title: Heparin-induced thrombocytopenia--therapeutic concentrations of danaparoid, unlike fondaparinux and direct thrombin inhibitors, inhibit formation of platelet factor 4-heparin complexes.
abstract: 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.
  
  
  OBJECTIVE
  To compare the effects of these various non-heparin anticoagulants in disrupting the formation of PF4-heparin complexes, and PF4-containing immune complexes.
  
  
  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.
authors.affiliation: Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Krauel
authors.forename: B
authors.initials: B
authors.lastname: Fürll
authors.forename: T E
authors.initials: TE
authors.lastname: Warkentin
authors.forename: W
authors.initials: W
authors.lastname: Weitschies
authors.forename: T
authors.initials: T
authors.lastname: Kohlmann
authors.forename: J I
authors.initials: JI
authors.lastname: Sheppard
authors.forename: A
authors.initials: A
authors.lastname: Greinacher
mesh_terms: D000906:Antibodies / Q000097:blood / Q000276:immunology; D000915:Antibody Affinity; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D003871:Dermatan Sulfate / Q000494:pharmacology*; D000077425:Fondaparinux; D006493:Heparin / Q000009:adverse effects / Q000378:metabolism*; D006497:Heparan Sulfate / Q000494:pharmacology*; D006801:Humans; D015539:Platelet Activation; D010978:Platelet Factor 4 / Q000378:metabolism*; D011134:Polysaccharides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors; D013921:Thrombocytopenia / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control
chemical_list: D000906:Antibodies; D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D000077425:Fondaparinux; D006493:Heparin; D006497:Heparan Sulfate; D010978:Platelet Factor 4; D011134:Polysaccharides; D015842:Serine Proteinase Inhibitors; D013917:Thrombin; C035838:danaparoid