Download PDF
Semin Respir Crit Care Med 2000; 21(6): 523-532
DOI: 10.1055/s-2000-13185
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Low Molecular Weight Heparins: Background and Pharmacology

Timothy A. Morris
  • Division of Pulmonary and Critical Care Medicine, University of California, San Diego Medical Center, San Diego, California
Further Information

Publication History

Publication Date:
31 December 2000 (online)

    Permissions and Reprints

ABSTRACT

Low molecular weight heparins (LMWHs) are a class of drugs designed to improve on the therapeutic effects and complications of unfractionated heparin (UH). The two drug types share many structural properties and have multiple mechanisms of action in common. The relative potencies with which the mechanisms are expressed differ between LMWH and UH and among specific LMWHs. The pharmacokinetics of LMWHs and UH are often compared according to the results of plasma activity against purified factor Xa, although the correlation between ``anti-Xa'' assays and the actual mechanisms of action of the drugs is questionable. Animal models of thrombosis give some information regarding the antithrombotic efficacy of different LMWHs compared with UH and with other LMWHs, but the results are varied and may not be applicable to human thrombosis. Similarly, clinical measurements of clot suppression have yielded conflicting results when the two types of anticoagulants have been directly compared. Numerous clinical outcome studies support the conclusion that subcutaneous regimens of LMWH (and of UH) are at least as effective and safe as intravenous UH for the treatment of clinically stable patients with venous thromboembolism. However, the superiority of one subcutaneous regimen over the others can be established only by the performance of well-planned comparative clinical trials.

KEYWORD

Pulmonary embolism - deep venous thrombosis - anticoagulation - heparin - low molecular weight heparin

