Thrombophilia

There is no universally accepted definition of thrombophilia. In practice, the term is used to describe patients who are at significantly increased long-term risk of venous thromboembolism (VTE). This may be on the basis of clinical or laboratory criteria.

The cause may be heritable, acquired or mixed.

Heritable causes

• Activated protein C (APC) resistance - the commonest cause of inherited thrombophilia; due to a single gene mutation - Factor V Leiden mutation.
• Protein S deficiency
• Prothrombin G200210A mutation
• Protein C deficiency
• Antithrombin deficiency
• Dysfibrinogenaemias

Acquired causes

• Antiphospholipid antibody:
  • Associated with both venous and arterial thrombosis.
  • May be primary (venous or arterial thrombosis, or recurrent first trimester abortions) or secondary (linked to other other conditions, e.g. systemic lupus erythematosus, collagenosis).
• Myeloproliferative disorders
• Cancer
• Hyperhomocysteinaemia due to mild folic acid, vitamin B12 or vitamin B6 deficiency
• Certain inflammatory conditions, e.g. inflammatory bowel disease
• Thrombocytosis
• Polycythaemia
• Paroxysmal nocturnal haemoglobinuria
• Behçet's disease
• Nephrotic syndrome
• Heart failure
• Recent myocardial infarction or stroke

The risk of VTE will also be influenced by other acquired factors such as age, obesity, immobility, surgery, hormone use, pregnancy and puerperium.

Mixed aetiology (heritable and environmental)

• Elevated factor VIII
• Hyperhomocysteinaemia

The frequency of some inherited thrombophilias is given in the table below. Patients may have more than one inherited thrombophilic condition, which will further increase their VTE risk.

Possible presentations are:

• A strong family history of venous thromboembolism
• VTE which is spontaneous or with minimal provoking factors
• VTE at a young age
• Thrombosis in an unusual site (e.g. mesenteric, portal vein, sagittal sinus thrombosis) or in multiple sites
• Recurrent VTE
• Recurrent miscarriage
• Neonatal thrombosis (e.g. neonatal purpura fulminans - rare)

History

Take a careful personal and family history:

• Specifically ask about VTE events.
• Enquire whether the VTE diagnosis was confirmed - if not, is the history plausible, was the patient anticoagulated?
• Were there any provoking factors for the VTE event (see Aetiology above)?

Who should be investigated for thrombophilia?¹

• Consider referral/investigation for patients with:
  • Spontaneous thrombosis, particularly at a young age, or associated with pregnancy.
  • Thrombosis at an unusual site, e.g. Budd-Chiari syndrome, sagittal sinus thrombosis.
  • Recurrent thrombosis.
  • Patients with VTE plus a first-degree relative with history of VTE.
• Bear in mind the limits of investigation. There may be heritable defects that have not yet been discovered. Therefore a normal thrombophilia screen does not guarantee that there is no increased risk of thrombosis in the future, or in another family member.
• Results may be influenced by other conditions/treatments, e.g. pregnancy, intercurrent illness, oestrogen-containing contraception, anticoagulation, etc. It may be better to test when these are no longer present, if feasible.
• Consider whether the test results will affect management:
  • The immediate treatment of VTE is not usually affected by a diagnosis of thrombophilia.
  • However, the results may be relevant in preventing further thrombosis, or for counselling other family members so as to reduce their risk of VTE. This particularly applies to women contemplating pregnancy, to reduce the risk of pregnancy-associated VTE (the most common cause of pregnancy-related death).

Family members:

• For relatives of someone with known heritable thrombophilia, consider investigation. This depends on the clinical scenario. Investigation will be more relevant for women contemplating pregnancy, hormonal contraception or HRT.
• Testing for heritable thrombophilia during childhood should be avoided, unless there is a very strong clinical indication.²

Investigation in pregnancy:³

• Women with previous VTE should be screened for inherited and acquired thrombophilia, ideally before pregnancy.

Tests for heritable thrombophilia²

Because of the complexity with interpreting results, and the need to provide specific advice and management for each individual patient, current guidance suggests that only physicians with a specialist knowledge should undertake screening tests for hereditary thrombophilia, and only after appropriate counselling of the patient.

The initial tests should include:

• Full blood count and film - for myeloproliferative disorders.
• Assays for antiphospholipid antibodies, factor V Leiden, prothrombin G20210A, protein C, protein S and antithrombin.
• The initial screen must also include APPT (activated partial thromboplastin time) and prothrombin time.
• Details of which assays to use are given in published guidelines.^2,4

Other possible investigations

• Full blood count and film - for myeloproliferative disorders, paroxysmal nocturnal haemoglobinuria, thrombocytosis, polycythaemia.
• ESR and/or CRP, antinuclear antibodies - for connective tissue disorders or inflammation.
• Clotting screen - prothrombin time, APTT, raised fibrinogen, raised prothrombin, raised Factor VIII, plasminogen, Factor XII.
• Homocysteine levels.
• Investigations for cardiac disease, liver disease, nephrotic syndrome, or other causes of acquired thrombophilia as appropriate.
• Consider occult malignancy and investigate appropriately.

