Hemostasis in Pre-Eclampsia

ABSTRACT

Pre-eclampsia (P-EC) is a multisystem disorder exclusive to pregnancy. It complicates ~2 to 8% of all pregnancies and remains a major cause of maternal mortality. P-EC is characterized by a profound hypercoagulable state. The delicate hemostatic balance that must be maintained in the uteroplacental circulation during pregnancy makes this system vulnerable to perturbation. An abnormal hemostatic pattern occurs within the uteroplacental circulation in P-EC compared with normal pregnancy. Much recent research has focused on the epidemiological link between inherited thrombophilia and P-EC. The data suggest a weak statistical association, indicating an improbable primary role in the pathogenesis. Without clear evidence, low molecular weight heparins have been widely used to reduce recurrence of P-EC in thrombophilia-positive women. This practice now should be reviewed. Future research needs to focus on improving our basic scientific understanding of the role of the hemostatic system in human placentation.

KEYWORDS

Pre-eclampsia - pregnancy - hemostasis - coagulation - fibrinolysis

REFERENCES

• 1 Roberts J M, Gammill H S. Preeclampsia: recent insights.  Hypertension. 2005;  46 (6) 1243-1249
• 2 Lain K Y, Roberts J M. Contemporary concepts of the pathogenesis and management of preeclampsia.  JAMA. 2002;  287 (24) 3183-3186
• 3 Roberts J M, Lain K Y. Recent insights into the pathogenesis of pre-eclampsia.  Placenta. 2002;  23 (5) 359-372
• 4 Eichinger S, Weltermann A, Philipp K et al. Prospective evaluation of hemostatic system activation and thrombin potential in healthy pregnant women with and without factor V Leiden.  Thromb Haemost. 1999;  82 (4) 1232-1236
• 5 Baglin T. The measurement and application of thrombin generation.  Br J Haematol. 2005;  130 (5) 653-661
• 6 Rosenkranz A, Hiden M, Leschnik B et al. Calibrated automated thrombin generation in normal uncomplicated pregnancy.  Thromb Haemost. 2008;  99 (2) 331-337
• 7 Rafik Hamad R, Curvers J, Berntorp E, Eriksson M, Bremme K. Increased thrombin generation in women with a history of preeclampsia.  Thromb Res. 2009;  123 (4) 580-586
• 8 Macey M G, Bevan S, Alam S et al. Platelet activation and endogenous thrombin potential in pre-eclampsia.  Thromb Res. 2010;  125 (3) e76-e81
• 9 Duley L, Henderson-Smart D J, Meher S, King J F. Antiplatelet agents for preventing pre-eclampsia and its complications.  Cochrane Database Syst Rev. 2007;  (2) CD004659
• 10 Stirling Y, Woolf L, North W R, Seghatchian M J, Meade T W. Haemostasis in normal pregnancy.  Thromb Haemost. 1984;  52 (2) 176-182
• 11 Hellgren M, Blombäck M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. I. Normal condition.  Gynecol Obstet Invest. 1981;  12 (3) 141-154
• 12 Wickström K, Edelstam G, Löwbeer C H, Hansson L O, Siegbahn A. Reference intervals for plasma levels of fibronectin, von Willebrand factor, free protein S and antithrombin during third-trimester pregnancy.  Scand J Clin Lab Invest. 2004;  64 (1) 31-40
• 13 Tanjung M T, Siddik H D, Hariman H, Koh S C. Coagulation and fibrinolysis in preeclampsia and neonates.  Clin Appl Thromb Hemost. 2005;  11 (4) 467-473
• 14 Bonnar J, Redman C W, Denson K W. The role of coagulation and fibrinolysis in preeclampsia.  Perspect Nephrol Hypertens. 1976;  5 85-93
• 15 Edstrom 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 (2) 77-84
• 16 Kisiel W, Sprecher C A, Foster D C. Evidence that a second human tissue factor pathway inhibitor (TFPI-2) and human placental protein 5 are equivalent.  Blood. 1994;  84 (12) 4384-4385
• 17 Chand H S, Foster D C, Kisiel W. Structure, function and biology of tissue factor pathway inhibitor-2.  Thromb Haemost. 2005;  94 (6) 1122-1130
