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.
KEYWORDS
Female sex hormones - hemostasis - thrombosis - pregnancy - contraception
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
-
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
-
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
-
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
-
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
-
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
-
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
-
8
Lethagen S.
Desmopressin in the treatment of women’s bleeding disorders.
Haemophilia.
1999;
5
(4)
233-237
-
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
-
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
-
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
-
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
-
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
-
14
van Rooijen M, Silveira A, Thomassen S et al.
APC resistance during the normal menstrual cycle.
Thromb Haemost.
2007;
98
(6)
1246-1251
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
23
Kadir R A, Chi C, Bolton-Maggs P.
Pregnancy and rare bleeding disorders.
Haemophilia.
2009;
15
(5)
990-1005
-
24
Uchikova E H, Ledjev I I.
Changes in haemostasis during normal pregnancy.
Eur J Obstet Gynecol Reprod Biol.
2005;
119
(2)
185-188
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
35
Vandenbroucke J P, Rosendaal F R.
End of the line for “third-generation-pill” controversy?.
Lancet.
1997;
349
(9059)
1113-1114
-
36
Norris L A, Bonnar J.
Haemostatic changes and the oral contraceptive pill.
Baillieres Clin Obstet Gynaecol.
1997;
11
(3)
545-564
-
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
-
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
-
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
-
40
Vandenbroucke J P, Rosendaal F R.
End of the line for “third-generation-pill” controversy?.
Lancet.
1997;
349
(9059)
1113-1114
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
Rezan A KadirM.D.
Consultant Obstetrician and Gynaecologist
The Royal Free Hospital, London NW3 2QG, UK
eMail: Rezan.abdul-kadir@royalfree.nhs.uk
