Immune mechanisms in heparin-induced thrombocytopenia: no evidence for immunoglobulin M anti-idiotype antibodies.
BACKGROUND
Heparin-induced thrombocytopenia (HIT), which is caused by platelet (PLT)-activating immunoglobulin (Ig)G antibodies against platelet factor 4 (PF4)/heparin complexes, differs from other immune responses seen in immunohematology: IgG antibodies are formed as early as 5 days even without previous heparin exposure; antibodies are remarkably transient (<100 days); HIT is more frequent in postsurgery patients compared with medical patients despite administering the same type and dose of heparin; and increasing evidence implicates autoantibody-like reactivity of anti-PF4/heparin antibodies. We hypothesized that these unusual features could be caused by loss of regulatory anti-idiotype IgM antibodies due to disturbance (e.g., by surgery) of an idiotype-anti-idiotype network.


METHODS
Sera were obtained prospectively before heparin administration and during the immunization phase of HIT and also from patients with previous HIT after waning of antibodies to nondetectable levels. To detect inhibitory IgM anti-idiotype antibodies, we performed serum coincubation experiments and IgG purification by protein G and size filtration to exclude coprecipitating IgM. Sera (n = 3) containing known anti-PF4/heparin IgG or IgM antibodies and normal sera (n = 20) were processed as controls.


RESULTS
Fifteen preimmune response sera (seroconverting in the PF4/heparin-IgG enzyme-linked immunosorbent assay only [n = 4] or additionally in a PLT activation assay [n = 5] or in both assays plus thrombosis [n = 6]) and four sera of previously immunized patients were included. Neither did the neat sera inhibit binding of anti-PF4/heparin antibodies nor did the purified IgG fractions show enhanced binding to PF4/heparin complexes.


CONCLUSIONS
The atypical immunologic features of HIT do not appear to be caused by disruption of an idiotype (IgG)-anti-idiotype (IgM) network.
Selleng
Kathleen
K
Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt Universität, Greifswald, Germany. selleng@uni-greifswald.de
Warkentin
Theodore E
TE
Sheppard
Jo-Ann I
JA
Greinacher
Andreas
A
D000888:Antibodies, Anti-Idiotypic / Q000276:immunology* / Q000302:isolation & purification; D000925:Anticoagulants / Q000009:adverse effects*; D004797:Enzyme-Linked Immunosorbent Assay; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000302:isolation & purification; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology*
D000888:Antibodies, Anti-Idiotypic; D000925:Anticoagulants; D007074:Immunoglobulin G; C044203:anti-IgM; D006493:Heparin