Role of monocytes and endothelial cells in heparin-induced thrombocytopenia
Role of monocytes and endothelial cells in heparin-induced thrombocytopenia
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DOI：
10.1160/th16-02-0162
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发表时间：
2016-11-01
影响因子：
6.7
通讯作者：
Rauova, Lubica
中科院分区：
文献类型：
--
作者：
Madeeva, Daria;Cines, Douglas B.;Rauova, Lubica
肝素诱导的血小板减少症（HIT）是一种以血小板减少和血栓形成为特征的自身免疫性疾病。导致血小板破坏的机制很复杂，HIT 的血栓并发症似乎是由于多种不同的血管内靶点造成的。 HIT 抗体与血小板表面 PF4/GAG 复合物和 Fc gamma RIIA 的双重结合可能导致血小板清除及其直接激活。单核细胞和内皮细胞以比血小板更高的亲合力结合 PF4，并且在肝素存在的情况下更能抵抗表面结合的 PF4 的竞争性去除。 HIT 抗体与这些细胞表面上的 PF4/糖胺聚糖复合物的结合导致其激活并增加促凝血活性。活化血小板释放的较高水平的 PF4 与内皮细胞的结合可能会导致糖萼的抗凝特性发生变化，并使 HIT 抗体靶向内皮细胞。与内皮细胞结合的致病性抗体通过一种独立于 Fc gamma R 激活的机制进一步促进血栓前状态，但尚未完全了解。对单核细胞和内皮细胞作用的更详细了解可能会确定新的干预目标，以减轻血栓形成的风险，并且与目前治疗这种严重疾病的方法相比，对全身止血的影响更小。
Heparin-induced thrombocytopenia (HIT) is an autoimmune disorder characterised by thrombocytopenia and thrombosis. The mechanisms leading to platelet destruction are complex and the thrombotic complications of HIT appear to be due to multiple different intravascular targets. The dual binding of HIT antibodies to platelet surface PF4/GAG complexes and to Fc gamma RIIA likely leads to both platelet clearance and to their direct activation. Monocytes and endothelial cells bind PF4 with higher avidity than platelets and are more resistant to competitive removal of surface-bound PF4 in the presence of heparin. Binding of HIT antibodies to PF4/glycosaminoglycan complexes on the surface on these cells leads to their activation and increased procoagulant activity. Binding of higher levels of PF4 released from activated platelets to the endothelium may lead to changes of the anticoagulant properties of the glycocalyx and target the endothelial cells for HIT antibodies. Pathogenic antibodies bound to endothelial cells further promote prothrombotic conditions by a mechanism that is independent of Fc gamma R activation, yet not completely understood. A more detailed understanding of the role of monocytes and endothelium may identify new targets for intervention to mitigate the risk of thrombosis with less impact on systemic haemostasis than current approaches to treatment for this serious disorder.