Download PDF
Thromb Haemost 1998; 80(03): 382-387
DOI: 10.1055/s-0037-1615216
Rapid Communications
Schattauer GmbH

Hemostatic Effects of Oral Contraceptives in Women who Developed Deep-vein Thrombosis while Using Oral Contraceptives

Kitty W. M. Bloemenkamp
1   From the Department of Obstetrics, Gynaecology and Reproductive Medicine (K. W. M. Bloemenkamp, F. M. Helmerhorst), Department of Clinical Epidemiology (T. Koster, F. R. Rosendaal, J. P. Vandenbroucke), Thrombosis and Hemostasis Research Center (F. R. Rosendaal, R. M. Bertina), University Hospital Leiden, Leiden, The Netherlands
,
Frits R. Rosendaal
1   From the Department of Obstetrics, Gynaecology and Reproductive Medicine (K. W. M. Bloemenkamp, F. M. Helmerhorst), Department of Clinical Epidemiology (T. Koster, F. R. Rosendaal, J. P. Vandenbroucke), Thrombosis and Hemostasis Research Center (F. R. Rosendaal, R. M. Bertina), University Hospital Leiden, Leiden, The Netherlands
,
Frans M. Helmerhorst
1   From the Department of Obstetrics, Gynaecology and Reproductive Medicine (K. W. M. Bloemenkamp, F. M. Helmerhorst), Department of Clinical Epidemiology (T. Koster, F. R. Rosendaal, J. P. Vandenbroucke), Thrombosis and Hemostasis Research Center (F. R. Rosendaal, R. M. Bertina), University Hospital Leiden, Leiden, The Netherlands
,
Ted Koster
1   From the Department of Obstetrics, Gynaecology and Reproductive Medicine (K. W. M. Bloemenkamp, F. M. Helmerhorst), Department of Clinical Epidemiology (T. Koster, F. R. Rosendaal, J. P. Vandenbroucke), Thrombosis and Hemostasis Research Center (F. R. Rosendaal, R. M. Bertina), University Hospital Leiden, Leiden, The Netherlands
,
Rogier M. Bertina
1   From the Department of Obstetrics, Gynaecology and Reproductive Medicine (K. W. M. Bloemenkamp, F. M. Helmerhorst), Department of Clinical Epidemiology (T. Koster, F. R. Rosendaal, J. P. Vandenbroucke), Thrombosis and Hemostasis Research Center (F. R. Rosendaal, R. M. Bertina), University Hospital Leiden, Leiden, The Netherlands
,
Jan P. Vandenbroucke
1   From the Department of Obstetrics, Gynaecology and Reproductive Medicine (K. W. M. Bloemenkamp, F. M. Helmerhorst), Department of Clinical Epidemiology (T. Koster, F. R. Rosendaal, J. P. Vandenbroucke), Thrombosis and Hemostasis Research Center (F. R. Rosendaal, R. M. Bertina), University Hospital Leiden, Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 07 July 1997

Accepted after resubmission 13 May 1998

Publication Date:
08 December 2017 (online)

    Permissions and Reprints

Summary

Objective: Comparison of the effect of oral contraceptives on hemostatic variables in venous thrombosis patients (thrombosis while using oral contraceptives) with the effect in healthy control subjects. Our aim was to assess whether some of these effects were more pronounced in women who had suffered thrombosis, i.e., whether these were “hemostatic hyperresponders”. Study Design: A population-based case-control study, the Leiden Thrombophilia Study. Materials and Methods: We investigated 99 pre-menopausal women, age 15-49 years, who had used oral contraceptives at the time of a first, objectively confirmed episode of deep-vein thrombosis. They were not pregnant, nor in puerperium, nor had had a recent miscarriage, and were not using injectable progestogens, nor suffering from inherited coagulation defects. The median time between occurrence of deep-vein thrombosis and venepuncture was 18 months, and 30 of the 99 women were still using oral contraceptives, while 69 had discontinued oral contraceptive use. In addition, a group of 153 control women (54 of them were oral contraceptive users and 99 were non-users) were studied. The following hemostatic variables were measured: APTT, factor VII, factor VIII, factor XII, fibrinogen, prothrombin, total antithrombin, normalised activated protein C sensitivity ratio (n-APC-sr), protein C, protein S and free protein S. Results: We found marked and significant effects of oral contraceptive use on the levels of several clotting factors, with an increase in factor VII, factor XII, protein C and a decrease in antithrombin, n-APC-sr and protein S. Less marked effects that were non-significant or only significant in either patients or controls, were an increase in factor VIII, fibrinogen and prothrombin and a decrease in the APTT and free protein S. In the former thrombosis patients several of these effects of oral contraceptives were more pronounced than in healthy women: specifically on factor VII, antithrombin, n-APC-sr and protein C. Conclusions: Our results of the effects of oral contraceptives generally confirm previous reports in healthy volunteers. Our data also show that in former deep-vein thrombosis patients these effects are more pronounced. Apparently some women become “high hemostatic responders” when exposed to oral contraceptives, and they may be the women most vulnerable to its thrombogenic effects.

