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 isoty ped in 38 patients who developed severe heparin-induced thrombocytopen ia (type II HIT), All the patients had a platelet count < 120 x 10(9)/ 1 or a reduction of > 30% of the initial value, occurring at least 5d after the onset of heparin. Thrombocytopenia, which rapidly reversed f ollowing the withdrawal of heparin, was associated with thrombosis in nine patients, Although IgG isotypes were found in most cases (it = 26 ), the presence of only IgM and/or IgA was observed in 12 patients, in cluding three cases showing a thrombotic complication. Our results ind icate that type II HIT may be induced by IgA and/or IgM anti-H-PF4 ant ibodies even in the absence of IgG isotypes. This finding demonstrates that platelet Fc receptors (Fc gamma RII) are not necessarily involve d 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 subseque nt 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 t he mediation of neutrophils, monocytes and lymphocytes which expose re ceptors for IgA (Fc alpha R) or IgM (Fc mu R). IgM-platelet complexes may also bind and activate complement, leading to platelet activation or destruction. Moreover, the reactivity of the antibodies with glycos aminoglycans-PF4 complexes present on the endothelial surface could al so induce endothelial lesions and promote procoagulant activity and pr edisposition to thrombosis.