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Factor V Leiden (FVL) is a point mutation of factor V resulting in an elimination of the cleavage site in factor V and factor Va. This genetic defect increases the risk of thrombosis, especially in homozygous or pseudo-homozygous FVL-mutated individuals. Many individuals with the mutation will never develop a venous thrombotic event (VTE). The decision about VTE risk reduction (both primary and secondary) requires a great deal of clinical acumen, given that most people who carry the mutation will never have VTE. FVL is an autosomal dominant genetic condition that exhibits incomplete penetrance, meaning that not every person with the mutation will develop the disease. This activity reviews the pathophysiology and implications of factor V Leiden and highlights the role of the interprofessional team in its management. Objectives: Describe the pathophysiology of FVL. Review the clinical manifestations of FVL, including the importance of combined thrombophilia conditions. Review the prophylaxis for venous thromboembolism during pregnancy and during the postpartum period for women with FVL with or without a family history of thromboembolism. Summarize the treatment options for FVL. Access free multiple choice questions on this topic.

Factor V Leiden is a point mutation in factor V that eliminates the cleavage site between factor V and factor Va. This genetic defect increases the risk of thrombosis, especially in homozygous or pseudo-homozygous carriers of factor V Leiden mutations. Many individuals with the mutation never develop a venous thrombotic event (VTE). The decision about VTE risk reduction (both primary and secondary and prevention of recurrence) requires a great deal of clinical acumen, given that most people who carry the mutation never have VTE.

Normally, factor V synthesis principally occurs in the liver. Thrombin activates factor V, and once activated, it converts prothrombin to thrombin. Activated protein C, one of the principal physiologic inhibitors of coagulation, degrades factor V. In the presence of thrombomodulin, thrombin decreases clotting by activating protein C; therefore, the concentration and activity of protein C are important determinants of the negative feedback loop through which thrombin limits its activation. Factor V Leiden is an autosomal-dominant genetic condition with incomplete penetrance, meaning not every person with the mutation develops the disease. Factor V Leiden, also known as factor V R506Q 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 because activated protein C, a natural anticoagulant, cannot bind to and inactivate factor V due to a mutation in the binding site on factor V for activated protein C. Therefore, because factor V is not inactivated, it remains active, increasing the risk of thrombosis.

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.

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 include enhanced procoagulant activity of factor Va and reduced anticoagulant activity of factor V.[1]

The primary clinical manifestation of the factor V Leiden mutation is an increased risk of 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 develop VTE in their lifetime, with an estimated risk of 5% in the general population and up to 20% in thrombophilic families. Venous Thromboembolism The most common sites of VTE are 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 than in the general population, a phenomenon known as 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 any effect is likely 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 per 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.

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, such as 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 is usually not performed in individuals with a first episode, especially if it is provoked or occurs in people older than 50 years. 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 thrombophilic families, patients with antiphospholipid syndrome, and those who need to take anticoagulants. 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 the factor V Leiden mutation. The DNA from individuals without the mutation would be 'cut' by a restriction enzyme. In contrast, it does not cut DNA in patients with the 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.

Management of venous thromboembolism in people with the factor V Leiden mutation is the same as that of the general population, and the factor V Leiden mutation does 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 (DOACs) 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 does not differ between factor V Leiden carriers and the general population; 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] Individuals with the factor V Leiden homozygous 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: Inherite d 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

A proportion of the population with factor V Leiden 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.

Patient counseling and education include emphasizing specific aspects of a healthy lifestyle to improve prognosis. Maintain a healthy weight, and lose weight if necessary. Eat a healthy diet. Get at least 2.5 hours of exercise per week. Walking is a good choice, but other activities, such as swimming, cycling, running, or playing tennis or team sports, are also good choices. Do not smoke since it increases the risk of blood clots. Clinicians can assist with stop-smoking programs and medicines to improve the patient's chances of quitting permanently.

Pertinent to factor V Leiden, it is essential to understand the relative risk of VTE compared with other thrombophilia conditions to guide management decisions. This risk is depicted in the format below for easy understanding. Table Protein S deficiency So a patient with conditions such as a heterozygous factor V Leiden mutation, a heterozygous prothrombin gene mutation, and deficiencies of protein C and protein S does not require lifelong anticoagulation. Thus, for patients with these thrombophilia conditions, management is no different from the general population's management guidelines. Per ASH guidelines, 3 to 6 months of anticoagulation is recommended for the first episode of venous thrombosis. The duration of anticoagulation in individuals with underlying other thrombosis-provoking conditions, like malignancy, that increase their risk for recurrent DVT needs to be determined based on the underlying condition rather than based on these thrombophilia conditions.

Factor V Leiden is not a common disorder, but because there is a potential risk of developing VTE, healthcare professionals should be aware of this disorder. Patients may present with either venous or arterial thrombotic events, both of which are associated with high morbidity and mortality. The condition is best managed by an interprofessional team that includes a hematologist, internist, pharmacist, obstetrician, nurses, and 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. Therefore, all interprofessional team members need to familiarize themselves with the condition, provide patient counseling, and monitor for signs of VTE. This requires interprofessional care coordination and open communication between team members. The other difficulty in managing these patients is the duration of therapy. At the moment, data indicate that VTE in factor V Leiden 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 are good, but the outcomes in pregnant women with the disorder are serious because of the morbidity associated with VTE development and VTE-associated complications in pregnancy.[14][15] To decrease the morbidity and mortality associated with VTE and post-thrombotic syndrome and complications in pregnant women with VTE, anticoagulation recommendations are put forward by the American Society of Hematology (ASH) and the American College of Obstetricians and Gynecologists (ACOG).[16] Pregnancy being a prothrombotic condition, specific guidelines in managing thrombosis in pregnancy and inherited thrombophilias like factor V Leiden and compound thrombophilias put forward by ASH are summarised in the following table.[16] Table Anticoagulation postpartum Choice of anticoagulant DOACs: Direct oral anticoagulants (examples include rivaroxaban, apixaban, dabigatran, or edoxaban); LMWH: Low molecular weight heparin; DVT: Deep venous thrombosis; PE: Pulmonary embolism