REFERENCES

  • 1 Linhardt R J, Gunay N S. Production and chemical processing of low molecular weight heparins.  Semin Thromb Hemost . 1999;  25(Suppl 3) 5-16
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Casu B, Torrington K G. Structural characterization of low molecular weight heparins.  Semin Thromb Hemost . 1999;  25(Suppl 3) 17-25
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Jeske W, Fareed J. In vitro studies on the biochemistry and pharmacology of low molecular weight heparin.  Semin Thromb Hemost . 1999;  25(Suppl 3) 27-33
    PubMedSearch in Google Scholar
  • 4 Anand S, Ginsberg J S, Kearon C, Gent M, Hirsh J. The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous heparin.  Arch Intern Med . 1996;  156 1677-1681
    CrossrefPubMedSearch in Google Scholar
  • 5 Wester J P, de Valk W H, Nieuwenhuis H K. Risk factors for bleeding during treatment of acute venous thromboembolism.  Thromb Haemost . 1996;  76 682-688
    PubMedSearch in Google Scholar
  • 6 Hirsch D R, Lee T H, Morrison R B, Carlson W, Goldhaber S Z. Shortened hospitalization by means of adjusted-dose subcutaneous heparin for deep venous thrombosis.  Am Heart J . 1996;  131 276-280
    CrossrefPubMedSearch in Google Scholar
  • 7 Gould M K, Dembitzer A D, Sanders G D, Garber A M. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A cost-effectiveness analysis.  Ann Intern Med . 1999;  130 789-799
    PubMedSearch in Google Scholar
  • 8 Hirsh J, Levine M N. Low molecular weight heparin.  Blood . 1992;  79 1-17
    PubMedSearch in Google Scholar
  • 9 Carter C J, Kelton J G, Hirsh J, Cerskus A, Santos A V, Gent M. The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits.  Blood . 1982;  59 1239-1245
    PubMedSearch in Google Scholar
  • 10 Dolovich L R, Ginsberg J S, Dpiletos J D, Holbrook A M, Cheah G. A meta-analysis comparing low-molecular-weight heparin with unfractionated heparin in the treatment of venous thromboembolism.  Arch Intern Med . 2000;  160 181-188
    CrossrefPubMedSearch in Google Scholar
  • 11 Bendetowicz A V, Beguin S, Caplain H, Hemker H C. Pharmacokinetics and pharmacodynamics of a low molecular weight heparin (enoxaparin) after subcutaneous injection, comparison with unfractionated heparin: a three way cross over study in human volunteers.  Thromb Haemost . 1994;  71 305-313
    PubMedSearch in Google Scholar
  • 12 Majerus P W, Broze G J, Miletich J P, Tollefsen D M. Anticoagulant, thrombolytic and antiplatelet drugs. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. Godman and Gilman's The Pharmacological Basis of Therapeutics New York: Pergamon Press 1990: 1311-1331
    Search in Google Scholar
  • 13 Leizorovicz A, Bara L, Samama M M, Haugh M C. Factor Xa inhibition: Correlation between the plasma levels of anti-Xa activity and occurrence of thrombosis and haemorrhage.  Haemostasis . 1993;  23(Suppl 1) 89-98
    PubMedSearch in Google Scholar
  • 14 Brieger D, Dawes J. Production method affects the pharmacokinetic and ex vivo biological properties of low molecular weight heparins.  Thromb Haemost . 1997;  77 317-322
    PubMedSearch in Google Scholar
  • 15 Lindhoff-Last E, Mosch G, Breddin H K. Treatment doses of different low molecular weight heparins and unfractionated heparins differ in their anticoagulating effects in respect to aPTT, Heptest, anti-IIa- and anti-Xa-activity.  Lab Med . 1992;  16 174-177
    PubMedSearch in Google Scholar
  • 16 Bara L, Bloch M F, Zitoun D. Comparative effects of enoxaparin and unfractionated heparin in healthy volunteers on prothrombin consumption in whole blood during coagulation, and release of tissue factor pathway inhibitor.  Thromb Res . 1993;  69 443-452
    CrossrefPubMedSearch in Google Scholar
  • 17 Hirsh J. Heparin.  N Engl J Med . 1991;  324 1565-1574
    CrossrefPubMedSearch in Google Scholar
  • 18 Hirsh J, Fuster V. Guide to anticoagulant therapy. Part 1: Heparin. American Heart Association.  Circulation . 1994;  89 1449-1468
    PubMedSearch in Google Scholar
  • 19 Bendetowicz A V, Pacaud E, Baeguin S, Uzan A, Hemker H C. On the relationship between molecular mass and anticoagulant activity in a low molecular weight heparin (enoxaparin).  Thromb Haemost . 1992;  67 556-562
    PubMedSearch in Google Scholar
  • 20 Krishnaswamy S, Mann K G, Nesheim M E. The prothrombinase-catalyzed activation of prothrombin proceeds through the intermediate meizothrombin in an ordered, sequential reaction.  J Biol Chem . 1986;  261 8977-8984
    PubMedSearch in Google Scholar
  • 21 Bovill E G, Tracy R P, Hayes T E, Jenny R J, Bhushan F H, Mann K G. Evidence that meizothrombin is an intermediate product in the clotting of whole blood.  Arterioscler Thromb Vasc Biol . 1995;  15 754-758
    PubMedSearch in Google Scholar
