The first case report of clot formation or venous thromboembolism (VTE) attributed to the use of oral contraceptives (birth control pills) occurred in 1961.1  This female suffered a pulmonary embolism shortly after starting the oral contraceptives.  Since this inciting event, considerable debate has continued regarding the absolute risk of developing a symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE) as a result of taking various formulations of oral contraceptives.2-9  Consequently, there has been significant research done to determine which factors contribute to the development of VTE in patients taking oral contraceptives. 

With research and additional clinical experience, a number of risk factors for the development of VTE have emerged.  These include the type of estrogen containing oral contraceptive being used, the dose of estrogen, smoking, age of the patient, past history of VTE, surgery, major trauma, pregnancy, malignancy and prolonged immobilization.5,6,8  In addition, a number of genetic risk factors have been identified.  The most common genetic risk factors for developing VTE include antithrombin, protein C and S deficiency, factor V Leiden, and prothrombin 20210A mutation.7,10-17  The focus of this newsletter will be how does having factor V Leiden significantly increase the risk for VTE.

Factor V Leiden is now a well known genetic variation in the population.  Its frequency is highest in people of Caucasian descent and is present in 2-15% of the general population and up to 50% of patients with VTE.18-20  The genetic variation or polymorphism (G1691A or R506Q) is from a single nucleotide substitution at position 1691 where a guanine (G) is substituted for an adenine (A).8  This type of nucleotide substitution results in a missense mutation.  This single change in the nucleotide sequence (or missense mutation) causes a change in the amino acid placed at position 506 on the protein molecule; the amino acid changes from an arginine (R; Arg) to a glutamine (Q; Gln), thus the reason the polymorphism is identified as R506Q.8  This single change in an amino acid can alter the activity and binding characteristics of factor V because at normal pH (7.35-7.45), Gln is not charged however Arg is positively charged.  In fact, this is one of the sites where activated protein C cleaves factor V to inactivate it, but now it can't because of this change.  Thus, the mutated protein structure of factor V is now less responsive to the inhibitory action of activated protein C.  This allows factor V to continue to be available for use in the propagation and formation of a clot.7,8,14,15  

Why is the risk of developing a clot amplified in patients taking oral contraceptives?    
As just mentioned, the resistance to activated protein C inhibition allows factor V to facilitate clot formation.  This shift towards favoring clot formation is exaggerated by estrogen containing oral contraceptives as they are known to increase the concentrations of clotting factors.21-23   While oral contraceptives can decrease factor V levels, this reduction is not significant enough to offset the increase in factors II, VII, VIII, XI and thrombin activatable fibrinolysis inhibitor (TAFI) activity.  Oral contraceptives, especially those containing desogestrel, shift the coagulation system in favor of clot formation and prevention of clot dissolution.21-23   

How significant is this increased risk for clot formation?   
The estimated relative risk for developing VTE in patients with factor V Leiden who are also taking oral contraceptives has been reported to be 10-30 fold greater in heterozygous patients and up to 80-100 fold greater in patients who are homozygous for the mutation.25  The risk also appears to be even greater when using third generation oral contraceptives specifically (i.e., oral contraceptives that contain desogestrel, gestodene, or norgestimate as the progestin).  In addition to the traditional complications DVT and PE, patients with factor V Leiden who use oral contraceptives are at a 20-fold greater risk for developing cerebral vein thrombosis.26

As a result of the substantial increase in relative risk of VTE and cerebral vein thrombosis in patients homozygous for factor V Leiden, some have suggested that genetic testing may be useful in preventing VTE.  Unfortunately, such an immense effort to screen the general population may not be cost-effective since the absolute risk is much lower.14,25   To date, we are not aware of any recommendations for screening the general population for genetic polymorphisms prior to initiating oral contraceptives in female patients.

References:

1. Jordan WM.  Pulmonary embolism.  Lancet  1961;278(7212):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;14:651-7.  
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.  Pharmacogenetics 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. Griffin JH, Evatt B, Zimmerman TS et al.  Deficiency of protein C in congenital thrombotic disease.  J Clin Invest  1981;68:1370-3.  
11. Schwarz HP, Fischer M, Hopmeier P et al.  Plasma protein S deficiency in familial thrombotic disease.  Blood  1984;64:1297-300.  
12. Seligsohn U, Berger A, Abend M et al.  Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn.  N Engl J Med  1984;310:559-62.  
13. Bertina RM, Koeleman BP, Koster T et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature  1994;369:64-7.  
14. Vandenbroucke JP, Koster T, Briet E et al.  Increased risk of venous thrombosis in oral-containing users who are carriers of factor V Leiden mutation.  Lancet  1994;344:1453-7.  
15. 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.  
16. Poort SR, Rosendaal FR, Reitsma PH et al.  A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.  Blood  1996;88:3698-703.  
17. Brown K, Luddington R, Williamson D et al.  Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3'-untranslated region of the prothrombin gene.  Br J Haematol  1997;98:907-9.  
18. Rees DC, Cox M, Clegg JB.  World distribution of factor V Leiden.  Lancet 1995;346:1133-4.  
19. Lucotte G, Mercier G.  Population genetics of factor V Leiden in Europe.  Blood Cells Mol Dis  2001;27:362-7.  
20. Svensson PJ, Dahlback B.  Resistance to activated protein C as a basis for venous thrombosis.  N Engl J Med  1994;330:517-22.  
21. 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.  
22. 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.  
23. 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.  
24. Meijers JC, Middeldrop S, Tekelenburg W et al.  Increased fibrinolytic activity during use of oral contraceptives is counter acted by an enhanced factor XI-independent down regulation of fibrinolysis: a randomized cross-over study if two low-dose oral contraceptives.  Thromb Haemost  2000;84:9-14.  
25. Rosendaal FR, Koster T, Vandenbroucke JP et al.  Hihg risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).  Blood  1995;85:1504-8.  
26. Martinelli I, Sacchi E, Landi G et al.  High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.  N Engl J Med  1998;338:1793-7.

• Pharmacology: The Mechanism of Estrogen Induced Risk for Thrombus Formation
  

Oral Contraceptives, Birth Control Pills, Venous Thromboembolism, VTE, DVT, Deep Vein Thrombosis, Pulmonary Embolism, Factor V Leiden