Heparin‐induced thrombocytopenia – therapeutic concentrations of danaparoid, unlike fondaparinux and direct thrombin inhibitors, inhibit formation of platelet factor 4–heparin complexes Journal Articles uri icon

  • Overview
  • Research
  • Identity
  • Additional Document Info
  • View All


  • 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.


  • FÜRLL, B
  • Warkentin, Ted

publication date

  • December 2008

has subject area