Procoagulant and Anticoagulant Mechanisms in Human Placenta

 

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ABSTRACT

The placenta is a highly vascularized organ functioning as the interface between fetal blood, which is confined within the villous blood vessels, and maternal blood, which flows in decidual arteries and washes the intervillous spaces in contact with syncytiotrophoblast (STB) cells. The STB adopts vascular characteristics such as the presence of von Willebrand factor (vWF), CD31 markers, adhesion molecules, and coagulation components. The special structure of the placenta requires efficient mechanisms for fast activation and localized regulation of coagulation. The presence of procoagulant and anticoagulant components on placental vascular endothelial cells (EC) and STB is essential for hemostasis. Activation of coagulation may be a favored process, as suggested by elevated fibrin depositions documented in some pathologic states. Increased localized procoagulant components such as tissue factor (TF) and plasminogen activator inhibitors (PAI-1, PAI-2), are associated with some pregnancy complications. Several anticoagulants regulate placental coagulation: tissue factor pathway inhibitor (TFPI) is primarily produced in EC; TFPI-2, a variant of TFPI, has been purified from the placenta and was identified in the STB lining the villi; thrombomodulin, a membrane glycoprotein that activates protein C, is localized in EC and apical membranes of STB; annexin V, an anticoagulant that binds to negative membrane phospholipids, is abundant on normal placental STB, whereas reduced STB annexin V was associated with the presence of antiphospholipid antibodies. The placenta is a putative source of coagulation components. However, the interplay between local procoagulant and anticoagulant mechanisms and their association with pregnancy complications need to be assessed.

