see also:

• deep venous thrombosis (DVT)
• pulmonary embolism (PE)

• thrombophilia is a term generally used for persons with a hereditary risk of venous thrombosis due to hypercoagulability
• such patients are at increased risk of venous thrombosis such as:
  • deep venous thrombosis (DVT)
  • pulmonary embolism (PE)
  • upper limb DVT
  • hepatic vein thrombosis and Budd-Chiari syndrome (BCS)
  • splanchnic vein thrombosis (SVT)
• patients with lupus anticoagulant are also at risk of arterial thrombosis and recurrent miscarriages
• patients aged under 40yrs with spontaneous deep venous thrombosis (DVT) or pulmonary embolism (PE) without obvious precipitating cause (such as surgery, long travel, injury, or cancer), are usually investigated for thrombophilia with a “thrombophilia screen” batch of blood tests which generally include:
  • factor V Leiden
  • lupus anticoagulant (an acquired auto-immune condition which results in the antiphospholipid syndrome)
  • antithrombin III deficiency
  • protein C deficiency
  • protein S deficiency
• other haematologic conditions predisposing to thrombosis:
  • JAK2 V617F mutation with or without essential thrombocytosis or overt myeloproliferative neoplasm mainly associated with splanchnic vein or cerebral vein thromboses
• high VTE polygenic risk score people
  • polygenic risk score for DVT includes rs6025 (FVL) (effect allele T; allele frequency, 0.02) in the F5 gene and rs1799963 (PTM) (effect allele A; allele frequency, 0.01) in the F2 gene
  • 6x more likely to develop DVT in 1st 2yrs of combined oral contraceptive pill (OCP) use, twice the rate of all women; Those with high polygenic risk score AND Factor V Leiden and prothrombin variant carrier had 9-23x risk (HR 14.8 95% CI, 9.28–23.6)! ¹⁾

• patient has commenced on anticoagulant Rx
• routine screening not recommended:
  • obvious precipitant (eg. post-op, trauma, immobilization, active cancer)
  • prior screening negative
  • thrombosis risk not life threatening or not likely to be due to thrombophilia
    • arterial thrombosis
    • upper limb thrombosis
    • retinal vein thrombosis
    • heparin-induced thrombocytopaenia with thrombosis
    • pre-eclampsia
    • systemic lupus erythematosus (SLE)
    • inflammatory bowel disease (IBD)
    • myeloproliferative disorders
• lack of cost effectiveness
  • even a positive thrombophilia screen may not substantially alter risk of recurrent VTE and thus may not need to alter duration of anticoagulant Rx:
    • screening results appeared to alter Mx in only ~20% of patients with unprovoked VTE ²⁾
      • in reality though, Mx should probably only differ if patient is found to have antiphospholipid syndrome (APS) or multiple hereditary prothrombotic disorders and thus perhaps only 1-2% would have change in Mx
    • whether or not a thrombophilic condition is identified, all patients with idiopathic VTE are at substantial risk for recurrence and the presence of VTE event is a much stronger determinant of recurrence than an underlying thrombophilia
    • recurrence of VTE over 3 years is NOT higher in those with a positive screen whether or not they had extended anticoagulation Rx ³⁾
    • recurrence of VTE is NOT higher in those with a positive screen than in those with unprovoked VTE with a negative screen
      • Leiden Thrombophilia Study - risk of recurrence similar in positive vs negative screening
      • Ridker et al. N Engl J Med. 2003;348(15):1425 - low intensity long term warfarin Rx reduced risk of recurrence with risk reduction similar whether screening positive or negative
      • Hron et al. Am J Med. 2006;119(1):50 - A family history for venous thromboembolism does not segregate patients into high- or low-risk categories
      • heterozygosity for factor V Leiden is only a modest risk factor for a first episode of DVT and is most likely NOT associated with an increased risk for recurrent DVT ⁴⁾
• risk of over-aggressive Rx and family anxiety/stress if positive screen

• ~50% of patients with idiopathic venous thrombosis have an underlying thrombophilia - although this may not be clinically important - see above
  • patients with recurrent venous thromboembolism who have lupus anticoagulant may benefit from INR target higher than normal (eg. higher than the usual target of 2.0-3.0)
• identifies the 1-2% with multiple prothrombotic defects who have very high risk of VTE
  • such patients may benefit from 12 months, or in some cases, life long anticoagulation to prevent venous thromboses
• may prevent initial VTE in asymptomatic family members, particularly those considering OCP or pregnancy
  • relatives with no thrombophilic defects have 1st VTE risk of 0.05%/year
  • relatives with low risk thrombophilic defects (factor V Leiden, the prothrombin gene mutation, or elevated levels of factor VIII) have 1st VTE risk of ~0.4%/year
  • relatives with high risk thrombophilic defects (deficiencies of antithrombin, protein C, or protein S) have 1st VTE risk of ~1.7%/year
  • women with a prothrombotic mutation who are taking oral oestrogen have a 25-fold greater risk of venous thrombosis than women without the mutation who are on oestrogen (see also combined oral contraceptive pill (OCP))

• strong FH of VTE
• unprovoked 1st VTE and patient's desire for testing after discussion of pros and cons

• antithrombin III, protein S, and protein C levels may be increased during acute thromboembolism.
• thus, both protein assays and functional assays of these proteins could be inaccurate during the acute phase of thromboembolic disease
• anticoagulation Rx will affect testing
  • however, protein C or protein S deficiency can be confirmed in the patient by testing after warfarin has been discontinued for two weeks under the cover of intravenous or subcutaneous heparin or subcutaneous low molecular weight heparin at therapeutic doses
• most now recommend timing of thrombophilia screening to occur at least 2wks after ceasing the initial 3-6 month anticoagulant Rx course

• patients with an unprovoked VTE should have basic malignancy screening (as cancer prevalence is ~12% and most will be suggested by this initial screening, most common associated with VTE are haematologic, ovarian, pancreatic, liver, renal, and lung) including:
  • history and exam looking for malignancy
  • PR exam
  • PV exam
  • FBE, U&E, ESR, CaP, LFTs
  • urinalysis
  • routine age-appropriate cancer screening
  • CXR
  • NB. routine CT abdo scan is probably not indicated as, although it increases cancer detection rate, it does not appear to improve mortality