title: Studies of the immune response in heparin-induced thrombocytopenia.
abstract: Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize PF4/heparin complexes. Uncertainties remain regarding HIT immunobiology, including the temporal relation of antibody formation to onset of thrombocytopenia, and whether immunoglobulin class switching occurs. Using serial plasma samples from 2 heparin thromboprophylaxis trials, we determined the time of onset, antibody levels, and immunoglobulin class distributions (IgG, IgA, IgM) for 12 patients with HIT and 36 patients who formed anti-PF4/heparin antibodies, but did not develop HIT ("seropositive non-HIT controls"). In patients with HIT, anti-PF4/heparin antibodies became detectable 4 days (median) after starting heparin; antibody detection preceded the platelet count decline by 2 days (median). Patients with HIT produced higher levels of IgG antibodies, but similar IgA and IgM levels, compared with seropositive non-HIT controls. Among all 48 seroconverting patients, the first day of a positive antibody test (median, day 6) did not differ among the immunoglobulin classes. Thus, the HIT immune response does not exhibit the classic paradigm of IgM class precedence/immunoglobulin class switching; rather, relatively rapid formation of IgG antibodies is observed, sometimes with concomitant IgA and IgM formation. Compared with seropositive non-HIT controls, HIT patients develop significantly higher anti-PF4/heparin IgG levels that are detectable before the onset of thrombocytopenia.
authors.affiliation: Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada. twarken@mcmaster.ca
authors.forename: Theodore E
authors.initials: TE
authors.lastname: Warkentin
authors.forename: Jo-Ann I
authors.initials: JA
authors.lastname: Sheppard
authors.forename: Jane C
authors.initials: JC
authors.lastname: Moore
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cook
authors.forename: John G
authors.initials: JG
authors.lastname: Kelton
mesh_terms: D000906:Antibodies / Q000097:blood / Q000378:metabolism; D016022:Case-Control Studies; D006493:Heparin / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D017578:Immunoglobulin Class Switching / Q000502:physiology; D007075:Immunoglobulin M / Q000097:blood / Q000378:metabolism; D010976:Platelet Count; D010978:Platelet Factor 4 / Q000276:immunology / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced* / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000906:Antibodies; D007075:Immunoglobulin M; D010978:Platelet Factor 4; D006493:Heparin