24th July 2024

Thrombophilia

Overview of thrombophilia

Thrombophilia is a predisposition to clot formation and manifests clinically as VTE. These causes will be discussed:

• Factor V Leiden (FVL)
• Proteins C and S deficiency
• Antiphospholipid syndrome (APLS)

When the aetiology of a VTE is not known, it may be tempting to investigate whether there is an underlying thrombophilia. However, NICE only recommends screening for these conditions in certain circumstances:

• Consider testing for APLS in patients with unprovoked VTE where there are plans to stop anticoagulation
• Consider testing for hereditary thrombophilia in patients with unprovoked VTE who have a first-degree relative who has had a VTE and where there are plans to stop anticoagulation

These tests should not be offered routinely to family members of patients with a history of VTE. When thrombophilia testing is performed whilst patients are on anticoagulation the results will have to be interpreted with caution as they may be affected by the medication.

Factor V Leiden

FVL is the most commonly inherited thrombophilic condition in caucasian populations and is an autosomal dominant condition. Most patients are heterozygotes. Though many may have the genotype, only around 5-10% develop VTE. Homozygotes have a higher risk of VTE than heterozygotes.

Factor V is a key component of the conversion of fibrinogen to fibrin and, therefore, clot production. Protein C is an endogenous anticoagulant, inhibiting factor V. In FVL a mutation factor V means it cannot be inactivated by protein C and thus, more fibrin can be produced and clots formed.

Screening for FVL is only required in those who present with recurrent VTE, those at a young age with no other obvious risk factor and those with unusual clot location, e.g. cerebral vein. FVL testing includes genetic testing and functional aPC (activated protein C) resistance testing (higher values in FVL). Functional resistance can be affected by DOACs and in these cases genetic testing may be more reliable.

Management of a confirmed VTE is the same in FVL patients as in those without.

Protein C deficiency

Protein C is a vitamin K-dependent anticoagulant whose main role is to inactivate factor V. Low levels can, therefore, lead to a prothrombotic state. Deficiency can either be inherited or acquired – secondary to conditions such as liver disease, use of vitamin K antagonists, infection and uraemia.

The vast majority of patients remain asymptomatic. Skin necrosis as a side effect of warfarin is more prevalent in those with protein C deficiency.

Diagnosis is by demonstrating low protein C levels. Acquired cases tend to have higher levels than inherited forms.

If VTE is confirmed, warfarin is to be avoided if possible, and another anticoagulant used. No other specific management is required.

Protein S deficiency

Protein S works synergistically with protein C to inactivate factor V. As with protein C, a deficiency of protein S leads to a prothrombotic state. It also is dependent on vitamin K. Conditions such as nephrotic syndrome, liver failure, pregnancy and oral contraceptive use lead to lower levels of protein S.

Free protein S levels can aid diagnosis, though can be complicated by the fact that these vary within the population.

If a patient has confirmed VTE and protein S deficiency the choice of anticoagulant does not differ from regular management.

Antiphospholipid syndrome

APLS is an autoimmune condition that presents with both venous and arterial thrombosis as well as obstetric complications such as first trimester miscarriage.

The exact mechanism of thrombus generation in APLS is not known, however it is thought that the presence of antiphospholipid antibodies along with minor vascular injuries or increased inflammation predispose the body to vascular events.

Investigations in APLS

General screening is not recommended. Testing should be aimed at those with a high probability of having APLS, such as patients with clots in unusual locations, unprovoked VTE in under 50s and obstetric complications associated with autoimmune disease.

Diagnosis is made using clinical and serological features:

• Clinical features suggestive of APLS include arterial and venous clots and complications in pregnancy, such as recurrent miscarriage or intrauterine growth restriction
• There must be positive serology in the form of lupus anticoagulant, anti-cardiolipin antibodies or anti-beta2 glycoprotein. The antibodies must be present on at least two occasions, 12 weeks apart. Antiphospholipid antibodies alone do not satisfy the criteria for APLS diagnosis

Management of APLS

Often, anticoagulation is given indefinitely.

In non-pregnant patients, LMWH followed by long-term use of warfarin is the standard treatment. INR targets vary. In those with confirmed APLS and a first venous thrombosis, INR target should be 2-3. However, if there is an arterial thrombosis, the INR target should be >3 or 2-3 with aspirin.

Pregnant women should be treated with LMWH only.

Risk factor modification is vital and patients should be encouraged to modify traditional cardiovascular risk factors such as obesity, smoking and hyperlipidaemia.

References

• Bauer, K. Factor V Leiden and activated protein C resistance [Internet]. Leung L, Tirnaeur J, editors. UpToDate. 2021 [cited 3 January 2022]. Available from: https://www.uptodate.com/contents/factor-v-leiden-and-activated-protein-c-resistance
• Bauer, K. Protein C deficiency [Internet]. Leung L, Tirnaeur J, editors. UpToDate 2021 [cited 3 January 2022]. Available from:https://www.uptodate.com/contents/protein-c-deficiency
• Bauer, K. Protein S deficiency [Internet]. Leung L, Tirnaeur J, editors. UpToDate 2021 [cited 16 June 2022]. Available from:https://www.uptodate.com/contents/protein-s-deficiency
• Breen KA, Hunt B. Antiphospholipid syndrome [Internet]. BMJ Best Practice. BMJ Publishing Group; 2021 [cited 16 December 2021]. Available from: https://bestpractice.bmj.com/topics/en-gb/469
• Schreiber, K., Sciascia, S., de Groot, P. et al. Antiphospholipid syndrome., Nature Reviews Disease Primers. 17103. 2018 [cited 16 December 2021]. https://doi.org/10.1038/nrdp.2017.103
• NICE Guidelines. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. March 2020 [cited June 16 2022]. Available from: https://www.nice.org.uk/guidance/ng158/chapter/Context