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)

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.

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
  • 2 Casu B, Torrington K G. Structural characterization of low molecular weight heparins.  Semin Thromb Hemost . 1999;  25(Suppl 3) 17-25
  • 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
  • 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
  • 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
  • 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
  • 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
  • 8 Hirsh J, Levine M N. Low molecular weight heparin.  Blood . 1992;  79 1-17
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 17 Hirsh J. Heparin.  N Engl J Med . 1991;  324 1565-1574
  • 18 Hirsh J, Fuster V. Guide to anticoagulant therapy. Part 1: Heparin. American Heart Association.  Circulation . 1994;  89 1449-1468
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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; 
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 48 Gando S, Tedo I. Diagnostic and prognostic value of fibrinopeptides in patients with clinically suspected pulmonary embolism.  Thromb Res . 1994;  75 195-202
  • 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)
  • 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
  • 51 Dempfle CE: The use of soluble fibrin in evaluating the acute and chronic hypercoagulable state. Thromb Haemost .  1999;  82 673-683
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 60 Cornelli U, Fareed J. Human pharmacokinetics of low molecular weight heparins.  Semin Thromb Hemost . 1999;  25(Suppl 3) 57-61
  • 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
  • 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
  • 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
  • 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
    >