Fatal thrombosis of antithrombin deficient mice is rescued differently in the heart and liver by intercrossing with low tissue factor mice

通过与低组织因子小鼠杂交，抗凝血酶缺陷小鼠的心脏和肝脏致命血栓得到不同程度的挽救

• 批准号: 16590933
• 负责人: MATSUSHITA Tadashi
• 金额: $ 2.05万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590933/
• 关键词: Antithrombin; Tissue factor; Genetically altered mice; portal vein; coronary artery; transgenic muse; thrombosis; hemostasis; 組織因子; ノックアウトマウス; アンチトロンビン; 血栓症; 凝固異常症

We previously reported that targeted disruption of murine antithrombin (AT) gene resulted in embryonic lethality before 16.5gd because of severe cardiac and hepatic thrombosis. To investigate influences of lowered tissue factor (TF) activity upon hypercoagulation of AT^<-/-> embryos, we crossed AT^<+/-> with low TF (mTF^<-/->hTF^+) mice to yield homozygous AT deficient mice with extremely low TF activity, that is expressed from the inserted human TF mini gene. AT^<-/-> embryos either with 50% TF (AT^<-/->mTF^<+/->hTF^+) or with low (〜1% TF, AT^<-/->mTF^<-/->hTF^+) were not born, although the survival was prolonged until 18.5gd. In both genotypes, histological examination showed disseminated thrombosis in hepatic sinusoidal space or in the portal veins, suggesting that thrombogenesis caused loss of hepatic blood flow. As in original AT^<-/->, AT^<-/->mTF^<+/->hTF^+ showed subcutaneous bleeding and also suffered from myocardial degeneration apparently due to coronary thrombus formation. However, AT^<-/->mTF^<-/->hTF^+ had no skin hemorrhage and the thrombosis and degeneration was completely abolished in the heart. Myocardium of adult low TF mice had exhibited fibrosis secondary to hemorrhage, however, it was significantly decreased in low TF mice with AT^<+/->. Our current model suggest that in the heart, TF plays an important role in the thrombogenesis and it counterbalances AT-dependent anticoagulation. AT may be a potent anticoagulant during mice development and the activation and subsequent regulation of TF-procoagulant activity take place differently between the liver and the heart. These differences appear to point to local regulatory mechanisms in murine hemostasis.

我们以前报道过，靶向破坏小鼠抗凝血酶（AT）基因导致胚胎死亡前16.5gd，因为严重的心脏和肝脏血栓形成。为了研究降低的组织因子（TF）活性对AT^<-/->胚胎高凝状态的影响，我们将AT^<+/->与低TF（mTF^<-/->hTF^+）小鼠杂交，以产生具有极低TF活性的纯合子AT缺陷小鼠，其由插入的人TF迷你基因表达。含50%TF（AT^-/->mTF^<+/->hTF^+）或低TF（约1%TF，AT^-/->mTF^<-/->hTF ^+）的AT^-/->胚胎均未出生，但存活时间延长至18.5gd。在这两种基因型中，组织学检查显示肝窦间隙或门静脉内弥漫性血栓形成，表明血栓形成导致肝血流损失。与原始AT^<-/->一样，AT^<-/->mTF^<+/->hTF^+显示皮下出血，并且还遭受明显由于冠状动脉血栓形成引起的心肌变性。而AT^<-/->mTF^<-/->hTF^+无皮肤出血，心脏内血栓形成和变性完全消失。成年低TF小鼠的肌纤维化表现出继发于出血的纤维化，然而，在具有AT^<+/->的低TF小鼠中，其显著降低。我们目前的模型表明，在心脏中，TF在血栓形成中起着重要作用，它抵消了AT依赖性抗凝作用。在小鼠发育过程中，AT可能是一种有效的抗凝剂，TF-促凝血活性的激活和随后的调节在肝脏和心脏之间发生不同。这些差异似乎指向小鼠止血的局部调节机制。

项目成果

凝固制御因子ノックアウトマウス

凝血调节因子敲除小鼠

• 发表时间: 2005
• 期刊: 別冊・医学の歩み 血液疾患state of arts ver.3
• 作者: Ooi J;Iseki T;Soda Y;et al.;松下 正
• 通讯作者: 松下 正

Targeted disruption of mouse ortholog of the human MYH9 responsible for macrothrombocytopenia with different organ involvement:: hematological, nephrological, and otological studies of heterozygous KO mice

• DOI: 10.1016/j.bbrc.2004.10.147
• 发表时间: 2004-12-24
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Matsushita, T;Hayashi, H;Saito, H
• 通讯作者: Saito, H

Identification of protein Salpha gene mutations including four novel mutationsin eight unrelated patients with protein S deficiency

蛋白 Sα 基因突变的鉴定，包括 8 名不相关的蛋白 S 缺乏症患者的四种新突变

• 发表时间: 2004
• 期刊: Br J Haematol 126(2)
• 作者: Soda Y;Tani K;Li X;et al.;高須信行;Okada H
• 通讯作者: Okada H

三輪血液病学

三和血液学

• 发表时间: 2005
• 作者: 共同執筆 浅野茂隆;池田康夫;内山卓
• 通讯作者: 内山卓

急性白血病治療時の出血対策

急性白血病治疗过程中的出血对策

• 发表时间: 2006
• 期刊: 最新医学 別冊 36
• 作者: Inoue Y;Tojo A;Soda Y;et al.;松下 正
• 通讯作者: 松下 正