title: Formation of anti-platelet factor 4/heparin antibodies after cardiac surgery: influence of perioperative platelet activation, the inflammatory response, and histocompatibility leukocyte antigen status.
abstract: BACKGROUND
  Anticoagulation therapy with heparin induces antibodies that recognize multimolecular complexes of platelet factor 4 bound to heparin (anti-platelet factor 4/heparin antibodies). Considering that cardiac surgery induces an intense platelet activation and proinflammatory response, we examined the relationship between formation of anti-platelet factor 4/heparin antibodies and plasma levels of platelet factor 4 and interleukin 6. We also examined the relationship between anti-platelet factor 4/heparin seroconversion and the histocompatibility leukocyte antigen system.
  
  
  METHODS
  In 71 patients undergoing cardiac surgery, anti-platelet factor 4/heparin antibody levels were evaluated by means of enzyme-linked immunosorbent assay preoperatively and 14 days postoperatively. Platelet serotonin release assays were performed to assess the platelet-activating potential of the antibodies. Plasma levels of platelet factor 4 and interleukin 6 were assayed at prespecified time points. Histocompatibility leukocyte antigen status was assessed preoperatively in all patients and was compared with that of 6156 healthy subjects.
  
  
  RESULTS
  Thirty-seven (52%) patients had anti-platelet factor 4/heparin antibodies with an OD value of 0.45 or greater in 1 or more of the assays. Applying strict seroconversion criteria (>2-fold increase in Optical Density), only 16 (22.5%) patients had evidence of anti-platelet factor 4/heparin antibody seroconversion after the operation. Neither the presence of anti-platelet factor 4/heparin antibodies nor seroconversion influenced postoperative outcomes. The CW4 allele was significantly more frequent among seroconverted patients (46.9% vs 19.1%, P = .002). Platelet factor 4 levels did not influence seroconversion. Patients with anti-platelet factor 4/heparin levels of 0.45 OD units or greater 14 days after the operation had significantly higher interleukin 6 levels measured 1 hour after protamine administration.
  
  
  CONCLUSIONS
  Patients with a greater amount of perioperative inflammation could be more likely to have anti-platelet factor 4/heparin antibodies 1 to 2 weeks later. We provide additional evidence that the histocompatibility leukocyte antigen CW4 confers genetic susceptibility in an acquired inflammatory disorder that includes the anti-platelet factor 4/heparin immune response.
authors.affiliation: Division of Cardiac Surgery, Department of Emergency and Organ Transplant, University of Bari, Bari, Italy. dpaparella@cardiochir.uniba.it
authors.forename: Domenico
authors.initials: D
authors.lastname: Paparella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scrascia
authors.forename: Antonella
authors.initials: A
authors.lastname: Galeone
authors.forename: Maria
authors.initials: M
authors.lastname: Coviello
authors.forename: Giangiuseppe
authors.initials: G
authors.lastname: Cappabianca
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Venneri
authors.forename: Biagio
authors.initials: B
authors.lastname: Favoino
authors.forename: Michele
authors.initials: M
authors.lastname: Quaranta
authors.forename: Luigi de Luca Tupputi
authors.initials: Lde L
authors.lastname: Schinosa
authors.forename: Theodore E
authors.initials: TE
authors.lastname: Warkentin
mesh_terms: D000368:Aged; D000906:Antibodies / Q000276:immunology*; D006348:Cardiac Surgical Procedures; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D006493:Heparin / Q000276:immunology*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000276:immunology*; D010978:Platelet Factor 4 / Q000276:immunology*
chemical_list: D000906:Antibodies; D006680:HLA Antigens; D015850:Interleukin-6; D010978:Platelet Factor 4; D006493:Heparin