Different platelet specificities of heparin‐dependent platelet aggregating factors in heparin‐associated immune thrombocytopenia

Abstract

Delayed onset heparin-associated thrombocytopenia (HAT) is thought to be a result of formation of antiplatelet antibodies which cause platelet aggregation in the presence of heparin. Platelet aggregation in response to serum from patients with HAT has been studied in platelet-rich plasma (PRP) from a panel of normal blood donors. Heparin-dependent aggregation with any HAT serum occurred in PRP from only some donors. PRP from the non-responding donors did, however, aggregate in the presence of heparin with other HAT sera. The same patterns of aggregation or lack of response to HAT sera were seen in washed platelet suspensions. Heparin (0.06-2 U/ml) did not cause aggregation in the presence of normal serum with PRP from these donors. However, in PRP from four of the 17 individuals studied, heparin (0.25-1 U/ml) alone caused rapid platelet aggregation and some HAT sera heated at 56 degrees C caused platelet aggregation without added heparin. Sub-aggregating concentrations of adrenaline could replace heparin in promoting aggregation by heated HAT sera in PRP of the other donors. HAT IgG showed the same platelet specificities as the serum in causing either heparin- or adrenaline-dependent aggregation. Thus in HAT, antibodies are directed towards different platelet antigens which are expressed differently in different individuals. Platelet activation by heparin and adrenaline either exposes these antigens or causes aggregation of antibody-coated platelets.

Increased risk of thrombosis in FcγRIIA 131RR patients with HIT due to defective control of platelet activation by plasma IgG2

“…1 Despite having thrombocytopenia, affected patients usually develop thrombosis, and this particular clinical presentation is explained by the central role of Fcg receptors in the pathophysiology of HIT, particularly FcgRIIA, which mediates platelet activation induced by immunoglobulin (Ig) G-PF4/H immune complexes (ICs). In addition, platelets from healthy donors exhibit wide variability in their response to HIT antibodies, [2][3][4] and many patients who synthesize significant levels of antibodies to PF4/H while being treated with heparin do not develop HIT. [5][6][7] The FCGR2A gene, which encodes FcgRIIA, displays a functional allelic dimorphism generating 2 codominantly expressed allotypes with either a histidine (H) or an arginine (R) at amino acid position 131 in the second Ig-like extracellular domain.…”

Decision Analysis for Use of Platelet Aggregation Test, Carbon 14–Serotonin Release Assay, and Heparin–Platelet Factor 4 Enzyme-Linked Immunosorbent Assay for Diagnosis of Heparin-lnduced Thrombocytopenia

“…[7][8][9] Other functional methods have therefore been developed, such as the heparin-induced platelet activation test, performed in microplates with washed platelets,An enzyme-linked immunosorbent assay (ELISA; Asserachrom-HPIA; Diagnostica Stago, Asnieres, France) has been developed that detects antibodies that bind to H-PF4 complexes covalently coated in microwells at optimal concentrations. 1213 This ELISA technique apparently provides higher sensitivity than platelet aggregation or activation tests 1415 and can detect antibodies to H-PF4 in patients receiving heparin before thrombocytopenia develops.…”

Heparin-Associated Thrombocytopenia : No Association of Immune Response with HLA

“…Several groups have demonstrated that the IgG fraction of HAT sera activates platelets in the presence of heparin [7][8][9][10]. In spite of parenteral anticoagulation and throm bocytopenia, these patients are at risk of developing se vere arterial and venous thromboembolic complications, resulting in a high rate of morbidity and mortality [11].…”