Rauova Lubica, Bdeir Khalil, Rux Ann H, Kalathottukaren Manu Thomas, Oberg Jenna, La Chanel C, Lim David T E, Hayes Vincent, Koma Gavin T, Sarkar Amrita, Poncz Mortimer, Kizhakkedathu Jayachandran N, Cines Douglas B
Hematology Division, Children's Hospital of Philadelphia, Philadelphia, PA.
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Blood. 2025 Jun 19;145(25):3030-3040. doi: 10.1182/blood.2024025653.
Heparin-induced thrombocytopenia (HIT) is initiated by antibodies that recognize large antigenic complexes composed of multiple molecules of cationic platelet factor 4 (PF4) and polyanions such as unfractionated heparin (UFH) that bind to each other primarily through electrostatic interactions. We asked whether the formation and stability of these HIT antigenic or ultralarge immune complexes (ULICs) would be inhibited by biocompatible synthetic polycationic molecules shown previously to dissociate UFH from antithrombin III and to inhibit polyphosphates. Members of this family of molecules, designated universal heparin reversal agents (UHRAs), inhibited formation and dissociated preformed ultralarge PF4-UFH (antigenic) complexes (ULCs), dissociated ULICs composed of the HIT-like monoclonal antibody KKO and ULCs, blocked binding of human HIT immunoglobulin G antibodies to PF4/heparin, binding of KKO to platelets, KKO-induced adhesion of platelets to activated human endothelium under flow, and microvascular thrombosis induced by KKO in a mouse model of HIT. These data suggest that UHRAs might provide a rationale intervention that acts at an early step in the pathogenesis of HIT to enhance the benefits and lessen the risks of nonheparin anticoagulants. Destabilization of immune complexes using polycationic inhibitors might also find a role in management of other polyanion PF4-antibody-mediated conditions, including vaccine-induced thrombocytopenia/thrombosis, postviral, and autoimmune HIT.
肝素诱导的血小板减少症（HIT）由抗体引发，这些抗体识别由多个阳离子血小板因子4（PF4）分子和诸如普通肝素（UFH）等多聚阴离子组成的大抗原复合物，它们主要通过静电相互作用彼此结合。我们研究了这些HIT抗原性或超大免疫复合物（ULICs）的形成和稳定性是否会受到生物相容性合成聚阳离子分子的抑制，这些分子先前已被证明能使UFH与抗凝血酶III解离并抑制多磷酸盐。该分子家族的成员，称为通用肝素逆转剂（UHRAs），抑制了形成并使预先形成的超大PF4-UFH（抗原性）复合物（ULCs）解离，使由HIT样单克隆抗体KKO和ULCs组成的ULICs解离，阻断了人HIT免疫球蛋白G抗体与PF4/肝素的结合、KKO与血小板的结合、KKO在流动状态下诱导的血小板与活化人内皮细胞的黏附以及KKO在HIT小鼠模型中诱导的微血管血栓形成。这些数据表明，UHRAs可能提供一种合理的干预措施，在HIT发病机制的早期阶段发挥作用，以增强非肝素抗凝剂的益处并降低风险。使用聚阳离子抑制剂破坏免疫复合物的稳定性也可能在管理其他多阴离子PF4抗体介导的病症中发挥作用，包括疫苗诱导的血小板减少症/血栓形成、病毒感染后和自身免疫性HIT。
