Platelet FcγRIIA HIS131ARG polymorphism and platelet function: antibodies to platelet-bound fibrinogen induce platelet activation

Abstract

Summary. The His131Arg polymorphism of platelet FcgRIIA affects the binding affinity of certain IgG subclasses. The Arg131 allele has been associated with (auto)immune thrombocytopenia and heparin-induced thrombocytopenia in some studies. Because FcgRIIA can transmit platelet activation signals, we studied platelet responsiveness from 73 healthy donors to determine if this polymorphism modulated platelet function. Platelet function was studied by agonist and shear-induced activation, and standard aggregation. FcgRIIA was genotyped by allele-specific PCR. Compared with His131, the Arg131 allele was associated with significantly greater binding of activation-dependent antibodies. This effect was most prominent for the receptor-induced binding site (RIBS) antibodies F26 (P < 0.0001) and RIBS1 (P ¼ 0.0057), and the ligandinduced binding site antibody LIBS1 (P ¼ 0.0367). Unexpectedly, Arg131-positive platelets did not show greater fibrinogen binding, platelet aggregation or shear-induced platelet activation. We considered whether enhanced Fc binding and FcgRIIA cross-linking were responsible for those discrepancies. The increased binding of the two RIBS antibodies to the Arg131 isoform was abolished by blocking FcgRIIA, and the FcgRIIA genotype effect on F26 IgG binding was lost when F26 F(ab 0 ) 2 fragments were used. Furthermore, intact F26 and RIBS1 IgG directly and specifically induced P-selectin expression, and this effect was greatest in Arg131-positive platelets. We concluded that (a) the His131Arg polymorphism of FcgRIIA does not affect intrinsic platelet reactivity; (b) RIBS antibodies are able to cross-link FcgRIIA and activate platelets, and this activation has a modest effect on Arg131 platelets; and (c) flow cytometric based platelet assays may need to compensate for this FcgRIIA His131Arg effect on platelet activation.

The FcγRIIa His131Arg polymorphism and its association with myocardial infarction

“…These results lead us to conclude that the FccRIIa G507A polymorphism does not contribute to risk of MI in the population examined, either alone or in combination with established cardiovascular risk factors. Our findings support those of an earlier study [12], which demonstrated differential binding of activation-dependent antibodies by platelets that was dependent on the FccRIIa G507A polymorphism, but which also failed to demonstrate genotype-dependent differences in intrinsic platelet function as assessed by agonist and shear-induced platelet activation and aggregation.…”

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

“…It has been recently shown that monocytes preferentially bound HIT ICs because of the higher affinity of monocyte surface glycosaminoglycans for PF4 compared with platelet chondroitin sulfate molecules. 28 However, monocytes express only 5% of the total amount of FcgRIIA receptors in whole blood, 30 whereas 80% are present in circulating platelets 31 and ;5% are present in neutrophils. 32 The activation of monocytes in HIT might therefore also depend in vivo on platelet activation induced by IgG-PF4/H ICs.…”

Anti–miR-148a regulates platelet FcγRIIA signaling and decreases thrombosis in vivo in mice

“…13 Platelet FcgRIIA surface protein expression level and the H/R131 SNV genotype (rs1801274) were determined for each donor, because these variations have previously been reported as contributing to variation in platelet activation via FcgRIIA. 10,[36][37][38] We chose a mIgG 1 agonist specifically to see if our work replicated the known dependence on the RH polymorphism. R/R131 homozygotes were highly responsive to the mIgG 1 anti-CD9, and H/H homozygotes were weakly responsive (Figure 1), as expected.…”

“…R/R131 homozygotes were highly responsive to the mIgG 1 anti-CD9, and H/H homozygotes were weakly responsive (Figure 1), as expected. 36 We used linear regression to calculate the dependence of the aggregation on the HR polymorphism and on the FcgRIIa level. Across all 154 donors, the HR polymorphism explains 47% of the observed variance.…”