Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice
Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice
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DOI：
10.1182/blood.v90.3.944.944_944_951
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发表时间：
1997-08-01
期刊：
影响因子：
20.3
通讯作者：
Broze, GJ
中科院分区：
文献类型：
--
作者：
Huang, ZF;Higuchi, D;Broze, GJ
组织因子途径抑制剂（TFPI）是一种多价Kunitz型蛋白酶抑制剂，可直接抑制因子Xa，并以因子Xa依赖性方式对负责启动凝血的因子VIIa/TF催化复合物产生反馈抑制。为了进一步确定TFPI的生理作用，使用基因靶向技术来破坏小鼠中TFPI基因的外显子4。该外显子编码TFPI的Kunitz结构域-1，其是因子VIIa/TF抑制所需的。在TFPI基因破坏的杂合子小鼠中，TFPIK 1（+/-），一种缺乏Kunitz结构域-1的TFPI的改变形式，以与野生型TFPI相似的40%的浓度在血浆中循环。基于测量因子VIIa/TF抑制的功能测定，TFPIK 1（+/-）动物的血浆TFPI活性与野生型小鼠的血浆TFPI活性的50%相似，并且具有正常表型。60%的TFPIK 1（-/-）小鼠在胚胎期E9.5和E11.5之间死亡，并伴有卵黄囊出血的迹象。卵黄囊血管系统内结构异常的程度似乎反映了胚胎的状况，这表明胚胎和胚外组织都对相同的损伤做出反应，推测是循环功能不全。器官发生在TFPIK 1中是正常的，在E11.5之后进展的无效动物，但是出血，特别是在中枢神经系统和尾部，在妊娠后期是明显的，并且没有TFPIK 1（-/-）小鼠存活到新生期。肝脏和血管内血栓中免疫反应性纤维蛋白（原）的存在与以下观点一致：未调节的因子VIIa/TF作用和随后的消耗性凝血病是这些老年胚胎出血素质的基础。人TFPI缺陷型胚胎可能遭受类似的命运，因为尚未确定TFPI缺陷型个体。(C)1997年，美国血液学会。
Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type proteinase inhibitor that directly inhibits factor Xa and, in a factor Xa-dependent fashion, produces feedback inhibition of the factor VIIa/TF catalytic complex responsible for the initiation of coagulation. To further define the physiologic role of TFPI, gene-targeting techniques were used to disrupt exon 4 of the TFPI gene in mice. This exon encodes Kunitz domain-1 of TFPI, which is required for factor VIIa/TF inhibition. In mice heterozygous for TFPI gene-disruption, TFPIK1(+/-), an altered form of TFPI lacking Kunitz domain-1, circulates in plasma at a concentration similar to 40% that of wildtype TFPI. TFPIK1(+/-) animals have plasma TFPI activity similar to 50% that of wild-type mice, based on a functional assay that measures factor VIIa/TF inhibition, and have a normal phenotype. Sixty percent of TFPIK1(-/-) mice die between embryonic days E9.5 and E11.5 with signs of yolk sac hemorrhage. The extent of structural abnormalities within the yolk sac vascular system appears to mirror the condition of the embryo, suggesting that the embryonic and extra-embryonic tissues are both responding to same insult, presumably circulatory insufficiency. Organogenesis is normal in TFPIK1, null animals that progress beyond E11.5, but hemorrhage, particularly in the central nervous system and tail, is evident during later gestation and none of the TFPIK1(-/-) mice survive to the neonatal period. The presence of immunoreactive fibrin(ogen) in the liver and intravascular thrombi is consistent with the notion that unregulated factor VIIa/TF action and a consequent consumptive coagulopathy underlies the bleeding diathesis in these older embryos, Human TFPI-deficient embryos may suffer a similar fate because an individual with TFPI deficiency has not been identified. (C) 1997 by The American Society of Hematology.