title: Antibodies to platelet factor 4/heparin are associated with elevated endothelial cell activation markers in patients with acute coronary ischemic syndromes.
abstract: BACKGROUND
  We postulated that antibodies to platelet factor 4/heparin complex lead to a heightened inflammatory state, contributing to an increased risk of recurrent thrombotic events.
  
  
  METHODS
  We analyzed serum from a subset of patients in the placebo/unfractionated heparin arm of the GUSTO IV-ACS trial who had prior heparin exposure. We selected 109 patients with the 30 day primary endpoint (death, MI or revascularization) and an equal number of controls, excluding patients with thrombocytopenia. Anti-platelet factor 4/heparin antibodies and inflammatory markers (sVCAM-1, sICAM-1, sE-selectin, sP-selectin, us-CRP, IL-6) were measured on serum samples.
  
  
  RESULTS
  Patients with anti-PF4/heparin antibodies were more likely to have death or MI (30.4% vs. 11.3%, p = 0.01), or MI (21.7% vs. 6.2%, p = 0.01) than patients who were antibody negative. In a multiple logistic regression model that included inflammatory markers and clinical risk factors, antibody to PF4/heparin was a strong predictor of 30 day MI (odds ratio: 9.0; 95% confidence intervals 2.1-38.6; p < 0.01), with IL-6 being the only other predictor (odds ratio: 1.1; 95% confidence intervals 1.0-1.2; p = 0.03). Antibody positive patients had higher levels of sVCAM-1 (892 +/- 263 microg/l versus 780 +/- 228 microg/l; p = 0.04) and sICAM-1(246 +/- 50 microg/l versus 222 +/- 71microg/l; p = 0.02) than antibody-negative patients.
  
  
  CONCLUSIONS
  Antibodies to the platelet factor 4/heparin complex were associated with elevated levels of endothelial but not platelet activation markers, or markers of a systemic inflammatory state. Anti-PF4/heparin antibodies were associated with a 9-fold increased risk of recurrent MI at 30 days. We measured soluble cell adhesion molecules, CRP and IL-6 from 218 non-thrombocytopenic patients, 23 of whom had antibodies to PF4/heparin. Antibody positive patients had higher levels of sVCAM-1 (892 +/- 263 microg/l versus 780 +/- 228 microg/l; p = 0.04) and sICAM-1(246 +/- 50 microg/l versus 222 +/- 71 microg/l; p = 0.02). In a multiple logistic regression model, antibody to PF4/heparin was a predictor of 30 day MI (odds ratio: 9.0; 95% CI: 2.1-38.6; p < 0.01). The presence of antibodies to PF4/heparin, even in the absence of thrombocytopenia, is a stronger predictor of 30 day MI than clinical variables or inflammatory markers.
authors.affiliation: Centocor, Malvern, PA, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Mascelli
authors.forename: Efthymios N
authors.initials: EN
authors.lastname: Deliargyris
authors.forename: Lakshmi V
authors.initials: LV
authors.lastname: Damaraju
authors.forename: Elliot S
authors.initials: ES
authors.lastname: Barnathan
authors.forename: Robert M
authors.initials: RM
authors.lastname: Califf
authors.forename: Maarten L
authors.initials: ML
authors.lastname: Simoons
authors.forename: David C
authors.initials: DC
authors.lastname: Sane
mesh_terms: D000208:Acute Disease; D000368:Aged; D015415:Biomarkers / Q000097:blood; D042783:Endothelial Cells / Q000378:metabolism*; D006493:Heparin / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000097:blood*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood*; D010978:Platelet Factor 4 / Q000378:metabolism*; D013577:Syndrome
chemical_list: D015415:Biomarkers; D007518:Isoantibodies; D010978:Platelet Factor 4; D006493:Heparin