title: Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin.
abstract: Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differs in that unfractionated heparin (UFH) induces more anti-PF4/heparin antibodies than low-molecular-weight heparin (LMWH) and UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be nonimmunogenic. We tested 2726 patients for anti-PF4/heparin antibodies after they were randomized to receive antithrombotic prophylaxis with fondaparinux or LMWH (enoxaparin) following hip or knee surgery. We also evaluated in vitro cross-reactivity of the IgG antibodies generated against PF4 in the presence of UFH, LMWH, danaparoid, or fondaparinux. We found that anti-PF4/heparin antibodies were generated at similar frequencies in patients treated with fondaparinux or enoxaparin. Although antibodies reacted equally well in vitro against PF4/UFH and PF4/LMWH, and sometimes weakly against PF4/danaparoid, none reacted against PF4/fondaparinux, including even those sera obtained from patients who formed antibodies during fondaparinux treatment. At high concentrations, however, fondaparinux inhibited binding of HIT antibodies to PF4/polysaccharide, indicating that PF4/fondaparinux interactions occur. No patient developed HIT. We conclude that despite similar immunogenicity of fondaparinux and LMWH, PF4/fondaparinux, but not PF4/LMWH, is recognized poorly by the antibodies generated, suggesting that the risk of HIT with fondaparinux likely is very low.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. twarken@mcmaster.ca
authors.forename: Theodore E
authors.initials: TE
authors.lastname: Warkentin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cook
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Marder
authors.forename: Jo-Ann I
authors.initials: JA
authors.lastname: Sheppard
authors.forename: Jane C
authors.initials: JC
authors.lastname: Moore
authors.forename: Bengt I
authors.initials: BI
authors.lastname: Eriksson
authors.forename: Andreas
authors.initials: A
authors.lastname: Greinacher
authors.forename: John G
authors.initials: JG
authors.lastname: Kelton
mesh_terms: D000925:Anticoagulants / Q000276:immunology* / Q000627:therapeutic use; D003429:Cross Reactions; D004311:Double-Blind Method; D017984:Enoxaparin / Q000627:therapeutic use*; D000077425:Fondaparinux; D006615:Hip / Q000601:surgery; D006801:Humans; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000097:blood; D007717:Knee / Q000601:surgery; D019637:Orthopedic Procedures / Q000009:adverse effects; D010978:Platelet Factor 4 / Q000276:immunology*; D011134:Polysaccharides / Q000276:immunology* / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000139:chemically induced; D020246:Venous Thrombosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D017984:Enoxaparin; D007074:Immunoglobulin G; D011134:Polysaccharides; D010978:Platelet Factor 4; D000077425:Fondaparinux