National Hemophilia Center, Sheba Medical Center, Tel Hashomer, Israel.
Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Pediatr Res. 2023 May;93(6):1546-1550. doi: 10.1038/s41390-022-02268-5. Epub 2022 Aug 31.
Hemophilia A (HA) therapy requires intravenous replacement infusions of factor (F) VIII concentrate. Inhibitors are high-affinity immunoglobulin G that are directed against FVIII and thereby render replacement therapy ineffective. This complication has significant prognostic implications. We aimed to examine the immune system involvement in inhibitor formation specifically T-cell excision circles (TRECs) and B-cell excision circles (KRECs), markers of new T and B cells, respectively, and examine them as surrogate markers for inhibitor formation.
Blood samples were collected from 35 children with severe HA. Children were divided into two groups: with FVIII inhibitors and without FVIII inhibitors. TRECs and KRECs were measured in peripheral blood.
A total of 11 patients with inhibitors and 24 without were evaluated. Children with inhibitors had higher levels of TRECs however not statistically significant (p = 0.085). CjKREC levels were higher in the inhibitor patients (p = 0.003). Moreover, the sj/cjKREC ratio was lower in the inhibitor patients (p = 0.015).
Our findings may add to the notion that inhibitor formation is attributed to humoral immunity due to peripheral B-cell expansion and loss of peripheral tolerance. Improved knowledge regarding the involvement of the immune system in the formation of FVIII inhibitors will enable better therapy tailoring in the era of non-replacement therapies.
The etiology of FVIII inhibitor formation is multifactorial, in which the immune system plays a pivotal role. Our findings may add to the notion that inhibitor formation is attributed to humoral immunity due to peripheral B-cell expansion and production of antibodies against FVIII. Improved knowledge regarding the involvement of the immune system in the development of FVIII inhibitors will enable the identification of patients prone to inhibitor development and better therapy tailoring in the new era of non-replacement therapies.
血友病 A（HA）的治疗需要静脉输注因子（F）VIII 浓缩物进行替代治疗。抑制剂是针对 FVIII 的高亲和力免疫球蛋白 G，从而使替代治疗无效。这种并发症具有重要的预后意义。我们旨在专门研究免疫系统在抑制剂形成中的作用，即 T 细胞切除环（TRECs）和 B 细胞切除环（KRECs），分别是新 T 细胞和 B 细胞的标志物，并将它们作为抑制剂形成的替代标志物进行研究。
从 35 名重型 HA 儿童中采集血样。儿童分为两组：有 FVIII 抑制剂和无 FVIII 抑制剂。在外周血中测量 TRECs 和 KRECs。
共评估了 11 名有抑制剂和 24 名无抑制剂的患者。有抑制剂的儿童 TRECs 水平较高，但无统计学意义（p=0.085）。抑制剂患者的 CjKREC 水平较高（p=0.003）。此外，抑制剂患者的 sj/cjKREC 比值较低（p=0.015）。
我们的发现可能表明，由于外周 B 细胞扩增和外周耐受丧失，抑制剂的形成归因于体液免疫。更好地了解免疫系统在 FVIII 抑制剂形成中的作用将使我们能够在非替代治疗时代更好地调整治疗方案。
FVIII 抑制剂形成的病因是多因素的，免疫系统在其中起着关键作用。我们的发现可能表明，由于外周 B 细胞扩增和针对 FVIII 的抗体产生，抑制剂的形成归因于体液免疫。更好地了解免疫系统在 FVIII 抑制剂形成中的作用将使我们能够识别易发生抑制剂形成的患者，并在新的非替代治疗时代更好地调整治疗方案。
