Factor V Leiden Mutation

Etiology

Normally, factor V synthesis principally occurs in the liver. Thrombin activates factor V, and once activated, it will convert prothrombin to thrombin. Activated protein C, one of the principal physiologic inhibitors of coagulation, degrades factor V. In the presence of what is called thrombomodulin, thrombin acts to decrease clotting by activating protein C; therefore, the concentration and the action of protein C are important determinants in the negative feedback loop through which thrombin limits its activation.

Factor V Leiden is an autosomal dominant genetic condition that exhibits incomplete penetrance, meaning that not every person with the mutation will develop the disease. 

Factor V Leiden, also known as factor VR506Q and factor V Arg506 Gln, results from a single-point mutation in the factor V gene (guanine to adenine at nucleotide 1691), which leads to a single amino acid change (replacement of arginine with glutamine at amino acid 506). This abolishes the Arg506 cleavage site for activated protein C in Factor V and Va.[1] Factor V Leiden increases the risk of thrombosis as activated protein C, a natural anticoagulant, can not bind and inactivate factor V as there is a mutation in the binding site on factor V for activated protein C. Therefore, as factor V is not inactivated, it continues to be active and increases thrombosis risk.

Epidemiology

Heterozygosity of the factor V Leiden mutation is the most common inherited thrombophilia in the unselected White population (prevalence, approximately 1% to 5%) and is considered the most common inherited thrombophilia in individuals with venous thromboembolism (prevalence of roughly 10% to 20%).[2] Heterozygosity of this genetic mutation increases the lifetime risk of thrombosis by about 7-fold, while homozygosity (which is rare) increases the risk by approximately 20-fold. Despite the increase in the risk of VTE, there is no clinical evidence that heterozygosity of factor V Leiden increases overall mortality.

Pathophysiology

Factor V Leiden results from a single-point mutation in the factor V gene (guanine to adenine at nucleotide 1691) that would lead to the replacement of arginine with glutamine at amino acid 506. This abolishes the Arg506 cleavage site for activated protein C in factor V and factor Va. The consequences are enhancing the procoagulant role of factor Va and the reduced anticoagulant role of factor V.[1]

History and Physical

The primary clinical manifestation of the factor V Leiden mutation is the risk for venous thromboembolism (VTE). However, the most common finding in individuals with factor V Leiden is a laboratory-only abnormality. Only a small percentage of individuals with factor V Leiden will develop VTE in their lifetime, with an approximate risk of 5% for factor V Leiden heterozygotes in the general population and up to 20% in thrombophilic families.

Venous Thromboembolism

• The most common site of VTE is deep vein thrombosis (DVT) and pulmonary embolism (PE), but other sites, including superficial veins of the legs or cerebral, portal, and hepatic veins, may be involved.[3]
• Isolated PE is a less common presentation. Without evidence of DVT, factor V Leiden patients can still present with PE. But this is a less common presentation of VTE in individuals with factor V Leiden compared with the general population, a phenomenon called the factor V Leiden paradox.[4]  
• Cerebral vein thrombosis can occur in factor V Leiden individuals, especially in patients using oral contraceptive pills. Studies have shown that factor V Leiden can be associated with an increased risk of Budd-Chiari syndrome.[5]

Arterial Thromboembolism

• The association between factor V Leiden and arterial thromboembolism remains controversial, and it is likely to be small if present.
• Myocardial infarction: Studies have shown a modest increase in the risk of coronary artery disease in patients with factor V Leiden. It has been observed that the factor V Leiden mutation is associated with an increased risk of stroke, especially in women, smokers, and younger individuals.[6]

Pregnancy and Postpartum Thromboembolism Risk

• Thromboembolism affects 1.2 of every 1000 deliveries.[7] Increased morbidity and mortality are reported with pregnancy-associated VTE for women [8][9]. However, based on current clinical evidence, inherited thrombophilias like factor V Leiden are neither considered risk factors for recurrent pregnancy losses nor implicated in affecting obstetrical outcomes.[10]
• Women with factor V Leiden and other inherited thrombophilia with or without a family history of VTE are at increased risk of VTE and VTE-related complications during pregnancy. 

