Unité Mixte de Recherche 7292, Centre National de la Recherche Scientifique, Université François Rabelais, Tours, France; Laboratoire d'Hématologie-Hémostase, and.
Unité Mixte de Recherche 7292, Centre National de la Recherche Scientifique, Université François Rabelais, Tours, France;
Blood. 2015 Apr 9;125(15):2397-404. doi: 10.1182/blood-2014-09-594515. Epub 2015 Feb 13.
Thrombosis results in heparin-induced thrombocytopenia (HIT) from cellular activation involving Fc receptors. In this study, the FcγRIIA 131RR genotype was found to increase the risk of thrombosis in HIT patients (odds ratio: 5.9; 95% confidence interval: 1.7-20). When platelet aggregation tests (PATs) were performed with platelet-rich plasma (PRP), a shorter lag time was measured in 131RR donors compared to individuals with the HR and HH genotypes in response to HIT plasma or 5B9, a recently developed humanized monoclonal antibody to PF4/heparin. Importantly, this difference was no longer detectable when PATs were performed with washed platelets or immunoglobulin (Ig)G-depleted PRP. Moreover, polyclonal IgG or monoclonal IgG1 added to IgG-depleted PRP increased the lag time in response to 5B9. HH platelets were also sensitive to IgG2, which in contrast, failed to inhibit the response of 131RR platelets to 5B9. Finally, higher tissue factor messenger RNA levels were measured in the whole blood of 131RR donors after activation by HIT antibodies, with increased phospholipid procoagulant activity. These results demonstrate that HIT patients homozygous for the FcγRIIA 131R allele have a higher risk of thrombosis, probably due to increased cell activation by antibodies to PF4/heparin, with a lower inhibitory effect of endogenous IgG, especially from the IgG2 subclass.
血栓形成导致肝素诱导的血小板减少症（HIT），这是一种涉及 Fc 受体的细胞激活。在这项研究中，发现 FcγRIIA 131RR 基因型会增加 HIT 患者发生血栓的风险（比值比：5.9；95%置信区间：1.7-20）。当使用富含血小板的血浆（PRP）进行血小板聚集试验（PAT）时，与 HR 和 HH 基因型的个体相比，131RR 供体对 HIT 血浆或最近开发的针对 PF4/肝素的人源化单克隆抗体 5B9 的反应中，测量到的潜伏期更短。重要的是，当使用洗涤血小板或免疫球蛋白（Ig）G 耗尽的 PRP 进行 PAT 时，这种差异不再可检测到。此外，添加到 IgG 耗尽的 PRP 中的多克隆 IgG 或单克隆 IgG1 增加了对 5B9 的反应潜伏期。HH 血小板也对 IgG2 敏感，相比之下，IgG2 未能抑制 5B9 对 131RR 血小板的反应。最后，在 HIT 抗体激活后，131RR 供体的全血中测量到更高的组织因子信使 RNA 水平，并且存在增加的磷脂促凝血活性。这些结果表明，HIT 患者纯合子 FcγRIIA 131R 等位基因具有更高的血栓形成风险，可能是由于针对 PF4/肝素的抗体引起的细胞激活增加，内源性 IgG 的抑制作用降低，尤其是 IgG2 亚类。
