Factor V Leiden

Factor V Leiden is a genetically acquired trait that can result in a thrombophilic

(hypercoaguable) state resulting in the phenomenon of activated protein C resistance
(APCR) as described below. Associated with factor V Leiden, APCR was first described
in 1993; factor V Leiden was subsequently discovered in 1994. Over 95% of patients
with APCR have factor V Leiden. Factor V Leidens overall impact on the coagulation
cascade described below.
Mechanism of Action of Factor V Leiden:
Factor V Leiden is characterized by a phenomenon called APCR where a genetic
mutation in the factor V gene causes a change in the factor V protein making it resistant
to inactivation by protein C.
A detailed description of the clotting process is found on the clotting information web
page. The function of protein C is to inactivate factor Va and factor VIIIa (the a denotes
the active form). The first step in this process is the activation of thrombomodulin by
thrombin. Subsequently, protein C combines with thrombomodulin in order to produce
activated Protein C (see Figure 1). Activated protein C then combines with protein S on
the surface of a platelet (platelets are the clotting cells that circulate in the blood and
provide phospholipids to support that clotting process). Activated protein C can then
degrade factor Va and factor VIIIa (see Figure 2). When one has factor V Leiden, the
factor Va is resistant to the normal effects of activated protein C, thus the term activated
protein C resistance. The result is that factor V Leiden is not inactivated by activated
protein C at a much slower rate (see Figure 3), thus leading to a thrombophilic
(propensity to clot) state by having increased activity of factor Va in the blood.
Epidemiology of Factor V Leiden:
In discussing any genetic mutation, including factor V Leiden, it is necessary to
understand what is meant by the terms heterozygous and homozygous. To illustrate this,
we will discuss the protein factor V. Normally, one has 2 copies of factor V that are
normal (factor V/factor V). When one is heterozygous for factor V Leiden, one copy is
normal and the other has the factor V Leiden mutation (factor V/factor V Leiden). When
one is homozygous for factor V Leiden, then both copies have the mutation (factor V
Leiden/factor V Leiden).
Factor V Leiden is seen more commonly in the northern European populations. About 4-
7% of the general population is heterozygous for factor V Leiden. About 0.06 to 0.25%
of the population is homozygous for factor V Leiden. The factor V Leiden mutation is
relatively uncommon in the native populations of Asia, Africa and North America. In
contrast, in Greece and southern Sweden, rates above 10% have been reported.
Risks of Factor V Leiden:
The overall estimated incidence of deep venous thrombosis is 1 episode for every 1000
persons. This figure does not separate patients who had predisposing conditions from
those who do not.
At this time, the data available do not suggest any role between factor V Leiden and
arterial thrombosis (stroke, heart attack).
The role of factor V Leiden and venous thromboembolic disease is shown in the table
below. The table shows the increase in risk compared with a patient without a known
thrombophilic state.
Thrombophilic Status Relative Risk of Venous
Thrombosis
Normal 1
Oral contraceptive (birth control pill) use in a
patient with otherwise normal clotting
system
4
Factor V Leiden, heterozygous 5-7
Factor V Leiden, heterozygous combined
with oral contraceptive use.
30-35
Factor V Leiden, homozygous 80
Factor V Leiden, homozygous combined
with oral contraceptive use.
??? >100
Prothrombin Gene Mutation, heterozygous 3
Prothrombin Gene Mutation, homozygous ??? Also possible risk of
arterial thrombosis
Prothrombin Gene Mutation, heterozygous
combined with oral contraceptive use.
16
Protein C deficiency, heterozygous 7
Protein C deficiency, homozygous Severe thrombosis at birth
Protein S deficiency, heterozygous 6
Protein S deficiency, homozygous Severe thrombosis at birth
Antithrombin deficiency, heterozygous 5
Antithrombin deficiency, homozygous Thought to be lethal prior to
birth
Hyperhomocysteinemia 2-4
Hyperhomocysteinemia combined with
Factor V Leiden, heterozygous
20
Treatment of Factor V Leiden:
Treatment of a patient with factor V Leiden depends upon the individual patients risk of
recurrent thromboembolic disease. When one has a venous clot, regardless of what
thrombophilic state(s) one may have, that person will receive anticoagulation. This is
accomplished by several different medications: 1) heparin, 2) warfarin and 3) low-
molecular-weight heparins. These medications are generally used for 3-6 months.
Further continuation is generally not indicated in factor V Leiden heterozygotes after a
single thromboembolic episode given the risk of bleeding associated with
anticoagulation. Patients that have had multiple thromboembolic episodes or are at high
risk of further episodes (for example, multiple deficiencies or factor V Leiden
homozygotes) are likely started on long-term anticoagulation.
The use of long-term anticoagulation has risks associated with it (approximately a 3%
chance per year of having a major hemorrhage, of which approximately 1/5 are fatal).
Beginning long-term anticoagulation is influenced by the patients overall risk of
recurrent thrombosis balanced against the risks associated with long-term anticoagulation
on an individual basis.
Further Information:
For further information on the other thrombophilic states, please refer to their respective
pages. Brief information on the various medications that are discussed above and are
regularly used to treat clotting disorders is discussed on the medication pages. A
selection of the references used to compile this information is listed on the references
page.