Role of Sulfated Polysaccharides in the Pathogenesis of Heparin Induced Thrombocytopenia

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Susanne Alban

Christian-Albrechts-University of Kiel, Kiel, Germany Andreas Greinacher

Ernst-Moritz-Arndt-University-Greifswald, Greifswald, Germany


Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are the anticoagulants of choice when parenteral anticoagulation is required. Both can be given subcutaneously or intravenously, and both are effective in a variety of clinical settings (Hirsh and Raschke, 2004). UFH, in particular, has several limitations. These include its poor bioavailability after subcutaneous injection as well as the marked variability in the anticoagulant response to UFH treatment in patients with acute thromboembolism (Hirsh and Raschke, 2004; Young et al., 1992). Another problem is the risk of inducing heparin-induced thrombocytopenia (HIT). These limitations are closely linked (Greinacher, 1995): the underlying cause is the high density of negative charges of the heparin molecule, leading to nonspecific interactions of heparin with cells and plasma proteins other than antithrombin (AT). This results in reduced anticoagulant effects of heparin as well as in conformational changes of the proteins bound to heparin, with the potential for exposure of neoepitopes, or cryptic epitopes, which may induce an immune response.

In this chapter, the mechanism and structural requirements for complex formation between sulfated carbohydrates, especially heparin, and proteins, such as platelet factor 4 (PF4), are reviewed. The pathophysiological consequences of these interactions in causing HIT are summarized. From these considerations, the prospects for development of carbohydrate-based heparin alternatives with a lower risk for immune thrombocytopenia are discussed.


Heparin activity is neutralized by PF4, a protein released from the a-granules of activated platelets (Sear and Poller, 1973; Klener and Kubisz, 1978; Luscher and Kaser-Glanzman, 1975; Niewiarowski, 1976), which attaches to the endothelial surface by binding to glycosaminoglycans (GAGs) (Novotny et al., 1993). PF4 is a compact homotetrameric globular protein with a subunit molecular weight (MW) of 7780 Da (70 amino acid residues per subunit) (Kaplan and Niewiarowski, 1985; Mayo et al., 1995). With its content of 6.0% arginine, 3.2% histidine, and 12.3% lysine, PF4 is a basic (positively charged) protein (Moore et al., 1975). The NH2 terminal residues form antiparallel b-sheet-like structures that induce non-covalent

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