Nitroglycerin prevents coagulopathies and foetal death associated with abnormal maternal inflammation in rats

Tiziana Cotechini; Maha Othman; Charles H. Graham

doi:10.1160/TH11-10-0730

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 107(05): 864-874
DOI: 10.1160/TH11-10-0730

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Nitroglycerin prevents coagulopathies and foetal death associated with abnormal maternal inflammation in rats

Authors

Tiziana Cotechini

¹Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada
Maha Othman

¹Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada
Charles H. Graham

¹Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada

Abstract

Summary

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 antioxidant, 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.

Keywords

Thromboelastography - pregnancy - disseminated intravascular coagulation (DIC) - nitric oxide/NO - etanercept

Full Text

References

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