van Mens Thijs E, Liang Hai-Po H, Basu Sreemanti, Hernandez Irene, Zogg Mark, May Jennifer, Zhan Min, Yang Qiuhui, Foeckler Jamie, Kalloway Shawn, Sood Rashmi, Karlson Caren Sue, Weiler Hartmut
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee WI.
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Blood Adv. 2017 Jun 27;1(15):1148-1158. doi: 10.1182/bloodadvances.2017005058. Epub 2017 Jun 23.
Thrombomodulin (Thbd) exerts pleiotropic effects on blood coagulation, fibrinolysis, and complement system activity by facilitating the thrombin-mediated activation of protein C and thrombin-activatable fibrinolysis inhibitor and may have additional thrombin- and protein C (pC)-independent functions. In mice, complete Thbd deficiency causes embryonic death due to defective placental development. In this study, we used tissue-selective and temporally controlled Thbd gene ablation to examine the function of Thbd in adult mice. Selective preservation of Thbd function in the extraembryonic ectoderm and primitive endoderm via the Meox2Cre-transgene enabled normal intrauterine development of Thbd-deficient (Thbd) mice to term. Half of the Thbd offspring expired perinatally due to thrombohemorrhagic lesions. Surviving Thbd animals only rarely developed overt thrombotic lesions, exhibited low-grade compensated consumptive coagulopathy, and yet exhibited marked, sudden-onset mortality. A corresponding pathology was seen in mice in which the Thbd gene was ablated after reaching adulthood. Supplementation of activated PC by transgenic expression of a partially Thbd-independent murine pC zymogen prevented the pathologies of Thbd mice. However, Thbd females expressing the PC transgene exhibited pregnancy-induced morbidity and mortality with near-complete penetrance. These findings suggest that Thbd function in nonendothelial embryonic tissues of the placenta and yolk sac affects through as-yet-unknown mechanisms the penetrance and severity of thrombosis after birth and provide novel opportunities to study the role of the natural Thbd-pC pathway in adult mice and during pregnancy.
血栓调节蛋白(Thbd)通过促进凝血酶介导的蛋白C激活和凝血酶可激活的纤维蛋白溶解抑制剂,对血液凝固、纤维蛋白溶解和补体系统活性发挥多效性作用,并且可能具有其他不依赖凝血酶和蛋白C(pC)的功能。在小鼠中,完全缺乏Thbd会因胎盘发育缺陷导致胚胎死亡。在本研究中,我们使用组织选择性和时间可控的Thbd基因敲除来研究Thbd在成年小鼠中的功能。通过Meox2Cre转基因在胚外外胚层和原始内胚层中选择性保留Thbd功能,使Thbd基因缺陷(Thbd)小鼠能够在子宫内正常发育至足月。一半的Thbd后代在围产期因血栓出血性病变死亡。存活的Thbd动物很少发生明显的血栓形成病变,表现为低度代偿性消耗性凝血病,但仍表现出明显的、突然发作的死亡率。在成年后敲除Thbd基因的小鼠中也观察到了相应的病理变化。通过转基因表达部分不依赖Thbd的小鼠pC酶原补充活化的PC,可预防Thbd小鼠的病变。然而,表达PC转基因的Thbd雌性小鼠在妊娠期间出现发病率和死亡率,且几乎完全显性。这些发现表明,胎盘和卵黄囊非内皮胚胎组织中的Thbd功能通过未知机制影响出生后血栓形成的显性和严重程度,并为研究天然Thbd-pC途径在成年小鼠和妊娠期间的作用提供了新的机会。