Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by complexes between platelet factor 4 (PF4) and heparin or other polyanions, but the risk of thrombosis extends beyond exposure to heparin implicating other PF4 partners. We recently reported that peri-thrombus endothelium is targeted by HIT antibodies, but the binding site(s) has not been identified. We now show that PF4 binds at multiple discrete sites along the surface of extended strings of von Willebrand Factor (VWF) released from the endothelium following photochemical injury in an endothelialized microfluidic system under flow. The HIT-like monoclonal antibody KKO and HIT patient antibodies recognize PF4-VWF complexes, promoting platelet adhesion and enlargement of thrombi within the microfluidic channels. Platelet adhesion to the PF4-VWF-HIT antibody complexes is inhibited by antibodies that block FcgRIIA or the glycoprotein Ib-IX complex on platelets. Disruption of PF4-VWF-HIT antibody complexes by drugs that prevent or block VWF oligomerization attenuate thrombus formation in a murine model of HIT. Together, these studies demonstrate assembly of HIT immune complexes along VWF strings released by injured endothelium that might propagate the risk of thrombosis in HIT. Disruption of PF4-VWF complex formation may provide a new therapeutic approach to HIT.

中文翻译：

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肝素诱导的血小板减少抗体对 PF4-VWF 复合物的识别有助于血栓传播

肝素诱导的血小板减少症 (HIT) 是一种由血小板因子 4 (PF4) 和肝素或其他聚阴离子之间的复合物介导的血栓形成前疾病，但血栓形成的风险超出了肝素暴露的范围，这与其他 PF4 伴侣有关。我们最近报道了 HIT 抗体靶向血栓周围内皮，但尚未确定结合位点。我们现在表明，PF4 在流动下的内皮化微流体系统中光化学损伤后从内皮释放的血管性血友病因子 (VWF) 延伸串表面的多个离散位点结合。HIT 样单克隆抗体 KKO 和 HIT 患者抗体可识别 PF4-VWF 复合物，促进微流体通道内的血小板粘附和血栓扩大。血小板与 PF4-VWF-HIT 抗体复合物的粘附受到阻断血小板上 FcgRIIA 或糖蛋白 Ib-IX 复合物的抗体的抑制。预防或阻断 VWF 寡聚化的药物破坏 PF4-VWF-HIT 抗体复合物可减弱 HIT 小鼠模型中的血栓形成。总之，这些研究表明 HIT 免疫复合物沿着受损内皮释放的 VWF 串组装，这可能会增加 HIT 血栓形成的风险。PF4-VWF 复合物形成的破坏可能为 HIT 提供一种新的治疗方法。这些研究表明 HIT 免疫复合物沿着受损内皮释放的 VWF 串组装，这可能会增加 HIT 血栓形成的风险。PF4-VWF 复合物形成的破坏可能为 HIT 提供一种新的治疗方法。这些研究表明 HIT 免疫复合物沿着受损内皮释放的 VWF 串组装，这可能会增加 HIT 血栓形成的风险。PF4-VWF 复合物形成的破坏可能为 HIT 提供一种新的治疗方法。