http://hdl.handle.net/10564/2598 2026-04-09T17:49:07Z 2026-04-09T17:49:07Z Fujimura, Yoshihiro Matsumoto, Masanori Isonishi, Ayami Yagi, Hideo Kokame, Koichi Soejima, Kenji Murata, Mitsuru Miyata, Toshiyuki http://hdl.handle.net/10564/1744 2017-06-11T23:20:26Z 2011-07-21T15:00:00Z

タイトル: Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan 著者: Fujimura, Yoshihiro; Matsumoto, Masanori; Isonishi, Ayami; Yagi, Hideo; Kokame, Koichi; Soejima, Kenji; Murata, Mitsuru; Miyata, Toshiyuki 抄録: Upshaw–Schulman syndrome (USS) is an extremely rare hereditary deficiency of ADAMTS13 activity, termed congenital TTP. The clinical signs are usually mild during childhood, often with isolated thrombocytopenia. But their symptoms become more evident when patients have infections or get pregnant. We identified 43 USS-patients in Japan, who ranged in age from early childhood to 79 years of age. Analysing the natural history of these USS patients based on ADAMTS13 gene mutations may help characterise their clinical phenotypes. Severe neonatal jaundice that requires exchange blood transfusion, a hallmark of USS, was found in 18 of 43 patients (42%). During childhood, 25 of 43 patients were correctly diagnosed with USS without gender disparity. These 25 patients were categorised as having ‘the early-onset phenotype’. Between 15 and 45 years of age, 15 were correctly diagnosed, and, interestingly, they were all female. The remaining three patients were male and were diagnosed when they were older than 45 years of age, suggesting that they were ‘the late-onset phenotype’. Two of these three males developed sudden overt TTP when they were 55 and 63 years old, respectively. These two men had two different homozygous ADAMTS13 gene mutations, p.R193W/p.R193W and p.C1024R/p.C1024R, respectively. Both of which were not discovered in the US or Western countries. In vitro expression studies showed that these two proteins were consistently secreted into the culture medium but to a lesser extent and with reduced activity compared to the wild-type protein. Our results indicate that ‘the late-onset phenotype’ of USS is formed with ethnic specificity. 内容記述: ・The definitive version is available at " http://dx.doi.org/10.1111/j.1538-7836.2011.04341.x "; ・State of the Art 2011 : XXIII Congress of the International Society on Thrombosis and Haemostasis Invited Review

2011-07-21T15:00:00Z 藤村, 吉博 松本, 雅則 植村, 正人 杉本, 充彦 小亀, 浩市 宮田, 敏行 http://hdl.handle.net/10564/1743 2017-06-11T23:20:26Z 2009-02-09T15:00:00Z

