title: Nitroglycerin prevents coagulopathies and foetal death associated with abnormal maternal inflammation in rats.
abstract: 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.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cotechini
authors.forename: Maha
authors.initials: M
authors.lastname: Othman
authors.forename: Charles H
authors.initials: CH
authors.lastname: Graham
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001778:Blood Coagulation Disorders / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D000068800:Etanercept; D005260:Female; D005313:Fetal Death / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D005865:Gestational Age; D007074:Immunoglobulin G / Q000494:pharmacology; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D010641:Phenotype; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor; D013916:Thrombelastography; D013997:Time Factors; D057968:Transdermal Patch; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D005996:Nitroglycerin; D000068800:Etanercept