Heritable Thrombophilia

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The MDC provides a diagnostic referral service for genetic risk factors for venous thromboembolism (VTE), specifically for the identification of the FV Leiden mutation and the prothrombin gene variant (PGV).

Phenotypic assays to measure antithrombin, protein C and protein S, rare deficiencies of which are associated with increased risk for VTE, and also lupus anticoagulant screening, are available from the Blood Coagulation Laboratory at central site MFT.

Note: There is convincing evidence that homozygosity for the methylenetetrahydrofolate reductase (MTHFR) genetic variant C677T is not a risk factor for VTE. There is no rationale for MTHFR C677T genotyping for clinical diagnostic purposes in VTE, hence this is not offered by the MDC.

Background and general principles of heritable thrombophilia

Thrombophilia testing is not appropriate and should not be carried out unless the results may influence clinical management.

Thrombophilia is a multifactorial condition with heritable, acquired and circumstantial components which interact to give rise to an increased risk for VTE. VTE most commonly manifests as deep vein thrombosis (DVT) in the leg. This may progress to pulmonary embolism (PE) if the clot dislodges and travels to the lung. The incidence of venous thromboembolism (VTE) in the general population increases with age.

Up to 50% of individuals with VTE may have an identifiable heritable thrombophilia. This has led to a large demand for thrombophilia testing, despite the fact that there is frequently a lack of evidence in the literature that this testing has clinical utility. In most cases patient management is unlikely to be altered by the presence or absence of a thrombophilia risk factor.

Heritable thrombophilias include factor V Leiden (F5 gene c.1601G>A) and a prothrombin gene variant (F2 gene c.*97G>A) – PGV, both of which are common in Caucasians but generally rare in other ethnic groups, and deficiencies of antithrombin (AT), protein C (PC) and protein S (PS), all of which are rare.

The majority of the VTE events occurring in individuals with heritable thrombophilia are provoked by one or more predisposing factors, eg surgery, immobility, increasing age, pregnancy, combined oral contraceptive pill, malignancy.

The magnitude of risk associated with a positive thrombophilia test result is often perceived by the patient to be greater than it actually is, with associated negative psychological impact.

Testing for heritable thrombophilia is not indicated in unselected patients who present with a first episode of VTE.

Initiation and intensity of anticoagulant therapy following a diagnosis of acute VTE is not generally influenced by the presence or absence of a heritable thrombophilia. Patients with PC or PS deficiency, however, should have initiation of anticoagulation with low molecular weight heparin for an adequate period of time alongside Warfarin.

Decisions regarding duration of anticoagulation should be made taking into account whether or not a first VTE was provoked and considering the risk of anticoagulant therapy related bleeding, regardless of whether or not a heritable thrombophilia is known to be present.

Finding a common heritable thrombophilia (heterozygosity for FV Leiden or PGV) does not typically predict the likelihood of VTE recurrence. There is a higher recurrence risk in patients with AT, PC, or PS deficiency or with multiple defects.

Evidence suggests that thrombophilia testing does not reduce the risk of VTE recurrence in clinical practice.

Patients who have recurrently normal D-dimers after completion of anticoagulation therapy have a comparatively low risk of VTE recurrence.

Family testing

Thrombophilia testing of asymptomatic relatives of patients with a history of VTE has not been shown to reduce the incidence of VTE. The annual risk of unprovoked thrombosis in affected family members is low.

Case-finding of asymptomatic relatives with low risk thrombophilias such as heterozygosity for FV Leiden or PGV is not indicated. Screening for AT deficiency is warranted in family members of individuals with AT deficiency.

If family history suggests a high degree of genetic penetrance it may be informative to test symptomatic patients and their asymptomatic relatives with a view to informing clinical management at times of high thrombotic risk.

VTE has a clear familial component, independent of the presence or absence of a known thrombophilia risk factor. In symptomatic families negative thrombophilia test results may be falsely reassuring.

