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
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
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).
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.
- 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?
- Busti AJ, Lehew DS, Daves BJ, McKeever GC. What is the
difference between heparin associated thrombocytopenia (HAT) and heparin
induced thrombocytopenia (HIT)?
- 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.
I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and
management update. Postgrad Med J 2007;83:575-82.
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.
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.
- Dalteparin (Fragmin®) product package insert. Pfizer Inc. New York, NY. April 2007.
- Enoxaparin (Lovenox®) product package insert. Sanofi-Aventis U.S. LLC. Bridgewater, NJ. 2008.
- Tinzaparin (Innohep®) product package insert. Leo Pharmaceutical Products. Ballerup, Denmark. December 2008.
- Fondaparinux (Arixtra®) product package insert. GlaxoSmithKline. Research Triangle Park, NC. October 2008.
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.