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Factor V Leiden
Marina Rasnow-Hill, MD
image BASICS
DESCRIPTION
  • Factor V Leiden is a genetic mutation at the activated protein C (APC) cleavage site on the factor V and Va molecule leading to the most common form of inherited thrombophilia.
  • System(s) affected: cardiovascular, gastrointestinal, hemo-/lymphatic/immunologic, nervous, pulmonary, reproductive
  • Synonym(s): factor V Leiden thrombophilia; factor V Leiden mutation; hereditary APC resistance
Pediatric Considerations
Potential for increased thrombosis risk in patients with factor V Leiden and concomitant risks
Pregnancy Considerations
  • Recurrent late pregnancy loss is a possible complication.
  • Increased thrombotic risk in pregnancy and postpartum (additive) especially in homozygous state
  • Possible increased risk of IUGR, preeclampsia, placental abruption, evidence mixed (1)
EPIDEMIOLOGY
Prevalence
Studies estimate ˜5-8% occurrence of heterozygosity in Caucasians, Hispanic Americans ˜2%, African Americans ˜1%, and Asian Americans ˜0.45%.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Factor V circulates in the plasma. When exposed to tissue factor from endothelial activation, factor V amplifies the production of thrombin which in turn further promotes clotting by activating factor V into procoagulant factor Va.
  • For balance, thrombin also promotes APC production which will cleave and inactivate factor V, Va, and VIII, thereby keeping the clotting cascade in check (negative feedback loop).
  • In factor V leiden, a point mutation at the binding site of APC (Arg506Glu) renders it less able to cleave factor V or Va. This, in turn, reduces the anticoagulant role of factor V as a cofactor to APC, and increases the procoagulant role of activated factor V, as there is now 20-fold slower degradation of factor Va Leiden.
RISK FACTORS
  • Risk for venous thromboembolism (VTE) is ˜7-fold in heterozygous and ˜80-fold in homozygous factor V Leiden individuals, compared with individuals without the mutation (2). This risk is compounded/increased by the presence of the following:
    • Having non-O blood type (A, B, or AB) (increased risk 2- to 4-fold)
    • Oral contraceptives: homozygotes up to 100-fold; heterozygotes, 35-fold. The increased risk is halved when the patient uses desogestrel-containing oral contraceptives.
    • Hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs) both increase the risk of thrombosis; in patients with factor V Leiden, that risk is compounded.
    • Pregnancy and homozygous factor V Leiden increase the risk of thrombosis 7- to 16-fold during pregnancy and the puerperium.
  • Data are conflicting with regard to risk for recurrent VTE for patients with factor V Leiden but trend toward an increased risk (1,3).
GENERAL PREVENTION
COMMONLY ASSOCIATED CONDITIONS
Venous thrombosis
image DIAGNOSIS
PHYSICAL EXAM
  • Family history of factor V Leiden mutation
  • Findings suggestive of VTE in any form (DVT, PE, cerebral vein thrombosis); 10-26% of patients with VTE are carriers of the factor V Leiden mutation.
  • Thrombosis in unusual locations, such as the sagittal sinus, or mesentery and portal systems, although these are less common in patients with factor V Leiden than in patients with deficiency of protein C or S.
  • There is a weak, however significant, association between procoagulant states (including factor V Leiden) and coronary events in younger patients (4).
DIFFERENTIAL DIAGNOSIS
  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin deficiency
  • Other causes of APC resistance (e.g., antiphospholipid antibodies)
  • Dysfibrinogenemia
  • Dysplasminogenemia
  • Homocystinemia
  • Prothrombin 20210 mutation
  • Elevated factor VIII levels
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • For evaluation of a new clot in patient at risk: CBC with peripheral smear, PT/INR, aPTT, thrombin time, lupus anticoagulant, antiphospholipid antibodies, factor VIII, anticardiolipin antibody, anti-&bgr;(2)GP-I antibodies, APC resistance, protein S antigen and resistance, antithrombin III assay, fibrinogen, factor V Leiden, prothrombin G20210A
  • Genetic test: DNA-based test for factor V mutation; will be unaffected by anticoagulation and other drugs
  • Functional test: plasma-based coagulation assay using factor V-deficient plasma to which patient plasma is added along with purified APC. The relative prolongation of the activated partial thromboplastin time (aPTT) is used to assay for the defect. Heparin, direct thrombin inhibitors, and factor Xa inhibitor may cause false-negative results. In the absence of exposure to anticoagulants, functional testing is preferred to genomic for cost and time to diagnosis (5)[A].
  • Extremity US for DVT
  • V/Q scan or spiral CT for PE
Follow-Up Tests & Special Considerations
  • US may not show DVT acutely; repeat in 5 to 7 days if strong suspicion.
  • V/Q scan for evaluation of PE may be difficult to interpret in smokers or those with underlying lung disease.
Diagnostic Procedures/Other
Magnetic resonance angiography (MRA), venography, or arteriography to detect thrombosis
image TREATMENT
Only indicated if thrombotic event
GENERAL MEASURES
  • Like general VTE treatment, patients with factor V Leiden and a first thrombosis should be anticoagulated initially with heparin or LMWH and warfarin for at least 3 months.
  • Treatment with low-molecular-weight heparin (LMWH) is recommended over unfractionated heparin, unless the patient has severe renal failure (6)[A].
  • Treat as outpatient, if possible (6)[A]
  • Initiate warfarin with LMWH on the first treatment day and discontinue LMWH after minimum of 5 days and when INR >2 for two consecutive days (6)[A].
  • Patients should be maintained on warfarin with an INR of 2 to 3 for at least 3 months (6)[A].
