Download PDF
Semin Vasc Med 2003; 03(1): 013-024
DOI: 10.1055/s-2003-38329
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Changes of Hemostasis Variables during Pregnancy

Peter Clark
  • Department of Transfusion Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom
Further Information

Publication History

Publication Date:
27 March 2003 (online)

    Permissions and Reprints

ABSTRACT

Normal pregnancy results in significant changes in maternal plasma coagulation factors, elements of the protein C/protein S natural anticoagulant system, and markers of fibrinolysis. These changes result in an increase in thrombin and fibrin generation, which is necessary for the hemostatic challenge of delivery and for normal placental implantation and development. In this review, the evidence for these changes in both the antenatal and peripartum period is discussed. An understanding of these physiological changes is required to allow a diagnosis of inherited or acquired thrombophilic or bleeding disorders during pregnancy and may give insight into the development of the thrombosis-linked disorders associated with pregnancy.

KEYWORDS

Pregnancy - coagulation - fibrinolysis

REFERENCES

  • 1 Preston F, Rosendaal F, Walker I. et al . Increased fetal loss in women with heritable thrombophilia.  Lancet . 1996;  348 913-916
    CrossrefPubMedGoogle Scholar
  • 2 Dekker G A, De Vries I P J, Doelitzsch P M. et al . Underlying disorders associated with severe early-onset preeclampsia.  Am J Obstet Gynecol . 1995;  173 1042-1048
    CrossrefPubMedGoogle Scholar
  • 3 Brenner B, Lanir N, Thaler I. HELLP syndrome associated with factor V R 506Q mutation.  Br J Haematol . 1996;  92 999-1001
    CrossrefPubMedGoogle Scholar
  • 4 Clark P, Sattar N, Walker I, Greer I. The Glasgow Outcome, APCR and Lipid (GOAL) Pregnancy Study: significance of pregnancy associated activated protein C resistance.  Thromb Haemost . 2001;  85 30-35
    PubMedGoogle Scholar
  • 5 Pabinger I, Kyrle P A, Heistinger M. et al . The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: a prospective cohort study.  Thromb Haemost . 1994;  71 441-445
    PubMedGoogle Scholar
  • 6 Dizon-Townson D S, Meline L, Nelson L M, Varner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction.  Am J Obstet Gynecol . 1997;  177 402-405
    CrossrefPubMedGoogle Scholar
  • 7 Stirling Y, Woolf L, North W RS, Seghatchian M J, Meade T W. Haemostasis in normal pregnancy.  Thromb Haemost . 1984;  52 176-182
    PubMedGoogle Scholar
  • 8 Clark P, Brennand J, Conkie J A. et al . Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy.  Thromb Haemost . 1998;  79 1166-1170
    PubMedGoogle Scholar
  • 9 Kjellberg U, Andersson N, Rosen S, Tengborn L, Hellgren M. APC resistance and other haemostatic variables during pregnancy and puerperium.  Thromb Haemost . 1999;  81 527-531
    PubMedGoogle Scholar
  • 10 Condie R. A serial study of coagulation factors XII, XI and X in plasma in normal pregnancy and in pregnancy complicated by preeclampsia.  Br J Obstet Gynaecol . 1976;  83 636-639
    CrossrefPubMedGoogle Scholar
  • 11 Nilsson I, Kullander S. Coagulation and fibrinolytic studies during pregnancy.  Acta Obstet Gynecol Scand . 1967;  46 273-285
    PubMedGoogle Scholar
  • 12 Hellgren M, Blomback M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium.  Gynecol Obstet Invest . 1981;  12 141-154
    CrossrefPubMedGoogle Scholar
  • 13 Lefkowitz J B, Clarke A H, Barbour L A. Comparison of protein S functional and antigenic assays in normal pregnancy.  Am J Obstet Gynecol . 1996;  175 657-660
    CrossrefPubMedGoogle Scholar
  • 14 Walker M C, Garner P R, Keely E J, Rock G A, Reis M D. Changes in activated protein C resistance during normal pregnancy.  Am J Obstet Gynecol . 1997;  177 162-169
    CrossrefPubMedGoogle Scholar
  • 15 Phillips L, Rosano L, Skrodelis V. Changes in plasma factor XI (plasma thromboplastin antecedent) levels during pregnancy.  Am J Obstet Gynecol . 1973;  116 1114-1116
    PubMedGoogle Scholar
