The 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). 

There 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   

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 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.  

As 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 fondaparinux administration.5 

Due 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.

References:

1. Linkins LA et al.  Treatment and Prevention of Heparin Induced Thrombocytopenia: American College of Chest Physicians Evidence-Base Clinical Practice Guidelines.  (9^thEdition).  Chest 2012;141:e495S-e530S.  
2. Shaughnessy SG, Young E, Deschamps P etal.  The effects of low molecular weight and standard heparin on calcium loss from fetal rat calvaria.  Blood  1995;86:1368-73.  
3. Hirsh J.  Heparin.  N Engl J Med  1991;324:1565-74.  
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 (8^th 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.

• Pharmacology:  The Rationale for Differences in Dosing of LWMHs