use of anticoagulants, such as unfractionated heparin (UFH) and low-molecular
weight heparin (LMWH) have significantly improved patient oriented outcomes for
medical conditions related to thrombotic events. However, they are also
known to cause clinically relevant side effects, or adverse drug events, such
as bleeding (including hemorrhagic stroke, gastrointestinal bleeding,
osteoporosis (long-term use)), priapism, and hyperkalemia (from inhibition of
aldosterone synthesis).1-3 Paradoxically, their use can also put patients
at risk for fatal thrombosis that can cause such things as deep vein thrombosis
(DVT), pulmonary embolism (PE), myocardial infarction (MI), thrombotic stroke,
cerebral vein thrombosis and disseminate intravascular coagulation.4,5
This condition is called heparin induced thrombocytopenia (HIT).
are number of risk factors associated with increasing the chance for a patient
to develop HIT, one of which is the type of anticoagulant used. For
example, it is known that unfractionated heparin use, especially beyond 4 days
of treatment, is known to have a greater risk for causing HIT when compared to
LMWH (dalteparin, enoxaparin, and tinzaparin).1,4,5 Within various formulations
of UFH, it is known that bovine origin heparin has a greater incidence than
porcine origin heparin formulations.4 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 creating 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 LMWH range from 2,000 to 10,000 daltons.7-9 Within the
LMWHs, there is no appreciable difference in the risk for developing HIT.
However, the longer the use (especially if used at therapeutic doses) the
greater the incidence of HIT.
noted above, the length of the chain (which influences the molecular weight)
contributes, in part, to heparin's ability to bind to PF4 that triggers the
immune mediated response seen in HIT. The reference to the chain is
related to the part of the heparin molecule attached to the pentasaccharide
sequence that is used in binding to antithrombin when exerting its
antithrombotic effect.1 However, if no chain exists on the
pentasaccharide sequence, such as exists with fondaparinux, then the
pentasaccharide sequence bound to antithrombin can only inhibit factor X.1,10
Because of its pharmacological characteristics, fondaparinux is not considered
a heparin related molecule and does not appear to cause immune mediated HIT, as
seen with any of the heparin related products.5 Interestingly, the
product package insert for fondaparinux does report that up to 3% of patients
developed thrombocytopenia. In addition, other studies have shown that
antiPF4/heparin complex antibodies can form with fondaparinux.10 However,
these antibodies do not appear to bind to PF4 nor with UFH or LMWH and may, in
part, be due to the size of the molecule. It is also worth noting that
some patients with HIT have been shown to have platelet recovery with
to this data, the current American College of Chest Physicians (ACCP) Evidence
Based Clinical Practice Guidelines (9th Edition) recommend fondaparinux as
one alternative antithrombotic medication that can be used in patients with
HIT.5 However, because the data is limited with fondaparinux in patients
with HIT and it is not FDA approved for this indication, the recommendation for
its was given a Grade 2C rating which is lower when compared to danaparoid, lepirudin, and argatroban.
- Linkins LA et al. Treatment and Prevention of Heparin Induced Thrombocytopenia:
American College of Chest Physicians Evidence-Base Clinical Practice
Guidelines. (9thEdition). Chest 2012;141:e495S-e530S.
SG, Young E, Deschamps P etal. The effects of low molecular weight and
standard heparin on calcium loss from fetal rat calvaria. Blood
- Hirsh J. Heparin. N Engl J Med 1991;324:1565-74.
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.