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Semin Thromb Hemost 2000; Volume 26(Number s1): 005-022
DOI: 10.1055/s-2000-9498
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

An Update on Heparins at the Beginning of the New Millennium

Jawed Fareed1 , Debra A. Hoppensteadt1 , Rodger L. Bick2
  • 1Hemostasis & Thrombosis Research Laboratories, Department of Pathology and Pharmacology, Loyola University Medical Center, Maywood, Illinois
  • 2University of Texas Southwestern Medical School, Dallas, Texas
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Publication History

Publication Date:
31 December 2000 (online)

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ABSTRACT

Unfractionated heparin has enjoyed the sole anticoagulant status for almost half a century. Besides an effective anticoagulant, this drug has been used in several additional indications. Despite the development of newer anticoagulant drugs, unfractionated heparin has remained the drug of choice for surgical anticoagulation and interventional cardiology. In the area of hematology and transfusion medicine, unfractionated heparin has continued to play a major role as an anticoagulant drug. The development of low-molecular-weight heparins (LMWHs) represents a refinement for the use of heparin. These drugs represent a class of depolymerized heparin derivatives with a distinct pharmacologic profile that is largely determined by their composition. These drugs produce their major effects by combining with antithrombin and exerting antithrombin and anti-Xa inhibition. In addition, the LMWHs also increase non-antithrombin-dependent effects such as TFPI release, modulation of adhesion molecules, and release of profibrinolytic and antithrombotic mediators from the blood vessels. The cumulative effects of each of the different LMWHs differ and each product exhibits a distinct profile. Initially these agents were developed for the prophylaxis of postsurgical deep-vein thrombosis. However, at this time these drugs are used not only for prophylaxis, but also for the treatment of thrombotic disorders of both the venous and arterial type. To a large extent, the LMWHs have replaced unfractionated heparin in most subcutaneous indications. With the use of these refined heparins, outpatient anticoagulant management has gone through a dramatic evolution. For the first time, patients with thrombotic disorders can be treated in an outpatient setting. Thus, the introduction of LMWHs represents a major advance in improving the use of heparin. The development of the oral formulation of heparin and LMWHs also provides an important area that may impact on the use of heparin and LMWHs. The increased awareness of heparin-induced thrombocytopenia has necessitated the development of newer methods to identify patients at risk of developing this catastrophic syndrome. Furthermore, a strong interest has developed in alternate drugs or the management of patients with this syndrome. Despite the development of alternate anticoagulants that are mostly antithrombin derived (hirudins, hirulog), these agents have failed to provide similar clinical outcome as heparin in many indications. However, antithrombin drugs are useful in the anticoagulant management of heparin-compromised patients. The FDA has approved a recombinant hirudin (Refludan℗) and a synthetic antithrombin agent, argatroban (Novastan℗), for this indication. The development of synthetic heparin pentasaccharide and anti-Xa agents may have an impact on the prophylaxis of thrombotic disorders. However, these monotherapeutic agents do not mimic the polytherapeutic actions of heparin. Furthermore, these agents do not inhibit thrombin. Heparin and LMWHs are capable of inhibiting not only factor Xa and thrombin, but other serine proteases in the coagulation network. The only way the newer drugs can mimic the actions of heparin is in combination modalities (polytherapeutic approaches).

It has been suggested that newer antiplatelet drugs also exhibit anticoagulant actions. While these drugs may exhibit weak effects on thrombin generation, none of the currently available antiplatelet drugs exhibit any degree of antithrombin actions. It is likely that heparins synergize or augment the effects of the new antiplatelet drugs. Currently, combination approaches are used to anticoagulate patients in these studies. The dosage of heparins has been arbitrarily reduced. This may not be an optimal procedure. Additional clinical studies are needed to study these combinations where the alterations of these drugs are compared. Such combinations will require newer monitoring approaches. The development of oral thrombin agents, GP IIb/IIIa inhibitors, has met with some significant obstacles. Thus, it is unlikely that this approach will be very feasible in the indications where heparins are used. It is fair to state that heparins will continue to play a major role in the overall management of thrombotic disorders in monotherapeutic and polytherapeutic modalities.

