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Semin Thromb Hemost 2011; 37(2): 153-157
DOI: 10.1055/s-0030-1270343
© Thieme Medical Publishers

Sources of Thrombomodulin in Pre-Eclampsia: Renal Dysfunction or Endothelial Damage?

Luci Dusse1 , Lara Godoi1 , Rashid S. Kazmi2 , Patrícia Alpoim1 , Juliane Petterson3 , Bashir A. Lwaleed4 , Maria Carvalho1
  • 1Departments of Clinical and Toxicological Analysis, Federal University of Minas Gerais, Brazil
  • 2Haematology, Southampton University Hospitals NHS Trust, Southampton, United Kingdom
  • 3Gynecology and Obstetrics, Maternidade Odete Valadares, Belo Horizonte, Brazil
  • 4Urology, Southampton University Hospitals NHS Trust and School of Health Sciences, University of Southampton, Southampton, United Kingdom
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Publikationsverlauf

Publikationsdatum:
02. März 2011 (online)

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ABSTRACT

A plethora of evidence exists to show that endothelial perturbations underlie many of the clinical features of pre-eclampsia (P-EC), and consequently the markers signifying endothelial disturbance exhibit a rise in plasma. Among others, plasma thrombomodulin (TM) level rises significantly. TM is a transmembrane glycoprotein expressed abundantly on the endothelium of the microvasculature. It neutralizes the thrombotic potential of thrombin, mediating this anticoagulant effect through activation of protein C. Endothelial injury results in a localized loss of TM with a focal impairment of protein C activation and resultant thrombotic tendency. Mainly expressed on the endothelial cells, a small amount of TM is found in plasma with levels rising in certain pathological conditions. Although elevation in levels of TM can be due to endothelial TM proteolysis secondary to endothelial insult, ineffective clearance may account for this in renal and hepatic dysfunction. In P-EC not only is there ongoing endothelial injury, but renal function is also affected. To establish the cause of elevated TM level in P-EC, three groups of pregnant women were investigated. It appears that the elevation in plasma TM is not related to renal or hepatic dysfunction in P-EC. It is more likely that plasma TM is derived from placental or vascular endothelial cells subsequent to activation or damage, confirming the hypothesis that damage to vascular endothelial cells is the primary underlying cause of P-EC.

