Thrombophilia

The term thrombophilia is used to describe disorders of the haemostatic mechanisms which are likely to predispose to thrombosis. There are many conditions in which this state may occur, some of which are congenital/hereditary and others which are acquired.¹ Prothrombotic states may be:²

• Heritable: a limited number of genetic variants are proven to be independent risk factors for venous thromboembolism. These include mutations in the genes encoding the natural anticoagulants antithrombin, protein C and protein S, and the clotting factors fibrinogen, prothrombin and factor V.
• Combined thrombophilias: because of the high prevalence of factor V Leiden and the prothrombin 20210A mutation in many populations, individuals and families with more than one heritable thrombophilic condition are encountered. The prevalence of thrombosis is often higher in family members with combinations of thrombophilic conditions.
• Acquired: the main acquired thrombophilic abnormality is the antiphospholipid antibody which can be associated with both venous and arterial thrombosis. The antiphospholipid antibody can be primary when it is only associated with venous or arterial thrombosis, and with recurrent first trimester abortions. The antibody is described as secondary when it is found in conjunction with other conditions, e.g. systemic lupus erythematosus.
• Mixed: the result of the environment (e.g. pregnancy, combined contraceptive pill, HRT, obesity, immobility, trauma, surgery, malignancy and chronic inflammatory conditions) interacting with genetic background.

• Activated protein C (APC) resistance: commonest cause inherited thrombophilia; caused by a single point mutation - Factor V Leiden mutation
• Protein C deficiency
• Protein S deficiency
• Deficiency of antithrombin III
• Hyperhomocysteinaemia
• Prothrombin G200210A polymorphism
• Elevated levels of Factors I,II, VIII, IX and XI
• Elevated levels of von-Willibrand Factor (vWF)
• Dysfibrinogenaemias

• The presence of antiphospholipid antibodies, e.g. antiphospholipid syndrome, SLE or Hughes' Syndrome³
• Cancer (increases risk x 7 )
• Hyperhomocysteinaemia due to mild folic acid, Vitamin B12 or B6 deficiency
• As a result of some persistent inflammatory conditions e.g. inflammatory bowel disease
• In association with myeloproliferative disorders.
• Thrombocytosis
• Polycythaemia
• Paroxysmal nocturnal haemoglobinuria
• Behcet's disease
• Nephrotic syndrome
• Heart failure
• Recent myocardial infarction or stroke

Thrombophilia should be suspected if there is a strong family history of venous thromboembolism, thrombosis in an unusual site (e.g. mesenteric, portal vein), in a young person (aged under 40 years) or recurrent episodes. Thrombophilia may present in many different ways depending on the underlying cause and the age at presentation. The clinical manifestations may include:

• Venous thromboembolism occurring at a young age. May present with unexplained neonatal thrombosis.
• Thromboses affecting more than one site typically involving the larger vessels e.g. of the brain, heart, lungs and limbs resulting in strokes, myocardial infarctions, pulmonary embolus and deep venous thrombosis. Myocardial infarction and/or stroke may occur at a young age without any additional risk factors
• Recurrent miscarriage
• Pre-eclampsia
• Family history of thromboembolism

Because of the difficulty in interpretation of results and the need to provide specific advice and management for each individual patient, the 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.⁴

• When an individual is thought to have a hereditary form of thrombophilia, it is now possible to perform a range of tests in order to determine the precise mutation.
• It has been suggested that the range of tests performed should include, Factor V Leiden, prothrombin G20210A, protein C, protein S and anti-thrombin III deficiency mutations.
• Although the polymerase chain reaction for the presence of the factorV Leiden mutation is 99% accurate, the other tests are less so, and are influenced by various factors such as age, gender, pregnancy, the pill or HRT and use of anti-coagulants.
• Other appropriate screening tests include:
  • Clotting screen: prothrombin time, APTT, raised fibrinogen, raised prothrombin, raised Factor VIII, plasminogen, Factor XII
  • Full blood count and film: myeloproliferative disorders, paroxysmal nocturnal haemoglobinuria, thrombocytosis, polycythaemia
  • ESR and/or CRP, antinuclear antibodies: to screen for possibility of connective tissue disorders
  • Homocysteine levels
  • Investigations for cardiac disease, liver disease, nephrotic syndrome and other causes acquired thrombophilia as appropriate
  • Consider occult malignancy and investigate appropriately
• Some believe that thrombophilia testing should not routinely be performed on young people who have already suffered a thrombosis as the results are unlikely to change the management. They may however be appropriately used in those patients with a strong family history of venous thrombosis, or a history of recurrent miscarriage.

As the current guidance suggests that only physicians with a specialist knowledge should undertake screening tests for hereditary thrombophilia, consideration must be given to referring patients with²:

• Thromboses without apparent cause, occurring at a young age or in association with pregnancy.
• Thromboses at an unusual site e.g. sagittal sinus thrombosis.
• Any patient with recurrent thromboses.
• Patients with a first thrombosis, who also have a first degree relative with a history of thromboses.
• Patients with a history of recurrent miscarriage (3 or more) for which no other cause is evident.

All patients with a thrombophilic state need to be given advice as to how to minimise their risk of thrombotic episodes. This should include advice on:

• Mobilisation
• Adequate hydration
• The use of graduated compression stockings or mechanical compression devices during periods of immobility
• The use of combined oral contraceptives and HRT
• Pre-pregnancy counselling

Drugs

• Aspirin at a dose of 150mgs per day may be used as prophylaxis in some patients with thrombophilia with no previous thromboembolism.
• Low molecular weight heparin may be used as prophylaxis peri-operatively or during pregnancy.
• Patients who have had a thrombotic episode may be treated with warfarin .Heparin should be used in addition to warfarin initially until the INR has reached a level of 2.0-3.0. After a confirmed thrombosis, oral anticoagulation should be continued for a period of at least 3 months.⁵ Oral anticoagulation may need to be continued on a long term basis if the thrombophilic state continues, and this decision should be taken in conjunction with local specialists.

The prognosis for any individual will depend on the cause of the thrombophilia, and the size and site of any thrombosis. Death or significant morbidity occurs most frequently as a result of pulmonary embolus, CVA or MI.