Traditional attempts to identify an underlying cause of familial thrombosis by testing for
antithrombin III, protein C, and protein S have only rarely provided an explanation for a
patient's thrombotic event. Recently, studies have clearly shown that a mutation of
clotting factor V is highly associated with thrombosis and may account for as much as 25%
of all cases of venous thrombosis of unknown cause. In addition, knowledge that a patient
carries this gene may have significant clinical implications.
The factor V mutation, named factor V Leiden after the site of its
discovery, is due to a point mutation in the normal factor V molecule. This mutation
renders the factor V molecule insensitive to the action of activated protein C, a natural
anticoagulant. This in turn appears to shift the patient's overall hemostatic balance
toward thrombosis, especially venous thrombosis.
The incidence of the factor V Leiden mutation in both European and
American populations has been repeatedly found to be surprisingly high. The best evidence
from the United States indicates that 6% of the population carries the gene for the factor
V mutation. The reason for its persistence at such a high level is unclear.
Recent studies indicate that a person heterozygous for the factor V
Leiden mutation has a risk of thrombosis seven times that of the general population. The
homozygous state confers a 79 fold increased risk compared to a control population. Of
particular importance is a study from the United Kingdom indicating that women with the
mutation who take oral contraceptives have a risk of thrombosis which is 35 times greater
than the general population. This has prompted a concern that women who are considering
the use of oral contraceptives might need to be screened for the mutation beforehand.
Initially, a screening test for the mutation called the activated
protein C (APC) resistance test was described. This modification of the activated partial
thromboplastin time (APTT) basically evaluates the ability of a thrombotic patient to
mount an anticoagulant response to activated protein C. If the APC resistance screening
test is positive, confirmatory testing for the factor V Leiden mutation by a polymerase
chain reaction (PCR) test is recommended.
Published reports and our experience indicate that positive APC
resistance test results may be seen in patients with systemic lupus, lupus anticoagulants,
protein S deficiency, patients who are taking estrogens or oral contraceptives, and those
who are pregnant, without having the factor V mutation present. In addition, heparinized
patients cannot be tested for APC resistance. Patients taking oral anticoagulants
(Coumadin) may be tested for APC resistance using a special procedure but the laboratory
needs to be notified in advance and the results may be less reliable. In contrast the PCR
test for the mutation is done on white blood cells and is not affected by any of the
aforementioned clinical situations and provides a definitive answer albeit at a slightly
higher cost. Therefore, we sometimes recommend testing directly for the mutation in
clinical situations where the APC resistance test is not practical.
Adult patients diagnosed with the factor V mutation who have had a
venous thrombosis are currently advised to take lifelong Coumadin. In addition,
post-operative prophylaxis should be mandatory for any surgical procedures. Women who have
the mutation should not take oral contraceptives, and should be counseled with regard to
the increased risk of thrombosis during pregnancy. Lastly, testing of family members
should be undertaken when a relative is found to have the mutation.
The newly described factor V Leiden mutation represents a major advance
in the ability to diagnose and counsel patients with thrombosis. It is extremely common,
affective 6% of the U.S. population and may account for a large proportion of patients
with previously unrecognized causes of thrombosis.
Dahlback B: Inherited Thrombophilia: Resistance to Activated Protein C
as a Pathogenic Factor of Venous Thromboembolism. Blood 85:606-614, 1995.
Ridker PM, Hennekens CH, Lindpainter K, Stampfer MJ, Eisenberg PR,
Miletich JP: Mutation in the gene coding for coagulation factor V and the risk of
myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Eng J
Med 332:912-7, 1995.
For further information regarding the factor V mutation
Bontempo at 412-622-7310
Dr. Cortese-Hassett at 412-622-7336.