Evaluation

Testing for thrombophilia conditions in patients diagnosed with the first episode of DVT/PE is being discouraged according to the American Society of Hematology (ASH) guidelines as it is expensive with no clinically meaningful benefit.

Testing for factor V Leiden is indicated for individuals with venous thromboembolism, especially if:

• VTE occurs at a young age, generally speaking, less than 50 yrs of age
• Atypical sites of clotting like visceral vein thromboses like an ovarian vein, portal vein, or renal vein thrombosis 
• Unexplained arterial thrombosis
• Significant family history of thrombophilia
• In a hospitalized patient developing VTE despite being on prophylactic anticoagulation with no other definite explanation for VTE 
• Unexplained recurrent deep venous thrombosis/PE

Testing usually is not performed in individuals with a first episode, especially if it is provoked or if it occurs in people who are older than 50 years of age.

Factor V Leiden can be diagnosed by mutation analysis (genetic testing) or using a functional coagulation test for APC resistance.

• Genetic testing is indicated for those with a family history of factor V Leiden. It is also preferred for members of a thrombophilic family, patients with antiphospholipid syndrome, or those who need to be on an anticoagulant. Individuals with a positive functional assay for APC resistance should have genetic testing to confirm a diagnosis.[11]
• Mutation testing: Polymerase chain reaction methods can detect factor V Leiden mutation. The DNA from individuals without the mutation would be 'cut' by a restriction enzyme. In contrast, it will not cut DNA in patients with factor V Leiden mutation resulting in a different banding pattern on a DNA gel.[12]
• Functional APC resistance assays: These tests cost less than genetic testing, but in rare cases, they can give a misleading, falsely normal result, especially in individuals on therapy with direct thrombin inhibitors or factor Xa inhibitors, as well as in the presence of a lupus anticoagulant.

Treatment / Management

Management of venous thromboembolism in people with factor V Leiden mutation is the same as that of the general population, and factor V Leiden mutation will not affect the decision about which anticoagulant one should use. The choice of anticoagulant is based on some factors like patient preference, adherence to therapy, the severity of thrombosis, and drug interactions. 

Generally, direct oral anticoagulants (DOAC) are usually used for patients with typical VTE presentations. Warfarin is preferred if there is a concern about adherence or for those who present with a submassive/massive pulmonary embolism who would benefit from maintaining INR at the high end of the therapeutic range.

The duration of VTE treatment is not different between factor V Leiden and the general population, and it depends on the risk of recurrent VTE. It is highly recommended that one continue indefinite anticoagulation for unprovoked, life-threatening venous thromboembolism, VTE at an unusual location or if it is recurrent.[13](B3)

Individuals with factor V Leiden homozygous mutation who undergo surgery should be treated as a high-risk group and receive prophylactic anticoagulation.

Differential Diagnosis

The differential diagnosis for deep vein thrombosis (DVT) includes the following:

Inherited Thrombophilia

• Prothrombin G20210A mutation
• Protein S deficiency 
• Protein C deficiency
• Antithrombin (AT) deficiency

Others

• Malignancy
• Trauma/surgery
• Pregnancy or use of oral contraceptives
• Immobilization/obesity
• Nephrotic syndrome
• Antiphospholipid syndrome 
• Paroxysmal nocturnal hemoglobinuria
• Myeloproliferative disorders
• Heart failure 
• Severe liver disease.cirrhosis
• Medications like tamoxifen, thalidomide, or lenalidomide

Prognosis

A proportion of the population with factor V Leiden will suffer from venous thrombosis. Thromboembolism, including pulmonary embolism, carries significant morbidity and mortality. However, despite the increase in the risk of VTE, there is no evidence that heterozygosity to factor V Leiden increases overall mortality.