title: Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes.
abstract: BACKGROUND
  Platelet-activating antiplatelet factor 4/heparin (anti-PF4/heparin) antibodies are the major cause of heparin-induced thrombocytopenia (HIT). However, the relative utility of functional (platelet activation) vs. antigen [enzyme-immunoassay (EIA)] assays, and the significance of assay discrepancies remain unresolved.
  
  
  METHODS
  Consecutive patient sera (n = 1650) referred for diagnostic HIT testing were screened prospectively by both the heparin-induced platelet activation (HIPA) test and anti-PF4/heparin EIA - including individual classes (IgG, IgA, IgM) - with clinical correlations studied. Platelet microparticle and annexin-V-binding properties of the sera were also investigated.
  
  
  RESULTS
  Only 205 (12.4%) sera tested positive in either the HIPA and/or EIA: 95 (46.3%) were positive in both, 109 (53.1%) were only EIA-positive, and, notably, only one serum was HIPA-positive/EIA-negative. Of 185 EIA-positive sera, only 17.6% had detectable IgM and/or IgA without detectable IgG. Among sera positive for EIA IgG, optical density values were higher when the sera were HIPA-positive (1.117 vs. 0.768; P < 0.0001), with widely overlapping values. Two HIPA-positive but EIA-IgG-negative sera became HIPA-negative following IgG depletion, suggesting platelet-activating antibodies against non-PF4-dependent antigens. Clinical correlations showed that HIPA-negative/EIA-positive patients did not develop thrombosis and had reasons other than HIT to explain thrombocytopenia. IgM/A antibodies did not increase microparticle penetration, but increased annexin-V binding.
  
  
  CONCLUSIONS
  The anti-PF4/heparin EIA has high ( approximately 99%) sensitivity for HIT. However, only about half of EIA-positive patients are likely to have HIT. Anti-PF4/heparin antibodies of IgM/A class and non-PF4-dependent antigens have only a minor role in HIT.
authors.affiliation: Institut für Immunologie und Transfusionsmedizin Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany. greinach@uni-greifswald.de
authors.forename: A
authors.initials: A
authors.lastname: Greinacher
authors.forename: D
authors.initials: D
authors.lastname: Juhl
authors.forename: U
authors.initials: U
authors.lastname: Strobel
authors.forename: A
authors.initials: A
authors.lastname: Wessel
authors.forename: N
authors.initials: N
authors.lastname: Lubenow
authors.forename: K
authors.initials: K
authors.lastname: Selleng
authors.forename: P
authors.initials: P
authors.lastname: Eichler
authors.forename: T E
authors.initials: TE
authors.lastname: Warkentin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006493:Heparin / Q000276:immunology* / Q000494:pharmacology*; D006801:Humans; D007070:Immunoglobulin A / Q000737:chemistry*; D007074:Immunoglobulin G / Q000737:chemistry*; D007075:Immunoglobulin M / Q000737:chemistry*; D008875:Middle Aged; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry; D010978:Platelet Factor 4 / Q000276:immunology*; D011446:Prospective Studies; D013921:Thrombocytopenia / Q000139:chemically induced*
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010975:Platelet Aggregation Inhibitors; D010978:Platelet Factor 4; D006493:Heparin