KEYWORDS

Pre-eclampsia - thrombomodulin - renal function

REFERENCES

  • 1 Boffa M-C, Burke B, Haudenschild C C. Preservation of thrombomodulin antigen on vascular and extravascular surfaces.  J Histochem Cytochem. 1987;  35 (11) 1267-1276
    CrossrefPubMedGoogle Scholar
  • 2 Imada M, Imada S, Iwasaki H, Kume A, Yamaguchi H, Moore E E. Fetomodulin: marker surface protein of fetal development which is modulatable by cyclic AMP.  Dev Biol. 1987;  122 (2) 483-491
    CrossrefPubMedGoogle Scholar
  • 3 Imada S, Yamaguchi H, Nagumo M, Katayanagi S, Iwasaki H, Imada M. Identification of fetomodulin, a surface marker protein of fetal development, as thrombomodulin by gene cloning and functional assays.  Dev Biol. 1990;  140 (1) 113-122
    CrossrefPubMedGoogle Scholar
  • 4 Boehme M W, Deng Y, Raeth U et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-α and neutrophils: in vivo and in vitro studies.  Immunology. 1996;  87 (1) 134-140
    PubMedGoogle Scholar
  • 5 Lohi O, Urban S, Freeman M. Diverse substrate recognition mechanisms for rhomboids; thrombomodulin is cleaved by Mammalian rhomboids.  Curr Biol. 2004;  14 (3) 236-241
    PubMedGoogle Scholar
  • 6 Walker F J, Fay P J. Regulation of blood coagulation by the protein C system.  FASEB J. 1992;  6 (8) 2561-2567
    PubMedGoogle Scholar
  • 7 Esmon C T. The roles of protein C and thrombomodulin in the regulation of blood coagulation.  J Biol Chem. 1989;  264 (9) 4743-4746
    PubMedGoogle Scholar
  • 8 Esmon C T. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface.  FASEB J. 1995;  9 (10) 946-955
    PubMedGoogle Scholar
  • 9 Bouma B N, Mosnier L O. Thrombin activatable fibrinolysis inhibitor (TAFI) at the interface between coagulation and fibrinolysis.  Pathophysiol Haemost Thromb. 2003/2004;  33 (5–6) 375-381
    CrossrefPubMedGoogle Scholar
  • 10 Bajzar L, Morser J, Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex.  J Biol Chem. 1996;  271 (28) 16603-16608
    CrossrefPubMedGoogle Scholar
  • 11 Wang W, Nagashima M, Schneider M, Morser J, Nesheim M. Elements of the primary structure of thrombomodulin required for efficient thrombin-activable fibrinolysis inhibitor activation.  J Biol Chem. 2000;  275 (30) 22942-22947
    CrossrefPubMedGoogle Scholar
  • 12 Takaya M, Ichikawa Y, Kobayashi N et al. Serum thrombomodulin and anticardiolipin antibodies in patients with systemic lupus erythematosus.  Clin Exp Rheumatol. 1991;  9 (5) 495-499
    PubMedGoogle Scholar
  • 13 Asakura H, Jokaji H, Saito M et al. Plasma levels of soluble thrombomodulin increase in cases of disseminated intravascular coagulation with organ failure.  Am J Hematol. 1991;  38 (4) 281-287
    CrossrefPubMedGoogle Scholar
  • 14 Salomaa V, Matei C, Aleksic N et al. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study.  Lancet. 1999;  353 (9166) 1729-1734
    CrossrefPubMedGoogle Scholar
  • 15 Wu K K. Soluble thrombomodulin and coronary heart disease.  Curr Opin Lipidol. 2003;  14 (4) 373-375
    CrossrefPubMedGoogle Scholar
  • 16 Wu K K, Aleksic N, Ballantyne C M, Ahn C, Juneja H, Boerwinkle E. Interaction between soluble thrombomodulin and intercellular adhesion molecule-1 in predicting risk of coronary heart disease.  Circulation. 2003;  107 (13) 1729-1732
    CrossrefPubMedGoogle Scholar
  • 17 National High Blood Pressure Education Program Working Group Report on High Pressure in Pregnancy . National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy.  Am J Obstet Gynecol. 1990;  163 (5 Pt 1) 1691-1712
    PubMedGoogle Scholar
  • 18 Roberts J M. Endothelial dysfunction in preeclampsia.  Semin Reprod Endocrinol. 1998;  16 (1) 5-15
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 19 Granger J P, Alexander B T, Bennett W A, Khalil R A. Pathophysiology of pregnancy-induced hypertension.  Am J Hypertens. 2001;  14 (6 Pt 2) 178S-185S
    CrossrefPubMedGoogle Scholar
  • 20 Arias F, Mancilla-Jimenez R. Hepatic fibrinogen deposits in pre-eclampsia. Immunofluorescent evidence.  N Engl J Med. 1976;  295 (11) 578-582
    CrossrefPubMedGoogle Scholar
  • 21 Brown M A. The physiology of pre-eclampsia.  Clin Exp Pharmacol Physiol. 1995;  22 (11) 781-791
    CrossrefPubMedGoogle Scholar
  • 22 Bonnar J, McNicol G P, Douglas A S. Coagulation and fibrinolytic systems in pre-eclampsia and eclampsia.  Br Med J. 1971;  2 (5752) 12-16
    CrossrefPubMedGoogle Scholar
  • 23 Redman C W, Sacks G P, Sargent I L. Preeclampsia: an excessive maternal inflammatory response to pregnancy.  Am J Obstet Gynecol. 1999;  180 (2 Pt 1) 499-506
    CrossrefPubMedGoogle Scholar
  • 24 Redman C WG, Sargent I L. Pre-eclampsia, the placenta and the maternal systemic inflammatory response—a review.  Placenta. 2003;  24 (Suppl A) S21-S27
    CrossrefPubMedGoogle Scholar
  • 25 Dusse L M, Carvalho M G, Getliffe K, Voegeli D, Cooper A J, Lwaleed B A. Increased circulating thrombomodulin levels in pre-eclampsia.  Clin Chim Acta. 2008;  387 (1-2) 168-171
    CrossrefPubMedGoogle Scholar
  • 26 Boffa M C, Valsecchi L, Fausto A et al. Predictive value of plasma thrombomodulin in preeclampsia and gestational hypertension.  Thromb Haemost. 1998;  79 (6) 1092-1095
    PubMedGoogle Scholar
