Michael J. Paidas, M.D.
Director, Program for Thrombosis and Hemostasis in Women's Health ResearchMajor research interest: The role of decidual cell hemostasis, the protein C system in adverse pregnancy outcome. Other research interests: Prevention of Adverse Pregnancy Outcome with low molecular weight heparin: a multicenter, randomized, clinical trial; Preimplantation Factor and Decidual Cell Hemostasis; Prediction of Venous Thromboembolism Risk in Women Receiving Postmenopausal Hormone Replacement Therapy; Sonoembryology of the first trimester sonographic assessment of the embryo and uteroplacental circulation; Single nucleotide polymorphism genetic screening and adverse pregnancy outcome: a case control study; Establishment of statewide uniform assessment fetal death, as part of CDC Fetal Infant Mortality Review study. The role of decidual cell hemostasis, the protein C system in adverse pregnancy outcome Adverse Pregnancy Outcome, collectively referring to fetal death ≥ 20 weeks gestation, preeclampsia intrauterine growth restriction, or abruption, has been linked to excessive thrombosis, vascular and endothelial cell injury, fibrin deposition at the uteroplacental bed. Accelerated systemic activation of the clotting cascade, pathologic placental thrombosis and vasculopathy have been demonstrated in these poor outcomes. Our research focuses on the role of the maternal decidual cells in the pathogenesis of poor pregnancy outcome. Decidual cells are capable of being a rich source of tissue factor, the initiator of the extrinsic clotting cascade, which ultimately results in thrombin generation, and later fibrin formation. Poised at the maternal fetal interface, decidual cells must be involved with the recognition of pregnancy, acceptance of the implanting blastocyst, and nurturing of the developing placenta. At delivery, hemostatic mechanisms must be in place to prevent maternal hemorrhage. We posit that dysregulation of thrombin generation, due to perturbations of components of the protein C (PC) system in maternal uterine decidual cells, contribute to the excessive thrombosis, fibrin deposition and vascular damage at the uteroplacental bed of pregnancies with adverse pregnancy outcomes. The prothrombotic or anticoagulant functions of decidual cells may be influenced by inherited abnormalities of the protein C system or by acquired thrombophilic conditions that affect the function of components of the protein C system. Recently, we have demonstated that first trimester and term decidual cells express thrombomodulin (TM) and soluble endothelial protein C receptor (EPCR) by real time PCR. The effect of estrogen priming is primarily stimulatory regarding TM expression, while proinflammatory cytokines diminish the hormonally induced upregulation of TM. Proinflammatory cytokines, known to interfere with the protein C system, may foster a prothrombotic process, by down regulating thrombomodulin and endothelial protein C receptor in decidual cells. Synergistic perturbations of the regulation of the prothrombotic and anti-coagulant pathways in the systemic and uteroplacental circulations may play key roles in the generation of localized thrombosis and vascular damage in the placenta. In the murine model, favorable actions of APC via TM and EPCR include stimulation of protease activated receptor -1 (PAR-1) to augment trophoblast proliferation, while thrombin generation is associated with stimulation of PARs 2-4 to inhibit trophoblast growth. Further, the effect of fibrin split products on trophoblast cells causes apoptosis. Hence, the PC system may be critical to hemostatic regulation and trophoblast proliferation. Our group has had a long standing interest in identifying useful biomarkers in the prediction of adverse prothrombotic events. In this regard, we have shown a decreased anticoagulant response to exogenous thrombomodulin when added to the plasma of patients with a history of adverse pregnancy outcome. First trimester elevated plasma levels of soluble fibrin polymer, and recently decreased levels of Protein Z, a plasma protein that serves as a co-factor for the protease inhibitor of factor Xa, a key regulator for thrombin generation, have been linked to the development of adverse pregancy outcomes in thrombophilic patients. By defining the regulation of decidual cell thrombin generation in normal and pathologic pregnancies, better screening, and potentially prevention and therapeutic strategies can then be developed to reduce the significant fetal, neonatal, and maternal morbidity and mortality associated with adverse pregnancy outcome. We welcome your support of Dr. Paidas and Maternal Fetal Medicine. Your gift provides essential resources to advance research and clinical care for women and children. Make a gift online (please note, when making an online gift please choose School of Medicine and specify Dr. Michael Paidas, Maternal Fetal Medicine) All gifts to Dr. Paidas and the Yale School of Medicine are tax deductable. For more information please contact Chip Edmonds, Yale School of Medicine Development Office, at chip.edmonds@yale.edu. Thank you for your support. |