タイトル: 動脈血栓症の制圧 : VWF-GPIb軸依存性血小板血栓形成を調節するADAMTS13の基礎・臨床病態解析 著者: 藤村, 吉博; 松本, 雅則; 植村, 正人; 杉本, 充彦; 小亀, 浩市; 宮田, 敏行 抄録: The mortality due to arterial thrombosis such as myocardial infarction and cerebral infarction exceeds that of malignant neoplasm, is increasing further, and is also becoming a big social issue in our country. Currently, arterial thrombosis is assumed to be established in vivo under rheological conditions where blood flow creates high shear stress. Under such conditions, the von Willebrand factor (VWF)-platelet glycoprotein (GP) Ib interaction plays a definitive role on platelet adhesion and aggregation that could be a key event for the formation of arterial thrombosis. In this regard. the biological activity of VWF under high shear stress is absolutely dependent upon its unique multimeric structure, the size of which is thought to be precisely regulated in vivo by the recently identified specific VWF-cleaving protease (ADAMTS13). Thus, the aim of our research project is to overcome arterial thrombosis targeting the functional relationships between the VWF-GPIb axis and ADAMTS13 in platelet thrombus formation. In the initial stage of our research, we have focused on the structure-function relationships of VWF. We have clarified the several functional sites within the VWF molecule critical for platelet thrornbus formation. In addition, our functional studies of VWF using a perfusion chamber system that can reproduce physiologic blood flow in vitro elucidated the shear-dependent function of VWF in platelet adhesion and aggregation, as well as the molecular mechanisms of the VWF-GPIb axis regulation by ADAMTS13 under blood flow conditions. Thus, our results altogether contributed to extend our understandings of molecular mechanisms for the arterial thrombosis. In the progressed stage of our research. our focus was shifted to the pathophysiology of the ADAMTS13 molecule. In particular, analyzing the phenotype-genotype relationships of congenital deficiency of ADAMTS13, termed Upshaw-Schulman syndrome (USS), due to ADAMTS13 gene mutations, can provide in vivo prototypic model of platelet thrombus formation under high shear stress. But USS is an extremely rare disease or often masqueraded as an isolated thrombocytopenia with mild clinical signs during childhood. During the past 10 years, we have diagnosed 37 patients with USS by assaying ADAMTS13 activity and its inhibitor titers in the laboratory of Nara Medical University. Further, through analyzing the natural history and ADAMTS13 gene mutations in these patients, we found that severe neonatal jaundice that requires exchange blood transfusions, a classic hallmark of USS, was seen in only 16 (43%) of 37 patients. Twenty-nine (79%) of the 37 patients had a history of thrombocytopenia during childhood that was misdiagnosed as idiopathic thrombocytopenic purpura(ITP). Nine women from 6 families were first diagnosed during pregnancy. Further, we documented that thrombocytopenia inevitably developed during the 2nd or 3rd trimesters of all 16 pregnancies in these 9 women. Often the initial isolated thrombocytopenia was followed by overt signs of microangiopathic hemolytic anemia and thrombotic thrombocytopenic purpura (TTP). Notably, of their 16 pregnancies,8 infants were stillborn or died soon after birth; the remaining 8 were all premature but survived. Six of these 9 women had the episodes of severe-to-mild thrombocytopenia during childhood that had been incorrectly diagnosed as ITP. In extension of the abovementioned studies, we have identified that the following disorders including TTP are related to acquired deficiencies of ADAMTS13 activity with an appearance of UL-VWFM; brain infarction, renal insufficiency, habitual abortion, liver cirrhosis，liver transplantation, acute severe pancreatitis, hepatic ven←occlusive disease, cardiac infarction, and sleeping apnea syndrome. Thus, during the past few years, Copernican-like conversion has been made on the understanding these diseases. Evolution of new rapid assays evaluating ADAMTS13 activity developed by our research group certainly accelerated this. Further, the idea of contraindication for platelet transfusions to the patients with severe deficiency of ADAMTS13 activity has also been well established, because of confident observations on platelet hyperaggregability under high shear stress in the presence of UL-VWFM. 内容記述: 第45回2008年度 ベルツ賞2等賞受賞論文; この文献は著作者（共著者も含む）及び出版社（最新医学社、ベーリンガーインゲルハイム社）の許諾を得て掲載しております。

2009-02-09T15:00:00Z 松本, 雅則 藤村, 吉博 辻内, 智美 島, 正幸 下山, 丈人 成田, 亘啓 小林, 恵子 吉田, 佳嗣 谷口, 繁樹 北村, 惣一郎 米田, 龍生 平尾, 佳彦 吉田, 克法 岡島, 英五郎 http://hdl.handle.net/10564/777 2017-05-29T06:06:31Z 1995-10-09T15:00:00Z

タイトル: 腎移植患者17例における血中サイトメガロウイルスのPCRによる検出とその臨床的意義 著者: 松本, 雅則; 藤村, 吉博; 辻内, 智美; 島, 正幸; 下山, 丈人; 成田, 亘啓; 小林, 恵子; 吉田, 佳嗣; 谷口, 繁樹; 北村, 惣一郎; 米田, 龍生; 平尾, 佳彦; 吉田, 克法; 岡島, 英五郎 内容記述: 著作権者：日本移植学会

1995-10-09T15:00:00Z