 

  • References

  • 1 Jordan WM. Pulmonary embolism. Lancet 1961; 2: 1146-7.
    PubMedGoogle Scholar
  • 2 Inman WHW, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives a report to the committee on safety of drugs. British Medical Journal 1970; 2: 203-9.
    CrossrefPubMedGoogle Scholar
  • 3 Meade TW. Risks and mechanism of cardiovascular events in users of oral contraceptives. Am J Obstet Gynecol 1988; 158: 1646-52.
    CrossrefPubMedGoogle Scholar
  • 4 Gerstman BB, Piper JM, Tomita DK, Frerguson WJ, Stadel BV, Lundin FE. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. American Journal of Epidemiology 1991; 133: 32-7.
    CrossrefPubMedGoogle Scholar
  • 5 Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Evidence that currently available pills are associated with cardiovascular disease: venous disease. In: Hannaford PC, Webb AMC. Evidence-guided Prescribing of the Pill. 1996: 61-76 (Carnforth, UK: Parthenon Publishing).
    PubMedGoogle Scholar
  • 6 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.. Venous thromboembolic disease and combined oral contraceptives: Results of international multicentre case-control study. Lancet 1995; 346: 1575-82.
    CrossrefPubMedGoogle Scholar
  • 7 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346: 1582-8.
    CrossrefPubMedGoogle Scholar
  • 8 Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589-93.
    CrossrefPubMedGoogle Scholar
  • 9 Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing third-generation progestagen. Lancet 1995; 346: 1593-6.
    CrossrefPubMedGoogle Scholar
  • 10 Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M. MacRae KD on behalf of Transnational Research Group on Oral Contraceptives and the Health of Young women.. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996; 312: 83-8.
    CrossrefPubMedGoogle Scholar
  • 11 Thomas DP. Pathogenesis of venous thrombosis. In: Haemostasis and Thrombosis, 3rd edition. Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. (eds). New York:: Churchill-Livingstone; 1994. pp. 1335-47.
    Google Scholar
  • 12 Goldhaber SZ. Epidemiology of pulmonary embolism and deep venous thrombosis. In: Haemostasis and Thrombosis. 3rd edition. Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. (eds). New York:: Churchill-Livingstone; 1994. pp. 1327-33.
    Google Scholar
  • 13 Fotherby K, Caldwell ADS. New progestogens in oral contraception. Contraception 1994; 49: 1-32.
    CrossrefPubMedGoogle Scholar
  • 14 Robinson GE. Low-dose combined oral contraceptives. British J Obstet and Gynaecol 1994; 101: 1036-42.
    PubMedGoogle Scholar
  • 15 Beller FK, Ebert C. Effects of oral contraceptives on blood coagulation. A review. Obstetrical and Gynecological Survey 1985; 40: 425-36.
    CrossrefPubMedGoogle Scholar
  • 16 Kluft C, Lansink M. Effect of oral contraceptives on haemostasis variables. Thromb Haemost 1997; 78: 315-26.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Mammen EF. Oral contraceptives and blood coagulation: a critical review. Am J Obstet Gynecol 1982; 142: 781-90.
    CrossrefPubMedGoogle Scholar
  • 18 Meade TW. Oral contraceptives, clotting factors, and thrombosis. Am J Obstet Gynecol 1982; 142: 758-61.
    CrossrefPubMedGoogle Scholar
  • 19 Wessler S. Estrogen-associated thromboembolism. Ann Epidemiol 1992; 2: 439-43.
    CrossrefPubMedGoogle Scholar
  • 20 Bertina RM, Koeleman RPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
    CrossrefPubMedGoogle Scholar
  • 21 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance) [see comments]. Blood 1995; 85: 1504-8.
    PubMedGoogle Scholar
  • 22 Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Inceased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 334: 1453-7386.
    PubMedGoogle Scholar
  • 23 Bick RL, Pegram M. Syndromes of hypercoagulability and Thrombosis: a review. Seminars in Thrombosis and Hemostasis 1994; 20 (01) 109-32.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Girolami A, Simioni P, Girolami B, Zanardi S. The role of drugs, paticularly oral contraceptives, in triggering thrombosis in congenital defects of coagulation inhibitors: a study of six patients. Blood Coagulation and Fibrinolysis 1991; 2: 673-8.
    CrossrefPubMedGoogle Scholar
  • 25 Girolami A, Simioni P, Sartori MT, Zanardi S. Oral contraceptives caused thrombosis in a monoovular twin with protein C deficiency, while the other, without medication, remained asymptomatic [letter]. Blood Coagul Fibrinolysis 1992; 3: 119-20.
    CrossrefPubMedGoogle Scholar
