Bravo María Isabel, Raventós Aida, Pérez Alba, Costa Montserrat, Willis Todd
Bioscience Research Group, Grifols, Barcelona, Spain.
Bioscience Research Group, Grifols, Raleigh, NC, USA.
J Thromb Haemost. 2020 Aug;18(8):1934-1939. doi: 10.1111/jth.14887. Epub 2020 Jun 25.
Emicizumab is an alternative non-factor approach for treating patients with hemophilia A. However, there is a potential risk of thrombotic events when emicizumab is concomitantly administered with pro-hemostatic therapies.
To assess the hemostatic effect in vitro when a plasma-derived factor VIII concentrate containing von Willebrand factor (pdFVIII/VWF) was added to hemophilia A plasma (HAp) in combination with emicizumab.
HAp and HAp with FVIII inhibitors (HAp-i) samples with different concentrations of emicizumab (50 and 100 μg/mL) were combined with activated prothrombin complex concentrate at 0.5 to 1 U/mL, recombinant activated factor VII (rFVIIa) at 0.5 to 7 μg/mL, and pdFVIII/VWF at 0.1 to 4.5 IU/mL. Thrombin generation (TG; thrombin peak and endogenous thrombin potential) was determined using a Calibrated Automated Thrombogram assay.
When activated prothrombin complex concentrate was added to HAp and HAp-i with emicizumab, TG dramatically increased (multiplier effect > 4.5×). Addition of rFVIIa to HAp or HAp-i with emicizumab moderately increased TG in a concentration-related manner compared with rFVIIa alone. Addition of pdFVIII/VWF to HAp or HAp-i with emicizumab induced a TG response equivalent to those samples without emicizumab. In an in vitro model of immune tolerance induction with bleeds (HAp-i 15 Bethesda units), combination of pdFVIII/VWF, emicizumab, and rFVIIa did not trigger a multiplying effect on TG.
pdFVIII/VWF showed a non-additive effect on TG when combined in vitro with emicizumab. This finding suggests that emicizumab has limited ability to promote factor X activation in the presence of pdFVIII/VWF, thus reducing the risk of thrombotic events.
艾美赛珠单抗是治疗甲型血友病患者的一种非因子替代方法。然而，当艾美赛珠单抗与促止血疗法同时使用时，存在血栓形成事件的潜在风险。
评估在含有血管性血友病因子的血浆源性凝血因子VIII浓缩物（pdFVIII/VWF）与艾美赛珠单抗联合添加到甲型血友病血浆（HAp）中时的体外止血效果。
将含有不同浓度艾美赛珠单抗（50和100μg/mL）的HAp和含FVIII抑制剂的HAp（HAp-i）样本与0.5至1U/mL的活化凝血酶原复合物浓缩物、0.5至7μg/mL的重组活化因子VII（rFVIIa）以及0.1至4.5IU/mL的pdFVIII/VWF混合。使用校准自动血栓图分析法测定凝血酶生成（TG；凝血酶峰值和内源性凝血酶潜力）。
当将活化凝血酶原复合物浓缩物添加到含有艾美赛珠单抗的HAp和HAp-i中时，TG显著增加（倍增效应>4.5倍）。与单独使用rFVIIa相比，将rFVIIa添加到含有艾美赛珠单抗的HAp或HAp-i中会以浓度相关的方式适度增加TG。将pdFVIII/VWF添加到含有艾美赛珠单抗的HAp或HAp-i中诱导的TG反应与未使用艾美赛珠单抗的样本相当。在出血诱导的免疫耐受体外模型（HAp-i 15贝塞斯达单位）中，pdFVIII/VWF、艾美赛珠单抗和rFVIIa的组合未引发对TG的倍增效应。
pdFVIII/VWF在体外与艾美赛珠单抗联合时对TG显示出非累加效应。这一发现表明，在存在pdFVIII/VWF的情况下，艾美赛珠单抗促进因子X活化的能力有限，从而降低了血栓形成事件的风险。
