Hormonal Influences on Hemostasis in Women

 

 Buy Article Permissions and Reprints

ABSTRACT

Hemostasis in women is influenced by physiological changes in hormone status associated with the menstrual cycle, pregnancy and hormone-based contraceptives, and hormone replacement therapy (HRT) preparations. These hormonal influences can lead to an increase in the risk of venous thromboembolism (VTE) due to altered levels of clotting factors and an acquired resistance to the actions of activated protein C. This articles reviews recent evidence for these changes. During the menstrual cycle, changes are observed in levels of von Willebrand factor (VWF), fibrinogen, and activated factor VII. No such effect has been demonstrated in protein S or protein C levels or activated protein C resistance. Pregnancy is a procoagulant state with progressive increase in levels of factors VII, VIII, X, and XII, fibrinogen, and VWF, as well as increased resistance to activated protein C. Hormonal contraceptives and HRT are widely used and have undergone many changes over the years. Recent modifications to the preparations used in combined oral contraceptives (COC) aimed at improving side-effect profiles have also been shown to increase the risk of VTE for third- and fourth-generation COC compared with second-generation COC. This has been shown to be due to changes in activated protein C resistance. This risk of VTE represents a significant public health issue, but increased awareness and further research may allow development of safer future therapies leading to improvements in women’s health.