KEYWORD

Heparin - LMW heparin - heparinomimetics - pentasaccharide - tissue factor pathway inhibitor

REFERENCES

  • 1 Fareed J, Walenga J M, Pifarre R. Newer approaches to the pharmacologic management of acute myocardial infarction.  Cardiac Surgery: State of the Art Reviews . 1992;  6 101-112
    PubMedGoogle Scholar
  • 2 Fareed J, Bacher P, Messmore H L. Pharmacological modulation of fibrinolysis by antithrombotic and cardiovascular drugs.  Prog Cardiovasc Dis . 1992;  34 379-398
    PubMedGoogle Scholar
  • 3 Fareed J, Walenga J M, Hoppensteadt D, Racanelli A, Coyne E. Chemical and biological heterogeneity in low molecular weight heparins: Implications for clinical use and standardization.  Semin Thromb Hemost . 1989;  15 440-463
    PubMedGoogle Scholar
  • 4 Walenga J M, Jeske W P, Bara L, Samama M M, Fareed J. Biochemical and pharmacologic rationale for the development of a synthetic heparin pentasaccharide.  Thromb Res . 1997;  86 1-36
    CrossrefPubMedGoogle Scholar
  • 5 Rabah M M, Premmereur J, Graham M. Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris.  Am J Cardiol . 1999;  84 1391-1395
    CrossrefPubMedGoogle Scholar
  • 6 Hirsh J, Warkentin T E, Raschke R. Heparin and low-molecular-weight heparin. Mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety [published erratum appears in Chest 1999 Jun;115:1760].  Chest . 1998;  114(suppl) 489S-510S
    PubMedGoogle Scholar
  • 7 Fareed J. Basic and applied pharmacology of low molecular weight heparins.  Pharmacy Therapeutics . 1995;  20(suppl) 16S-24S
    PubMedGoogle Scholar
  • 8 Fareed J, Walenga J M, Hoppensteadt D, Huan X, Racanelli A. Comparative study on the in vitro and in vivo activities of seven low-molecular-weight heparins.  Haemostasis . 1988;  18(suppl 3) 3-15
    PubMedGoogle Scholar
  • 9 Béguin S, Welzel D, Al Dieri R, Hemker H C. Conjectures and refutations on the mode of action of heparins. The limited importance of anti-factor Xa activity as a pharmaceutical mechanism and a yardstick for therapy.  Haemostasis . 1999;  29 170-178
    CrossrefPubMedGoogle Scholar
  • 10 Kakkar V V, Djazaeri B, Fok J. Low-molecular-weight heparin and prevention of postoperative deep vein thrombosis.  BMJ (Clin Res Ed) . 1982;  284 375-379
    PubMedGoogle Scholar
  • 11 Koopman M MW, Prandoni P, Piovella F. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home.  N Engl J Med . 1996;  334 682-687
    CrossrefPubMedGoogle Scholar
  • 12 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
    CrossrefPubMedGoogle Scholar
  • 13 Samama M M, Cohen A T, Darmon J-Y. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients.  N Engl J Med . 1999;  341 793-800
    CrossrefPubMedGoogle Scholar
  • 14 Zacharski L R, Ornstein D L. Heparin and cancer.  Thromb Haemost . 1998;  80 10-23
    PubMedGoogle Scholar
  • 15 Kay R, Wong K S, Yu Y L. Low-molecular-weight heparin for the treatment of acute ischemic stroke.  N Engl J Med . 1995;  333 1588-1593
    CrossrefPubMedGoogle Scholar
  • 16 Gillis S, Dann E J, Eldor A. Low molecular weight heparin in the prophylaxis and treatment of disseminated intravascular coagulation in acute promyelocytic leukemia [letter].  Eur J Haematol . 1995;  54 59-60
    PubMedGoogle Scholar
  • 17 Aguilar D, Goldhaber S Z. Clinical uses of low-molecular-weight heparins.  Chest . 1999;  115 1418-1423
    CrossrefPubMedGoogle Scholar
  • 18 Dalen J E, Hirsh J. Fifth ACCP Consensus Conference on Antithrombotic Therapy.  Chest . 1998;  114(suppl) 439S-769S
    PubMedGoogle Scholar
  • 19 Weitz J I. Low-molecular-weight heparins.  N Engl J Med . 1997;  337 688-698
    CrossrefPubMedGoogle Scholar