  • 26 Pabinger I, Schneider B. Thrombotic risk of women with hereditary anti-thrombin III-, protein C- and protein S-deficiency taking oral contraceptive medication. The GTH Study Group on Natural Inhibitors. Thromb Haemost 1994; 71: 548-52.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Alving BM, Comp PC. Recent advances in understanding clotting and evaluating patients with recurrent thrombosis. Am J Obstet Gynecol 1992; 167: 1184-91.
    CrossrefPubMedGoogle Scholar
  • 28 Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-6.
    CrossrefPubMedGoogle Scholar
  • 29 Koster T, Rosendaal FR, Briët E, Van der Meer FJM, Colly LP, Trienekens PH, Poort SR, Vandenbroucke JP. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995; 85: 2756-61.
    PubMedGoogle Scholar
  • 30 Koster T, Rosendaal FR, Reitsma PH, Van der Velden PA, Briët E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms, Leiden thrombophilia Study. Thromb Haemost 1994; 71: 719-22.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-5.
    CrossrefPubMedGoogle Scholar
  • 32 Koster T, Rosendaal FR, Briët E, Vandenbroucke JP. John Hageman’s factor and deep-vein thrombosis: Leiden thrombophilia Study. Br J Haematol 1994; 87: 422-4.
    CrossrefPubMedGoogle Scholar
  • 33 De Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the devlopment of diagnostic criteria. Thromb Haemost 1994; 72: 880-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Quehenberger P, Loner U, Kapiotis S, Handler S, Schneider B, Huber J, Speiser W. Increased levels of activated factor VII and decreased plasma protein S activity and circulating thrombomodulin during use of oral contraceptives. Thromb Haemost 1996; 76 (05) 729-34.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Basdevant A, Conard J, Pelissier C, Guyene TT, Lapousterle C, Mayer M, Gran BG, Degrelle H. Hemostatic and metabolic effects of lowering the ethinyl-estradiol dose from 30 μg to 20 μg in oral contraceptives containing desogestrel. Contraception 1993; 48: 193-204.
    CrossrefPubMedGoogle Scholar
  • 36 Melissari E, Kakkar VV. The effects of oestrogenadministration on the plasma free protein S and C4-b-binding protein. Thromb Res 1988; 49: 489-95.
    CrossrefPubMedGoogle Scholar
  • 37 Beller FK, Ebert CH. The coagulation and fibrinolytic system in pregnancy and in the puerperium. Eur J Obstet Gynecol Reprod Biol 1982; 13: 177-97.
    CrossrefPubMedGoogle Scholar
  • 38 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briët E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341: 134-8.
    CrossrefPubMedGoogle Scholar
  • 39 Winkler UH, Schindler AE, Endrikat J, Dusterberg B. A comparative study of the effects of the hemostatic system of two monophasic gestodene oral contraceptives containing 20 μg and 30 μg ethinylestradiol. Contraception 1996; 53: 75-84.
    CrossrefPubMedGoogle Scholar
  • 40 Petersen KR, Sidelmann J, Skouby SO, Jespersen J. Effects of monophasic low-dose oral contraceptives on fibrin formation and resolution in young women. Am J Obstet Gynecol 1993; 168: 32-8.
    CrossrefPubMedGoogle Scholar
  • 41 Jespersen J, Petersen KR, Skouby SO. Effects of newer oral contraceptives on the inhibition of coagulation and fibrinolysis in relation to dosage and type of steroid. Am J Obstet Gynecol 1990; 163: 396-403.
    CrossrefPubMedGoogle Scholar
  • 42 Cachrimanidou A-C, Hellberg D, Nilsson S, von Schoulz B, Crona N, Siegbahn A. Hemostasis profile and lipid metabolism with long-interval use of a desogestrel-containing oral contraceptive. Contraception 1994; 50: 153-65.
    CrossrefPubMedGoogle Scholar
  • 43 Henkens CMA, Bom VJJ, Seinen AJ, Meer van der J.. Sensitivity to activated protein C; Influence of oral contraceptoives and sex. Thromb Haemost 1995; 73 (03) 402-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Østerud B, Robertsen R, Åsvang GB, Thijssen F. Resistance to activated protein C is reduced in women using oral contraceptives. Blood Coagul and Fibrinolysis 1994; 5: 853-4.
    PubMedGoogle Scholar
  • 45 Olivieri O, Friso S, Manzato F, Guella A, Bernardi F, Lunghi B. et al. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995; 91: 465-70.
    CrossrefPubMedGoogle Scholar
  • 46 Bokarewa MI, Falk G, Sten-Linder M, Egberg N, Blomback M, Bremme K. Thrombotic risk factors and oral contraception. J Lab Clin Med 1995; 126: 294-8.
    PubMedGoogle Scholar
  • 47 Rosing J, Tans G, Nicolaes GAF. et al. Oral contraceptives and venous thrombosis; different sensitivities to activated protein C in women using second- and third generation oral contraceptives. Br J Haematol 1997; 97: 233-38.
    CrossrefPubMedGoogle Scholar