title: Maternal Par4 and platelets contribute to defective placenta formation in mouse embryos lacking thrombomodulin.
abstract: Absence of the blood coagulation inhibitor thrombomodulin (Thbd) from trophoblast cells of the mouse placenta causes a fatal arrest of placental morphogenesis. The pathogenesis of placental failure requires tissue factor, yet is not associated with increased thrombosis and persists in the absence of fibrinogen. Here, we examine the role of alternative targets of coagulation that might contribute to the placental failure and death of Thbd(-/-) embryos. We demonstrate that genetic deficiency of the protease-activated receptors, Par1 or Par2, in the embryo and trophoblast cells does not prevent the death of Thbd(-/-) embryos. Similarly, genetic ablation of the complement pathway or of maternal immune cell function does not decrease fetal loss. In contrast, Par4 deficiency of the mother, or the absence of maternal platelets, restores normal development in one-third of Thbd-null embryos. This finding generates new evidence implicating increased procoagulant activity and thrombin generation in the demise of thrombomodulin-null embryos, and suggests that platelets play a more prominent role in placental malfunction associated with the absence of thrombomodulin than fibrin formation. Our findings demonstrate that fetal prothrombotic mutations can cause localized activation of maternal platelets at the feto-maternal interface in a mother with normal hemostatic function.
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin 53226, USA. rsood@mcw.edu
authors.forename: Rashmi
authors.initials: R
authors.lastname: Sood
authors.forename: Lynette
authors.initials: L
authors.lastname: Sholl
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.forename: Mark
authors.initials: M
authors.lastname: Zogg
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Coughlin
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000502:physiology*; D004622:Embryo, Mammalian; D005260:Female; D008431:Maternal-Fetal Exchange; D051379:Mice; D018345:Mice, Knockout; D009035:Mothers; D010922:Placenta Diseases / Q000209:etiology*; D011247:Pregnancy; D044462:Receptors, Proteinase-Activated / Q000172:deficiency / Q000502:physiology*; D018180:Thrombomodulin / Q000172:deficiency*; D019851:Thrombophilia
chemical_list: D044462:Receptors, Proteinase-Activated; D018180:Thrombomodulin; C481942:protease-activated receptor 4, mouse