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.
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.
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
is the risk of developing a clot amplified in patients taking oral
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
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
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
- Jordan WM. Pulmonary embolism. Lancet 1961;278(7212):1146-7.
PE, Masi AT, Arthes FG et al. Thromboembolism and oral contraceptives:
an epidemiologic case-control study. Am J Epidemiol 1969;90:365-80.
MP, Doll R. Investigation of relation between use of oral
contraceptives and thromboembolic disease. A further report. Br Med J
- Drill VA. Oral contraceptives and thromboembolic disease. I. prospective and retrospective studies. JAMA 1972;219:583-92.
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.
BB, Piper JM, Tomita DK et al. Oral contraceptive estrogen dose and
the risk of deep vein thromboembolic disease. Am J Epidemiol
I, Battaglioli T, Mannucci PM. Pharmacogenetic aspects of the use of
oral contraceptives and the risk of thrombosis. Pharmacogenetics
- Martinelli I. Risk factors in venous thromboembolism. Thromb Haemost 2001;86:395-403.
- Hannaford P. Health consequences of combined oral contraceptives. Br Med Bull 2000;56:749-60.
JH, Evatt B, Zimmerman TS et al. Deficiency of protein C in congenital
thrombotic disease. J Clin Invest 1981;68:1370-3.
HP, Fischer M, Hopmeier P et al. Plasma protein S deficiency in
familial thrombotic disease. Blood 1984;64:1297-300.
U, Berger A, Abend M et al. Homozygous protein C deficiency manifested
by massive venous thrombosis in the newborn. N Engl J Med
RM, Koeleman BP, Koster T et al. Mutation in blood coagulation factor V
associated with resistance to activated protein C. Nature
JP, Koster T, Briet E et al. Increased risk of venous thrombosis in
oral-containing users who are carriers of factor V Leiden mutation.
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.
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.
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
- Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995;346:1133-4.
- Lucotte G, Mercier G. Population genetics of factor V Leiden in Europe. Blood Cells Mol Dis 2001;27:362-7.
- Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;330:517-22.
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.
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.
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.
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
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.
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.