Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
Research Division, Chugai Pharmaceutical Co., Kamakura, Kanagawa, Japan.
Thromb Haemost. 2021 Mar;121(3):279-286. doi: 10.1055/s-0040-1716542. Epub 2020 Sep 9.
Emicizumab is a bispecific antibody to factor (F) IXa and FX that mimics the FVIIIa cofactor function. Emicizumab prophylaxis markedly decreases bleeding episodes in patients with hemophilia A (PwHAs), irrespective of the presence of FVIII inhibitors. However, thrombotic microangiopathy (TMA) was reported when repeated high doses of activated prothrombin complex concentrates (aPCC) were concomitantly used with emicizumab. Although bypassing agents (BPAs) are vital in the hemostatic treatment for PwHAs with inhibitors, the mechanism of emicizumab-related TMA remains unclear.
To assess the risk of excessive thrombus formation associated with BPAs and emicizumab under high shear conditions.
Perfusion flow-chamber experiments under high shear conditions were performed using whole blood from PwHAs in the presence of emicizumab without or together with FVIII or BPAs ex vivo.
Emicizumab (100 μg/mL) added ex vivo to whole blood from PwHAs improved defective thrombus formation in a similar manner to that observed with the addition of recombinant FVIII at the early phase, while FVIII continued to be important at the later stages. aPCC (1.2 U/mL equivalent to 100 U/kg) or recombinant FVIIa (1.1 µg/mL; equivalent to 90 µg/kg) together with emicizumab further promoted platelet interactions and fibrin formation ex vivo but did not induce excessive thrombus formation.
Emicizumab enhanced thrombin generation at local sites and improved defective hemostasis in whole blood from PwHAs under high shear conditions. Simple concomitant use of BPAs with emicizumab did not mediate excessive thrombus formation and remains an option for hemostatic management of emicizumab-treated PwHAs with inhibitors.
依库珠单抗是一种针对因子（F）IXa 和 FX 的双特异性抗体，可模拟 FVIIIa 的辅助因子功能。依库珠单抗预防治疗可显著减少血友病 A 患者（PwHA）的出血发作，无论是否存在 FVIII 抑制剂。然而，当反复给予高剂量激活的凝血酶原复合物浓缩物（aPCC）与依库珠单抗同时使用时，会发生血栓性微血管病（TMA）。虽然旁路制剂（BPA）在有抑制剂的 PwHA 的止血治疗中至关重要，但依库珠单抗相关 TMA 的机制仍不清楚。
评估高剪切条件下 BPA 和依库珠单抗与过度血栓形成相关的风险。
使用 PwHA 的全血在高剪切条件下进行灌注流室实验，依库珠单抗体外添加到全血中，无论是否存在 FVIII 或 BPA。
依库珠单抗（100μg/mL）体外添加到 PwHA 的全血中，在早期阶段类似于添加重组 FVIII 改善了缺陷性血栓形成，而 FVIII 在后期阶段仍然很重要。aPCC（1.2 U/mL 相当于 100 U/kg）或重组 FVIIa（1.1μg/mL；相当于 90μg/kg）与依库珠单抗一起进一步促进了血小板相互作用和纤维蛋白形成，但没有诱导过度血栓形成。
依库珠单抗增强了局部血栓生成酶的生成，并改善了高剪切条件下 PwHA 全血中的缺陷性止血。BPA 与依库珠单抗的简单同时使用不会介导过度血栓形成，并且仍然是依库珠单抗治疗有抑制剂的 PwHA 止血管理的一种选择。
