Semin Thromb Hemost 2004; 30: 89-104
DOI: 10.1055/s-2004-823007
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Differentiation of Low-Molecular-Weight Heparins: Impact on the Future of the Management of Thrombosis

Jawed Fareed1 , Qing Ma1 , Michelle Florian1 , Jyothi Maddineni1 , Omer Iqbal1 , Debra A. Hoppensteadt1 , Rodger L. Bick2
  • 1Departments of Pathology and Pharmacology, Hemostasis and Thrombosis Research Laboratories, Loyola University Chicago, Maywood, Illinois
  • 2Departments of Medicine and Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
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Publikationsdatum:
13. April 2004 (online)

Low-molecular-weight heparins (LMWHs) are now universally accepted as drugs of choice for postsurgical prophylaxis and treatment of deep vein thrombosis (DVT). Currently, these agents are also being developed for the treatment of various cardiovascular conditions. Because of manufacturing differences, each of the LMWHs exhibits distinct pharmacologic and biochemical profiles. The specific activity of these agents in anticoagulant assays ranges from 35 to 45 anti-IIa U/mg, whereas the activity in terms of anti-Xa units is designated as 80 to 145 U/mg. These LMWHs are also capable of producing product-specific dose- and time-dependent antithrombotic effects in animal models of thrombosis. Although the ex vivo effects are initially present at dosages that are antithrombotic, these agents have been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. In experimental animal models and various clinical trials, these agents also have been found to release tissue factor pathway inhibitor and von Willebrand factor. In addition, LMWHs have been reported to produce fibrinolytic effects. The effect of repeated administration also exhibits product-based augmentation of the antithrombotic and hemorrhagic effects. Several new agents are being investigated as possible substitutes for heparins. These include anti-thrombin, anti-Xa, anti-TF (tissue factor), heparinoids, oral formulations of heparin, activated protein C, and biotechnologically derived serpins. These agents may not have the broad clinical spectrum as that observed with the heparins. More recently, several pharmaceutical companies have produced generic LMWHs.

REFERENCES

  • 1 Fareed J, Hoppensteadt D. Management of thrombotic and cardiovascular disorders in the 21st century. In: Sasahara AA, Loscalzo J New Therapeutic Agents in Thrombosis and Thrombolysis, 2nd ed. New York; Marcel Dekker 2002: 687-693
  • 2 Linhardt R J, Gunay S N. Production and chemical processing of low molecular weight heparins.  Semin Thromb Hemost. 1999;  25(suppl 3) 5-16
  • 3 Casu B, Torri G. Structural characterization of low molecular weight heparins.  Semin Thromb Hemost. 1999;  25(suppl 3) 17-25
  • 4 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
  • 5 Houbouyan L, Padilla A, Gray E, Longstaff C, Barrowcliffe T W. Inhibition of thrombin generation by heparin and LMW heparins: a comparison of chromogenic and clotting methods.  Blood Coagul Fibrinolysis. 1996;  7 24-30
  • 6 Montalescot G, Collet J P, Lison L, Choussat R, Anki A. Effects of various anticoagulant treatments on von Willebrand factor release in unstable angina.  J Am Coll Cardiol. 2000;  36 110-114
  • 7 Marmur J D, Anand S X, Bagga R S et al.. The activated clotting time can be used to monitor the low molecular weight heparin dalteparin after intravenous administration.  J Am Coll Cardiol. 2003;  41 394-402
  • 8 Kaiser B, Kirchmaier M, Breddin K H, 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
  • 9 Dietrich C P, Shinjo S K, Moraes F A et al.. 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
  • 10 Cornelli U, Fareed J. Human pharmacokinetics of low molecular weight heparins.  Semin Thromb Hemost. 1999;  25(suppl 3) 57-61
  • 11 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
  • 12 Fareed J, Fu L, Yang L H, Hoppensteadt D A. Pharmacokinetics of low molecular weight heparins in animal models.  Semin Thromb Hemost. 1999;  25(suppl 3) 51-55
  • 13 Mammen E F, Arcelus J, Messmore H, Altman R, Nurmohamed M, Eldor A. Clinical differentiation of low molecular weight heparins.  Semin Thromb Hemost. 1999;  25(suppl 3) 135-144
  • 14 Nightingale S L. From the Food and Drug Administration.  JAMA. 1993;  270 1672
  • 15 McCart G M, Kayser S. Therapeutic equivalency of low molecular weight heparins.  Ann Pharmcother. 2002;  36 1042-1057
  • 16 Nenci G. Low molecular weight heparins: are they interchangeable? No.  J Thromb Hemost. 2003;  1 12-13
  • 17 Merli G, Vanscoy G, Rihn T L, Grace III J B, McCormick W. Applying scientific criteria to therapeutic interchange: a balanced analysis of low molecular weight heparins.  J Thromb Thrombolysis. 2001;  11 247-259
  • 18 Cohen M. Low molecular weight heparins in the management of unstable angina/non-Q-wave myocardial infarction.  Semin Thromb Hemost. 1999;  25(suppl 3) 113-121
  • 19 Gulba D. Differentiation of low molecular weight heparins in acute coronary syndromes: an interventionalist's perspective.  Semin Thromb Hemost. 1999;  25(suppl 3) 123-127
  • 20 Leong W, Hoppensteadt D A. Generic forms of low molecular weight heparins. Some practical issues.  Clin Appl Thromb Hemost. 2003;  9 293-297
  • 21 Jeske W, Fareed J. In vitro studies on the biochemistry and pharmacology of low molecular weight heparins.  Semin Thromb Hemost. 1999;  25(suppl 3) 27-33
  • 22 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
  • 23 Fareed J, Walenga J M, Williamson K, Emanuele R M, Kumar A, Hoppensteadt D. Studies on the antithrombotic effects and pharmacokinetics of heparin fractions and fragments.  Semin Thromb Hemost. 1985;  11 56-74
  • 24 Abboud L. Bush acts to speed generics to market. The Wall Street Journal. June 12, 2003: A3

Jawed FareedPh.D. 

Departments of Pathology and Pharmacology, Hemostasis and Thrombosis Research Laboratories, Loyola University Chicago

2160 S. First Avenue, Maywood, IL 60153

eMail: jfareed@lumc.edu