Heparin-induced thrombocytopenia--therapeutic concentrations of danaparoid, unlike fondaparinux and direct thrombin inhibitors, inhibit formation of platelet factor 4-heparin complexes

J Thromb Haemost. 2008 Dec;6(12):2160-7. doi: 10.1111/j.1538-7836.2008.03171.x. Epub 2008 Oct 3.


Background: Treatment of heparin-induced thrombocytopenia (HIT), a disorder in which anti-platelet factor 4 (PF4)-heparin antibodies cause platelet activation and hypercoagulability, requires alternative (non-heparin) anticoagulation. Treatment options include direct thrombin inhibitors [lepirudin and argatroban (approved), and bivalirudin], danaparoid (approved) (mixture of anticoagulant glycosaminoglycans), or fondaparinux (synthetic heparin-mimicking pentasaccharide). PF4-heparin complexes form at optimal stoichiometric ratios.

Objectives: To compare the effects of these various non-heparin anticoagulants in disrupting the formation of PF4-heparin complexes, and PF4-containing immune complexes.

Patients/methods: Sera were obtained from patients with serologically confirmed HIT. The effects of the alternative anticoagulants on PF4 and PF4-heparin complex interactions with platelets, as well as HIT antibody binding and platelet activation, were investigated.

Results: Danaparoid at very low concentrations increased PF4 binding to platelets. In therapeutic concentrations, however, it decreased PF4 binding to platelets (P = 0.0004), displaced PF4-heparin complexes from platelets (P = 0.0033) and PF4 from the surface of a PF4-transfected HEK-293 EBNA cell line expressing the PF4 receptor CXCR3-B (P = 0.0408), reduced PF4-heparin complex size (P = 0.025), inhibited HIT antibody binding to PF4-heparin complexes (P = 0.001), and prevented platelet activation by HIT antibodies (P = 0.046). Although fondaparinux also interfered with PF4 binding to platelets, HIT antibody binding to PF4-heparin complexes, and activation of platelets by HIT antibodies, these effects occurred only at supratherapeutic concentrations. The direct thrombin inhibitors had no effect at any concentrations.

Conclusions: Danaparoid uniquely interferes with the pathogenesis of HIT by disrupting PF4-containing immune complexes at therapeutic dose concentrations. It is possible that these effects contribute to its therapeutic efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / blood
  • Antibodies / immunology
  • Antibody Affinity
  • Cells, Cultured
  • Chondroitin Sulfates / pharmacology*
  • Dermatan Sulfate / pharmacology*
  • Fondaparinux
  • Heparin / adverse effects
  • Heparin / metabolism*
  • Heparitin Sulfate / pharmacology*
  • Humans
  • Platelet Activation
  • Platelet Factor 4 / metabolism*
  • Polysaccharides / pharmacology
  • Protein Binding / drug effects
  • Serine Proteinase Inhibitors / pharmacology
  • Thrombin / antagonists & inhibitors
  • Thrombocytopenia / chemically induced
  • Thrombocytopenia / drug therapy*
  • Thrombocytopenia / prevention & control


  • Antibodies
  • Polysaccharides
  • Serine Proteinase Inhibitors
  • Dermatan Sulfate
  • Platelet Factor 4
  • Heparin
  • Chondroitin Sulfates
  • Heparitin Sulfate
  • danaparoid
  • Thrombin
  • Fondaparinux