Nakajima Yuto, Osuna Mitsumasa, Mizumachi Kuniyoshi, Shimonishi Naruto, Furukawa Shoko, Ogiwara Kenichi, Nogami Keiji
Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara, Japan.
Res Pract Thromb Haemost. 2024 Jun 18;8(4):102479. doi: 10.1016/j.rpth.2024.102479. eCollection 2024 May.
Venous thromboembolic events have been reported in persons with hemophilia A who received emicizumab and activated prothrombin complex concentrate (APCC) concomitantly, but the relevant mechanism(s) remains unclear. We speculated that activated protein C (APC) and antithrombin (AT) resistance might be associated with these adverse events.
To investigate APC and AT resistance in factor (F)VIII-deficient (FVIIIdef) plasma in the presence of emicizumab and APCC.
In pooled normal plasma or FVIIIdef plasma samples mixed with emicizumab (50 μg/mL) and FVIII-bypassing agents, including recombinant FVIIa (2.2 μg/mL), APCC (1.3 IU/mL), or plasma-derived FVIIa/FX (1.5 μg/mL), the suppression effect of AT (0-2.4 μM) and APC (0-16 nM) was assessed by tissue factor-triggered thrombin generation assay. The APC effects in FVIIIdef plasma with the copresence of emicizumab, FII (1.3 μM), and/or FIXa (280 pM) were also examined.
The AT resistance in emicizumab and each bypassing agent was not observed. Moreover, APC dose-dependent suppression effect was observed in pooled normal plasma or FVIIIdef plasma mixed with emicizumab and recombinant FVIIa or plasma-derived FVIIa/FX. However, APC-catalyzed inactivation had little effect on thrombin generation assay potential in FVIIIdef plasma spiked with emicizumab and APCC. The addition of FIXa to emicizumab in FVIIIdef plasma could lead to partial APC resistance. Furthermore, FVIIIdef plasma spiked with emicizumab, FIXa, and FII was markedly resistant to APC-mediated inactivation.
FII and FIXa in APCCs were key clotting factors for APC resistance in FVIIIdef plasma supplemented with emicizumab and APCCs. The APC resistance in persons with hemophilia A receiving emicizumab and APCC may contribute to venous thromboembolic events.
有报道称，接受艾美赛珠单抗和活化凝血酶原复合物浓缩剂（APCC）的甲型血友病患者发生了静脉血栓栓塞事件，但其相关机制仍不清楚。我们推测活化蛋白C（APC）和抗凝血酶（AT）抵抗可能与这些不良事件有关。
研究在艾美赛珠单抗和APCC存在的情况下，因子（F）VIII缺乏（FVIIIdef）血浆中的APC和AT抵抗情况。
在混合的正常血浆或与艾美赛珠单抗（50μg/mL）和FVIII旁路制剂混合的FVIIIdef血浆样本中，包括重组FVIIa（2.2μg/mL）、APCC（1.3IU/mL）或血浆源性FVIIa/FX（1.5μg/mL），通过组织因子触发的凝血酶生成试验评估AT（0-2.4μM）和APC（0-16nM）的抑制作用。还检测了在艾美赛珠单抗、FII（1.3μM）和/或FIXa（280pM）同时存在的情况下，FVIIIdef血浆中的APC作用。
未观察到艾美赛珠单抗和每种旁路制剂中的AT抵抗。此外，在混合的正常血浆或与艾美赛珠单抗和重组FVIIa或血浆源性FVIIa/FX混合的FVIIIdef血浆中，观察到APC剂量依赖性抑制作用。然而，APC催化的失活对添加了艾美赛珠单抗和APCC的FVIIIdef血浆中的凝血酶生成试验潜力影响很小。在FVIIIdef血浆中向艾美赛珠单抗中添加FIXa可导致部分APC抵抗。此外，添加了艾美赛珠单抗、FIXa和FII的FVIIIdef血浆对APC介导的失活具有明显抗性。
APCC中的FII和FIXa是补充了艾美赛珠单抗和APCC的FVIIIdef血浆中APC抵抗的关键凝血因子。接受艾美赛珠单抗和APCC的甲型血友病患者中的APC抵抗可能导致静脉血栓栓塞事件。
