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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3791-3796.
Prepublished online as a Blood First Edition Paper on August 18, 2005; DOI 10.1182/blood-2005-05-1938.
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Submitted May 19, 2005
Accepted August 7, 2005
Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin
Theodore E Warkentin*, Richard J Cook, Victor J Marder, Jo-Ann I Sheppard, Jane C Moore, Bengt I Eriksson, Andreas Greinacher, and John G Kelton
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada
Department of Statistics and Actuarial Sciences, University of Waterloo, Waterloo, ON, Canada
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, Canada
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
Department of Medicine, McMaster University, Hamilton, ON, Canada
Department of Orthopedics, Surgical Sciences, Goteborg University, Goteborg, Sweden
Institute for Immunology and Transfusion Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
* Corresponding author; email: twarken{at}mcmaster.ca.
Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differ: unfractionated heparin (UFH) induces more anti-PF4/heparin antibodies than low-molecular-weight heparin (LMWH); UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be non-immunogenic. We tested 2,726 patients randomized to receive antithrombotic prophylaxis with fondaparinux or LMWH (enoxaparin) following hip or knee surgery for anti-PF4/heparin antibodies. 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.
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