The use of combined oral contraceptives (containing estrogen and progesterone) is common across the world.  Unfortunately, their use has resulted in considerable adverse drug events that have caused much debate about their safety in the general population.  One such adverse drug event that dates back to the early 1960's is the development of venous thromboembolism (VTE), which includes both deep vein thrombosis (DVT) and pulmonary embolism (PE).1-7  It has been estimated that the annual incidence of venous thromboembolism (VTE) in women of child bearing age who are not taking oral contraceptives is 1 in 10,000.8  The incidence is increased 3-5 fold when women of child bearing age use estrogen containing oral contraceptives.9  This risk is even greater in patients taking higher doses of estrogen, those with an underlying hypercoaguable disorder, such as factor V Leiden, and in patients taking third generation oral contraceptives containing desogestrel, gestodene, or norgestimate.2-7,9-17  

How do estrogen containing oral contraceptives increase the risk for VTE?
Estrogen containing oral contraceptives increase the plasma concentrations of clotting factors II, VII, X, XII, factor VIII, fibrinogen, and thrombin activatable fibrinolysis inhibitor (TAFI) (see figure 1).13,17-19  However, not all of the increases in clotting factors are of the same magnitude.  Factor VII appears to have the greatest magnitude of increase and factor VIII the least magnitude of increase, comparatively.13,17  As it relates to the magnitude of increase in factor VII concentrations, it appears that desogestrel containing oral contraceptives confer the greatest impact (26-32% increase) when compared to a second generation oral contraceptive containing levonorgestrel (9-12% increase).13,17  All of these effects shift the balance towards thrombus formation and prevention of clot breakdown.  There is also an effect that favors reduced clot formation.  There is a small decrease in factor V, which is necessary for the activation of prothrombin (II) to thrombin (IIa).13,17  While a decrease in factor V may appear to be beneficial, factor V actually works synergistically with protein S to inhibit factor VIII; thus, the potential reduction in risk of thrombus that may have been realized by a reduction in factor V levels is effectively negated.20,21  Therefore, the overall effect on the coagulation system is a shift in favor of clot formation and prevention of clot dissolution.  

How does estrogen increase clotting factors and other components that result in a net increase in the risk for clot formation?
Estrogen, like many lipophilic hormones, affects the gene transcription of various proteins.  Thus, estrogen increases plasma concentrations of these clotting factors by increasing gene transcription.  While the exact mechanism is complicated and not entirely known, estrogen crosses the cell membrane for a particular target tissue, which there are many that estrogen influence, and once inside the cytoplasm binds to nuclear receptors (i.e., estrogen receptors).20-22  The estrogen/nuclear receptor complex then travels into the nucleus where it recognizes and binds to specific recognition sites, called hormone response elements or in this case, "estrogen response elements".22-24  This binding then turns on gene transcription by allowing RNA polymerase II to transcribe the protein in that region of the DNA.22-24  In this case, these new proteins are the clotting factors and proteins described above.  However, just as the estrogen/nuclear receptor complex can turn on gene transcription, they can also have the opposite effect and repress gene transcription, which may be the reason for the reductions in factor V concentrations.  The degree of influence that estrogen has on gene transcription is unfortunately more complex and not limited to nuclear receptor binding to DNA.  Estrogen bound to nuclear receptors (estrogen receptors) also regulates gene expression through protein-protein interaction with other transcription factors.  Again, this effect on gene expression can result in increased or decreased gene expression.  Also, estrogen receptors influence intracellular signaling pathways, such as MAPK and IP3 kinase pathways, that may also influence overall gene expression.22  As stated earlier, higher doses of estrogen appear to confer a greater risk of venous thrombus formation.  This can be explained by a greater degree of nuclear receptor binding and overall activation of gene transcription for these clotting factors.  

To our knowledge this has not been fully determined, but there are data supporting the hypothesis that desogestrel containing oral contraceptives cause a greater increase in plasma concentrations of factor VII when compared to a second generation contraceptive that contains levonorgestrel.17  This would further tip the balance of the coagulation cascade in the direction of enhanced clot formation.  Therefore, it is likely that a combination of all of these intracellular reactions brought about by estrogen and the type of progesterone used influence gene expression and excess production of clotting factors.

References:

1. Jordan WM.  Pulmonary embolism.  Lancet  1961;278:1146-7. 
2. Sartwell PE, Masi AT, Arthes FG et al.  Thromboembolism and oral contraceptives: an epidemiologic case-control study.  Am J Epidemiol  1969;90:365-80.  
   