  • 16 Aznar J, Gilabert J, Estelles A, Espana F. Fibrinolytic activity and protein C in preeclampsia.  Thromb Haemost . 1986;  55 314-317
    PubMedGoogle Scholar
  • 17 Hopmeier P, Halbmayer M, Schwarz H, Heuss F, Fischer M. Protein C and protein S in mild and moderate preeclampsia.  Thromb Haemost . 1987;  58 794-795
    PubMedGoogle Scholar
  • 18 Lao T T, Yuen P M, Yin J A. Protein S and protein C levels in Chinese women during pregnancy, delivery and the puerperium.  Br J Obstet Gynaecol . 1989;  96 167-170
    PubMedGoogle Scholar
  • 19 Espana F, Gilabert J, Aznar J. et al . Complexes of activated protein C with alpha 1-antitrypsin in normal pregnancy and in severe preeclampsia.  Am J Obstet Gynecol . 1991;  164 1310-1316
    PubMedGoogle Scholar
  • 20 Woodhams B G, Candotti G, Shaw R, Kernoff P BA. Changes in coagulation and fibrinolysis during pregnancy: evidence of activation of coagulation preceding spontaneous abortion.  Thromb Res . 1989;  55 99-107
    CrossrefPubMedGoogle Scholar
  • 21 Gatti L, Tenconi P M, Guarneri D. et al . Hemostatic parameters and platelet activation by flow-cytometry in normal pregnancy: a longitudinal study.  Int J Clin Lab Res . 1994;  24 217-219
    CrossrefPubMedGoogle Scholar
  • 22 Faught W, Garner P, Jones G, Ivey B. Changes in protein C and protein S levels in normal pregnancy.  Am J Obstet Gynecol . 1995;  172 147-150
    CrossrefPubMedGoogle Scholar
  • 23 Mannucci P, Vigano S, Botasso B. et al . Protein C antigen during pregnancy, delivery and the puerperium.  Thromb Haemost . 1984;  52 217
    PubMedGoogle Scholar
  • 24 Malm J, Laurell M, Dalhback B. Changes in the plasma levels of vitamin K-dependent proteins C and S and of C4b-binding protein during pregnancy and oral contraception.  Br J Haematol . 1988;  68 437-443
    PubMedGoogle Scholar
  • 25 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;  101 488-492
    PubMedGoogle Scholar
  • 26 Comp P C, Thurnau G R, Welsh J, Esmon C T. Functional and Immunologic protein S levels are decreased during pregnancy.  Blood . 1986;  68 881-885
    PubMedGoogle Scholar
  • 27 Fernandez J A, Estelles A, Gilabert J, Espana F, Aznar J. Functional and immunologic protein S in normal pregnant women and in full-term newborns.  Thromb Haemost . 1989;  61 474-478
    PubMedGoogle Scholar
  • 28 Bremme K, Ostlund E, Almqvist I, Heinonen K, Blomback M. Enhanced thrombin generation and fibrinolytic activity in normal pregnancy and the puerperium.  Obstet Gynecol . 1992;  80 132-137
    PubMedGoogle Scholar
  • 29 Dahlback B, Carlsson M, Svensson P J. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.  Proc Natl Acad Sci U S A . 1993;  90 1004-1008
    PubMedGoogle Scholar
  • 30 Bertina R, Koeleman B, Koster T. et al . Mutation in blood-coagulation factor-V associated with resistance to activated protein-C.  Nature . 1994;  369 64-67
    CrossrefPubMedGoogle Scholar
  • 31 Cumming A M, Tait R C, Fildes S. et al . Development of resistance to activated protein C during pregnancy.  Br J Haematol . 1995;  90 725-727
    CrossrefPubMedGoogle Scholar
  • 32 Mathonet F, de Mazancourt P, Bastenaire B. et al . Activated protein C sensitivity ratio in pregnant women at delivery.  Br J Haematol . 1996;  92 244-246
    CrossrefPubMedGoogle Scholar
  • 33 Nicolaes G AF, Thomassen M, Tans G, Rosing J, Hemker H C. Effect of activated protein C on thrombin generation and on the thrombin potential in plasma of normal and APC-resistant individuals.  Blood Coagul Fibrinolysis . 1997;  8 28-38
    PubMedGoogle Scholar
  • 34 Osterud B, Robertsen R, Asvang G, Thijssen F. Resistance to activated protein C is reduced in women using oral contraceptives.  Blood Coagul Fibrinolysis . 1994;  5 853-854
    PubMedGoogle Scholar
  • 35 Mathonet F, de Mazancourt P, Denninger M-H. et al . Role of factor VIII on activated protein C resistance ratio in inflammatory diseases.  Br J Haematol . 1996;  95 423-425
    CrossrefPubMedGoogle Scholar