Management of acute VTE

For an acute VTE, use standard treatment, i.e. heparin initially, followed (if not pregnant) by warfarin.

Minimising VTE risk

• Patients should be aware of their condition and how to recognise symptoms of VTE.
• Ensure mobility and adequate hydration.
• Extra precautions and short-term thromboprophylaxis may be needed at times of increased risk, e.g. surgery, immobility, pregnancy and postnatal.
• Avoid oestrogen-containing contraceptives and HRT:
  • These increase VTE risk (the extent of risk depending on the nature of the thrombophilia) - and should generally be avoided.
  • WHO guidelines state that known thrombogenic mutations, or a history of VTE, are absolute contra-indications to the combined contraceptive preparations.⁵
  • Progestogen-only contraceptives can be used.
• Pre-conception advice is important for women of childbearing age, especially if taking warfarin. More detailed guidance is available for this situation.²

Consider thromboprophylaxis²

The use of short- or long-term anticoagulation should be considered, weighing up the reduction of VTE risk against the risk of serious haemorrhage. This depends on the individual diagnosis and any other medical conditions. Guidelines suggest that, as a general rule:

• All patients with known thrombophilia or previous VTE - consider short-term thromboprophylaxis at times of increased VTE risk.
• Patients with a first VTE event - long-term anticoagulation is not indicated (the risks outweigh the benefits).
• Patients with ≥2 spontaneous VTEs - consider indefinite anticoagulation.
• Patients with recurrent VTEs linked to a provoking factor (e.g. surgery, pregnancy, oestrogen use) - may not require long-term anticoagulation, but do require prophylaxis during any further high-risk situations.
• Asymptomatic family members found to have a thrombophilic genotype - the risk of long-term anticoagulation outweighs the benefits. Consider short-term prophylaxis to cover periods of high VTE risk.

Pregnancy and postnatal

Pregnancy and the puerperium confer increased risk of VTE. Women with thrombophilia have a further increased risk (the extent of increased risk depending on the specific diagnosis). The risk is greater postpartum than antenatally.²

For prevention of VTE during pregnancy and the puerperium, detailed guidance is available from the Royal College of Obstetricians and Gynaecologists (RCOG).³ This covers both those with a previous VTE and those with known thrombophilia. As an overview:

• All pregnant women - assess risk factors for VTE; avoid immobility and dehydration.
• Depending on the likely VTE risk, thromboprophylaxis may be offered to cover the pregnancy and postnatally.
  • This may use low molecular weight heparin (LMWH).
  • Alternatively, low-dose aspirin may be appropriate in situations where the risk of VTE is increased, but is not deemed high enough to merit heparin.
• Women with known thrombophilia should be stratified according to the level of VTE risk associated with their thrombophilia and their other VTE risk factors (particularly any previous VTE):
  • Depending on the estimated level of risk, antenatal thromboprophylaxis is not always necessary. However, postnatal prophylaxis may be advisable (even if not requiring antenatal thromboprophylaxis) if there are other risk factors.
  • Antenatal thromboprophylaxis is indicated for pregnant women with combined thrombophilia defects, those homozygous for defects or those with antithrombin deficiency.
  • Women with antithrombin deficiency should always receive thromboprophylaxis in pregnancy and postnatally.
  • Women with symptomatic thrombophilia need specialist advice as to the optimal dose of LMWH.

• Complications of VTE.
• Complications of anticoagulation, if used.
• Heritable thrombophilia is associated with other pregnancy complications, including an increased risk of late fetal loss, pre-eclampsia and intra-uterine growth restriction.²
• Heritable thrombophilia does not seem to be linked to arterial thrombosis.²

• The prognosis for any individual will depend on their nature of the thrombophilia, and the size and site of any thrombosis.
• VTE is a multifactorial disease. The VTE risk depends not only on the specific thrombophilia (see table above), but also on other factors such as:
  • Family history and previous history of VTE.
  • The presence of any additional thrombophilia (heritable or acquired).
  • Other VTE risk factors (immobility, surgery, pregnancy, etc).
• Many individuals with heritable thrombophilia diagnosed only by laboratory investigation, will not have a thrombotic event.
• Failure to identify a thrombophilic defect on laboratory testing, does not prove that no thrombophilia exists.
• Clinicians may tend to overestimate the risk of thrombosis and underestimate the risks of anticoagulation.