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How do Low-Molecular Weight Heparins (LMWH) Cause Less Heparin Induced Thrombocytopenia (HIT) than Regular Heparin?

Summary:

  • The incidence of heparin induced thrombocytopenia (HIT) is greater for unfractionated heparin (UFH) than low molecular weight heparin (LMWH).
  • Within UFH formulations, bovine origin heparin has a greater incidence of causing HIT than porcine origin heparin products, which is why most use porcine origin.
  • Within the LWMH there does not appear to be any differences in the incidence of HIT when used to treat similar medical conditions.
  • The risk of developing HIT is in part due to the molecular weight of the heparin.  As such, this is one reason why LWMH cause less HIT than UFH.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed:
August 2015

Explanation

  • Much of the current literature indicates that unfractionated heparin use, especially beyond 4 days of treatment, is known to have a greater risk for causing HIT when compared to LMWH.1-5  Within various formulations of UFH, it is known that bovine origin heparin has a greater incidence than porcine origin heparin formulations (see the below table).4  As such most countries use porcine origin heparin products.  The reason that LMWHs have a lower incidence of causing HIT has to do primarily with their lower molecular weights when compared to UFH.6  The ability of heparin molecules to bind to platelet factor 4 (PF4) released from platelets to create an antigenic complex is influenced by the heparin molecule's molecular weight, length of its chain and degree of sulfation.6   

    An evaluation of the molecular weights among the heparin related medications reveals that UFH's molecular weight ranges from 3,000 to 30,000 daltons whereas, the LMWHs range from 2,000 to 10,000 daltons.7-9  Within the LMWHs there does not appear to be any appreciable differences in the risk for developing HIT.  However, the longer the use (especially if used at therapeutic doses) the greater the incidence of HIT.5  Thus, in cancer patients using dalteparin for 6 months, the incidence was 13.6% compared to < 1% for non-cancer related indications that are generally treated with shorter durations of therapy.7 

    While fondaparinux is not a heparin molecule, it does contain the same pentasaccharide sequence that is used by both UFH and LMWHs for binding to antithrombin in order to exert its antithrombotic effect.  However, fondaparinux only inhibits the factor X because of its length and molecular weight, whereas UFH and LMWH inhibit factors II and X.3,10  An evaluation of fondaparinux's molecular weight compared to the other heparin related medications shows that fondaparinux is significantly smaller.10  This is relevant given that it does not appear to cause immune mediated HIT as seen with any of the heparin related products.5  In addition, there is some evidence that platelet counts improve when used in patients with HIT.  Interestingly, the American College of Chest Physicians (ACCP) Evidence Based Clinical Practice Guidelines recommends fondaparinux as one alternative antithrombotic medication that can be used in patients with HIT.5  However, the Food and Drug Administration (FDA) approved product package insert for fondaparinux does report that up to 3% of patients developed thrombocytopenia and is not indicated for patients with HIT.10  Due to the limited availability of data with fondaparinux in patients with HIT, the ACCP gives the recommendation for its use a Grade 2C, which is lower when compared to danaparoid (Grade 1B), lepirudin and argatroban (Grade 1C).    

    Therefore, the incidence of HIT appears to be lower for LMWH when compared to UFH and thus should be given greater consideration in higher risk patients.  This is, in part, explained by the different molecular weights of the products.  In addition, it is worth noting that a recent meta-analysis evaluating heparin and LMWH showed no significant difference in the development of heparin associated thrombocytopenia (HAT) and insufficient evidence to conclude any difference is the rate of HIT.11  It appears that the differences in risk for developing HIT may be most evident in postsurgical patients and in females.5  However, many trials are not powered enough to substantiate evidence for or against a difference.  Until such time, available evidence does indicate differences among heparin based products and should be considered especially when treating high risk patients. 

    References:

    1. Busti AJ, Nuzum DS, Daves BJ, McKeever GC.  What is the mechanism by which heparin and low-molecular weight heparins cause heparin induced thrombocytopenia (HIT) or a significant decrease in platelets?
    2. Busti AJ, Lehew DS, Daves BJ, McKeever GC.  What is the difference between heparin associated thrombocytopenia (HAT) and heparin induced thrombocytopenia (HIT)?
    3. Hirsh J, Bauer KA, Donati MB et al.  Parenteral anticoagulants: American College of Chest Physicians Evidence-Base Clinical Practice Guidelines.  (8thEdition).  Chest 2008;133:141S-159S.  
    4. Ahmed I, Majeed A, Powell R.  Heparin induced thrombocytopenia: diagnosis and management update.  Postgrad Med J  2007;83:575-82.  
    5. Warkentin TE, Greinacher A, Koster A et al.  Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest  2008;133:340S-380S.  
    6. Amiral J, Bridey F, Wolf M et al.  Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases.  Thromb Haemost  1995;73:21-8.  
    7. Dalteparin (Fragmin®) product package insert.  Pfizer Inc. New York, NY.  April 2007.
    8. Enoxaparin (Lovenox®) product package insert.  Sanofi-Aventis U.S. LLC.  Bridgewater, NJ.  2008.
    9. Tinzaparin (Innohep®) product package insert.  Leo Pharmaceutical Products.  Ballerup, Denmark.  December 2008.
    10. Fondaparinux (Arixtra®) product package insert.  GlaxoSmithKline.  Research Triangle Park, NC.  October 2008.
    11. Morris TA, Castrejon S, Devendra G, Gamst AC.  No differences in risk for thrombocytopenia during treatment of pulmonary embolism and deep vein thrombosis with either low-molecular-weight heparin or unfractionated heparin: a metaanalysis.  Chest  2007;132:1131-9.

MESH Terms & Keywords

  • LMWH, Low Molecular Weight Heparin, HIT, Heparin Induced Thrombocytopenia