberger H, Muller T H, Deichsel G, Krause J. Tolerability and platelet fibrinogen receptor occupancy (FRO) after oral treatment with bibu-104-xx in healthy-volunteers [abstract].  Thromb Haemost . 1995;  73 1315
• 14 Mousa S A, Bozarth J M, Lorelli W. Antiplatelet efficacy of XV459, a novel nonpeptide platelet GPIIb/IIIa antagonist: Comparative platelet binding profiles with c7E3.  J Pharmacol Exp Ther . 1998;  286 1277-1284
• 15 Fareed J, Jeske W, Hoppensteadt D, Clarizio R, Walenga J M. Low-molecular-weight heparins: Pharmacologic profile and product differentiation.  Am J Cardiol . 1998;  82 3L-10L
• 16 Young E, Wells P, Holloway S, Weitz J, Hirsh J. Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin.  Thromb Haemost . 1994;  71 300-304
• 17 Frydman A. Low-molecular-weight heparins: An overview of their pharmacodynamics, pharmacokinetics and metabolism in humans.  Haemostasis . 1996;  26(suppl 2) 24-38
• 18 Hoppensteadt D A, Jeske W, Fareed J, Bermes Jr W E. The role of tissue factor pathway inhibitor in the mediation of the antithrombotic actions of heparin and low-molecular-weight heparin.  Blood Coagul Fibrinolysis . 1995;  6(suppl 1) S57-S64
• 19 Hull R, Raskob G, Pineo G. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation.  N Engl J Med . 1993;  329 1370-1376
• 20 Hull R D, Pineo G F, Valentine K A. Treatment and prevention of venous thromboembolism.  Semin Thromb Hemost . 1998;  24(suppl 1) 21-31
• 21 Levine M, Gent M, Hirsh J. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.  N Engl J Med . 1996;  334 677-681
• 22 Hirsh J. Comparison of the relative efficacy and safety of low molecular weight heparin and unfractionated heparin for the treatment of deep venous thrombosis.  Semin Hematol . 1997;  34 (4 suppl4) 20-25
• 23 Simonneau G, Sors H, Charbonnier B. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire.  N Engl J Med . 1997;  337 663-669
• 24 Mousa S A, Khurana S, Forsythe M. Comparative in vitro efficacy of different platelet GPIIb/IIIa antagonists on platelet-mediated clot strength induced by tissue factor using thromboelastography: Differentiation among GPIIb/IIIa antagonists.  Arterioscler Thromb Vasc Biol . 2000;  20 1162-1167