Fondaparinux as a Treatment Option for Heparin-Induced Thrombocytopenia

Stella Papadopoulos, Pharm.D.; Jeremy D. Flynn, Pharm.D.; Daniel A. Lewis, Pharm.D.

Disclosures

Pharmacotherapy. 2007;27(6):921-926. 

In This Article

Pathophysiology of Heparin-Induced Thrombocytopenia

Both UFH and LMWH contain negatively charged sulfate groups with affinities for platelet factor 4 (PF4), a positively charged protein located in the a granules of platelets.[5,7] The degree to which heparin molecules alter PF4 is affected by both chain length (14–16 saccharide units) and the extent of sulfation. Thus, LMWH, which is chemically derived from UFH, has a shorter chain length and a weaker affinity for PF4.[5,7]

Contact between heparin molecules and PF4 results in the formation of heparin-PF4 complexes. Platelet factor 4 then undergoes conformational, epitopic changes, exposing antigenic sites for antibodies such as immunoglobulin G (IgG) to bind.[1,5–8] These antibodies bind to the Fab fragment of PF4, leaving the Fc region available to cross-link with platelet FcgIIa receptors. This results in platelet activation, which in turn leads to platelet aggre-gation, causing patients to develop thrombo-cytopenia as the number of available platelets decreases.[2] Cross-linkage of heparin-PF4 antibody complexes with FcgIIa receptors induces additional release of PF4, which perpetuates the cycle and leads to a highly thrombogenic state.[2,4] In addition to platelet activation, thrombin generation is increased (elevated levels of thrombin-antithrombin complexes are present), contributing to the prothrombotic nature of HIT. Thus, HIT is a prothrombotic condition,[1,2,6] and its manage-ment should be aimed at reducing both platelet activation and thrombin generation.[2,3]

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