Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
Thromb Haemost. 2012 May;107(5):864-74. doi: 10.1160/TH11-10-0730. Epub 2012 Jan 25.
Inflammation-associated foetal loss is often linked to maternal coagulopathies. Here, we characterised the role of maternal inflammation in the development of various systemic maternal coagulopathies and foetal death during mid-to-late gestation in rats. Since nitric oxide (NO) functions as an inhibitor of platelet aggregation and anti-oxidant, we also tested whether the NO mimetic nitroglycerin (glyceryl trinitrate, GTN) prevents inflammation-associated coagulopathies and foetal death. To induce chronic inflammation, pregnant Wistar rats were injected with low-doses of lipopolysaccharide (LPS; 10-40 μg/kg) on gestational days (GD) 13.5-16.5. To determine whether the effects of inflammation are mediated by tumour necrosis factor-α (TNF-α), the TNF-α inhibitor etanercept was injected on GD 13.5 and 15.5. Controls consisted of rats injected with saline. GTN was administered to LPS-treated rats via daily application of a transdermal patch on GD 12.5-16.5. Using thromboelastography (TEG), various coagulation parameters were assessed on GD 17.5; foetal viability was determined morphologically. Reference coagulation parameters were established based on TEG results obtained from control animals. LPS-treated rats exhibited distinct systemic coagulopathies: hypercoagulability, hypocoagulability, hyperfibrinolysis, and disseminated intravascular coagulation (DIC) stages I and III. A specific foetal death coagulation phenotype was observed, implicating TEG as a potential tool to identify inflammation-induced haemostatic alterations associated with pregnancy loss. Treatment with etanercept reduced the incidence of coagulopathy by 47%, while continuous delivery of GTN prevented foetal death and the inflammation-induced coagulopathies. These findings provide a rationale for investigating the use of GTN in the prevention of maternal coagulopathies and inflammation-mediated foetal death.
炎症相关的胎儿丢失通常与母体凝血病有关。在这里，我们研究了母体炎症在大鼠妊娠中期至晚期各种系统性母体凝血病和胎儿死亡发展中的作用。由于一氧化氮 (NO) 作为血小板聚集抑制剂和抗氧化剂发挥作用，我们还测试了硝酸甘油（硝化甘油，GTN）是否可以预防炎症相关的凝血病和胎儿死亡。为了诱导慢性炎症，在妊娠第 13.5-16.5 天给怀孕的 Wistar 大鼠注射低剂量的脂多糖 (LPS; 10-40 μg/kg)。为了确定炎症的作用是否由肿瘤坏死因子-α (TNF-α) 介导，在妊娠第 13.5 和 15.5 天给 TNF-α抑制剂依那西普注射。对照组由注射生理盐水的大鼠组成。在妊娠第 12.5-16.5 天，通过每天应用透皮贴剂向 LPS 处理的大鼠给予 GTN。使用血栓弹性描记术 (TEG) 在妊娠第 17.5 天评估各种凝血参数；通过形态学确定胎儿存活率。根据来自对照动物的 TEG 结果建立参考凝血参数。LPS 处理的大鼠表现出明显的全身性凝血病：高凝状态、低凝状态、纤维蛋白溶解亢进和弥漫性血管内凝血 (DIC) I 和 III 期。观察到特定的胎儿死亡凝血表型，表明 TEG 可能是一种潜在的工具，可识别与妊娠丢失相关的炎症诱导的止血改变。依那西普的治疗将凝血障碍的发生率降低了 47%，而持续给予 GTN 可预防胎儿死亡和炎症诱导的凝血障碍。这些发现为研究 GTN 在预防母体凝血病和炎症介导的胎儿死亡中的应用提供了依据。
