Prothrombin Thrombophilia
Prothrombin thrombophilia is a genetic condition characterized by an increase in blood
coagulation, or clotting. It is the second most common inherited thrombophilia next to
Factor V Leiden Thrombophilia (FVL).
How does prothrombin affect blood clotting?
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 becomes unregulated, then breeches in blood vessels may not be repaired
and hemorrhages may occur. Conversely, hypercoagulation may cause a clot or
“thrombus” to develop. If the clot breaks free it can migrate through the bloodstream,
lodge in a blood vessel, and block blood flow to surrounding tissues.
Prothrombin, also known as coagulation factor II (Factor II), is a protein involved in the
formation of clots. This disorder results in an abnormal increase in the level of
prothrombin in the blood and, therefore, an increase in clot formation. Thrombophilia
associated with increased levels of prothrombin coagulation factor is often revealed as
vascular blockages or venous thromboembolisms (VTE). The most common forms of
prothrombin-related VTE are deep vein thrombosis (DVT) in the legs and pulmonary
embolism (i.e. clot in the lungs).
Symptoms of Prothrombin Thrombophilia
The symptoms of prothrombin thrombophilia are variable and no specific features
distinguish the disorder. The principal characteristic of genetic thrombophilia is the
occurrence of VTE in individuals in the absence of other causes. General symptoms of
VTE in the legs include:
 Pain, swelling, a feeling of warmth in the affected leg(s)
 Discoloration or reddening of the affected leg(s)
 Leg(s) may fatigue easily
 Surface veins may be visible and slightly raised
VTE increases the risk of pulmonary embolism
There is a great risk that clots formed in the legs may break free, migrate through the
bloodstream, and lodge in the blood vessels of other tissues and organs in the body.
Pulmonary (lung) embolism is a common feature of prothrombin thrombophilia and
can be fatal. Immediate medical attention should be sought at the first sign of the
following:



Sudden dizziness or lightheaded feeling
Coughing, often with the appearance of blood
Shortness of breath; rapid breathing
What are some of the warning signs of prothrombin thrombophilia?
Prothrombin thrombophilia can be suspected if any of the following the VTE events
have occurred:
 A first VTE before age 50
 A first unprovoked VTE at any age
 A history of recurrent VTE
 Venous thrombosis at unusual sites (e.g. brain, mesentery, veins in the liver)
 VTE during pregnancy or the puerperium
 VTE associated with the use of oral contraceptives or hormone replacement
therapy
 A first VTE in an individual with a first-degree family member with VTE before
age 50
 Women with unexplained fetal loss after 10 weeks’ gestation
[ACOG guidelines; Practice Bulletin Number 113]
Genetics of Prothrombin Thrombosis
The instructions for the synthesis of the prothrombin protein, are encoded by the F2
gene (OMIM 176930). Prothrombin is also known as coagulation factor II or Factor II.
An individual with prothrombin thrombophilia has a defective (mutated) copy of the F2
gene. The most common mutation in F2, named G20210A causes cells to produce
elevated levels of prothrombin protein.
How is prothrombin thrombophilia inherited?
Each person has two copies of the F2 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 G20210A mutation is
said to be dominant. That is, an individual needs to possess only one defective copy of
F2 G20210A along with a normal copy of F2 to exhibit symptoms of prothrombin
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 F2 G20210A
mutation (i.e. homozygous for the mutation). The G20210A mutation causes higher
levels of prothrombin in the blood, and, thus, more clots to form.
The incidence of prothrombin thrombophilia varies among races. The disorder is
prevalent in 2-5% of Caucasians, 0-0.3% of African Americans, and is extremely rare in
Asian, African and Native American populations.
What are some of the risks associated with prothrombin thrombophilia?
The clinical features of prothrombin thrombophilia can vary widely. Some
heterozygous individuals (normal F2/G20210A) may have recurrent VTE before age 30,
while others may be asymptomatic until adulthood. Still, many individuals with the
common G20210A mutation do not develop thrombosis at all. In addition, patients who
are homozygous for the G20210A (G20210A/G20210A) mutation generally have greater
risk of thrombosis than heterozgotes.
In general, individuals with G20210A have a greater risk of thrombotic events and
complications than those with a normal F2 gene (Table 1).
Table 1
Risks and Complications Associated with Prothrombin Thrombosis
Deep Vein Thrombosis
Superficial Venous Thrombosis
Adults heterozygous for G20210A allele
have a 2-4 fold increased risk for DVT.
Children have a 3-4 fold increased risk
G20210A heterozygotes have a 4 fold
increased risk
Thrombosis in Unusual Locations
Cerebral vein thrombosis- 6-10 fold
increased in G20210A heterozygotes
Hepatic, portal and retinal vein thrombosis
Pregnancy Complications
Pregnancy loss
Placental abruption
Preeclampsia
Fetal growth retardation
Various factors may predispose G20210A-positive individuals to thrombosis. These
include both genetic and other causes (Table 2).
Table 2
Factors That Predispose G20210A Individuals to Thrombosis
Number of G20210A Alleles
Heterozygotes have a 2-4 fold risk of VTE
Homozygotes have a higher risk than
heterozygotes
Coexisting Genetic Abnormalities
Mutations in Clotting Factor V Leiden (FVL)FVL
- double heterozygotes
(G20210A/G20210A/FVL/FVL) have a 20-60fold increased risk of VTE
Circumstantial Risk Factors
Pregnancy: 3-115-fold increased risk of VTE
Oral Contraceptives: 16-59-fold increased risk of VTE
Selective estrogen receptor modifiers (SERMs):
Organ transplantation
Central venous catheters: 2-3-fold risk of VTE
Travel: 17-fold risk of VTE
[Kujovitch, 2011]
Genetic Testing for Prothrombin Thrombophilia
A physician who suspects that a patient may have prothrombin thrombophilia, based
on clinical symptoms, may order a genetic test to be performed. The patient’s blood
sample is obtained and the DNA is them isolated from the blood. The DNA is then
analyzed for the presence of the G20210A mutation. Diagnosis of prothrombin
thrombophilia is based the presence of one or two copies (i.e. alleles) of the G20210A
mutation.
References
Kujovitch JL. 2011. GeneReviews: Prothrombin-Related Thrombophilia (Last Update:
March 29, 2011)
American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin
Number 113. Inherited thrombophilias in pregnancy. 2010. Available online
(registration or institutional access required).
American College of Medical Genetics (ACMG). Technical standards and guidelines:
Venous thromboembolism (Factor V Leiden and prothrombin 20210G>A testing): A
disease-specific supplement to the standards and guidelines for clinical genetics
laboratories. 2005. Available online.
Additional Resources
PubMed: Prothrombin thrombophilia Current literature
National Blot Clot Alliance (http://stoptheclot.org/index.htm#.UbYfDOXD_IU)
Resources for patients and families
National Library of Medicine Genetics Home Reference: Prothrombin Thrombophilia
Varga EA and Moll S. 2004. Prothrombin 20210 Mutation (Factor II Mutation).
Circulation 110: e15-e18. Available online.