title: The thrombomodulin-protein C system is essential for the maintenance of pregnancy.
abstract: Disruption of the mouse gene encoding the blood coagulation inhibitor thrombomodulin (Thbd) leads to embryonic lethality caused by an unknown defect in the placenta. We show that the abortion of thrombomodulin-deficient embryos is caused by tissue factor-initiated activation of the blood coagulation cascade at the feto-maternal interface. Activated coagulation factors induce cell death and growth inhibition of placental trophoblast cells by two distinct mechanisms. The death of giant trophoblast cells is caused by conversion of the thrombin substrate fibrinogen to fibrin and subsequent formation of fibrin degradation products. In contrast, the growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of protease-activated receptors (PAR)-2 and PAR-4 by coagulation factors. These findings show a new function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta. This function is essential for the maintenance of pregnancy.
authors.affiliation: Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.forename: Rashmi
authors.initials: R
authors.lastname: Sood
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
authors.forename: Mark
authors.initials: M
authors.lastname: Zogg
authors.forename: Shawn
authors.initials: S
authors.lastname: Kalloway
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
mesh_terms: D000022:Abortion, Spontaneous; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D011255:Pregnancy Maintenance; D011486:Protein C / Q000378:metabolism*; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*
chemical_list: D011486:Protein C; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D018180:Thrombomodulin; D005337:Fibrin; D005340:Fibrinogen; D013925:Thromboplastin; D013917:Thrombin; D005341:Fibrinolysin