Factor V Leiden Deficiency

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

Venous Thromboembolism

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

Arterial Thromboembolism

• Association between FVL 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 FVL. It has been observed that the FVL mutation is associated with an increased risk of stroke especially in women, smokers, and younger individuals.[5]

Testing for FVL is indicated for individuals with venous thromboembolism, especially if VTE occurs at a young age and if the VTE occurs in an unusual location such as a portal vein or cerebral vein. It is also indicated in a member of a thrombophilic family.

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.

FVL can be diagnosed by mutation analysis (DNA testing) or a functional coagulation test for aPC resistance.

• Genetic testing is indicated for those with a family history of FVL. It is also preferred for members of a thrombophilic family, patients with an 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.[6]
• Mutation testing: Polymerase chain reaction methods can detect FVL 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 FVL mutation resulting in a different banding pattern on a DNA gel.[7]
• 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 inhibitor, as well as in presence of a lupus anticoagulant.

Management of venous thromboembolism in people with FVL mutation is the same as that of the general population, and FVL 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 anticoagulant (DOAC) are usually used for patients with typical VTE presentation. Warfarin is preferred if there is a concern about adherence or those who present with a submissive/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 FVL 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.[8]

Individuals with FVL heterozygous mutation who undergo surgery should be treated as a high-risk group and receive prophylactic anticoagulation.

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, oral contraceptives
• Immobilization/obesity
• Nephrotic syndrome
• Antiphospholipid syndrome 
• Paroxysmal nocturnal hemoglobinuria
• Myeloproliferative disorder
• Heart failure 
• Severe liver disease
• Medications like tamoxifen, thalidomide, lenalidomide

A proportion of the population with Factor V Leiden will suffer 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 FVL increases overall mortality.

Factor V Leiden deficiency is not a common disorder, but because there is a potential risk of developing VTE, healthcare workers should be aware of this disorder. Patients may present with either venous or arterial thrombotic events, both of which are associated with a high morbidity and mortality. The condition is best managed by an interprofessional team that includes a hematologist, internist, nurse practitioner, a pharmacist, and the primary care provider. The key reason for such a team is that even when a diagnosis is made, many patients with only a laboratory finding of the defect may not require therapy. Only patients with VTE require treatment. The other difficulty in managing these patients is the duration of therapy. At the moment, data indicate that VTE in factor Leiden deficiency should be managed in the same manner as the normal population, but those with recurrent VTE or thrombosis of vessels in unusual locations may require long-term therapy. The outcomes in most patients with factor V Leiden deficiency are good but the outcomes in pregnant families with the disorder are guarded, because the risk of anticoagulation can adversely affect the fetus.[9][10]