The emerging role of immunoregulation of fibrinogen-related procoagulant fgl2 in the success or spontaneous abortion of early pregnancy in mice and humans

PROBLEM: Abortion of chromosomally normal embryos in the CBA X DBA/2 mating combination is triggered by release of Th1 cytokines (tumor necrosis facto r [TNF]-alpha, interferon [IFN]-gamma, and interleukin [IL]-1), which cause abortion via a novel prothrombinase, fg12, and polymorphonuclear leukocyte s. The site of activation may be maternal vascular endothelium on arteries and veins nourishing the placenta. Activation of coagulation is also promin ent in spontaneous abortion of chromosomally normal human embryos. We asked where is fg12 up-regulated in the uterus in murine abortions, and if simil ar fg12 expression occurs in human pregnancy failure. METHODS: Control CBA X DBA/2 pregnant mice, or from mice injected with TNF- alpha + IFN-gamma on day 7.5 of gestation, were removed on day 8.5, fixed, sectioned, and subject to in situ hybridization for fg12. Sections were als o stained for fibrin. Elective first trimester termination samples or biops ies taken early in the course of a recurrent miscarriage were similarly fix ed, sectioned, and analyzed by in situ hybridization. Control and cytokine- treated mice were-anticoagulated with heparin, an activator of antithrombin III, and/or the direct anti-thrombin inhibitor hirudin. RESULTS: Low level fg12 expression localized to basal decidua remote from t he embryo was noted in control mice; cytokine treatment, which causes great er than 80% of abortions, produced a striking up-regulation in this area as well as in a band at the junction of decidua and myometrium. Trophoblast a lso became strikingly positive. Fg12 expression was associated with increas ed fibrin staining. Anticoagulation significantly protected against abortio ns, but doses were limited by the complication of retroplacental hemorrhage . In tissue from normal first trimester pregnancy, minimal fg12 positivity was seen in some villous syncytiotrophoblast, in villous stroma, cytotropho blast, and in some cells in decidua. In spontaneous abortion of normal embr yo, striking fg12 positivity was seen in syncytiotrophoblast and extravillo us cytotrophoblast, in association with areas of thrombus formation. CONCLUSIONS: Fg12 appears to be physiologically expressed and may protect a gainst the internal danger of maternal and/or fetal bleeding during pregnan cy and at parturition; a role in inhibiting transplacental traffic is also possible. External dangers in the form of stress, endotoxin, and antigens e liciting Th1 cytokine responses upregulate fg12 prothrombinase in trophobla st as well as in decidua, which results in spontaneous abortion of immunoge netically "weaker" embryos.