Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Thromb Haemost. 2023 Oct;123(10):955-965. doi: 10.1055/s-0043-1769788. Epub 2023 Jun 19.
Emicizumab is a bispecific antibody mimicking coagulation factor VIII (FVIII) employed to treat patients with hemophilia A (PwHA) regardless of FVIII inhibitor status. The identification of biological markers reflecting the hemostatic competence of patients under emicizumab therapy would have a great clinical value. Unfortunately, emicizumab over-corrects standard coagulation assays, precluding their use for evaluating the hemostatic correction achieved . Here, we investigated whether global coagulation assays (GCA) would allow monitoring the biological response to non-factor replacement therapy with emicizumab.
Six adults PwHA received a weekly dose of emicizumab of 3 mg/kg during weeks (W) 1 4 and 1.5 mg/kg from W5 onwards. Response to treatment was monitored weekly by emicizumab plasma concentration, thrombin generation (TG), and fibrin clot formation (FCF) and structure. TG and FCF results were compared to patient baseline, FVIII replacement, and healthy donors.
TG and FCF significantly increased in PwHA after the loading period, reaching a plateau that lasted until the end of monitoring. Similarly, fibrin clot network became denser with thinner fibrin fibers. However, TG contrary to FCF remained at the lower limits of reference values. Remarkably, despite having similar plateau concentrations of emicizumab some patients showed markedly different degrees of TG and FCF improvement.
Our study enriches the knowledge on the use of GCA to monitor non-factor replacement therapy, indicating that TG and FCF could act as direct markers of emicizumab biological activity. GCA allow to capture and visualize the individually variable response to emicizumab, leading a step forward to the personalization of patient treatment.
依库珠单抗是一种模拟凝血因子 VIII（FVIII）的双特异性抗体，用于治疗无论 FVIII 抑制剂状态如何的血友病 A（PwHA）患者。识别反映接受依库珠单抗治疗的患者止血能力的生物标志物将具有重要的临床价值。不幸的是，依库珠单抗过度纠正了标准凝血检测，使其无法用于评估达到的止血纠正情况。在这里，我们研究了是否可以使用整体凝血检测（GCA）来监测非因子替代疗法用依库珠单抗治疗的生物学反应。
6 名成年 PwHA 在第 1 至 4 周和第 5 周开始每周接受 3mg/kg 的依库珠单抗剂量，之后每周接受 1.5mg/kg 的依库珠单抗剂量。每周通过依库珠单抗血浆浓度、血栓生成（TG）和纤维蛋白凝块形成（FCF）和结构监测治疗反应。将 TG 和 FCF 结果与患者基线、FVIII 替代和健康供体进行比较。
在负荷期后，PwHA 的 TG 和 FCF 显著增加，达到持续到监测结束的平台期。同样，纤维蛋白凝块网络变得更密集，纤维蛋白纤维更细。然而，与 FCF 相反，TG 仍处于参考值的下限。值得注意的是，尽管依库珠单抗的平台浓度相似，但一些患者的 TG 和 FCF 改善程度差异很大。
我们的研究丰富了使用 GCA 监测非因子替代治疗的知识，表明 TG 和 FCF 可以作为依库珠单抗生物学活性的直接标志物。GCA 可以捕获和可视化个体对依库珠单抗的可变反应，为患者治疗的个体化迈出了一步。
