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

我们之前报道了靶向破坏小鼠抗凝血酶（AT）基因导致16.5gd之前的小鼠因严重的心脏和肝脏血栓形成而致胚胎死亡。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，得到TF活性极低的纯合子AT缺陷小鼠，该小鼠由插入的人TF mini基因表达。50% TF （AT^<-/->mTF^<+/->hTF^+）或低TF （~ 1% TF, AT^<-/->mTF^<-/->hTF^+）的胚胎均未出生，但存活时间延长至18.5gd。在两种基因型中，组织学检查均显示肝窦间隙或门静脉弥散性血栓形成，提示血栓形成导致肝血流减少。与原始AT^<-/->一样，AT^<-/->mTF^<+/->hTF^+表现为皮下出血，并明显因冠状动脉血栓形成而发生心肌变性。而AT^<-/->mTF^<-/->hTF^+无皮肤出血，心脏血栓和变性完全消除。成年低TF小鼠心肌出现继发性出血纤维化，而AT^<+/->的低TF小鼠心肌纤维化明显减少。我们目前的模型表明，在心脏中，TF在血栓形成中起重要作用，并平衡at依赖性抗凝。在小鼠发育过程中，AT可能是一种有效的抗凝血剂，肝脏和心脏对tf促凝活性的激活和随后的调节是不同的。这些差异似乎指向小鼠止血的局部调节机制。

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.