  • 22 Bendetowicz A V, Bara L, Samama M M. The inhibition of intrinsic prothrombinase and its generation by heparin and four derivatives in prothrombin poor plasma.  Thromb Res . 1990;  58 445-454
    CrossrefPubMedSearch in Google Scholar
  • 23 Samama M M, Bara L, Gerotziafas G T. Mechanisms for the antithrombotic activity in man of low molecular weight heparins (LMWHs).  Haemostasis . 1994;  24 105-117
    PubMedSearch in Google Scholar
  • 24 Harenberg J, Stehle G, Blauth M, Huck K, Mall K, Heene D L. Dosage, anticoagulant, and antithrombotic effects of heparin and low-molecular-weight heparin in the treatment of deep vein thrombosis.  Semin Thromb Hemost . 1997;  23 83-90
    PubMedSearch in Google Scholar
  • 25 Padilla A, Gray E, Pepper D S, Barrowcliffe T W. Inhibition of thrombin generation by heparin and low molecular weight (LMW) heparins in the absence and presence of platelet factor 4 (PF4).  Br J Haematol . 1992;  82 406-413
    PubMedSearch in Google Scholar
  • 26 Suh J S, Aster R H, Visentin G P. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis recognize different epitopes on heparin: platelet factor 4.  Blood . 1998;  91 916-922
    PubMedSearch in Google Scholar
  • 27 Weitz J I, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors.  J Clin Invest . 1990;  86 385-391
    CrossrefPubMedSearch in Google Scholar
  • 28 Baeguin 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
    CrossrefPubMedSearch in Google Scholar
  • 29 Kitchen S, Iampietro R, Woolley A M, Preston F E. Anti Xa monitoring during treatment with low molecular weight heparin or danaparoid: inter-assay variability.  Thromb Haemost . 1999;  82 1289-1293
    PubMedSearch in Google Scholar
  • 30 Kovacs M J, Keeney M, MacKinnon K, Boyle E. Three different chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin.  Clin Lab Haematol . 1999;  21 55-60
    CrossrefPubMedSearch in Google Scholar
  • 31 Prager N A, Abendschein D R, McKenzie C R, Eisenberg P R. Role of thrombin compared with factor Xa in the procoagulant activity of whole blood clots.  Circulation . 1995;  92 962-967
    CrossrefPubMedSearch in Google Scholar
  • 32 Barrow R T, Parker E T, Krishnaswamy S, Lollar P. Inhibition by heparin of the human blood coagulation intrinsic pathway factor X activator.  J Biol Chem . 1994;  269 26796-26800
    PubMedSearch in Google Scholar
  • 33 Fareed J, Jeske W, Hoppensteadt D, Clarizio R, Walenga J M. Are the available low-molecular-weight heparin preparations the same?.  Semin Thromb Hemost . 1996;  22 77-91
    PubMedSearch in Google Scholar
  • 34 Hoppensteadt D A, Walenga J M, Fasanella A, Jeske W, Fareed J. TFPI antigen levels in normal human volunteers after intravenous and subcutaneous administration of unfractionated heparin and a low molecular weight heparin.  Thromb Res . 1995;  77 175-185
    CrossrefPubMedSearch in Google Scholar
  • 35 Kong A N, Ludwig E A, Slaughter R L. Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects.  Clin Pharmacol Ther . 1989;  46 616-628
    PubMedSearch in Google Scholar
  • 36 Peteajea J, Fernaandez J A, Gruber A, Griffin J H. Anticoagulant synergism of heparin and activated protein C in vitro. Role of a novel anticoagulant mechanism of heparin, enhancement of inactivation of factor V by activated protein C.  J Clin Invest . 1997;  99 2655-2663
    PubMedSearch in Google Scholar
  • 37 Fernandez J A, Petaja J, Griffin J H. Dermatan sulfate and LMW heparin enhance the anticoagulant action of activated protein C.  Thromb Haemost . 1999;  82 1462-1468
    PubMedSearch in Google Scholar
  • 38 Carrie D, Caranobe C, Gabaig A M, Larroche M, Boneu B. Effects of heparin, dermatan sulfate and of their association on the inhibition of venous thrombosis growth in the rabbit.  Thromb Haemost . 1992;  68 637-641
    PubMedSearch in Google Scholar
  • 39 Carrie D, Caranobe C, Boneu B. A comparison of the antithrombotic effects of heparin and of low molecular weight heparins with increasing antifactor Xa/antifactor IIa ratio in the rabbit.  Br J Haematol . 1993;  83 622-626
    PubMedSearch in Google Scholar
  • 40 Morris T A, Marsh J J, Konopka R G, Pedersen C A, Chiles P G, Moser K M. Ability of low molecular weight heparin to inhibit propagation of deep venous thrombosis.  Am J Respir Crit Care Med . 1995;  151 A528
    PubMedSearch in Google Scholar
  • 41 Tapson V F, Carroll B A, Davidson B L. American Thoracic Society Position Paper: the diagnostic approach to acute venous thromboembolism.  Am J Respir Crit Care Med. in press; 
    PubMedSearch in Google Scholar
  • 42 Fiessinger J N, Lopez-Fernandez M, Gatterer E. Once-daily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis.  Thromb Haemost . 1996;  76 195-199
    PubMedSearch in Google Scholar
