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Expression of factor VIII activity in the presertce of anti-factor VIII inhibitor antibodies

存在抗因子 VIII 抑制剂抗体时因子 VIII 活性的表达

基本信息

批准号：
18591198
负责人：
TANAKA Ichiro
金额：
$ 2.44万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591198/
关键词：
Blood coagulation Factor VIII Inhibitor

项目摘要

The expression of factor VIII (FVIII) : C in the presence of and-FVIII antibodies was studied using clot waveform analysis and thrombin generation test. Seven kinds of alloantibodies and 4 kinds of monoclonal antibodies against human FVIII were used. The former contains 3 alloantibodies recognizing A2 domain in the heavy chain and 4 alloantibodies recognizing C2 domain in the light chain. The latter contains each monoclonal antibody recognizing A1 and A2 domain, and 2 monoclonal antibodies recognizing C2 domain. Ten or twenty Bethesda units (BU) /ml of inhibitor IgG diluted with FVIII deficient plasma were mixed with normal plasma. The mixture was removed after incubation with time, and then maximum coagulation acceleration (| Min2 |) and FVIII : C were measured by MDAII. Moreover, both Peak Height and Endogenous Thrombin Potential (ETP) were measured on thrombin generation assay system. In the presence of final concentration of over 5 BU/ml inhibitors, low levels of FVIII : C and | Min2 | were detected even after 120 min incubation. Especially, the low levels of FVIII : C were detected in the alloantibodies and monoclonal antibody recognizing A2 domain in the heavy chain. Similarly, in most cases, small amount of thrombin generation was detected even in the presence of 20 BU/ml of inhibitors, especially in the antibodies recognizing A2 domain rather than C2-recognized antibodies. These findings indicate the expression of low levels of FVIII : C in the presence of high titer inhibitor, and confirm the prophylactic effect during regular infusions of FVIII concentrates for patients with hemophilia and inhibitors.

采用血块波形分析和凝血酶生成试验，研究了在and-FVIII抗体存在下因子VIII (FVIII): C的表达。采用7种同种异体抗体和4种单克隆抗体。前者含有3个识别重链A2结构域的同种异体抗体和4个识别轻链C2结构域的同种异体抗体。后者包含识别A1和A2结构域的单克隆抗体，以及2个识别C2结构域的单克隆抗体。用FVIII缺陷血浆稀释10或20个Bethesda单位(BU) /ml的抑制剂IgG与正常血浆混合。经过一定时间的孵育后取出混合物，用mdai测定最大凝血加速（| Min2 |）和FVIII: C。在凝血酶生成测定系统上测定峰高和内源性凝血酶电位（ETP）。当抑制剂的终浓度超过5 BU/ml时，即使在孵育120分钟后也检测到低水平的FVIII: C和| Min2 |。特别是在识别重链A2结构域的同种抗体和单克隆抗体中检测到低水平的FVIII: C。同样，在大多数情况下，即使存在20 BU/ml的抑制剂，也检测到少量凝血酶生成，特别是在识别A2结构域的抗体而不是识别c2的抗体中。这些结果表明，在高效价抑制剂存在时，FVIII: C表达水平较低，并证实了血友病患者和抑制剂定期输注FVIII浓缩液的预防作用。