  • 36 Lowe G, Rumley A, Woodward M, Reid E, Rumley J. Activated protein C resistance and the FV:R506Q mutation in a random population sample-associations with cardiovascular risk factors and coagulation variables.  Thromb Haemost . 1999;  81 918-924
    PubMedGoogle Scholar
  • 37 Freyburger G, Javorschi S, Labrouche S, Bernard P. Proposal for objective evaluation of the performance of various functional APC-resistance tests in genotyped patients.  Thromb Haemost . 1997;  78 1360-1365
    PubMedGoogle Scholar
  • 38 Clark P, Rosing J, Curvers J. et al . The Glasgow Outcome, APC resistance and Lipid (GOAL) pregnancy study: pregnancy-associated APC resistance.  Thromb Haemost . 2001;  86(Suppl) 278
    PubMedGoogle Scholar
  • 39 Bauer K A, Rosenberg R D. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation.  Blood . 1987;  70 343-350
    PubMedGoogle Scholar
  • 40 de Boer K, ten Cate W J, Sturk A, Borm J JJ, Treffers P E. Enhanced thrombin generation in normal and hypertensive pregnancy.  Am J Obstet Gynecol . 1989;  160 95-100
    PubMedGoogle Scholar
  • 41 Reinthaller A, Mursch-Edlmayar G, Tatra G. Thrombin-antithrombin III complex levels in normal pregnancy, with hypertensive disorders and after delivery.  Br J Obstet Gynaecol . 1990;  97 506-510
    CrossrefPubMedGoogle Scholar
  • 42 Cadroy Y, Grandjean H, Pichon J. et al . Evaluation of six markers of haemostatic system in normal pregnancy and pregnancy complicated by hypertension or pre-eclampsia.  Br J Obstet Gynaecol . 1993;  100 416-20
    PubMedGoogle Scholar
  • 43 Comeglio P, Fedi S, Liotta A A. et al . Blood clotting activation during normal pregnancy.  Thromb Res . 1996;  84 199-202
    CrossrefPubMedGoogle Scholar
  • 44 Delorme M, Burrows R, Orfosu F, Andrew M. Thrombin regulation in mother and fetus during pregnancy.  Semin Thromb Hemost . 1992;  18 81-90
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Weenink G H, Treffers P E, Kahle L H, ten Cate W J. Antithrombin III in normal pregnancy.  Thromb Res . 1982;  26 281-287
    CrossrefPubMedGoogle Scholar
  • 46 Ramalakshmi B A, Raju L A, Raman L. Antithrombin III levels in pregnancy induced hypertension.  Nat Med J India . 1995;  8 61-62
    PubMedGoogle Scholar
  • 47 Maruyama I, Bell C, Majerus P. Thrombomodulin is found on endothelium of arteries, veins, capillaries and lymphatics and on syncytiotrophoblast of human placenta.  J Cell Biol . 1985;  101 363-371
    CrossrefPubMedGoogle Scholar
  • 48 Esmon C, Owen W. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C.  Proc Natl Acad Sci U S A . 1981;  78 2249-2252
    CrossrefPubMedGoogle Scholar
  • 49 Esmon C, Esmon N, Harris K. Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalysed fibrin formation and factor V activation.  J Biol Chem . 1982;  257 7944-7947
    PubMedGoogle Scholar
  • 50 Esmon N, Carroll R, Esmon C. Thrombomodulin blocks the ability of thrombin to activate platelets.  J Biol Chem . 1983;  258 12238-12242
    PubMedGoogle Scholar
  • 51 Hofsteenge J, Taguchi H, Stone S. Effect of thrombomodulin on the kinetics of the interaction of thrombin with substrate and inhibitors.  Biochem J . 1986;  237 243-251
    PubMedGoogle Scholar
  • 52 Ishii H, Majerus P. Thrombomodulin is present in human plasma and urine.  J Clin Invest . 1985;  76 2178-2181
    CrossrefPubMedGoogle Scholar
  • 53 Boffa M-C. Considering cellular thrombomodulin distribution and its modulating factors can facilitate the use of plasma thrombomodulin as a reliable endothelial marker.  Haemostasis . 1996;  26 233-243
    PubMedGoogle Scholar
  • 54 Boffa M-C, Valsecchi L, Fausto A. et al . Predictive value of plasma thrombomodulin in pre-eclampsia and gestational hypertension.  Thromb Haemost . 1998;  79 1092-1095
    PubMedGoogle Scholar
  • 55 Suzuki K, Nishioka J, Hashimoto S. Protein C inhibitor. Purification from human plasma and characterisation.  J Biol Chem . 1983;  258 163-168
    PubMedGoogle Scholar
  • 56 Heeb M J, Espana F, Griffin J H. Inhibition and complexation of activated protein C by two major inhibitors in plasma.  Blood . 1989;  73 446-454
    PubMedGoogle Scholar