REFERENCES

• 1 Favaloro E J, Soltani S, McDonald J, Grezchnik E, Easton L. Cross-laboratory audit of normal reference ranges and assessment of ABO blood group, gender and age on detected levels of plasma coagulation factors.  Blood Coagul Fibrinolysis. 2005;  16 (8) 597-605
  CrossrefPubMedGoogle Scholar
• 2 Kadir R A, Economides D L, Sabin C A, Owens D, Lee C A. Variations in coagulation factors in women: effects of age, ethnicity, menstrual cycle and combined oral contraceptive.  Thromb Haemost. 1999;  82 (5) 1456-1461
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Onundarson P T, Gudmundsdottir B R, Arnfinnsdottir A V, Kjeld M, Olafsson O. Von Willebrand factor does not vary during normal menstrual cycle [letter].  Thromb Haemost. 2001;  85 (1) 183-184
  PubMedGoogle Scholar
• 4 Miller C H, Dilley A B, Drews C, Richardson L, Evatt B. Changes in von Willebrand factor and factor VIII levels during the menstrual cycle [letter].  Thromb Haemost. 2002;  87 (6) 1082-1083
  PubMedGoogle Scholar
• 5 Ricci G, Cerneca F, Simeone R et al. Impact of highly purified urinary FSH and recombinant FSH on haemostasis: an open-label, randomized, controlled trial.  Hum Reprod. 2004;  19 (4) 838-848
  CrossrefPubMedGoogle Scholar
• 6 Kapiotis S, Jilma B, Pernerstorfer T, Stohlawetz P, Eichler H G, Speiser W. Plasma levels of activated factor VII decrease during the menstrual cycle.  Thromb Haemost. 1998;  80 (4) 588-591
  PubMedGoogle Scholar
• 7 Blombäck M, Eneroth P, Andersson O, Anvret M. On laboratory problems in diagnosing mild von Willebrand’s disease.  Am J Hematol. 1992;  40 (2) 117-120
  CrossrefPubMedGoogle Scholar
• 8 Lethagen S. Desmopressin in the treatment of women’s bleeding disorders.  Haemophilia. 1999;  5 (4) 233-237
  CrossrefPubMedGoogle Scholar
• 9 Au C L, Rogers P A. Immunohistochemical staining of von Willebrand factor in human endometrium during normal menstrual cycle.  Hum Reprod. 1993;  8 (1) 17-23
  PubMedGoogle Scholar
• 10 Bertina R M, Koeleman B PC, Koster T et al. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369 (6475) 64-67
  CrossrefPubMedGoogle Scholar
• 11 de Visser M C, Rosendaal F R, Bertina R M. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis.  Blood. 1999;  93 (4) 1271-1276
  PubMedGoogle Scholar
• 12 Tans G, van Hylckama Vlieg A, Thomassen M C et al. Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women.  Br J Haematol. 2003;  122 (3) 465-470
  CrossrefPubMedGoogle Scholar
• 13 Wramsby M L, Bokarewa M I, Blombäck M, Bremme A K. Response to activated protein C during normal menstrual cycle and ovarian stimulation.  Hum Reprod. 2000;  15 (4) 795-797
  CrossrefPubMedGoogle Scholar
• 14 van Rooijen M, Silveira A, Thomassen S et al. APC resistance during the normal menstrual cycle.  Thromb Haemost. 2007;  98 (6) 1246-1251
  PubMedGoogle Scholar
• 15 van Vliet H AAM, Rodrigues S P, Snieders M NE et al. Sensitivity to activated protein C during the menstrual cycle in women with and without factor V Leiden.  Thromb Res. 2008;  121 (6) 757-761
  CrossrefPubMedGoogle Scholar
• 16 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
  CrossrefPubMedGoogle Scholar
• 17 Stirling Y, Woolf L, North W R, Seghatchian M J, Meade T W. Haemostasis in normal pregnancy.  Thromb Haemost. 1984;  52 (2) 176-182
  PubMedGoogle Scholar
• 18 Clark P, Brennand J, Conkie J A, McCall F, Greer I A, Walker I D. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy.  Thromb Haemost. 1998;  79 (6) 1166-1170
  PubMedGoogle Scholar
• 19 Phillips L L, Rosano L, Skrodelis V. Changes in factor XI (plasma thromboplastin antecedent) levels during pregnancy.  Am J Obstet Gynecol. 1973;  116 (8) 1114-1116
  PubMedGoogle Scholar
• 20 Nossel H L, Lanzkowsky P, Levy S, Mibashan R S, Hansen J D. A study of coagulation factor levels in women during labour and in their newborn infants.  Thromb Diath Haemorrh. 1966;  16 (1) 185-197
  PubMedGoogle Scholar
• 21 Coopland A, Alkjaersig N, Fletcher A P. Reduction in plasma factor 13 (fibrin stabilizing factor) concentration during pregnancy.  J Lab Clin Med. 1969;  73 (1) 144-153
  PubMedGoogle Scholar
