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      Placental thrombomodulin expression in recurrent miscarriage

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          Abstract

          Background

          Early pregnancy loss can be associated with trophoblast insufficiency and coagulation defects. Thrombomodulin is an endothelial-associated anticoagulant protein involved in the control of hemostasis and inflammation at the vascular beds and it's also a cofactor of the protein C anticoagulant pathway.

          Discussion

          We evaluate the Thrombomodulin expression in placental tissue from spontaneous recurrent miscarriage and voluntary abortion as controls. Thrombomodulin mRNA was determined using real-time quantitative polymerase chain reaction. Reduced expression levels of thrombomodulin were found in recurrent miscarriage group compared to controls (1.82-fold of reduction), that corresponds to a reduction of 45% (from control group Delta CT) of thrombomodulin expression in spontaneous miscarriage group respect the control groups.

          Summary

          We cannot state at present the exact meaning of a reduced expression of Thrombomodulin in placental tissue. Further studies are needed to elucidate the biological pathway of this important factor in the physiopathology of the trophoblast and in reproductive biology.

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          Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation.

          Marlies Van de Wouwer, Désiré Collen, Edward Conway (2004)
          Late in the 18th century, William Hewson recognized that the formation of a clot is characteristic of many febrile, inflammatory diseases (Owen C. A History of Blood Coagulation. Rochester, Minnesota: Mayo Foundation; 2001). Since that time, there has been steady progress in our understanding of coagulation and inflammation, but it is only in the past few decades that the molecular mechanisms linking these 2 biologic systems have started to be delineated. Most of these can be traced to the vasculature, where the systems most intimately interact. Thrombomodulin (TM), a cell surface-expressed glycoprotein, predominantly synthesized by vascular endothelial cells, is a critical cofactor for thrombin-mediated activation of protein C (PC), an event further amplified by the endothelial cell protein C receptor (EPCR). Activated PC (APC), in turn, is best known for its natural anticoagulant properties. Recent evidence has revealed that TM, APC, and EPCR have activities that impact not only on coagulation but also on inflammation, fibrinolysis, and cell proliferation. This review highlights recent insights into the diverse functions of this complex multimolecular system and how its components are integrated to maintain homeostasis under hypercoagulable and/or proinflammatory stress conditions. Overall, the described advances underscore the usefulness of elucidating the relevant molecular pathways that link both systems for the development of novel therapeutic and diagnostic targets for a wide range of inflammatory diseases.
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            The anticoagulant protein C pathway.

            Björn Dahlbäck, Bruno Villoutreix (2005)
            The anticoagulant protein C system regulates the activity of coagulation factors VIIIa and Va, cofactors in the activation of factor X and prothrombin, respectively. Protein C is activated on endothelium by the thrombin-thrombomodulin-EPCR (endothelial protein C receptor) complex. Activated protein C (APC)-mediated cleavages of factors VIIIa and Va occur on negatively charged phospholipid membranes and involve protein cofactors, protein S and factor V. APC also has anti-inflammatory and anti-apoptotic activities that involve binding of APC to EPCR and cleavage of PAR-1 (protease-activated receptor-1). Genetic defects affecting the protein C system are the most common risk factors of venous thrombosis. The protein C system contains multi-domain proteins, the molecular recognition of which will be reviewed.
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              Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex.

              J Morser, Patrick R. Huber, Y Iwanaga … (2000)
              The serine proteinase alpha-thrombin causes blood clotting through proteolytic cleavage of fibrinogen and protease-activated receptors and amplifies its own generation by activating the essential clotting factors V and VIII. Thrombomodulin, a transmembrane thrombin receptor with six contiguous epidermal growth factor-like domains (TME1-6), profoundly alters the substrate specificity of thrombin from pro- to anticoagulant by activating protein C. Activated protein C then deactivates the coagulation cascade by degrading activated factors V and VIII. The thrombin-thrombomodulin complex inhibits fibrinolysis by activating the procarboxypeptidase thrombin-activatable fibrinolysis inhibitor. Here we present the 2.3 A crystal structure of human alpha-thrombin bound to the smallest thrombomodulin fragment required for full protein-C co-factor activity, TME456. The Y-shaped thrombomodulin fragment binds to thrombin's anion-binding exosite-I, preventing binding of procoagulant substrates. Thrombomodulin binding does not seem to induce marked allosteric structural rearrangements at the thrombin active site. Rather, docking of a protein C model to thrombin-TME456 indicates that TME45 may bind substrates in such a manner that their zymogen-activation cleavage sites are presented optimally to the unaltered thrombin active site.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Reprod Biol Endocrinol
                Title: Reproductive Biology and Endocrinology : RB&E
                Publisher: BioMed Central
                ISSN (Electronic): 1477-7827
                Publication date Collection: 2010
                Publication date (Electronic): 5 January 2010
                Volume: 8
                Page: 1
                Affiliations
                [1 ]Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
                [2 ]Department of Biochemistry Biology and Genetics, Polytechnic University of Marche, Ancona, Italy
                Article
                Publisher ID: 1477-7827-8-1
                DOI: 10.1186/1477-7827-8-1
                PMC ID: 2819244
                PubMed ID: 20051099
                SO-VID: 3d7fe412-22b9-4193-9c0f-9072ce491edf
                Copyright © Copyright ©2010 Stortoni et al; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 14 October 2009
                Date accepted : 5 January 2010
                Categories
                Subject: Debate

                ScienceOpen disciplines: Human biology
                Data availability:
                ScienceOpen disciplines: Human biology

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