Submitted September 10, 2007
Accepted March 4, 2008
Maternal Par4 and platelets contribute to defective placenta formation in mouse embryos lacking thrombomodulin
Rashmi Sood*, Lynette Sholl, Berend Isermann, Mark Zogg, Shaun R Coughlin, and Hartmut Weiler
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, United States
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI, United States
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States
* Corresponding author; email: rsood{at}mcw.edu.
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 1/3rd of Thbd-null embryos. This finding generates new evidence implicating increased pro-coagulant 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.