• 22 Cerneca F, Ricci G, Simeone R, Malisano M, Alberico S, Guaschino S. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis.  Eur J Obstet Gynecol Reprod Biol. 1997;  73 (1) 31-36
  CrossrefPubMedGoogle Scholar
• 23 Kadir R A, Chi C, Bolton-Maggs P. Pregnancy and rare bleeding disorders.  Haemophilia. 2009;  15 (5) 990-1005
  CrossrefPubMedGoogle Scholar
• 24 Uchikova E H, Ledjev I I. Changes in haemostasis during normal pregnancy.  Eur J Obstet Gynecol Reprod Biol. 2005;  119 (2) 185-188
  CrossrefPubMedGoogle Scholar
• 25 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 ((1 Pt 1)) 147-150
  CrossrefPubMedGoogle Scholar
• 26 Chi C, Kadir R A. Obstetric management. In:, Lee C A, Kadir R A, Kouides P A, eds. Inherited Bleeding Disorders in Women. Oxford, United Kingdom: Wiley-Blackwell; 2008: 122-148
  Google Scholar
• 27 Sánchez-Luceros A, Meschengieser S S, Marchese C et al. Factor VIII and von Willebrand factor changes during normal pregnancy and puerperium.  Blood Coagul Fibrinolysis. 2003;  14 (7) 647-651
  CrossrefPubMedGoogle Scholar
• 28 Saha P, Stott D, Atalla R. Haemostatic changes in the puerperium ’6 weeks postpartum’ (HIP Study)—implication for maternal thromboembolism.  BJOG. 2009;  116 (12) 1602-1612
  CrossrefPubMedGoogle Scholar
• 29 Hellgren M, Svensson P J, Dahlbäck B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives.  Am J Obstet Gynecol. 1995;  173 (1) 210-213
  CrossrefPubMedGoogle Scholar
• 30 Mahieu B, Jacobs N, Mahieu S et al. Haemostatic changes and acquired activated protein C resistance in normal pregnancy.  Blood Coagul Fibrinolysis. 2007;  18 (7) 685-688
  CrossrefPubMedGoogle Scholar
• 31 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 (1) 162-169
  CrossrefPubMedGoogle Scholar
• 32 Cumming A M, Tait R C, Fildes S, Yoong A, Keeney S, Hay C R. Development of resistance to activated protein C during pregnancy.  Br J Haematol. 1995;  90 (3) 725-727
  CrossrefPubMedGoogle Scholar
• 33 Bremme K, Ostlund E, Almqvist I, Heinonen K, Blombäck M. Enhanced thrombin generation and fibrinolytic activity in normal pregnancy and the puerperium.  Obstet Gynecol. 1992;  80 (1) 132-137
  PubMedGoogle Scholar
• 34 Shu H, Wramsby M, Bokarewa M, Blombäck M, Bremme K. Decrease in protein C inhibitor activity and acquired APC resistance during normal pregnancy.  J Thromb Thrombolysis. 2000;  9 (3) 277-281
  CrossrefPubMedGoogle Scholar
• 35 Vandenbroucke J P, Rosendaal F R. End of the line for “third-generation-pill” controversy?.  Lancet. 1997;  349 (9059) 1113-1114
  CrossrefPubMedGoogle Scholar
• 36 Norris L A, Bonnar J. Haemostatic changes and the oral contraceptive pill.  Baillieres Clin Obstet Gynaecol. 1997;  11 (3) 545-564
  CrossrefPubMedGoogle Scholar
• 37 Sabra A, Bonnar J. Hemostatic system changes induced by 50 micrograms and 30 micrograms estrogen/progestogen oral contraceptives. Modification of estrogen effects by levonorgestrel.  J Reprod Med. 1983;  28 ((1, Suppl)) 85-91
  PubMedGoogle Scholar
• 38 Norris L A, Bonnar J. The effect of oestrogen dose and progestogen type on haemostatic changes in women taking low dose oral contraceptives.  Br J Obstet Gynaecol. 1996;  103 (3) 261-267
  PubMedGoogle Scholar
• 39 Kadir R A, Economides D L, Sabin C A, Owens D, Lee C A. Variations in coagulation factors in women: effects of age, ethnicity, menstrual cycle and combined oral contraceptive.  Thromb Haemost. 1999;  82 (5) 1456-1461
  Article in Thieme ConnectPubMedGoogle Scholar
• 40 Vandenbroucke J P, Rosendaal F R. End of the line for “third-generation-pill” controversy?.  Lancet. 1997;  349 (9059) 1113-1114
  CrossrefPubMedGoogle Scholar
• 41 Winkler U H. Hemostatic effects of third- and second-generation oral contraceptives: absence of a causal mechanism for a difference in risk of venous thromboembolism.  Contraception. 2000;  62 ((2, Suppl)) 11S-20S; discussion 37S–38S
  CrossrefPubMedGoogle Scholar
• 42 Rosing J, Middeldorp S, Curvers J et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study.  Lancet. 1999;  354 (9195) 2036-2040
  CrossrefPubMedGoogle Scholar
• 43 Oelkers W, Berger V, Bolik A et al. Dihydrospirorenone, a new progestogen with antimineralocorticoid activity: effects on ovulation, electrolyte excretion, and the renin-aldosterone system in normal women.  J Clin Endocrinol Metab. 1991;  73 (4) 837-842
