Pathogenicity of IgA and/or IgM antibodies to heparin-PF4 complexes in patients with heparin-induced thrombocytopenia.
Antibodies to heparin-PF4 (H-PF4) complexes have been tested and isotyped in 38 patients who developed severe heparin-induced thrombocytopenia (type II HIT). All patients had a platelet count <120x10(9)/1 or a reduction of > 30% of the initial value, occurring at least 5d after the onset of heparin. Thrombocytopenia, which rapidly reversed following the withdrawal of heparin, was associated with thrombosis in nine patients. Although IgG isotypes were found in most cases (n=26), the presence of only IgM and/or IgA was observed in 12 patients, including three cases showing a thrombotic complication. Our results indicate that type II HIT may be induced by IgA and /or IgM anti-H-PF4 antibodies even in the absence of IgG isotypes. This finding demonstrates that platelet Fc receptors (FcgammaRII) are not necessarily involved in the pathogenicity of heparin-dependent antibodies and emphasizes the major role of platelet PF4 receptors. The increased expression of the latter following a slight activation by thrombin, and the subsequent binding of IgM and IgA antibodies to H-PF4 on the platelet surface, may directly trigger platelet activation aggregation and thrombosis. Alternatively, thrombocytopenia could be indirectly induced through the mediation of neutrophils, monocytes and lymphocytes which expose receptors for IgA (FcalphaR) or IgM FcmuR). IgM-platelet complexes may also bind and activate complement, leading to platelet activation or destruction. Moreover, the reactivity of the antibodies with glycosaminoglycans-PF4 complexes present on the endothelial surface could also induce endothelial lesions and promote procoagulant activity and predisposition to thrombosis.
Amiral
J
J
Serbio Research Laboratory, Gennevilliers, France.
Wolf
M
M
Fischer
A
A
Boyer-Neumann
C
C
Vissac
A
A
Meyer
D
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000276:immunology; D005260:Female; D006493:Heparin / Q000009:adverse effects* / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000627:therapeutic use*; D007075:Immunoglobulin M / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D010978:Platelet Factor 4 / Q000276:immunology*; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000628:therapy
D000906:Antibodies; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D010978:Platelet Factor 4; D006493:Heparin