REFERENCES

• 1 Benirschke K, Kaufmann P. Pathology of the Human Placenta, 2nd ed. New York: Springer Verlag; 1990;0:80-90. 
  Google Scholar
• 2 Zhou Y, Fisher S J, Janatpour M. et al . Human cytotrophoblasts adopt a vascular phenotype as they differentiate: a strategy for successful endovascular invasion.  J Clin Invest . 1997;  99 2139-2151
  CrossrefPubMedGoogle Scholar
• 3 Kliman H J, Nestler J E, Sermasi E, Sanger J M, Strauss J F. Purification, characterization and in vitro differentiation of cytotrophoblasts from human term placenta.  Endocrinology . 1986;  118 1567-1582
  CrossrefPubMedGoogle Scholar
• 4 Isermann B, Hendrickson S B, Hutley K. et al . Tissue restricted expression of thrombomodulin in the placenta rescues thrombomodulin deficient mice from early lethality and reveals a secondary development block.  Development . 2001;  128 827-838
  PubMedGoogle Scholar
• 5 Miyagi Y, Koshikawa N, Yasumitsu H. et al . CDNA cloning and mRNA expression of a serine proteinase inhibitor secreted by cancer cells: identification as placental protein 5 and tissue factor pathway inhibitor-2.  J Biochem . 1994;  116 939-942
  Google Scholar
• 6 Krikun G, Lockwood C J, Wu X X. et al . The expression of the placental anticoagulant protein annexin V, by villous trophoblasts; immunolocalization and in vitro regulation.  Placenta . 1994;  15 601-612
  CrossrefPubMedGoogle Scholar
• 7 Gris J C, Quere I, Monpeyroux F. et al . Case control study of the frequency of thrombophilic disorders in couples with late fetal loss and no thrombotic antecedent.  Thromb Haemost . 1999;  81 891-899
  PubMedGoogle Scholar
• 8 Cross J C, Werb Z, Fisher S J. Implantation and the placenta; key pieces of the puzzle.  Science . 1994;  266 1058-1518
  PubMedGoogle Scholar
• 9 Sue T T, Holmback K, Jensen N J. et al . Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen deficient mice.  Genes Dev . 1995;  9 794-807
  PubMedGoogle Scholar
• 10 Hodivala-Dilke Z, McHugh K P, Tsakiris D A. et al . Beta 3-integrin deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.  J Clin Invest . 1999;  103 229-238
  CrossrefPubMedGoogle Scholar
• 11 Kanfer A, Bruch J F, Nguyen G. et al . Increased placental antifibrinolytic potential and fibrin deposits in pregnancy induced hypertension and preeclampsia.  Lab Invest . 1996;  74 253-258
  PubMedGoogle Scholar
• 12 Estelles A, Gilabert J, Grancha S. et al . Abnormal expression of type I plasminogen activator inhibitor and tissue factor in severe preeclampsia.  Thromb Haemost . 1998;  79 500-508
  PubMedGoogle Scholar
• 13 Carson S D, Ramsey C A. Tissue factor is present in placental microvilli and cofractionates with microvilli membrane proteins.  Placenta . 1985;  6 5-13
  PubMedGoogle Scholar
• 14 Dalaker K, Haug E, Prydz H. Mouse trophoblast cells are constitutive producers of thromboplastin (factor III) in vitro.  Thromb Haemost . 1985;  54 438-441
  PubMedGoogle Scholar
• 15 Faulk W P, Labarrere C A, Carson S D. Tissue factor: identification and characterization of cell types in human placenta.  Blood . 1990;  76 86-96
  PubMedGoogle Scholar
• 16 Lakasing L, Campa J S, Poston R, Khamashta M A, Poston L. Normal expression of tissue factor, thrombomodulin and annexin V in placentas from women with antiphospholipid syndrome.  Am J Obstet Gynecol . 1999;  181 180-189
  PubMedGoogle Scholar
• 17 Revardieu P, Jarousseau A C, Thibault G. et al . Tissue factor activity of syncytiotrophoblasts plasma membranes and tumoral trophoblasts cells in culture.  Thromb Haemost . 1995;  73 49-54
  PubMedGoogle Scholar
• 18 Lanir N, Aharon A, Tennenbaum G, Brenner B. Cultured human placenta trophoblasts express vascular hemostatic functions that are affected by cytokines.  Thromb Haemost (Suppl):(Abst P2057). 2001; 
  PubMedGoogle Scholar
• 19 Erlich J, Parry G CN, Fearns C. et al . Tissue factor is required for uterine hemostasis and maintenance of the placental labyrinth during gestation.  Proc Natl Acad Sci USA . 1999;  96 8138-8143
  CrossrefPubMedGoogle Scholar
• 20 Astedt B, Hagerstrand I, Lecander I. Cellular localization in placenta of placental type plasminogen activator inhibitor.  Thromb Haemost . 1986;  56 63-69
  PubMedGoogle Scholar
• 21 Kruithof E KO, Tran-Thang C, Gudinchet A. et al . Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors.  Blood . 1987;  69 460-469
  PubMedGoogle Scholar
• 22 Kwanto T, Morimoto K, Uemura Y. Urokinase inhibitor in human placenta.  Nature . 1968;  217 253-254
  PubMedGoogle Scholar
• 23 Estelles A, Gilabert J, Keeton M. et al . Altered expression of plasminogen activator inhibitor type 1 in placentas from pregnant women with preeclampsia and/or intrauterine fetal growth retardation.  Blood . 1994;  84 143-150
  PubMedGoogle Scholar
• 24 Belin D. Biology and facultative secretion of plasminogen activator inhibitor 2.  Thromb Haemost . 1993;  70 144-147
  PubMedGoogle Scholar
• 25 Bajaj M S, Kuppuswamy M N, Saito H, Spitzer S G, Bajaj S P. Cultured normal human hepatocytes do not synthesize lipoprotein associated coagulation inhibitor: evidence that endothelium is the principal site of its synthesis.  Proc Natl Acad Sci USA . 1990;  87 8869-8873
  Google Scholar
• 26 Sprecher C A, Kisiel W, Mathewes S, Foster D C. Molecular cloning expression and partial characterization of a second human tissue factor pathway inhibitor.  Proc Natl Acad Sci USA . 1994;  91 3353-3357
  Google Scholar
• 27 Udagawa K, Miyagi Y, Hirahara F. et al . Specific expression of PP5/TFPI2 mRNA by syncytiotrophoblasts in human placenta as revealed by in situ hybridization.  Placenta . 1998;  19 217-223
  CrossrefPubMedGoogle Scholar
• 28 Udagawa K, Yasumitsu H, Esaki M. et al . Subcellular localization of PP5/TFPI-2 in human placenta: a possible role of PP5/TFPI2 as an anticoagulant on the surface of syncytiotrophoblasts.  Placenta . 2002;  23 145-153
  CrossrefPubMedGoogle Scholar
• 29 Edstrum C S, Calhoun D A, Christensen R D. Expression of tissue factor pathway inhibitor in human fetal and placental tissues.  Early Hum Dev . 2000;  59 77-84
  CrossrefPubMedGoogle Scholar
• 30 Bajaj M S, Kuppuswamy M N, Manepalli A N, Bajaj S P. Transcriptional expression of tissue factor pathway inhibitor, thrombomodulin and von Willebrand factor in normal human tissues.  Thromb Haemost . 1999;  82 1047-1052
  PubMedGoogle Scholar
• 31 Salem H H, Maruyama I, Ishii H, Majerus P W. Isolation and characterization of thrombomodulin from human placenta.  J Biol Chem . 1984;  259 12246-12251
  PubMedGoogle Scholar
• 32 Maruyama I, Bell C E, Majerus P W. Thrombomodulin is found on endothelium of arteries, veins, capillaries and lymphatics and on syncytiotrophoblasts of human placenta.  J Cell Biol . 1985;  101 363-371
  CrossrefPubMedGoogle Scholar
• 33 Fazel A, Vincenot A, Malssine A. et al . Increase in expression and activity of thrombomodulin in term human placenta syncytiotrophoblast microvilli.  Placenta . 1998;  19 261-268
  CrossrefPubMedGoogle Scholar
• 34 Weiler H, Isermann B. Gene targeting of coagulation factors and embryogenesis. In: Brenner B, Marder VJ, eds. Womens Issues in Thrombosis and Hemostasis London: Martin Dunitz 2002: 109-119
  Google Scholar
• 35 Rand J H, Wu X, Guller S. et al . Antiphospholipid immunoglobulin G antibodies reduce annexin V levels in syncytiotrophoblast apical membranes and in culture media of placental villi.  Am J Obstet Gynecol . 1997;  177 918-923
  CrossrefPubMedGoogle Scholar
• 36 Walsh S W. Preeclampsia: an imbalance in placental prostacyclin and thromboxane production.  Am J Obstet Gynecol . 1985;  23 311-314
  PubMedGoogle Scholar