  • 43 Ofusu F A, Levine M, Craven S, Dewar L, Shafai S, Blajchman M A. Prophylactically equivalent doses of enoxaprin and unfractionated heparin inhibit in vivo coagulation to the same extent.  Br J Haematol . 1992;  82 400-405
    PubMedSearch in Google Scholar
  • 44 Becker D M, Philbrick J T, Bachhuber T L, Humphries J E. D-dimer testing and acute venous thromboembolism. A shortcut to accurate diagnosis?.  Arch Intern Med . 1996;  156 939-946
    CrossrefPubMedSearch in Google Scholar
  • 45 Miller G J, Bauer K A, Barzegar S. The effects of quality and timing of venepuncture on markers of blood coagulation in healthy middle-aged men.  Thromb Haemost . 1995;  73 82-86
    PubMedSearch in Google Scholar
  • 46 The DVTENOX Study Group. Markers of hemostatic system activation in acute deep venous thrombosis: evolution during the first days of heparin treatment.  Thromb Haemost . 1993;  70 909-914
    PubMedSearch in Google Scholar
  • 47 van Hulsteijn H, Brieet E, Koch C, Hermans J, Bertina R. Diagnostic value of fibrinopeptide A and beta-thromboglobulin in acute deep venous thrombosis and pulmonary embolism.  Acta Med Scand . 1982;  211 323-330
    PubMedSearch in Google Scholar
  • 48 Gando S, Tedo I. Diagnostic and prognostic value of fibrinopeptides in patients with clinically suspected pulmonary embolism.  Thromb Res . 1994;  75 195-202
    CrossrefPubMedSearch in Google Scholar
  • 49 Yung G L, Marsh J J, Berstein R J, Hirsh A M, Channick R N, Moser K M. Fibrinopeptide A levels in primary pulmonary hypertension.  Am J Respir Crit Care Med . 1998;  157 A592 (Abstract)
    PubMedSearch in Google Scholar
  • 50 Mombelli G, Marchetti O, Haeberli A, Straub P W. Effect of intravenous heparin infusion on thrombin-antithrombin complex and fibrinopeptide A in unstable angina.  Am Heart J . 1998;  136 1106-1113
    PubMedSearch in Google Scholar
  • 51 Dempfle CE: The use of soluble fibrin in evaluating the acute and chronic hypercoagulable state. Thromb Haemost .  1999;  82 673-683
    PubMedSearch in Google Scholar
  • 52 Dempfle C E, Pfitzner S A, Dollman M, Huck K, Stehle G, Heene D L. Comparison of immunological and functional assays for measurement of soluble fibrin.  Thromb Haemost . 1995;  74 673-679
    PubMedSearch in Google Scholar
  • 53 Gould M K, Dembitzer A D, Doyle R L, Hastie T J, Garber A M. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.  Ann Intern Med . 1999;  130 800-809
    CrossrefPubMedSearch in Google Scholar
  • 54 Leizorovicz A, Simonneau G, Decousus H, Boissel J P. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis.  Br Med J . 1994;  309 299-304
    PubMedSearch in Google Scholar
  • 55 Lensing A WA, Prins M H, Davidson B L, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins: A meta-analysis.  Arch Intern Med . 1995;  155 601-607
    CrossrefPubMedSearch in Google Scholar
  • 56 Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg J S. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis.  Am J Med . 1996;  100 269-277
    CrossrefPubMedSearch in Google Scholar
  • 57 Kaiser B, Kirchmaier C M, Breddin H K, Fu K, Fareed J. Preclinical biochemistry and pharmacology of low molecular weight heparins in vivo: studies of venous and arterial thrombosis.  Semin Thromb Hemost . 1999;  25(Suppl 3) 35-42
    PubMedSearch in Google Scholar
  • 58 Dietrich C P, Shinjo S K, Moraes F A. Structural features and bleeding activity of commercial low molecular weight heparins: neutralization by ATP and protamine.  Semin Thromb Hemost . 1999;  25(Suppl 3) 43-50
    PubMedSearch in Google Scholar
  • 59 Fareed J, Fu K, Yang L H, Hoppensteadt D A. Pharmacokinetics of low molecular weight heparins in animal models.  Semin Thromb Hemost . 1999;  25(Suppl 3) 51-55
    PubMedSearch in Google Scholar
  • 60 Cornelli U, Fareed J. Human pharmacokinetics of low molecular weight heparins.  Semin Thromb Hemost . 1999;  25(Suppl 3) 57-61
    PubMedSearch in Google Scholar
  • 61 Nader H B, Walenga J M, Berkowitz S D, Ofosu F, Hoppensteadt D A, Cella G. Preclinical differentiation of low molecular weight heparins.  Semin Thromb Hemost . 1999;  25(Suppl 3) 63-72
    PubMedSearch in Google Scholar
  • 62 Hommes D W, Bura A, Mazzolai L, Buller H R, ten Cate W J. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. A meta-analysis.  Ann Intern Med . 1992;  116 279-284
    PubMedSearch in Google Scholar
  • 63 Lopaciuk S, Meissner A J, Filipecki S. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial.  Thromb Haemost . 1992;  68 14-18
    PubMedSearch in Google Scholar
  • 64 Anand S S, Bates S, Ginsberg J S. Recurrent venous thrombosis and heparin therapy: an evaluation of the importance of early activated partial thromboplastin times.  Arch Intern Med . 1999;  159 2029-2032
    CrossrefPubMedSearch in Google Scholar