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The thrombomodulin–protein C system is essential for the maintenance of pregnancy

Nature Medicine volume 9, pages 331–337 (2003)Cite this article

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.

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Figure 1: Growth inhibition and death of thrombomodulin-deficient trophoblast cells.
Figure 2: Anti-coagulation therapy inhibits resorption of Thbd−/− embryos.
Figure 3: Reduction or elimination of tissue factor activity restores normal development of Thbd−/− embryos.
Figure 4: Inhibition of fibrinolysis suppresses resorption and trophoblast cell death induced by fibrin degradation products.
Figure 5: Regulation of trophoblast proliferation by PARs.

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Acknowledgements

This work was supported by NIH grant HL-60655, by a grant-in-aid from the American Heart Association to H.W. and by a grant of the Deutsche Forschungsgemeinschaft (IS 67/1-2) to B.I.

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Authors and Affiliations

  1. Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, Wisconsin, USA

    Berend Isermann, Rashmi Sood, Mark Zogg, Shawn Kalloway & Hartmut Weiler

  2. Department of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California, USA

    Rafal Pawlinski & Nigel Mackman

  3. Basic Science Research, Children's Hospital Research Foundation, Cincinnati, Ohio, USA

    Jay L. Degen

  4. Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Hartmut Weiler

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Correspondence to Hartmut Weiler.

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Isermann, B., Sood, R., Pawlinski, R. et al. The thrombomodulin–protein C system is essential for the maintenance of pregnancy. Nat Med 9, 331–337 (2003). https://doi.org/10.1038/nm825

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