Increased Accumulation and Retention of rhFVIIa (eptacog beta) in Knee Joints of Hemophilia A Mice Compared to Wild-Type Mice.
Increased Accumulation and Retention of rhFVIIa (eptacog beta) in Knee Joints of Hemophilia A Mice Compared to Wild-Type Mice.
复制标题
与野生型小鼠相比，A 型血友病小鼠膝关节中 rhFVIIa (eptacog beta) 的积累和保留增加。
DOI：
10.1055/s-0039-1688907
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发表时间：
2019
影响因子：
6.7
通讯作者：
Rao,LVijayaMohan
中科院分区：
文献类型：
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作者：
Magisetty,Jhansi;Pendurthi,UshaR;Madhunapantula,SubbaRaoV;Grandoni,Jerry;Rao,LVijayaMohan
我们早期的研究表明，重组人凝血因子VIIa（rhFVIIa）在小鼠血管内给药迅速从循环中消失。然而，一小部分进入血管外的rhFVIIa在很长一段时间内保持功能活性。本研究的目的是调查剂量依赖性rhFVIIa积累和保留在小鼠膝关节和测试是否血友病条件影响rhFVIIa隔离在关节。野生型和FVIII−/−小鼠通过尾静脉注射三种剂量的rhFVIIa（eptacog beta、90、250和500 μg/kg）。在rhFVIIa给药后的不同时间，收集血液和膝关节以测量血浆和关节组织中的FVIIa活性和抗原水平。通过免疫组织化学分析关节组织切片中rhFVIIa的存在。通过伊文思蓝染料或荧光素葡聚糖外渗来评估血管通透性。该研究表明，rhFVIIa以剂量依赖性方式在野生型和FVIII−/−小鼠的膝关节中积累。rhFVIIa抗原和FVIIa活性可在关节中检测至少7天。与野生型小鼠相比，在FVIII−/−小鼠膝关节中观察到rhFVIIa蓄积水平显著较高。免疫组织化学分析证实，与野生型小鼠相比，FVIII−/−小鼠中rhFVIIa保留水平更高。其他研究表明，FVIII-/-小鼠更容易发生血管渗漏。总之，目前的数据表明，剂量依赖性的积累rhFVIIa在膝关节，血友病的条件下，增强了rhFVIIa从循环进入血管外。目前的数据将有助于改善rhFVIIa预防。
Our earlier studies showed that recombinant human factor VIIa (rhFVIIa) administered intravascularly in mice disappeared rapidly from the circulation. However, a small fraction of rhFVIIa that entered extravascular remained functionally active for an extended period. The present study aims to investigate the dose-dependency of rhFVIIa accumulation and retention in mouse knee joints and test whether the hemophilic condition affects rhFVIIa sequestration in joints. Wild-type and FVIII−/−mice were injected with three doses of rhFVIIa (eptacog beta, 90, 250, and 500 μg/kg) via the tail vein. At varying times following rhFVIIa administration, blood and knee joints were collected to measure FVIIa activity and antigen levels in plasma and joint tissues. Joint tissue sections were analyzed by immunohistochemistry for the presence of rhFVIIa. Vascular permeability was assessed by either Evans Blue dye or fluorescein dextran extravasation. The study showed that rhFVIIa accumulated in knee joints of wild-type and FVIII−/−mice in a dose-dependent manner. rhFVIIa antigen and FVIIa activity could be detectable in joints for at least 7 days. Significantly higher levels of rhFVIIa accumulation were observed in knee joints of FVIII−/−mice compared with that of wild-type mice. Immunohistochemical analyses confirmed higher levels of rhFVIIa retention in FVIII−/−mice compared with wild-type mice. Additional studies showed that FVIII−/−mice were more permissible to vascular leakage. In conclusion, the present data demonstrate a dose-dependent accumulation of rhFVIIa in knee joints, and the hemophilic condition enhances the entry of rhFVIIa from circulation to the extravascular. The present data will be useful in improving rhFVIIa prophylaxis.