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Diagnosis

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FVL is suspected in individuals with an unprovoked first VTE prior to age 50, recurrent VTEs or a family history of VTEs. Diagnosis is established by either an APC resistance assay or DNA analysis for the specific factor V mutation. 

Diagnostic Testing and Evaluation

Diagnostic criteria

  • APC resistance assay shows minimal increase in activated partial thromboplastin time (aPTT) with introduction of APC to patient’s plasma. Often done as a precursor to DNA analysis.
  • DNA Analysis confirms the specific G-to-A substitution at nucleotide 1691 on the F5 gene encoding Factor V that causes a single amino acid replacement (R506Q)

First Diagnostic Steps

Obtain risk factor history

  • Factors suggestive of inherited thrombophilia:
    • Personal history of previous VTE
    • Family history of VTE
  • Factors suggestive of environmental contribution:
    • Recent surgery
    • Immobilization
    • Oral contraceptive use,  estrogen replacement therapy (3rd generation progestagen desogestrel), SERMs use
    • malignancy
    • Pregnancy
    • Central venous catheter
    • Smoking
    • Obesity
    • Other common VTE risk factors

Testing Strategy

Indications for testing

  • Definite
    • Unprovoked VTE, especially before the age of 50
    • VTE and history of first degree family member with VTE before age 50
    • VTE at unusual site such as cerebral, mesenteric, hepatic and portal venous systems
    • Recurrent VTE
    • VTE during pregnancy or postpartum period
    • VTE with concurrent estrogen contraception and hormone replacement therapy (HRT)
  • Possible
    • First provoked VTE before the age of 50
    • Recurrent unexplained first trimester pregnancy losses
    • Unexplained severe preeclampsia, placental abruption or severe intrauterine growth restriction
    • First VTE with concurrent use of tamoxifen or selective estrogen receptor modulators (SERMS)
    • Asymptomatic adult family member of someone with known Factor V mutation*
    • Female smoker under age of 50 with MI or stroke*
    • Neonate or children with unprovoked VTE or stroke*

*Disagreement among guidelines about whether to test these patients or not. Strategy based on test methodology
Available tests

  • APC Resistance Assay
      • Can be used in patients receiving anticoagulation and in the setting of acute thrombus, pregnancy, or inflammation
      • 2nd generation assay adds factor-deficient plasma so accurate results with concurrent warfarin or heparin use and with individuals known to have lupus inhibitors
      • Avoid use in patients with other known causes of prolonged aPTT, such as cirrhosis
      • If borderline APC resistance is found, DNA testing is recommended to confirm the diagnosis.
  • DNA testing
      • Recommended test following a positive APC resistance assay
      • Used to differentiate between heterozygous and homozygous mutations
      • Recommended when testing family members of known Factor V Leiden patients
      • More costly and time-consuming than resistance assay

Tests that are NOT helpful

  • Routine testing is not recommended for asymptomatic patients in the general population who are pregnant or initiating use of estrogen contraception, HRT or SERMS.
  • Testing is not recommended for patients with history of arterial thrombosis because arterial thrombosis has not been causally linked to FVL.
  • Coagulation markers, such as D-dimer, prothrombin fragment F1+F2, may be elevated at baseline for patients with FVL; however, testing for them is non-specific and non-diagnostic. 

Subsequent Diagnostic Evaluation

  • Patients with confirmed FVL should undergo additional testing for other thrombophilic disorders:
    • Prothrombin mutation
    • Anticardiolipin antibodies
    • Anti-beta-2 glycoprotein-1 antibodies
    • Phospholipid-dependent coagulation assay for lupus inhibitor
    • Protein C and S deficiency
    • Antithrombin deficiency

Lifestyle/Environmental Contributors to Disease

  • Pregnancy and the postpartum period ~ 8-52x increased risk - Even higher risk with obesity and advanced maternal age
  • Leg injuries – 50x increased risk
  • Oral contraceptive use with 3rd generation progestagen desogestrel – 50x increased risk
  • Oral contraceptive use – 30x increased risk
  • Extended travel – 14-16x increased risk
  • Malignancy – 12x increased risk
  • Obesity – 8x increased risk
  • Surgery – 5x increased risk
  • Tamoxifen use – 5x increased risk
  • Age (especially >60) – 3.6 increased risk 
  • HRT (estrogen and progesterone) – 2-4x increased risk
  • Evidence that transdermal estrogen carries less thrombotic risk than oral estrogen
  • Central venous catheter – 2-3x increased risk

Differential Diagnosis

  • Other thrombophilias
  • Prothrombin 20210G>A mutation
  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin deficiency
  • APC resistance without FVL allele
    • 5% of patients with APC resistance do not have an associated FVL mutation
    • Most likely the result of high Factor VIII levels, pregnancy, oral contraception use or antiphospholipid antibodies
  • Antiphospholipid antibodies
  • Hyperhomocysteinemia
  • Elevated clotting factor levels (Factor VIII,IX, XI, , prothrombin)

Consensus Statements and Guidelines

Grody WW, Griffin JH, Taylor AK et al. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001;3(2): 139-48.

Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait RC, Walker I, Watson H. Clinical guidelines for testing for heritable thrombophilia. Brit J Haematol. 2010;149(2):209–220.

Berg A et al. Recommendations from the EGAPP working group: routine testing for factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with history of idiopathic venous thromboembolism and their adult family members. Genet Med. 2011;13(1):67-76.