Factor V Leiden Thrombophilia
Factor V Leiden (FVL) thrombophilia (OMIM 188055) is the most common form of
inherited thrombophilia. Coagulation of blood is a very important function that is finely
tuned by several proteins that work in concert to regulate the balance between clotting
and bleeding. Clotting is necessary to repair minute breaks in blood vessels that
regularly occur. If coagulation is disregulated, then breeches in blood vessels may not
be repaired leading to hemorrhages. Conversely, hypercoagulation may cause a clot or
“thrombus” to develop and block blood flow through a blood vessel.
How does Factor V affect blood clotting?
Coagulation Factor V is important in promoting coagulation. Factor V is normally
inactivated by another protein, activated protein C , or aPC, which cleaves Factor V
protein at a specific site, thereby inactivating it. This slows or stops clotting (i.e
anticoagulation). However, the FVL mutation destroys that cleavage site in the protein,
preventing its inactivation by aPC. The active FVL persists and causes poor
anticoagulation leading to increased clotting and, therefore, an increased risk of venous
thromboembolism (VTE).
What are some of the warning signs of FVL thrombosis?
There are no clinical symptoms that are specific for FV Leiden thrombophilia. However,
there are several signs that are suggestive of this disorder [Kujovitch et al 2010]:
 A first VTE before age 50
 A first unprovoked VTE at any age
 A history of recurrent VTE
 Venous thrombosis at unusual sites (Cerebral, mesenteric, portal and hepatic
veins)
 VTE associated with use of OC or HRT
 VTE during pregnancy or the puerperium
 Women with unexplained fetal loss after 10 weeks’ gestation
 A first VTE in an individual with a first-degree family member with VTE before
age 50
Genetics of Factor V Leiden Thrombosis
Coagulation Factor V or Protein C Cofactor is encoded by the F5 gene (OMIM
612309)[Bertina et al 1994]. Proteins are comprised of linked building blocks called
amino acids. The sequence of amino acids in any protein is encoded in the DNA or
genes of an individual. In FVL thrombosis a defect, or mutation, in the F5 gene result in
the wrong amino acid being inserted into a protein sequence, and therefore, a
malfunction in Factor V protein. The particular mutation, designated R506Q, is also
known as Factor V Leiden (FVL).
How is FVL thrombophilia inherited?
Each person has two copies of the F5 gene, one copy acquired from each parent. An
individual with two normal copies (referred to as homozygous – same alleles) does not
have a genetic predisposition for prothrombin thrombophilia. The FVL mutation is said
to be dominant. That is, an individual needs to possess only one defective copy of F5
FVL along with a normal copy of F5 to exhibit symptoms of FVL thrombophilia. Such
an individual is said to be heterozygous for the mutation (different alleles for the gene).
An individual may also have two copies of the F5 FVL mutation (i.e. homozygous for
FVL).
Symptoms and Risks Associated with Factor V Leiden Thrombophilia
The clinical expression of FV Leiden thrombophilia can vary depending on the number
of FVL alleles an individual has. For example, heterozygotes (normal F5/FVL) have 3 to
8 times increased risk of developing VTE over those individuals who have two normal
F5 alleles. The risk of VTE jumps to 18 to 80 times in homogygous individuals
(FVL/FVL) [Kujovitch JL, 2010].
A person with FVL may have coexisting genetic or acquired thrombophilic disorders
that increase the risk of thrombophilic events. In addition, FVL various circumstantial
factors also affect the risk of thrombophilic events. These are summarized in Table 1.
Table 1
Risks and Complications Associated with FVL Thrombosis
Co-existing Genetic Thrombophilic Disorders
Heterozygotes (FVL or prothrombin G20210A): 4-5-fold
increase in thrombotic risk
Double heterozygotes (FVL and Prothrombin): 20-fold
increase in relative risk
Acquired Thrombophilic Disorders
Circumstantial Risk Factors
Central venous catheters- 2-3-fold increased risk
Surgery- 13-fold increased risk of upper extremity DVT
Organ transplantation- 12-fold increased risk of early graft
perfusion defect
Hormone replacement therapy- 2-4-fold increased risk
Oral contraceptive use- 3-fold increased risk
High factor VIII levels- 2-3-fold increased risk
Pregnancy- 5-16-fold increased risk
Hyperhomocysteinemia- 3-4-fold increased risk
Travel- 16-fold increased risk
Malignancy- 2-20-fold increased risk
Selective estrogen receptor modulators- unknown
Advancing age
Epidemiology
The FVL allele is present in 1 in 5000 people in the general population. Some
individuals with the FVL allele never develop thrombosis. The incidence of FVL varies
among races [Ridker et al 1997]:
 5.2% of Caucasian Americans
 2.2% of Hispanic Americans
 1.25% of Native Americans
 1.2% of African Americans
 0.45% in Asian Americans
Genetic Testing for FVL Thrombophilia
Normal Factor V is susceptible to activated Protein C (aPC) and this can be measured
using a biochemical test; the patient is diagnosed with prothrombin thrombophilia if
the test demonstrates the aPC-resistant form FVL.
Alternatively, a physician can obtain a small blood sample for analysis. Blood contains
the patient’s DNA, which can be tested for the presence of the FVL R506Q mutation.
References
Bertina RM, Koeleman BP, Koster T, et al. 1994. "Mutation in blood coagulation factor V
associated with resistance to activated protein C". Nature 369 (6475): 64–7.
Kujovitch JL. Gene Reviews: Factor V Leiden Thrombophilia. Last Update: March 9,
2010.
National Library of Medicine Genetics Home Reference: Factor V Leiden
Thrombophilia
Ridker PM, Miletich JP, Hennekens CH, Buring JE. 1997. Ethnic distribution of factor V
Leiden in 4047 men and women. Implications for venous thromboembolism screening.
JAMA. 277:1305–7.
American College of Medical Genetics. Technical standards and guidelines: Venous
thromboembolism (Factor V Leiden and prothrombin 20210G>A testing): A diseasespecific supplement
to the standards and guidelines for clinical genetics laboratories. 2005. Available online.
Additional Resources
PubMed FactorV Leiden (Current Literature)
Gene Reviews: Clinical Summary
American College of Medical Genetics (ACMG): Statement on Factor V Leiden Testing
Online Mendelian Inheritance in Man (OMIM): Factor V Leiden OMIM #188055
Living with Thrombophilia FVLeiden.org Excellent resources for patients, families and
physicians.