PATHOGENESIS OF ANTIPHOSPHOLIPID ANTIBODIES WHICH RECOGNIZE KININOGENS IN PATIENTS WITH THROMBOSIS AND PREGNANCY LOSSES

识别血栓形成和妊娠失败患者激肽原的抗磷脂抗体的发病机制

• 批准号: 11671653
• 负责人: SUGI Toshitaka
• 金额: $ 1.98万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671653/
• 关键词: antiphospholipid antibodies; kininogen; recurrentpregnancy losses; thrombosis; platelet aggregation; phosphatidylethanoamine

We have published that certain aPE are not specific for phosphatidylethanolamine (PE) per se, but are directed to PE-binding plasma proteins, e.g., kininogens (Blood, 86, 3083, 1995). We recently reported that 31.7% of patients with early recurrent pregnancy losses (RPL) were positive for aPE and 90.5% of the PE-binding protein dependent IgG aPE positive sera were kininogen-dependent (Fertil Steril, 71, 1061, 1999). Kininogens bind to platelets and inhibit thrombin-induced platelet aggregation. Kininogen domain 3 was found responsible for this activity. We demonstrated that kininogen-dependent aPE augments thrombin-induced platelet aggregation (Thromb Res, 84, 97, 1996). Therefore, is it possible that certain aPE recognize kininogen domain 3? By using synthetic peptides that span the third kininogen domain, we observed that some kininogen-dependent aPE from RPL patients recognized the Cys333-Lys345 peptide, which encompasses both the cell binding and cysteine protease inhibitory sites. … More Other RPL aPE patient sera recognized Pro258-Ala277 or Gly235-Glu259, which contain the thrombin inhibitory sequence (Leu271-Ala277) and cysteine protease inhibitory site, respectively, Inhibition of platelet cysteine protease, i.e., calpain, results in inhibition of thrombin-induced platelet aggregation. Our data support an hypothesis that kininogen-dependent aPE may promote thrombosis in vivo due to disruption of the normal antithrombotic effects of kininogen.aPA have been described in patients with thrombosis, thrombocytopenia, and RPL.We recently reported that a strong association between RPL and antiphosphatidylethanolamine antibodies (aPE) exists (Fertil Steril, 71, 1060, 1999) ; and that kininogen-dependent aPE augmented thrombin-induced platelet aggregation in vitro (Thromb Res, 84, 97, 1996). Historically, conventional aggregometers, which measure the changes in light transmission of a platelet suspension, have a limited ability to detect SSAF.Our earlier attempts showed that older instruments were not sufficiently sensitive to detect SSAF in RPL patients. By using a newly developed aggregometer based on laser light scattering (PA-20, Kowa, Tokyo, Japan), we looked again for platelet aggregation in 30 non-pregnant RPL patients. Twenty of the 30 RPL patients were positive for aPA, such as aPE, anticardiolipin antibodies and antiphosphatidylserine antibodies. SSAF was observed in 12/30 RPL patients, all of whom were positive for aPA.Among the 18 patients negative for SSAF, 8 patients (44.4%) were positive for aPA.None of the 10 RPL patients without aPA was found to have SSAF.Our data show a statistically significant association between SSAF and aPA (p=0.0016) in patients with RPL. Less

我们已经公开了某些aPE对磷脂酰乙醇胺（PE）本身不是特异性的，而是针对PE结合血浆蛋白，例如，激肽原（Blood，86，3083，1995）。我们最近报道，31.7%的早期复发性妊娠丢失（RPL）患者为aPE阳性，90.5%的PE结合蛋白依赖性IgG aPE阳性血清为激肽原依赖性（Fertil Steril，71，1061，1999）。激肽原与血小板结合并抑制凝血酶诱导的血小板聚集。激肽原结构域3被发现负责这种活动。我们证明了激肽原依赖性aPE增强凝血酶诱导的血小板聚集（Thromb Res，84，97，1996）。因此，某些aPE是否可能识别激肽原结构域3？通过使用跨越第三激肽原结构域的合成肽，我们观察到来自RPL患者的一些激肽原依赖性aPE识别Cys 333-Lys 345肽，其包含细胞结合和半胱氨酸蛋白酶抑制位点。 ...更多信息 其他RPL aPE患者血清识别Pro258-Ala 277或Gly 235-Glu 259，其分别含有凝血酶抑制序列（Leu 271-Ala 277）和半胱氨酸蛋白酶抑制位点。钙蛋白酶抑制凝血酶诱导的血小板聚集。我们的数据支持这样一个假设，即依赖于激肽原的阿帕可能由于破坏激肽原的正常抗血栓作用而促进体内血栓形成。（Fertil Steril，71，1060，1999）;以及激肽原依赖性aPE在体外增强凝血酶诱导的血小板聚集（Thromb Res，84，97，1996）。从历史上看，传统的凝集仪，测量血小板悬浮液的光透射的变化，有一个有限的能力来检测SSAF。我们早期的尝试表明，旧的仪器没有足够的灵敏度来检测RPL患者的SSAF。通过使用新开发的基于激光散射的聚集计（PA-20，Kowa，东京，日本），我们再次观察了30例非妊娠RPL患者的血小板聚集。30例RPL患者中有20例阿帕阳性，如aPE、抗心磷脂抗体和抗磷脂酰丝氨酸抗体。30例RPL患者中有12例检测到SSAF，均为阿帕阳性，18例SSAF阴性患者中有8例（44.4%）阿帕阳性，10例无阿帕的RPL患者中无一例检测到SSAF，我们的数据显示RPL患者中SSAF与阿帕之间存在显著相关性（p=0.0016）。少

项目成果

Sugi T, Izumi S, Makino T.: "Antiphospholipid antibodies and pregnancy losses."Obstetrics and Gynecology. (in press). (2001)

Sugi T、Izumi S、Makino T.：“抗磷脂抗体和妊娠丢失。”妇产科。

Makino T, Izumi S, Sugi T, Matsubayashi H.: "Abnormal pregnancy-abortion, recurrent pregnancy losses."Informaed Concent Guidance. 56-64 (2000)

Makino T、Izumi S、Sugi T、Matsubayashi H.：“异常妊娠流产、反复妊娠丢失。”知情浓度指导。

杉俊隆: "抗フォスファチジルエタノールアミン抗体はキニノーゲン・ドメイン3のprotease inhibitory siteを認識する"日本産婦人科新生児血液学会誌. 10. S99-S100 (2000)

Toshitaka Sugi：“抗磷脂酰乙醇胺抗体识别激肽原结构域 3 中的蛋白酶抑制位点”日本妇产科和新生儿血液学会杂志 10. S99-S100 (2000)。

Sugi, T: "Plasma contact system, kallikrein-kinin system and antiphospholipid-protein antibodies in thrombosis and pregnancy"J Reprod Immunol. (in press).

Sugi，T：“血栓形成和妊娠中的血浆接触系统、激肽释放酶-激肽系统和抗磷脂蛋白抗体”J Reprod Nutrition。

杉俊隆 他: "抗リン脂質抗体と不育症"産科と婦人科. (In press). (2001)

Toshitaka Sugi 等人：“抗磷脂抗体和不孕症”妇产科（2001 年出版）。