  CrossrefPubMedGoogle Scholar
• 44 Oelkers W, Foidart J M, Dombrovicz N, Welter A, Heithecker R. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism.  J Clin Endocrinol Metab. 1995;  80 (6) 1816-1821
  CrossrefPubMedGoogle Scholar
• 45 Lidegaard Ø, Løkkegaard E, Svendsen A L, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study.  BMJ. 2009;  339 b2890
  CrossrefPubMedGoogle Scholar
• 46 Seeger J D, Loughlin J, Eng P M, Clifford C R, Cutone J, Walker A M. Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives.  Obstet Gynecol. 2007;  110 (3) 587-593
  CrossrefPubMedGoogle Scholar
• 47 Dinger J C, Heinemann L A, Kühl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation.  Contraception. 2007;  75 (5) 344-354
  CrossrefPubMedGoogle Scholar
• 48 van den Heuvel M W, van Bragt A JM, Alnabawy A KM, Kaptein M CJ. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive.  Contraception. 2005;  72 (3) 168-174
  CrossrefPubMedGoogle Scholar
• 49 Fleischer K, van Vliet H A, Rosendaal F R, Rosing J, Tchaikovski S, Helmerhorst F M. Effects of the contraceptive patch, the vaginal ring and an oral contraceptive on APC resistance and SHBG: a cross-over study.  Thromb Res. 2009;  123 (3) 429-435
  CrossrefPubMedGoogle Scholar
• 50 Jensen J T, Burke A E, Barnhart K T, Tillotson C, Messerle-Forbes M, Peters D. Effects of switching from oral to transdermal or transvaginal contraception on markers of thrombosis.  Contraception. 2008;  78 (6) 451-458
  CrossrefPubMedGoogle Scholar
• 51 Cole J A, Norman H, Doherty M, Walker A M. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users.  Obstet Gynecol. 2007;  109 ((2 Pt 1)) 339-346
  CrossrefPubMedGoogle Scholar
• 52 Jick S, Kaye J A, Li L, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol.  Contraception. 2007;  76 (1) 4-7
  CrossrefPubMedGoogle Scholar
• 53 Shulman L P, Nelson A L, Darney P D. Recent developments in hormone delivery systems.  Am J Obstet Gynecol. 2004;  190 ((4, Suppl)) S39-S48
  CrossrefPubMedGoogle Scholar
• 54 van Vliet H A, Tchaikovski S N, Rosendaal F R, Rosing J, Helmerhorst F M. The effect of the levonorgestrel-releasing intrauterine system on the resistance to activated protein C (APC).  Thromb Haemost. 2009;  101 (4) 691-695
  PubMedGoogle Scholar
• 55 Caine Y G, Bauer K A, Barzegar S et al. Coagulation activation following estrogen administration to postmenopausal women.  Thromb Haemost. 1992;  68 (4) 392-395
  PubMedGoogle Scholar
• 56 Lowe G D, Upton M N, Rumley A, McConnachie A, O’Reilly D S, Watt G C. Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein—a cross-sectional population survey.  Thromb Haemost. 2001;  86 (2) 550-556
  PubMedGoogle Scholar
• 57 Canonico M, Plu-Bureau G, Lowe G DO, Scarabin P Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis.  BMJ. 2008;  336 (7655) 1227-1231
  CrossrefPubMedGoogle Scholar
• 58 Moher D, Cook D J, Eastwood S, Olkin I, Rennie D, Stroup D F. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses.  Lancet. 1999;  354 (9193) 1896-1900
  CrossrefPubMedGoogle Scholar
• 59 Oger E, Alhenc-Gelas M, Lacut K SARAH Investigators et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial.  Arterioscler Thromb Vasc Biol. 2003;  23 (9) 1671-1676
  CrossrefPubMedGoogle Scholar
• 60 Conard J, Samama M, Basdevant A, Guy-Grand B, de Lignières B. Differential AT III-response to oral and parenteral administration of 17 beta-estradiol.  Thromb Haemost. 1983;  49 (3) 252
  PubMedGoogle Scholar
• 61 Scarabin P Y, Oger E, Plu-Bureau G. EStrogen and THromboEmbolism Risk Study Group . Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.  Lancet. 2003;  362 (9382) 428-432
  CrossrefPubMedGoogle Scholar
• 62 Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy.  Lancet. 2002;  360 (9337) 942-944
  CrossrefPubMedGoogle Scholar
• 63 Canonico M, Fournier A, Carcaillon L et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study.  Arterioscler Thromb Vasc Biol. 2010;  30 (2) 136-137
  CrossrefPubMedGoogle Scholar

Rezan A KadirM.D. 

Consultant Obstetrician and Gynaecologist

The Royal Free Hospital, London NW3 2QG, UK

Email: Rezan.abdul-kadir@royalfree.nhs.uk