Leads to resistance to activated protein C and found in 1 of 5 patients with venous thrombosis.
Most common known inherited cause of thrombophilia.
Present in approximately 5% of the Caucasian population.
Allelic variants in coagulation factor genes appear to account for a much larger fraction of venous thromboembolism cases; the prothrombin 20210 G/A polymorphism and factor V Leiden present in approximately 2% and 5% of Caucasians, respectively, account for approximately 50% of cases in the Caucasian population.
Mutated factor V protein has normal procoagulant function in vitro but is resistant to inactivation by aPC.
Polymorphism F5 rs6025
F5 rs6025 yields and arginine to glutamine shift at position 506 of the mature factor V molecule, an important cleavage site for its inactivation by activated protein C, leading to slower inactivation of factor V and prolonged activation of coagulation.
Mutation has a carrier rate of 5%–10% in the Caucasian population.
Estimated prevalence of 1% in black populations.
Mutation is most common in Scandinavian and northern European ethnicities.
The inactivation of factor V is impaired with the Leiden mutation, blocking an important inhibitory feedback loop that regulates thrombin generation.
Associated with increased risk of recurrent venous thrombosis, cerebral sinus thrombosis, renal transplant rejection, venous thrombosis during pregnancy, and various obstetric complications, i.e. it appears to be associated with venous thrombosis.
A weaker association exists for arterial thrombosis or infarction.
Most patients are asymptomatic and often must be exposed to an additional risk factor such as pregnancy, immobilization following surgey or trauma,, severe illness, or other genetic factors associated with thrombophilia.
Prevalence up to 50% in patients with a personal or family history of thrombophilia.
Accounts for 90-95% of all patients with APC (activated protein C) resistance.
Refers to a single base change in the factor V gene (G1691A) that eliminates 1 of its 3 activated protein C cleavage sites, causing slower factor V inactivation and leading to more thrombin generation.
A single base substitution, adenosine for guanosine at position 1691, coded for a glutamine substitution for arginine at amino acid 506 is identified in almost all of the cases.
Leads to a prothrombic state with a 7-10-fold increases in thromboembolism in heterozygotes and 79-fold increase in homozygotes compared to the general population.
Highly prevalent in patients with postthrombotic venous ulcers.
6% of the U.S. Population and 4% of the white population worldwide.
Occurs in only 0.5% of Asians, 2% of Hispanics and less than 1% of African-Americans.
Autosomal dominant.
Homozygosity and heterozygosity for this mutation are predictive for venous thromboembolism for patients who have had a prior event.
Significant evidence exists for homozygosity for this mutation predicts a higher rate of incident venous thromboembolism
Lifelong anticoagulation may not be necessary for all patients since some patients never experience thrombosis.
Factor V Leiden and prothrombin G20220A mutation have low clinical penetrance of venous thrombosis and have only a 5-10% risk that they will ever have a clot in their lifetime.
Unprovoked thrombotic events with factor V Leiden or prothrombin G20210A mutation are not significantly associated with increased risk of recurrent VTE among heterozygotes, and such events do not merit long-term anticoagulation after a first event:risks of recurrent events are 2.12 for factor V Leiden and 1.45 for prothrombin G20210 mutation.
Approximately 80% of people who are homozygous for the mutation and 10 percent of those who are heterozygous will have thrombosis at some point.
Associated with fetal death in all trimesters, fetal growth restriction, early-onset preeclampsia, and HELLP syndrome.
Substitution of glutamine for arginine at position 506 prevents the degradation of factor V administration promotes clot formation.
Increases the risk of stroke, myocardial infarction and venous thrombosis in men.
Most common cause of thrombophilia and is identified in about 50% of individuals with recurrent venous-thromboembolism.
Doubles the risk of initial venous-thromboembolism and is associated with a 40% risk of recurrence over an eight year period.
Women with breast cancer and on tamoxifen have a 5 times higher risk of thromboembolism than women on tamoxifen without the Leiden mutation (Garber JE).
Protein C is converted to its biologically active form, aPC, by the thrombin-thrombomodulin complex on endothelium.
A common cause of resistance to aPC in Caucasians due to the loss of the aPC cleavage site, usually present at the arginine residue 506, on the factor V protein.
Proteolysis of activated factor V by aPC is usually rapid.
Activated Factor V Leiden molecule remains intact much longer because aPC cannot cleave it at its principal location.
Resistance to aPC increases thrombin formation which produces increased levels activation of a clot-stabilizing enzyme, TAFI, resulting in lysis resistant clots.
Factor Va cleavage by aPC facilitates cleavage of factor VIIIa, so Factor V Leiden increases factor VIIIa.
Clinical hypercoagulability directly related to the degree of aPC resistance.
Patients heterozygous for FVL exhibit a lifetime risk of venous thrombosis that is approximately 5–10 times more than that of FVL heterozygotes, whose risk is approximately 5–10 times that of the noncarrier Caucasian population.
In general, the added risk of venous thromboembolism in the patient with Factor V Leiden postoperatively, in a patient with standard postoperative antithrombotic therapy is not significant: since standard antithrombotic therapy is given and overpowers the relative mild effects of Factor V Leiden on
venous thromboembolism, routine screening for the disease is not recommended.
Peripheral arterial surgery not associated with decreased patency rates in the presence of FVL.
Coronary bypass graft frequency of vein graft occlusion may be as much as 10% within the first 10 days after surgery and as frequent as 26% by the first year in patients with factor V Leiden mutation.
Long-term occlusion rate after coronary artery vein graft approaches approximately 20% after 3–6 yr.
Venous thrombosis after orthopedic or general surgery does not appear to be increased in the presence of FVL heterozygosity when patients are treated with protocols for prophylactic anticoagulation.
No evidence for changng perioperative management on the basis of the finding of FVL, nor is there evidence to support a role of preoperative screening for FVL.
Cardiac surgery patients with factor V Leiden are likely to bleed less than noncarriers.
Coronary bypass graft occlusion after surgery may be increased in the presence of Factor V Leiden mutation.