Fatal thrombosis of antithrombin-deficient mice is rescued differently in the heart and liver by intercrossing with low tissue factor mice
Fatal thrombosis of antithrombin-deficient mice is rescued differently in the heart and liver by intercrossing with low tissue factor mice
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DOI：
10.1111/j.1538-7836.2005.01679.x
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发表时间：
2006-01-01
影响因子：
10.4
通讯作者：
Naoe, T
中科院分区：
文献类型：
--
作者：
Hayashi, M;Matsushita, T;Naoe, T
背景：我们之前报道过，由于严重的心脏和肝脏血栓形成，小鼠抗凝血酶（AT）基因的靶向破坏导致妊娠16.5天（gd）之前的胚胎死亡。目的和方法：为了研究组织因子（TF）活性降低对 AT（-/-）胚胎高凝的影响，我们将 AT（+/-）与低 TF（mTF（-/-）hTF（+））小鼠杂交，产生具有极低 TF 活性的纯合 AT 缺陷小鼠，该活性由插入的人 TF 小基因表达。结果：具有 50% TF（AT(-/-)mTF(+/-)hTF(+)）或低（类似于 1% TF，AT(-/-)mTF(-/-)hTF(+)）的 AT(-/-) 胚胎均未出生，但存活期延长至 18.5 gd。在这两种基因型中，组织学检查均显示肝窦间隙或门静脉中存在播散性血栓形成，表明血栓形成导致肝血流损失。与原来的AT(-/-)一样，AT(-/-)mTF(+/-)hTF(+)出现皮下(s.c.)出血，并且由于冠状动脉血栓形成而明显出现心肌变性。而AT(-/-)mTF(-/-)hTF(+)没有皮肤出血，心脏的血栓形成和变性也完全消失。成年低TF小鼠的心肌表现出继发于出血的纤维化；然而，在具有 AT(+/-) 的低 TF 小鼠中，其显着降低。结论：我们目前的模型表明，在心脏中，TF 在血栓形成中发挥重要作用，并且它抵消 AT 依赖性抗凝作用。 AT 可能是小鼠发育过程中的有效抗凝剂，并且 TF 促凝活性的激活和随后的调节在肝脏和心脏之间发生不同。这些差异似乎表明小鼠止血的局部调节机制。
Background: We previously reported that the targeted disruption of murine antithrombin (AT) gene resulted in embryonic lethality before 16.5 gestational days (gd) because of severe cardiac and hepatic thrombosis. Objective and Methods: To investigate the 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 the extremely low TF activity, that is expressed from the inserted human TF mini gene. Results: AT(-/-) embryos either with 50% TF (AT(-/-)mTF(+/-)hTF(+)) or with low (similar to 1% TF, AT(-/-)mTF(-/-)hTF(+)) were not born, although the survival was prolonged until 18.5 gd. In both genotypes, histological examination showed disseminated thrombosis in hepatic sinusoidal space or in the portal veins, suggesting that the thrombogenesis caused loss of hepatic blood flow. As in original AT(-/-), AT(-/-)mTF(+/-)hTF(+) showed subcutaneous (s.c.) bleeding and also suffered from the myocardial degeneration apparently because of coronary thrombus formation. However, AT(-/-)mTF(-/-)hTF(+) had no skin hemorrhage and the thrombosis and degeneration were 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(+/-). Conclusions: Our current model suggests 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.