  • For those patients with recurrence, the risks and benefits of indefinite anticoagulation need to be assessed.
MEDICATION
First Line
  • LMWH:
    • Enoxaparin (Lovenox): 1 mg/kg SC BID, start warfarin simultaneously, continue enoxaparin for minimum of 5 days and until INR is >2 for two consecutive days, at which time enoxaparin can be stopped.
    • Fondaparinux (Arixtra): 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) SC daily
    • P.371

    • Tinzaparin (Innohep): 175 anti-Xa IU/kg SC daily for minimum of 5 days and patient is adequately anticoagulated with warfarin (INR of at least 2 for two consecutive days)
    • Dalteparin (Fragmin): 200 IU/kg SC daily
  • Oral anticoagulant
    • Warfarin (Coumadin) PO with dose adjusted to an INR of 2 to 3 (3)[A].
  • Contraindications
    • Active bleeding precludes anticoagulation
    • Risk of bleeding is a relative contraindication to long-term anticoagulation.
    • Warfarin is contraindicated in patients with history of warfarin skin necrosis (6)[A].
    • Warfarin is contraindicated in pregnancy.
  • Precautions
    • Observe patient for signs of embolization, further thrombosis, or bleeding
    • Avoid IM injections. Periodically check stool and urine for occult blood; monitor CBCs, including platelets.
    • Heparin: thrombocytopenia and/or paradoxic thrombosis with thrombocytopenia
    • Warfarin: necrotic skin lesions (typically breasts, thighs, or buttocks)
    • LMWH: adjust dosage in renal insufficiency. May also need dose adjustment in pregnancy
  • Significant possible interactions
    • Agents that intensify the response to oral anticoagulants: alcohol, allopurinol, amiodarone, anabolic steroids, androgens, many antimicrobials, cimetidine, chloral hydrate, disulfiram, all NSAIDs, sulfinpyrazone, tamoxifen, thyroid hormone, vitamin E, ranitidine, salicylates, acetaminophen
    • Agents that diminish the response to anticoagulants: aminoglutethimide, antacids, barbiturates, carbamazepine, cholestyramine, diuretics, griseofulvin, rifampin, oral contraceptives
Second Line
  • Heparin 80 mg/kg IV bolus followed by 18 g/kg/hr continuous infusion
  • Adjust dose depending on aPTT.
  • In patients requiring large daily doses of heparin, measure an anti-Xa level for dose guidance.
  • Alternatively, for outpatients, weight-adjusted subcutaneous unfractionated heparin with 333 U/kg first, then 250 U/kg, without monitoring (6)[A]
  • Consider deficiency of antithrombin as a comutation in patients with significant elevated heparin requirements.
ISSUES FOR REFERRAL
  • Recurrent thrombosis on anticoagulation
  • Difficulty anticoagulating
  • Genetic counseling
  • Homozygous state in pregnancy
SURGERY/OTHER PROCEDURES
  • Anticoagulation must be held for surgical interventions.
  • For most patients with DVT, recommendations are against routine use of vena cava filter in addition to anticoagulation except when there is contraindication for anticoagulation (6)[A].
  • Thrombectomy may be necessary in some cases.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Complicated thrombosis, such as PE
Nursing
  • Teach LMWH and warfarin use.
  • See above for drug interactions.
Discharge Criteria
Stable on anticoagulation
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Warfarin use requires periodic (˜monthly after initial stabilization) INR measurements, with a goal of 2 to 3 (6)[A].
DIET
  • No restrictions
  • Large amounts of foods rich in vitamin K may interfere with anticoagulation with warfarin.
PATIENT EDUCATION
  • Patients should be educated about the following:
    • Use of oral anticoagulant therapy
    • Avoidance of NSAIDs while on warfarin
  • The role of family screening is unclear, as most patients with this mutation do not have thrombosis. In a patient with a family history of factor V Leiden, consider screening during pregnancy or if considering oral contraceptive use.
PROGNOSIS
  • Most patients heterozygous for factor V Leiden do not have thrombosis.
  • Homozygotes have about a 50% lifetime incidence of thrombosis.
  • Recurrence rates after a first thrombosis are not clear, with some investigators finding rates as high as 5% and others finding rates similar to the general population.
  • Despite the increased risk for thrombosis, factor V Leiden does not increase overall mortality.
REFERENCES
1. Lijfering WM, Middeldorp S, Veeger NJ, et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation. 2010;121(15):1706-1712.
2. Rosendaal FR, Koster T, Vandenbroucke JP, et al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995;85(6):1504-1508.
3. Eichinger S, Weltermann A, Mannhalter C, et al. The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism. Arch Intern Med. 2002;162(20):2357-2360.
4. Ye Z, Liu EH, Higgins JP, et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet. 2006;367(9511):651-658.
5. Prüller F, Weiss EC, Raggam RB, et al. Activated protein C resistance assay and factor V Leiden. N Engl J Med. 2014;371(7):685-686.
6. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(Suppl):7S-47S.
Additional Reading
&NA;
Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344(16):1222-1231.
See Also
&NA;
Deep Vein Thrombophlebitis
Codes
&NA;
ICD10
D68.51 Activated protein C resistance
Clinical Pearls
&NA;
  • Extremely rare in Asian and African populations
  • Asymptomatic patients with factor V Leiden do not need anticoagulation.
  • For pregnant women homozygous for factor V Leiden but no prior history of VTE, postpartum prophylaxis with prophylactic or intermediate-dose LMWH or vitamin K antagonists with target INR 2 to 3 for 6 weeks is recommended. Antepartum prophylaxis is added if there is positive family of VTE.