Leiden Mutation (Factor V) Causing Thrombophilia

Synonyms are 'Activated Protein C Resistance: Leiden Type' and 'Factor V:G1691A mutation'.

• Factor V Leiden mutation (named after the Dutch university where it was discovered) is a point mutation in the gene for clotting factor V.¹
• It has autosomal dominant inheritance and is the commonest cause of inherited thrombophilia.
• It leads to a hypercoagulable state. Heterozygous Factor V Leiden (FVL) mutation and the 20210G-A mutation in the prothrombin gene are the most frequent clotting abnormalities associated with venous thromboembolism.² The two mutations may co-exist.
• An individual may be heterozygote or homozygote for the FVL mutation. It is difficult to estimate the increased risk of thrombosis in given individuals, particularly heterozygotes, due to the variable penetrance of the thrombotic tendency (interaction with rest of genotype) and variation in other risk factors. One source states that heterozygous carriers have a 4 to 8 fold increased risk of VTE and homozygotes have an 80-fold increased risk.³
• The presence of major risk factors for thromboembolism such as obesity, immobility, surgery and pregnancy interacts with the thrombotic tendency caused by the mutation to provoke episodes of thrombosis. Episodes of VTE without co-existing risk factors are relatively infrequent.⁴

Factor V is one of the essential clotting factors in the coagulation cascade. Its active form, factor Va, acts as a cofactor allowing factor X to stimulate the conversion of prothrombin to thrombin. Thrombin is then able to cleave fibrinogen to fibrin and a fibrin clot is formed.

Activated protein C is a natural anticoagulant. It limits the extent of clotting by destroying factor V and reducing further thrombin formation. FVL mutation causes activated protein C resistance hence leading to the hypercoagulable state.

• FVL is present in 3-7% of Europeans and white North Americans.⁶
• The incidence of venous thromboembolism (VTE) amongst a community-based survey of carriers of the FVL mutation was found to be very low at 163 events per 100,000 person years.⁷

The condition is usually diagnosed following thrombophilia screening due to VTE in the patient or a close relative. It may also be detected after investigation for recurrent miscarriage.

• Screening tests for hereditary thrombophilia should only be carried out by physicians with a specialist knowledge who can explain the relevance of the findings to the patient and give any necessary therapy. The clinician needs to be wary of the long-term consequences of diagnosing the problem in terms of future life/health insurance etc.. Screening for thrombophilic disorders should not be conducted indiscriminately.
• Genetic testing can be performed. The polymerase chain reaction for the presence of the FVL mutation is 99% accurate. The separate article entitled 'Thrombophilia' describes general investigations for thrombophilia.

General

There is no evidence that the risk of venous thromboembolism is high enough to warrant long term anticoagulation in carriers of the gene, even in the homozygous state. Guidelines published by the British Society of Haematology in 2001¹ state that:

• Identification of thrombophilia should not influence decisions about the duration of anticoagulant therapy during a first thrombotic episode.
• In general, patients who have had two or more apparently spontaneous venous thrombotic events require consideration for indefinite anticoagulant thromboprophylaxis.
• All patients with a past history of VTE (with or without a thrombophilic defect) merit consideration for short-term thromboprophylaxis to cover periods of increased thrombotic risk (e.g. surgery, trauma, plaster casts, immobilisation, long distance travel).
• Affected (with an identifiable thrombophilia) but asymptomatic relatives of thrombophilic patients who have had a VTE should also be considered for short-term thromboprophylaxis to cover similar periods of increased thrombotic risk.

Factor V Leiden mutation and the COCP/HRT

• There is no evidence that routine screening of women starting the combined oral contraceptive pill (COCP) for the FVL mutation should be carried out.⁶
• The relative risk of venous thromboembolism is significantly increased but the absolute incidence of thromboembolic events is low and fatal pulmonary embolism is rare.⁶
• A study in the USA found that to prevent one venous thromboembolic death attributable to the use of the COCP in women with FVL mutation, > 92,000 carriers would need to be identified and stopped from using the pill.⁸ Such screening would not be cost effective and would potentially prevent 3-7% of women from using an effective and acceptable form of contraception.^6,9
• Screening should be considered in women with a history of previous VTE or a strong family history of VTE who wish to take the COCP. The same appears to be true for hormone replacement therapy.^9,6
• Women who are homozygous for the gene are up to 4 times more likely to suffer a thrombosis whilst taking the COCP, so alternative forms of contraception should be considered.⁴

Factor V Leiden mutation and pregnancy

Venous thromboembolism

• Inherited thrombophilia is present in 30-50% of women with pregnancy associated venous thromboembolism with factor V Leiden being the most frequently identified thrombophilia in the white population.¹⁰
• Heterozygotes who are pregnant have a 5–10 fold increase in the risk of VTE; homozygotes have a 50–100 fold increased risk.¹¹
• There is no robust randomised trial evidence upon which the decision to give prophylaxis against VTE or pregnancy loss in pregnant women with Factor V Leiden is based.^12,3,10 Current opinion is based on descriptive studies, consensus and clinical judgement of the benefits and risks of antithrombotic therapy in individual cases. Joint opinion of haematologist, obstetrician and patient should decide the issue in non-straightforward cases.
• The use of low molecular weight (LMW) heparin during pregnancy has been shown to be safe and effective in preventing VTE in susceptible patients with Factor V Leiden.³
• Homozygous women (or 'double' heterozygotes for V Leiden and prothrombin mutation G20210A/other thrombophilia) should be anticoagulated with LMW heparin.¹² They are considered as at higher risk of VTE.¹⁰
• Heterozygotes are not routinely anticoagulated but a personal or family history of VTE or other risk factors (e.g. obesity) may make them candidates for heparinisation.¹³ A history of another pregnancy complication such as pre-eclampsia, placental abruption or IUGR may also make them candidates for heparin prophylaxis.¹²
• Once a woman is in labour or thinks she is in labour, she should discontinue her heparin and be reassessed by medical staff on admission to hospital. Local guidelines should be followed.¹³
• Those considered to be in need of anticoagulation should receive warfarin for at least 6 weeks post partum, when the risk of VTE is high.¹² It is safe to breastfeed whilst taking warfarin.

Pregnancy loss

• Factor V Leiden mutation has been linked to an increased risk of early, late and recurrent pregnancy loss.^14,15,16

Other possible risks^3,17

• Pre-eclampsia
• Intrauterine growth retardation
• Placental abruption
• Fetal or neonatal stroke (further studies are needed to confirm this)

Screening

• At present there is no evidence to support routine screening for the mutation in pregnant women.^18,12 It does not appear to be cost-effective.¹⁹
• Those with a family or personal history of VTE should be considered for screening.^20,3,10,13
• Royal College of Obstetricians and Gynaecologists guidelines for the investigation and treatment of recurrent miscarriage suggest that women with recurrent miscarriage should be tested for the FVL mutation. Those with the mutation and evidence of placental thrombosis should be offered thromboprophylaxis. However, the guidelines state that randomised trial evidence for this is lacking.²¹