Combined Oral Contraceptive Pill (COCP)/HRT

Personal and family clinical history is key to identify women at risk of VTE. Unselected testing for heritable thrombophilia will provide an uncertain estimate of risk and is not warranted.

The absolute risk for VTE in previously asymptomatic women with FV Leiden or PGV using COCP or HRT is not high.

There is a substantial risk for VTE in women with AT, PC or PS deficiency, FV Leiden homozygosity, PGV homozygosity, or combined thrombophilia defects in association with COCP or HRT use. In these cases COCP or HRT use is contraindicated.

The baseline risk for VTE in women using HRT is higher than in women using COCP because the HRT-user population is older with a higher age-related risk for VTE.

Testing for heritable thrombophilia in selected cases may assist counselling of women considering COCP or HRT, for example if a high-risk thrombophilia has been identified in a symptomatic relative.

Irrespective of the presence or absence of a detected heritable thrombophilia, a personal history of VTE is a contraindication to COCP or oral HRT. The use of COCP by women with a family history of VTE in a first-degree relative aged under 45 years is not recommended. A family history of VTE in a first-degree relative is a relative contraindication to HRT.

VTE in pregnancy

There is a 5- to 10-fold increased risk for VTE during pregnancy. The risk is increased 100-fold in women with previous thrombosis.

In women with heterozygosity for FV Leiden or PGV, and no previous thrombotic history, the absolute risk for pregnancy-associated VTE is low. Women with AT deficiency, PC deficiency, PS deficiency, homozygosity for FV Leiden, homozygosity for PGV, or compound heterozygosity are at higher risk.

Women should be clinically assessed for risk of pregnancy-associated VTE. Testing for heritable thrombophilia is not generally required. Women with a previous unprovoked VTE should be tested for the presence of antiphospholipid antibodies.

In women with a VTE during pregnancy a screen for heritable thrombophilia (FV Leiden, PGV, AT deficiency, PC deficiency, PS deficiency) should be carried out 6 to 8 weeks after discontinuation of antithrombotic therapy. Screening for antiphospholipid syndrome should also be performed.

It may be clinically informative to test asymptomatic women with a family history of VTE if a thrombosis in a first-degree relative was unprovoked, or provoked by pregnancy, COCP use, or a minor risk factor, particularly if this is associated with a known thrombophilia.

Women with a family history of VTE and either AT deficiency or where a specific thrombophilia has not been detected should be tested for antithrombin deficiency.

Recurrent pregnancy loss

There is an association of FV Leiden and PGV with recurrent early and late pregnancy loss. However these are weak contributors to risk rather than the sole cause of pregnancy loss.

Testing for heritable thrombophilia is not recommended. Testing for the presence of antiphospholipid antibodies should be undertaken.

Recent large clinical trials of antithrombotic therapy have indicated no benefit of low molecular weight heparin in preventing recurrent early pregnancy loss in the absence of thrombophilia. Further research is required to determine if LMWH may improve live birth rates in women with recurrent pregnancy loss in the presence of thrombophilia.

Arterial Thrombosis

There is no established causal relationship between heritable thrombophilia and arterial thrombosis.

Testing for heritable thrombophilia is not indicated in patients with arterial thrombosis.

Children

Thrombophilia testing in children is only available after discussion with a clinical haematologist.

The annual incidence of VTE in children is about 1/100,000 in the general population. There is a bimodal distribution with peaks in the neonatal period and in adolescence.

More than 90% of paediatric thrombotic events are related to underlying medical or surgical risk factors, central venous lines in particular.

D-dimers should not be used to diagnose or exclude VTE in children.

Testing for heritable thrombophilia in unselected children presenting with a first VTE is not indicated. Testing has uncertain predictive value for recurrence.

Neonates and children with purpura fulminans should be tested urgently for PC and PS deficiency.

Children with early onset spontaneous thrombosis should be investigated for AT deficiency

Children presenting with unprovoked VTE should be tested for anti-phospholipid antibodies.

(Last reviewed October 2018)