Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tuebingen, University Hospital of Tuebingen, Tuebingen, Germany.
Center for Clinical Transfusion Medicine Tuebingen, Tuebingen, Germany.
Blood. 2022 Jun 9;139(23):3430-3438. doi: 10.1182/blood.2021013839.
Life-threatening thrombotic events at unusual sites have been reported after vector-based vaccinations against severe acute respiratory syndrome coronavirus 2. This phenomenon is now termed vaccine-induced immune thrombotic thrombocytopenia (VITT). The pathophysiology of VITT is similar to that of heparin-induced thrombocytopenia (HIT) and is associated with platelet-activating antibodies (Abs) against platelet factor 4 (PF4). Therefore, current guidelines suggest nonheparin anticoagulants to treat VITT patients. In this study, we investigated the interactions of heparin, danaparoid, fondaparinux, and argatroban with VITT-Ab/PF4 complexes using an ex vivo model for thrombus formation as well as in vitro assays to analyze Ab binding and platelet activation. We found that immunoglobulin Gs (IgGs) from VITT patients induce increased adherent platelets/thrombus formation in comparison with IgGs from healthy controls. In this ex vivo flow-based model, the procoagulant activity of VITT IgGs was effectively inhibited with danaparoid and argatroban but also by heparin. Interestingly, heparin and danaparoid not only inhibited IgG binding to PF4 but were also able to effectively dissociate the preformed PF4/IgG complexes. Fondaparinux reduced the in vitro generation of procoagulant platelets and thrombus formation; however, it did not affect platelet aggregation. In contrast, argatroban showed no effect on procoagulant platelets and aggregation but significantly inhibited VITT-mediated thrombus formation. Taken together, our data indicate that negatively charged anticoagulants can disrupt VITT-Ab/PF4 interactions, which might serve as an approach to reduce Ab-mediated complications in VITT. Our results should be confirmed, however, in a clinical setting before a recommendation regarding the selection of anticoagulants in VITT patients could be made.
在针对严重急性呼吸综合征冠状病毒 2 的基于载体的疫苗接种后，已经报道了在不常见部位发生危及生命的血栓事件。这种现象现在被称为疫苗诱导的免疫血栓性血小板减少症（VITT）。VITT 的病理生理学与肝素诱导的血小板减少症（HIT）相似，与针对血小板因子 4（PF4）的血小板激活抗体（Abs）有关。因此，目前的指南建议使用非肝素抗凝剂来治疗 VITT 患者。在这项研究中，我们使用体外血栓形成模型以及分析 Ab 结合和血小板激活的体外测定法，研究了肝素、达那肝素、磺达肝素和阿加曲班与 VITT-Ab/PF4 复合物的相互作用。我们发现，与健康对照者的 IgG 相比，VITT 患者的 IgG 可诱导增加的黏附血小板/血栓形成。在这种基于体外的流动模型中，达那肝素和阿加曲班可有效抑制 VITT IgG 的促凝活性，但肝素也可有效抑制。有趣的是，肝素和达那肝素不仅抑制 IgG 与 PF4 的结合，而且还能够有效地将预先形成的 PF4/IgG 复合物解离。磺达肝素可减少体外促凝血小板的生成和血栓形成；然而，它不影响血小板聚集。相比之下，阿加曲班对促凝血小板和聚集没有影响，但可显著抑制 VITT 介导的血栓形成。总之，我们的数据表明，带负电荷的抗凝剂可以破坏 VITT-Ab/PF4 相互作用，这可能是减少 VITT 中 Ab 介导的并发症的一种方法。然而，在提出关于 VITT 患者抗凝剂选择的建议之前，应在临床环境中确认我们的结果。