  • 27 Hsu C D, Copel J A, Hong S F, Chan D W. Thrombomodulin levels in preeclampsia, gestational hypertension, and chronic hypertension.  Obstet Gynecol. 1995;  86 (6) 897-899
    CrossrefPubMedGoogle Scholar
  • 28 Hsu C D, Iriye B, Johnson T R, Witter F R, Hong S F, Chan D W. Elevated circulating thrombomodulin in severe preeclampsia.  Am J Obstet Gynecol. 1993;  169 (1) 148-149
    PubMedGoogle Scholar
  • 29 Ishii H, Nakano M, Tsubouchi J et al. Establishment of enzyme immunoassay of human thrombomodulin in plasma and urine using monoclonal antibodies.  Thromb Haemost. 1990;  63 (2) 157-162
    PubMedGoogle Scholar
  • 30 Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases.  Blood. 1990;  76 (10) 2024-2029
    CrossrefPubMedGoogle Scholar
  • 31 Asakura H, Jokaji H, Saito M et al. Plasma levels of soluble thrombomodulin increase in cases of disseminated intravascular coagulation with organ failure.  Am J Hematol. 1991;  38 (4) 281-287
    CrossrefPubMedGoogle Scholar
  • 32 Hayashi M, Inoue T, Hoshimoto K, Negishi H, Ohkura T, Inaba N. Characterization of five marker levels of the hemostatic system and endothelial status in normotensive pregnancy and pre-eclampsia.  Eur J Haematol. 2002;  69 (5–6) 297-302
    CrossrefPubMedGoogle Scholar
  • 33 Abe H, Okajima K, Okabe H, Takatsuki K, Binder B R. Granulocyte proteases and hydrogen peroxide synergistically inactivate thrombomodulin of endothelial cells in vitro.  J Lab Clin Med. 1994;  123 (6) 874-881
    PubMedGoogle Scholar
  • 34 Boehme M W, Deng Y, Raeth U et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies.  Immunology. 1996;  87 (1) 134-140
    PubMedGoogle Scholar
  • 35 Greer I A, Dawes J, Johnston T A, Calder A A. Neutrophil activation is confined to the maternal circulation in pregnancy-induced hypertension.  Obstet Gynecol. 1991;  78 (1) 28-32
    PubMedGoogle Scholar
  • 36 Tsukimori K, Maeda H, Ishida K, Nagata H, Koyanagi T, Nakano H. The superoxide generation of neutrophils in normal and preeclamptic pregnancies.  Obstet Gynecol. 1993;  81 (4) 536-540
    PubMedGoogle Scholar
  • 37 Tsukimori K, Nakano H, Wake N. Difference in neutrophil superoxide generation during pregnancy between preeclampsia and essential hypertension.  Hypertension. 2007;  49 (6) 1436-1441
    CrossrefPubMedGoogle Scholar
  • 38 Minakami H, Takahashi T, Izumi A, Tamada T. Increased levels of plasma thrombomodulin in preeclampsia.  Gynecol Obstet Invest. 1993;  36 (4) 208-210
    CrossrefPubMedGoogle Scholar
  • 39 Nadar S K, Al Yemeni E, Blann A D, Lip G YH. Thrombomodulin, von Willebrand factor and E-selectin as plasma markers of endothelial damage/dysfunction and activation in pregnancy induced hypertension.  Thromb Res. 2004;  113 (2) 123-128
    CrossrefPubMedGoogle Scholar
  • 40 Hsu C D, Lucas R B, Johnson T R, Hong S F, Chan D W. Elevated urine thrombomodulin/creatinine ratio in severely preeclamptic pregnancies.  Am J Obstet Gynecol. 1994;  171 (3) 854-856
    PubMedGoogle Scholar
  • 41 Bontis J, Vavilis D, Agorastos T, Zournatzi V, Konstantinidis T, Tagou K. Maternal plasma level of thrombomodulin is increased in mild preeclampsia.  Eur J Obstet Gynecol Reprod Biol. 1995;  60 (2) 139-141
    CrossrefPubMedGoogle Scholar
  • 42 Rousseau A, Favier R, Van Dreden P V. Elevated circulating soluble thrombomodulin activity, tissue factor activity and circulating procoagulant phospholipids: new and useful markers for pre-eclampsia?.  Eur J Obstet Gynecol Reprod Biol. 2009;  146 (1) 46-49
    CrossrefPubMedGoogle Scholar
  • 43 Chavarría M E, Lara-González L, García-Paleta Y, Vital-Reyes V S, Reyes A. Adhesion molecules changes at 20 gestation weeks in pregnancies complicated by preeclampsia.  Eur J Obstet Gynecol Reprod Biol. 2008;  137 (2) 157-164
    CrossrefPubMedGoogle Scholar
  • 44 Salem H H, Maruyama I, Ishii H, Majerus P W. Isolation and characterization of thrombomodulin from human placenta.  J Biol Chem. 1984;  259 (19) 12246-12251
    PubMedGoogle Scholar
  • 45 Maruyama I, Bell C E, Majerus P W. Thrombomodulin is found on endothelium of arteries, veins, capillaries, and lymphatics, and on syncytiotrophoblast of human placenta.  J Cell Biol. 1985;  101 (2) 363-371
    CrossrefPubMedGoogle Scholar
  • 46 Uszyński M, Sztenc S, Zekanowska E, Uszyński W. Thrombomodulin in human gestational tissues: placenta, fetal membranes and myometrium.  Adv Med Sci. 2006;  51 312-315
    PubMedGoogle Scholar
  • 47 Bosco C, Parra M, Barja P et al. Increased immunohistochemical expression of thrombomodulin at placental perivascular myofibroblast in severe preeclampsia (PE).  Histol Histopathol. 2005;  20 (4) 1045-1055
    PubMedGoogle Scholar
  • 48 Magriples U, Chan D W, Bruzek D, Copel J A, Hsu C D. Thrombomodulin: a new marker for placental abruption.  Thromb Haemost. 1999;  81 (1) 32-34
    PubMedGoogle Scholar
  • 49 Strijbos M H, Snijder C A, Kraan J, Lamers C H, Gratama J W, Duvekot J J. Levels of circulating endothelial cells in normotensive and severe preeclamptic pregnancies.  Cytometry B Clin Cytom. 2010;  78 (6) 382-386
    PubMedGoogle Scholar

Luci DussePh.D. 

Department of Clinical and Toxicological Analysis

Federal University of Minas Gerais, Brazil

eMail: lucim@farmacia.ufmg.br

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