• 18 Erez O, Romero R, Hoppensteadt D et al. Tissue factor and its natural inhibitor in pre-eclampsia and SGA.  J Matern Fetal Neonatal Med. 2008;  21 (12) 855-869
• 19 Abdel Gader A M, Al-Mishari A A, Awadalla S A, Buyuomi N M, Khashoggi T, Al-Hakeem M. Total and free tissue factor pathway inhibitor in pregnancy hypertension.  Int J Gynaecol Obstet. 2006;  95 (3) 248-253
• 20 Oliver J J, Webb D J, Newby D E. Stimulated tissue plasminogen activator release as a marker of endothelial function in humans.  Arterioscler Thromb Vasc Biol. 2005;  25 (12) 2470-2479
• 21 Coolman M, de Groot C J, Steegers E A et al. Concentrations of plasminogen activators and their inhibitors in blood preconceptionally, during and after pregnancy.  Eur J Obstet Gynecol Reprod Biol. 2006;  128 (1-2) 22-28
• 22 Robb A O, Mills N L, Din J N et al. Acute endothelial tissue plasminogen activator release in pregnancy.  J Thromb Haemost. 2009;  7 (1) 138-142
• 23 Reith A, Booth N A, Moore N R, Cruickshank D J, Bennett B. Plasminogen activator inhibitors (PAI-1 and PAI-2) in normal pregnancies, pre-eclampsia and hydatidiform mole.  Br J Obstet Gynaecol. 1993;  100 (4) 370-374
• 24 Hunt B J, Missfelder-Lobos H, Parra-Cordero M et al. Pregnancy outcome and fibrinolytic, endothelial and coagulation markers in women undergoing uterine artery Doppler screening at 23 weeks.  J Thromb Haemost. 2009;  7 (6) 955-961
• 25 Lockwood C J, Krikun G, Schatz F. The decidua regulates hemostasis in human endometrium.  Semin Reprod Endocrinol. 1999;  17 (1) 45-51
• 26 Lanir N, Aharon A, Brenner B. Haemostatic mechanisms in human placenta.  Best Pract Res Clin Haematol. 2003;  16 (2) 183-195
• 27 Pijnenborg R, Robertson W B, Brosens I, Dixon G. Review article: trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals.  Placenta. 1981;  2 (1) 71-91
• 28 Lockwood C J, Krikun G, Runic R, Schwartz L B, Mesia A F, Schatz F. Progestin-epidermal growth factor regulation of tissue factor expression during decidualization of human endometrial stromal cells.  J Clin Endocrinol Metab. 2000;  85 (1) 297-301
• 29 Dusse L M, Carvalho M G, Cooper A J, Lwaleed B A. Tissue factor and tissue factor pathway inhibitor: a potential role in pregnancy and obstetric vascular complications?.  Clin Chim Acta. 2006;  372 (1–2) 43-46
• 30 Lockwood C J, Krikun G, Caze R, Rahman M, Buchwalder L F, Schatz F. Decidual cell-expressed tissue factor in human pregnancy and its involvement in hemostasis and preeclampsia-related angiogenesis.  Ann N Y Acad Sci. 2008;  1127 67-72
• 31 Chen J, Bierhaus A, Schiekofer S et al. Tissue factor—a receptor involved in the control of cellular properties, including angiogenesis.  Thromb Haemost. 2001;  86 (1) 334-345
• 32 Parry G C, Mackman N. Mouse embryogenesis requires the tissue factor extracellular domain but not the cytoplasmic domain.  J Clin Invest. 2000;  105 (11) 1547-1554
• 33 Pedersen B, Holscher T, Sato Y, Pawlinski R, Mackman N. A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice.  Blood. 2005;  105 (7) 2777-2782
• 34 Isermann B, Hendrickson S B, Hutley K, Wing M, Weiler H. Tissue-restricted expression of thrombomodulin in the placenta rescues thrombomodulin-deficient mice from early lethality and reveals a secondary developmental block.  Development. 2001;  128 (6) 827-838
• 35 Estellés A, Gilabert J, Grancha S et al. Abnormal expression of type 1 plasminogen activator inhibitor and tissue factor in severe preeclampsia.  Thromb Haemost. 1998;  79 (3) 500-508
• 36 Aharon A, Lanir N, Drugan A, Brenner B. Placental TFPI is decreased in gestational vascular complications and can be restored by maternal enoxaparin treatment.  J Thromb Haemost. 2005;  3 (10) 2355-2357
• 37 Ogawa M, Yanoma S, Nagashima Y et al. Paradoxical discrepancy between the serum level and the placental intensity of PP5/TFPI-2 in preeclampsia and/or intrauterine growth restriction: possible interaction and correlation with glypican-3 hold the key.  Placenta. 2007;  28 (2–3) 224-232
