title: Anti-PF4/heparin antibodies and venous graft occlusion in postcoronary artery bypass surgery patients randomized to postoperative unfractionated heparin or fondaparinux thromboprophylaxis.
abstract: BACKGROUND
  Anti-PF4/heparin antibodies are frequently generated after coronary artery bypass grafting (CABG) surgery, with platelet-activating IgG implicated in heparin-induced thrombocytopenia (HIT). It is controversial whether non-platelet-activating antibodies are associated with thrombosis.
  
  
  OBJECTIVE
  To determine in post-CABG patients whether thromboprophylaxis using fondaparinux vs. unfractionated heparin (UFH) reduces the frequency of anti-PF4/heparin antibodies, and whether anti-PF4/heparin antibodies are associated with early graft occlusion.
  
  
  METHODS
  In a pre-planned secondary analysis of a randomized control trial (RCT) comparing fondaparinux vs. UFH thromboprophylaxis post-CABG, we determined the frequency of anti-PF4/heparin antibody formation by solid-phase enzyme-immunoassay (EIA) and of platelet-activating antibodies by serotonin-release assay (SRA); the SRA and fluid-phase EIA were used to assess fondaparinux cross-reactivity. We also examined whether anti-PF4/heparin antibodies were associated with early arterial or venous graft occlusion (6-week CT angiography).
  
  
  RESULTS
  We found no significant difference in the frequency of antibody formation between patients who received fondaparinux vs. UFH (65.3% vs. 46.0%; P = 0.069), and no significant fondaparinux cross-reactivity. Venous graft occlusion(s) occurred in 6/26 patients who formed 'strong' IgG antibodies (≥ 1.0 optical density [OD] units and ≥ 2× baseline) vs. 3/66 who did not (P = 0.0139). In both unadjusted and adjusted analyses, strong postoperative (but not pre-operative) anti-PF4/heparin IgG responses were associated with a markedly increased risk of early venous (but not arterial) graft occlusion (adjusted OR, 9.25 [95% CI, 1.73, 49.43]; P = 0.0093); notably, none of the three SRA-positive patients developed a venous graft occlusion.
  
  
  CONCLUSIONS
  Fondaparinux vs. UFH thromboprophylaxis postCABG does not reduce anti-PF4/heparin antibody formation. Non-platelet-activating anti-PF4/heparin IgG antibodies generated post operatively are associated with early venous graft occlusion.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. twarken@mcmaster.ca
authors.forename: T E
authors.initials: TE
authors.lastname: Warkentin
authors.forename: J I
authors.initials: JI
authors.lastname: Sheppard
authors.forename: J C J
authors.initials: JC
authors.lastname: Sun
authors.forename: H
authors.initials: H
authors.lastname: Jung
authors.forename: J W
authors.initials: JW
authors.lastname: Eikelboom
mesh_terms: D000906:Antibodies / Q000097:blood*; D000925:Anticoagulants / Q000009:adverse effects / Q000276:immunology*; D001026:Coronary Artery Bypass / Q000009:adverse effects*; D003429:Cross Reactions; D000077425:Fondaparinux; D006083:Graft Occlusion, Vascular / Q000209:etiology* / Q000276:immunology; D006493:Heparin / Q000009:adverse effects / Q000276:immunology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000097:blood*; D016015:Logistic Models; D016017:Odds Ratio; D009864:Ontario; D010865:Pilot Projects; D010978:Platelet Factor 4 / Q000276:immunology*; D011134:Polysaccharides / Q000009:adverse effects / Q000276:immunology*; D018570:Risk Assessment; D012307:Risk Factors; D013921:Thrombocytopenia / Q000209:etiology / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D000925:Anticoagulants; D007074:Immunoglobulin G; D011134:Polysaccharides; D010978:Platelet Factor 4; D006493:Heparin; D000077425:Fondaparinux