Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications
Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications
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DOI：
10.1182/blood-2005-08-3122
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发表时间：
2006-03-15
期刊：
影响因子：
20.3
通讯作者：
Poncz, M
中科院分区：
文献类型：
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作者：
Rauova, L;Zhai, L;Poncz, M
肝素诱导的血小板减少症 (HIT) 抗体可识别肝素和血小板因子 4 (PF4) 之间的复合物。肝素和 PF4 仅以较小的摩尔比结合 HIT 抗体。我们探讨了血小板表面结合的 PF4 作为抗原在实验性 HIT 发病机制中的作用。我们发现细胞表面 PF4 复合物仅在有限的 PF4 浓度范围内才具有抗原性。 HIT 抗体结合不需要肝素，但可将最佳表面抗原性所需的 PF4 浓度提高到更高水平。这些数据得到体外研究的支持，该研究涉及人和鼠血小板与外源重组人 (h) PF4 和抗 PF4 肝素单克隆抗体 (KKO) 或 HIT 免疫球蛋白。将 KKO 注射到表达不同水平 hPF4 的转基因小鼠中，表明血小板减少症的严重程度与血小板 hPF4 表达之间存在相关性。该模型中使用高剂量肝素或硫酸鱼精蛋白的治疗干预支持表面 PF4 抗原复合物在 HIT 病因学中的致病作用。我们相信，对表面 PF4 的关注增进了我们对 HIT 发病机制的理解，提出了识别肝素暴露后发生 HIT 高风险患者的方法，并提供了新的治疗策略。
Heparin-induced thrombocytopenia (HIT) antibodies recognize complexes between heparin and platelet factor 4 (PF4). Heparin and PF4 bind HIT antibodies only over a narrow molar ratio. We explored the involvement of platelet surface-bound PF4 as an antigen in the pathogenesis of experimental HIT. We show that cellsurface PF4 complexes are also antigenic only over a restricted concentration range of PF4. Heparin is not required for HIT antibody binding but shifts the concentration of PF4 needed for optimal surface antigenicity to higher levels. These data are supported by in vitro studies involving both human and murine platelets with exogenous recombinant human (h) PF4 and either an anti-PF4-heparin monoclonal antibody (KKO) or HIT immunoglobulin. Injection of KKO into transgenic mice expressing different levels of hPF4 demonstrates a correlation between the severity of the thrombocytopenia and platelet hPF4 expression. Therapeutic interventions in this model using high-dose heparin or protamine sulfate support the pathogenic role of surface PF4 antigenic complexes in the etiology of HIT. We believe that this focus on surface PF4 advances our understanding of the pathogenesis of HIT, suggests ways to identify patients at high risk to develop HIT upon heparin exposure, and offers new therapeutic strategies.