Protein S antibody as an adjunct therapy for hemophilia B.
Protein S antibody as an adjunct therapy for hemophilia B.
复制标题
DOI：
10.1182/bloodadvances.2023010819
复制
发表时间：
2024-01-23
期刊：
影响因子：
7.5
通讯作者：
Majumder, Rinku
中科院分区：
文献类型：
--
作者：
Wilson, Hope P.;Pierre, Aliyah;Paysse, Ashley L.;Kumar, Narender;Cooley, Brian C.;Rudra, Pratyadipta;Dorsey, Adrianne W.;Polania-Villanueva, Diana;Chatterjee, Sabyasachi;Janbain, Maissaa;Velez, Maria C.;Majumder, Rinku
在儿童血友病B（HB）血浆中，凝血酶生成随着蛋白S（PS）抗体的增加而增加。在HB小鼠中，纤维蛋白和血小板蓄积随着PS抗体的增加而增加。血友病B（HB）是由遗传性血浆凝血因子IX（FIX）缺乏引起的。大约60%的儿童HB患者具有严重形式的FIX缺乏症（<1% FIX活性）。治疗通常需要通过FIX给药进行替代治疗。然而，外源性FIX的功能半衰期有限，天然抗凝蛋白S（PS）可抑制活化FIX（FIXa）。PS最终限制凝血酶形成，这限制了血浆凝固。PS对FIXa活性的这种调节使我们测试抑制PS是否会延长FIX的功能半衰期，从而延长基于FIX的HB治疗。我们测定了凝血时间和凝血酶生成，以测量PS抗体增加市售血浆和HB儿科患者血浆中FIX活性的疗效。我们纳入了11名没有其他合并症和凝血功能障碍的儿科患者。在体内，我们评估了存在FIXa ± PS抗体的HB小鼠中的血栓形成。我们发现PS抗体存在时凝血速度加快。类似地，在PS抗体的存在下，即使在严重HB患者的血浆中，形成的凝血酶峰值也显著更大。此外，与单独注射FIX的小鼠相比，注射PS抗体和FIX的HB小鼠在血栓诱导部位的纤维蛋白蓄积高4.5倍。我们的研究结果表明，PS抗体将是一种有价值的辅助治疗，以增加FIX替代治疗的有效性，在儿童患者有轻度，中度和重度HB。
In pediatric hemophilia B (HB) plasma, thrombin generation increased with protein S (PS) antibody. In HB mice, fibrin and platelet accumulation increased with PS antibodies. Hemophilia B (HB) is caused by an inherited deficiency of plasma coagulation factor IX (FIX). Approximately 60% of pediatric patients with HB possess a severe form of FIX deficiency (<1% FIX activity). Treatment typically requires replacement therapy through the administration of FIX. However, exogenous FIX has a limited functional half-life, and the natural anticoagulant protein S (PS) inhibits activated FIX (FIXa). PS ultimately limits thrombin formation, which limits plasma coagulation. This regulation of FIXa activity by PS led us to test whether inhibiting PS would extend the functional half-life of FIX and thereby prolong FIX-based HB therapy. We assayed clotting times and thrombin generation to measure the efficacy of a PS antibody for increasing FIX activity in commercially obtained plasma and plasma from pediatric patients with HB. We included 11 pediatric patients who lacked additional comorbidities and coagulopathies. In vivo, we assessed thrombus formation in HB mice in the presence of the FIXa ± PS antibody. We found an accelerated rate of clotting in the presence of PS antibody. Similarly, the peak thrombin formed was significantly greater in the presence of the PS antibody, even in plasma from patients with severe HB. Furthermore, HB mice injected with PS antibody and FIX had a 4.5-fold higher accumulation of fibrin at the thrombus induction site compared with mice injected with FIX alone. Our findings imply that a PS antibody would be a valuable adjunct to increase the effectiveness of FIX replacement therapy in pediatric patients who have mild, moderate, and severe HB.
登录
查看更多内容
影响因子：
3.9
作者：
Petrini, P.;Seuser, A.
通讯作者：
Seuser, A.
影响因子：
5.7
作者：
MARLAR, RA;NEUMANN, A
通讯作者：
NEUMANN, A
DOI：
10.1161/atvbaha.111.225334
发表时间：
2011-06-01
影响因子：
8.7
作者：
Cooley, Brian C.
通讯作者：
Cooley, Brian C.
影响因子：
3.9
作者：
Hacker, MR;Geraghty, S;Manco-Johnson, M
通讯作者：
Manco-Johnson, M
DOI：
10.1016/s0002-9378(99)70335-2
发表时间：
1999-10-01
影响因子：
9.8
作者：
De Groot, CJM;Bloemenkamp, KWM;Rosendaal, FR
通讯作者：
Rosendaal, FR