title: FcγRIIa proteolysis as a diagnostic biomarker for heparin-induced thrombocytopenia.
abstract: BACKGROUND
  A significant challenge in the management of heparin-induced thrombocytopenia (HIT) patients is making a timely and accurate diagnosis. The readily available enzyme immunoassays (EIAs) have low specificities. In contrast, platelet activation assays have higher specificities, but they are technically demanding and not widely available. In addition, ~ 10% of samples referred for HIT testing are initially classified as indeterminate by the serotonin release assay (SRA), which further delays accurate diagnosis. HIT is characterized by platelet activation, which leads to FcγRIIa proteolysis. This raises the possibility that identification of the proteolytic fragment of FcγRIIa could serve as a surrogate marker for HIT.
  
  
  OBJECTIVE
  To determine the specificity of platelet FcγRIIa proteolysis induced by sera from patients with HIT, and to correlate the results with those of the SRA.
  
  
  METHODS
  Sera from HIT patients and control patients with other thrombocytopenic/prothrombotic disorders were tested for their ability to proteolyse FcγRIIa. The results were correlated with anti-platelet factor 4 (PF4)/heparin antibodies (EIA), and heparin-dependent platelet activation (SRA).
  
  
  RESULTS
  Only HIT patient samples (20/20) caused heparin-dependent FcγRIIa proteolysis, similar to what was shown by the SRA. None of the samples from the other patient groups or hospital controls caused FcγRIIa proteolysis. Among nine additional samples that tested indeterminate in the SRA, FcγRIIa proteolysis resolved five samples that had a positive anti-PF4/heparin EIA result; three had no FcγRIIa proteolysis, and two were shown to have heparin-dependent FcγRIIa proteolysis
  
  
  CONCLUSIONS
  This study suggests that heparin-dependent FcγRIIa proteolysis is at least as specific as the SRA for the diagnosis of HIT.
authors.affiliation: Department of Medicine, Michael G DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. nazii@mcmaster.ca
authors.forename: I
authors.initials: I
authors.lastname: Nazi
authors.forename: D M
authors.initials: DM
authors.lastname: Arnold
authors.forename: J W
authors.initials: JW
authors.lastname: Smith
authors.forename: P
authors.initials: P
authors.lastname: Horsewood
authors.forename: J C
authors.initials: JC
authors.lastname: Moore
authors.forename: T E
authors.initials: TE
authors.lastname: Warkentin
authors.forename: M A
authors.initials: MA
authors.lastname: Crowther
authors.forename: J G
authors.initials: JG
authors.lastname: Kelton
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000737:chemistry; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000175:diagnosis; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism*; D006493:Heparin / Q000009:adverse effects* / Q000737:chemistry; D006801:Humans; D007124:Immunoenzyme Techniques; D015539:Platelet Activation; D010978:Platelet Factor 4 / Q000737:chemistry; D059748:Proteolysis; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000097:blood / Q000175:diagnosis; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood / Q000175:diagnosis; D017452:Receptors, IgG / Q000737:chemistry*; D015203:Reproducibility of Results; D012701:Serotonin / Q000378:metabolism; D013921:Thrombocytopenia / Q000097:blood* / Q000139:chemically induced / Q000175:diagnosis*
chemical_list: D000925:Anticoagulants; D015415:Biomarkers; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; D012701:Serotonin; D010978:Platelet Factor 4; D006493:Heparin
keywords: FcγRIIa proteolysis; enzyme immunoassay; heparin-induced thrombocytopenia; platelet activation; serotonin release assay