• 38 Fazel A, Vincenot A, Malassiné A et al. Increase in expression and activity of thrombomodulin in term human syncytiotrophoblast microvilli.  Placenta. 1998;  19 (4) 261-268
• 39 Estellés 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 (1) 143-150
• 40 Higgins J R, Walshe J J, Darling M R, Norris L, Bonnar J. Hemostasis in the uteroplacental and peripheral circulations in normotensive and pre-eclamptic pregnancies.  Am J Obstet Gynecol. 1998;  179 (2) 520-526
• 41 Kupferminc M J, Eldor A, Steinman N et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy.  N Engl J Med. 1999;  340 (1) 9-13
• 42 Robertson L, Wu O, Langhorne P et al. Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review.  Br J Haematol. 2006;  132 (2) 171-196
• 43 Said J M, Higgins J R, Moses E K et al. Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women.  Obstet Gynecol. 2010;  115 (1) 5-13
• 44 Silver R M, Zhao Y, Spong C Y et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (NICHD MFMU) Network. Prothrombin gene G20210A mutation and obstetric complications.  Obstet Gynecol. 2010;  115 (1) 14-20
• 45 Many A, Schreiber L, Rosner S, Lessing J B, Eldor A, Kupferminc M J. Pathologic features of the placenta in women with severe pregnancy complications and thrombophilia.  Obstet Gynecol. 2001;  98 (6) 1041-1044
• 46 Mousa H A, Alfirevic Z I. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome?.  Hum Reprod. 2000;  15 (8) 1830-1833
• 47 Greer I A, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy.  Blood. 2005;  106 (2) 401-407
• 48 Pabinger I, Grafenhofer H, Kaider A et al. Preeclampsia and fetal loss in women with a history of venous thromboembolism.  Arterioscler Thromb Vasc Biol. 2001;  21 (5) 874-879
• 49 Alguel G, Vormittag R, Simanek R et al. Preeclampsia and pregnancy loss in women with a history of venous thromboembolism and prophylactic low-molecular-weight heparin (LMWH) during pregnancy.  Thromb Haemost. 2006;  96 (3) 285-289
• 50 Rey E, Garneau P, David M et al. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial.  J Thromb Haemost. 2009;  7 (1) 58-64
• 51 Riyazi N, Leeda M, de Vries J I, Huijgens P C, van Geijn H P, Dekker G A. Low-molecular-weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study.  Eur J Obstet Gynecol Reprod Biol. 1998;  80 (1) 49-54
• 52 Kupferminc M J, Fait G, Many A et al. Low-molecular-weight heparin for the prevention of obstetric complications in women with thrombophilias.  Hypertens Pregnancy. 2001;  20 (1) 35-44
• 53 CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group . CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women.  Lancet. 1994;  343 (8898) 619-629
• 54 Rousseau A, Favier R, Van Dreden P. 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
• 55 Thornton C A, Bonnar J. Factor VIII-related antigen and factor VIII coagulant activity in normal and pre-eclamptic pregnancy.  Br J Obstet Gynaecol. 1977;  84 (12) 919-923
• 56 Bonnar J, McNicol G P, Douglas A S. Coagulation and fibrinolytic systems in pre-eclampsia and eclampsia.  BMJ. 1971;  2 (5752) 12-16
• 57 Halligan A, Bonnar J, Sheppard B, Darling M, Walshe J. Haemostatic, fibrinolytic and endothelial variables in normal pregnancies and pre-eclampsia.  Br J Obstet Gynaecol. 1994;  101 (6) 488-492
• 58 Chaiworapongsa T, Yoshimatsu J, Espinoza J et al. Evidence of in vivo generation of thrombin in patients with small-for-gestational-age fetuses and pre-eclampsia.  J Matern Fetal Neonatal Med. 2002;  11 (6) 362-367
• 59 Bellart J, Gilabert R, Anglès A et al. Tissue factor levels and high ratio of fibrinopeptide A:D-dimer as a measure of endothelial procoagulant disorder in pre-eclampsia.  Br J Obstet Gynaecol. 1999;  106 (6) 594-597