Formation of anti-platelet factor 4/heparin antibodies after cardiac surgery: Influence of perioperative platelet activation, the inflammatory response, and histocompatibility leukocyte antigen status

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. Discussion: 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.