  • 20 Fox K AA, Antman E M. Treatment options in unstable angina: A clinical update.  Eur Heart J . 1998;  19(suppl K) K8-K10
    PubMedGoogle Scholar
  • 21 Cohen M, Demers C, Gurfinkel E P. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group.  N Engl J Med . 1997;  337 447-452
    CrossrefPubMedGoogle Scholar
  • 22 The FRAX.I.S. Study Group. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAX.I.S. (FRAXiparine in Ischaemic Syndrome).  Eur Heart J . 1999;  20 1553-1562
    CrossrefPubMedGoogle Scholar
  • 23 Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Low-molecular-weight heparin during instability in coronary artery disease.  Lancet . 1996;  347 561-568
    PubMedGoogle Scholar
  • 24 Cohen M, Demers C, Gurfinkel E P. Low-molecular-weight heparins in non-ST-segment elevation ischemia: the ESSENCE trial.  Am J Cardiol . 1998;  82 19L-24L
    CrossrefPubMedGoogle Scholar
  • 25 Antman E M, McCabe C H, Gurfinkel E P. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 11B trial.  Circulation . 1999;  100 1593-1601
    PubMedGoogle Scholar
  • 26 Hommel M, for The FISS bis Investigators Group. Fraxiparine in Ischaemic Stroke Study (FISS bis).  Cerebrovasc Dis . 1998;  8(suppl 4) ((Abstr)) 19
    PubMedGoogle Scholar
  • 27 Zegers E, Meursing B J, Verheugt F WA. Routine heparinisation during coronary arteriography: is it still indicated?.  J Am Coll Cardiol . 2000;  35 ((Abstr)) 42A
    PubMedGoogle Scholar
  • 28 Hoppensteadt D A, Musabji A, Leya F. Simultaneous administration of glycoprotein IIb/IIIa inhibitors with low-molecular-weight heparins does not augment the release of tissue factor pathway inhibitor: Implications in the management of cardiovascular patients.  J Am Coll Cardiol . 2000;  35 277A ((Abstr))
    CrossrefPubMedGoogle Scholar
  • 29 Le Liboux A, Sanderink G-J, Grosjean P. Enoxaparin pharmacokinetics and pharmacodynamics after intravenous bolus administration alone and at initiation of a subcutaneous dosing regimen.  J Am Coll Cardiol . 2000;  35 373A-374A ((Abstr))
    PubMedGoogle Scholar
  • 30 Matthai W H, Kereiakes D J, Grines C L, Siegel J E. Comparative effects of low molecular weight heparin (with and without abciximab) and unfractionated heparin on antithrombin activity during coronary angioplasty.  J Am Coll Cardiol . 2000;  35 43A ((Abstr))
    PubMedGoogle Scholar
  • 31 Kereiakes D J, Grines C, Fry E. Abciximab-enoxaparin interaction during percutaneous coronary intervention: Results of the NICE 1 and 4 trials.  J Am Coll Cardiol . 2000;  35 92A ((Abstr))
    PubMedGoogle Scholar
  • 32 Dudek D, Bartus S, Zymek P. Abciximab and enoxaparin administration during elective high-risk PTCA in patients with more than 3 days of ticlopidine pretreatment.  J Am Coll Cardiol . 2000;  35 91A ((Abstr))
    PubMedGoogle Scholar
  • 33 Lau W C, Bates E R, Carville D GM. Rapid platelet function assessment using two concentrations of adenosine diphosphate after clopidogrel loading in patients undergoing cardiac catheterization.  J Am Coll Cardiol . 2000;  35 43A ((Abstr))
    PubMedGoogle Scholar
  • 34 Ross A. A randomized comparison of low-molecular-weight heparin and unfractionated heparin adjunctive to t-PA thrombolysis and aspirin (HART-II). ACC Scientific Session 2000. www.medscape.com/Medscape/CNO/2000/ACC/Story.cfm?story_id=1140. Accessed April 10, 2000
    Google Scholar
  • 35 Coussement P K. SR9010A/ORG31540, a new synthetic pentasaccharide, as an adjunct to fibrinolysis in ST-elevation acute myocardial infarction: The PENTALYSE study. ACC Scientific Session 2000. www.medscape.com/medscape/CNO/2000/ACC/Story.cfm?story_id=1140. Accessed April 10, 2000
    Google Scholar
      >