  • 57 Marlar R A, Kressin D C, Madden R M. Contribution of plasma proteinase inhibitors to the regulation of activated protein C in plasma.  Thromb Haemost . 1993;  69 16-20
    PubMedGoogle Scholar
  • 58 Hoogendoorn H, Toh C H, Nesheim M E, Giles A R. Alpha 2-macroglobulin binds and inhibits activated protein C.  Blood . 1991;  78 2283-2290
    PubMedGoogle Scholar
  • 59 Gruber A, Griffin J. Direct detection of activated protein C in blood from human subjects.  Blood . 1992;  79 2340-2348
    PubMedGoogle Scholar
  • 60 Bauer K A, Kass B L, Beeler D L, Rosenberg R D. Detection of protein C activation in humans.  J Clin Invest . 1984;  74 2033-2041
    PubMedGoogle Scholar
  • 61 Gerbasi F, Bottoms S, Farag A, Mammen E. Increased intravascular coagulation associated with pregnancy.  Obstet Gynecol . 1990;  75 385-389
    PubMedGoogle Scholar
  • 62 Condie R G, Ogston D. Sequential studies on components of the haemostatic mechanism in pregnancy with particular reference to the development of pre-eclampsia.  Br J Obstet Gynaecol . 1976;  83 938-942
    PubMedGoogle Scholar
  • 63 Caron C, Goudemand J, Marey A. et al . Are haemostatic and fibrinolytic parameters predictors of preeclampsia in pregnancy-associated hypertension?.  Thromb Haemost . 1991;  66 410-414
    PubMedGoogle Scholar
  • 64 Sattar N, Greer I, Rumley A. et al . A longitudinal study of the relationship between haemostatic, lipid and oestradiol changes during normal human pregnancy.  Thromb Haemost . 1999;  81 71-75
    PubMedGoogle Scholar
  • 65 Wright J, Cooper P, Astedt B. et al . Fibrinolysis during normal human pregnancy: complex inter-relationships between plasma levels of tissue plasminogen activator and inhibitors and the euglobulin clot lysis time.  Br J Haematol . 1988;  69 253-258
    CrossrefPubMedGoogle Scholar
  • 66 Ballegeer V, Mombaerts P, Declerck P. et al . Fibrinolytic response to venous occlusion and fibrin fragment D-dimer levels in normal and complicated pregnancy.  Thromb Haemost . 1987;  58 1030-1032
    PubMedGoogle Scholar
  • 67 Mercelina-Roumans P E, Ubachs J M, van Wersch W J. Coagulation and fibrinolysis in smoking and nonsmoking pregnant women.  Br J Obstet Gynaecol . 1996;  103 789-794
    PubMedGoogle Scholar
  • 68 Schlit A F, Col-De-Beys C, Moriau M, Lavenne-Pardonge E. Acquired activated protein C resistance in pregnancy.  Thromb Res . 1996;  84 203-206
    CrossrefPubMedGoogle Scholar
  • 69 Bonnar J, Prentice C, McNicol G, Douglas A. Haemostatic mechanism in the uterine circulation during placental separation.  Br Med J . 1970;  2 564-567
    PubMedGoogle Scholar
  • 70 Gilabert J, Aznar J, Parrilla J. et al . Alteration in the coagulation and fibrinolysis systems in pregnancy, labour and puerperium, with special reference to a possible transitory state of intravascular coagulation during labour.  Thromb Haemost . 1978;  40 387-396
    PubMedGoogle Scholar
  • 71 Henrikson K. Thrombin as a hormonally regulated growth factor in oestrogen-responsive tissue.  Semin Thromb Hemost . 1992;  18 53-59
    PubMedGoogle Scholar
  • 72 Jazin E E, Dickerman H W, Henrikson K P. Estrogen regulation of a tissue factor-like procoagulant in the immature rat uterus.  Endocrinology . 1990;  126 176-185
    PubMedGoogle Scholar
  • 73 Bonnar J, Sheppard B L. The vascular supply of the placenta in normal and abnormal pregnancy. In: Baustein A, ed. Pathology of the Female Genital Tract New York: Springer Verlag 1977: 673-689
    Google Scholar
  • 74 McColl M D, Ramsay J E, Tait R C. et al . Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost . 1997;  78 1183-1188
    PubMedGoogle Scholar
  • 75 Bokarewa M I, Wramsby M, Bremme K, Blomback M. Variability of the response to activated protein C during normal pregnancy.  Blood Coagul Fibrinolysis . 1997;  8 239-244
    PubMedGoogle Scholar
  • 76 Warwick R, Hutton R A, Goff L, Letsky E, Heard M. Changes in protein C and free protein S during pregnancy and following hysterectomy.  J R Soc Med . 1989;  82 591-594
    PubMedGoogle Scholar