3. Vessey MP, Doll R.  Investigation of relation between use of oral contraceptives and thromboembolic disease.  A further report.  Br Med J  1969;2:651-7.  
4. Drill VA.  Oral contraceptives and thromboembolic disease. I. prospective and retrospective studies.  JAMA 1972;219:583-92.  
5. Vessey M, Mant D, Smith A et al.  Oral contraceptives and venous thromboembolism: findings in a large prospective study.  Br Med J (Clin Red Ed) 1986;292:526.  
6. Gerstman BB, Piper JM, Tomita DK et al.  Oral contraceptive estrogen dose and the risk of deep vein thromboembolic disease.  Am J Epidemiol  1991;133:32-7.  
7. Martinelli I, Battaglioli T, Mannucci PM.  Pharmacogenetic aspects of the use of oral contraceptives and the risk of thrombosis.  Pharamcogenetics 2003;13:589-94.  
8. Martinelli I.  Risk factors in venous thromboembolism.  Thromb Haemost  2001;86:395-403.  
9. Hannaford P.  Health consequences of combined oral contraceptives.  Br Med Bull  2000;56:749-60.  
10. Vandenbroucke JP, Koster T, Briet E et al.  Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation.  Lancet  1994;344:1453-7.  
11. Spannagl M, Heinemann LA, Schramm W.  Are factor V Leiden carriers who use oral contraceptives at extreme risk for venous thromboembolism?  Eur J Contracept Reprod Health Care  2000;5:105-12.  
12. Hannaford P.  Cardiovascular events associated with different combined oral contraceptives: a review of current data.  Drug Saf  2000;22:361-71.  
13. Kemmeren JM, Algra A, Meijers JC et al.  Effects of second and third generation oral contraceptives and their respective progestagens on the coagulation system in the absence or presence of the factor V Leiden mutation.  Thromb Haemost  2002;87:199-205.  
14. WHO Scientific Group on Cardiovascular Disease and Steroid Hormone Contraception.  Cardiovascular Disease and Steroid Hormone Contraception: Report of a WHO Scientific Group.  WHO Technical Report Series, 877. Geneva, Switzerland: WHO, 1998.
15. Jick H, Jick SS, Gurewich V et al.  Risk of idiopathic death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components.  Lancet  1995;346:1589-93.                                                          
    
16. Lewis MA, Spitzer WO, Heinemann LA et al.  Third generation oral contraception and risk of myocardial infarction: an international case-control study.  Transnational Research Group on Oral Contraceptives and the Health of Young Women.  BMJ  1996;312:88-90.  
    
17. Middeldorp S, Meijers JC, van den Ende AE et al.  Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross over-study.  Thromb Haemost  2000;84:4-8.  
18. Gordon EM, Johnson TR, Ramos LP et al.  Enhanced expression of factor XII (Hageman factor) in isolated livers of estrogen- and prolactin-treated rats.  J Lab Clin Med  1991;117:353-8.  
19. Meijers JC, Middeldrop S, Tekelenburg W et al.  Increased fibrinolytic activity during use of oral contraceptives is counteracted by an enhanced factor XI-independent down regulation of fibrinolysis: a randomized cross-over study of two low-dose oral contraceptives.  Thromb Haemost  2000;84:9-14.  
20. Shen L, Dahlback B.  Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa.  J Biol Chem  1994;269:18735-8.  
21. Shen L, He X, Dahlback B.  Synergistic cofactor function of factor V and protein S to activated protein C in the inactivation of the cofactor VIIIa-factor IXa complex - species specific interactions of components of the protein C anticoagulant system.  Thromb Haemost  1997;78:1030-6.  
22. Nilsson S, Makela S, Treuter E et al.  Mechanisms of estrogen action.  Physiol Rev  2001;81:1535-65.  
23. Robinson-Rechavi M, Escriva Garcia H, Laudet V.  The nuclear receptor superfamily.  J Cell Sci  2003;116:585-6.  
24. Kishimoto M, Fujiki R, Takezawa S et al.  Nuclear receptor mediated gene regulation through chromatin remodeling and histone modifications.  Endocr J  2006;53:157-72.

• EBM Focused Topic: The PERC Rule for the Bedside Assessment of Pulmonary Embolism
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• Drug Monograph: Dalteparin (Fragmin)
  

Oral Contraceptives, Birth Control Pill, Venous Thromboembolism, VTE, Deep Vein Thrombosis, DVT, Estrogen Induced Clot Formation, Factor V Leiden