In mice, trophoblasts are equipped with a potent anticoagulant mechanism, the protein C pathway. In human placenta, no functional studies of the protein C pathway are available. Human first-trimester trophoblasts (CK++ HLA-G+/− Vim−) were isolated and kept in culture for a maximum of 48 hours. Activation of protein C on trophoblasts was at least as efficient as in endothelial cells (4.43 × 10−7 nmol/L/min/cell). Endothelial protein C receptor (EPCR) was expressed in syncytiotrophoblasts and extravillous trophoblasts. Downregulation of the messenger RNA of trophoblast EPCR occurred when trophoblasts were challenged with tumor necrosis factor α, and it could be prevented by unfractionated heparin but not by low-molecular-weight heparin at therapeutic doses. In conclusion, there is a functional protein C pathway on human first-trimester trophoblasts which can be modulated by inflammation. This finding has implications for the pathogenesis and prevention of placenta-mediated obstetric complications.
LunghiLFerrettiMEMediciSBiondiCVesceF. Control of human trophoblast function. Reprod Biol Endocrinol. 2007;5:6–20.
2.
EsmonCT. The protein C pathway. Chest. 2003;124
(3 suppl):26S–32S.
3.
IsermannBSoodRPawlinskiRThe thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nat Med. 2003;9
(3):331–337.
4.
WeilerH. Mouse models of thrombosis: thrombomodulin. Thromb Haemost. 2004;92
(3):467–477.
5.
GuJMCrawleyJTFerrellGDisruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J Biol Chem. 2002;277
(45):43335–43343.
6.
HoffmannEHedlundEPerinTLyndrupJ. Is thrombophilia a risk factor for placenta-mediated pregnancy complications?Arch Gynecol Obstet. 2012;286
(3):585–589.
7.
FranchiFBiguzziECetinIMutations in the thrombomodulin and endothelial protein C receptor genes in women with late fetal loss. Br J Haematol. 2001;114
(3):641–646.
8.
HossainNSchatzFPaidasMJ. Heparin and maternal fetal interface: why should it work to prevent pregnancy complications?Thromb Res. 2009;124
(6):653–655.
MartinelliIRuggenentiPCetinIHeparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial. Blood. 2012;119
(14):3269–3275.
11.
DoddJMMcLeodAWindrimRCKingdomJ. Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction. Cochrane Database Syst Rev. 2013;7:CD006780.
12.
RodgerMACarrierMLe GalGMeta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. Blood. 2014;123:822–828.
13.
LangstonCKaplanCMacphersonTPractice guideline for examination of the placenta: developed by the Placental Pathology Practice Guideline Development Task Force of the College of American Pathologists. Arch Pathol Lab Med. 1997;121:449–476.
14.
LaszikZMitroATaylorFBJrFerrellGEsmonCT. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation. 1997;96
(10):3633–3640.
15.
FaioniEMFerreroSFontanaGExpression of endothelial protein C receptor and thrombomodulin in the intestinal tissue of patients with inflammatory bowel disease. Crit Care Med. 2004;32
(5 suppl):S266–S270.
16.
SvenssonAMWatersBLLaszikZGThe protein C system in placental massive perivillous fibrin deposition. Blood Coagul Fibrinolysis. 2004;15
(6):491–495.
17.
IzmirlyPMBarisoniLBuyonJPExpression of endothelial protein C receptor in cortical peritubular capillaries associates with a poor clinical response in lupus nephritis. Rheumatology (Oxford). 2009;48
(5):513–519.
18.
Gillibert-DuplantierJRullierANeaudVKisielWRosenbaumJ. Liver myofibroblasts activate protein C and respond to activated protein C. World J Gastroenterol. 2010;16
(2):210–216.
19.
TarradeALai KuenRMalassinéACharacterization of human villous and extravillous trophoblasts isolated from first trimester placenta. Lab Invest. 2001;81
(9):1199–1211.
20.
YangCLingHZhangMOxidative stress mediates chemical hypoxia-induced injury and inflammation by activating NF-κB-COX-2 pathway in HaCaT cells. Mol Cells. 2011;31
(6):531–538.
21.
HockinMFKalafatisMShatosMMannKG. Protein C activation and factor Va inactivation on human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol. 1997;17
(11):2765–2775.
SalemHHMaruyamaIIshiiHMajerusPW. Isolation and characterization of thrombomodulin from human placenta. J Biol Chem. 1984;259
(19):12246–12251.
24.
MaruyamaIBellCEMajerusPW. 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.
25.
FazelAVincenotAMalassinéAIncrease in expression and activity of thrombomodulin in term human syncytiotrophoblast microvilli. Placenta. 1998;19
(4):261–268.
26.
FukudomeKEsmonCT. Identification, cloning and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem. 1994;269
(42):26486–26491.
27.
Woodley-CookJShinLYSwystunLCarusoSBeaudinSLiawPC. Effects of the chemotherapeutic agent doxorubicin on the protein C anticoagulant pathway. Mol Cancer Ther. 2006;5
(12):3303–3311.
