1st June 2023

Thrombophilia

Thrombophilia refers to both congenital and acquired conditions, which increase susceptibility to thrombosis.

Congenital causes

• Proteins C and S deficiency

Proteins C and S prevent coagulation, as these proteins mainly inactivate factors V and VIII. Deficiencies in these proteins, therefore, lead to hypercoagulable states. If there is suspicion of Protein C and Protein S deficiencies following thrombosis, testing should only be offered to patients who are stopping anticoagulation as results can be affected by anticoagulants.

• Factor V Leiden

The genetic mutation, Factor V Leiden causes a defect in factor V, meaning that protein C cannot inactivate it. Factor V is then working to continuously activate downstream clotting factors, causing a hypercoagulable state. Following acute thrombosis, if there is suspicion of Factor V Leiden, testing should only be offered to patients who are stopping anticoagulation as results can be affected by anticoagulants.

Acquired causes

• Antiphospholipid syndrome

Antiphospholipid syndrome can present with arterial or venous thrombosis and/or recurrent miscarriages. The patient must have one of the clinical features to make a diagnosis alongside one of the laboratory markers. Detection of anticardiolipin antibody, lupus anticoagulant or anti-b2-glycoprotein I antibody on >2 occasions at least 12 months apart is diagnostic. The lupus anticoagulant activity may prolong the APTT, therefore prolonged APTT alongside thrombosis or recurrent miscarriages should raise the question of antiphospholipid syndrome. It is important to consider prophylactic treatments (warfarin or anti-platelets) for antiphospholipid syndrome to reduce the risk of complications. As soon as a pregnancy is confirmed and throughout the pregnancy, LMWH alongside low-dose aspirin is recommended for patients with antiphospholipid syndrome and recurrent miscarriages. When there is no history of recurrent miscarriages but a history of intrauterine growth restriction or pre-eclampsia, monotherapy with low-dose aspirin should be considered.

• Paroxysmal nocturnal haemoglobinuria (PNH)

The incidence of arterial and venous thrombosis in patients with PNH is approximately 10%. PNH can cause hemolysis, thrombosis, and haemoglobinuria as a result of stem cell malfunction. CD55 and CD59 on the surface of the cell (GPI-anchored proteins) are deficient due to a mutation in the PIGA gene. The deficiency of these proteins results in complement activation, haemolysis and thrombosis. PNH is diagnosed by flow cytometric analysis looking at antibodies to GPI-anchored proteins. Treatment is with eculizumab or ravulizumab.

• Myeloproliferative neoplasms

Myeloproliferative neoplasms include polycythaemia vera, essential thrombocythemia and myelofibrosis. These conditions can cause venous and arterial thrombosis. Other signs of the underlying disorder would be present on the FBC, for instance thrombocytosis in essential thrombocythemia. On a peripheral blood sample, testing for JAK2, CALR and MPL can be sent. Myeloproliferative neoplasms are often associated with these mutations and identifying if a mutation is present can also guide treatment, for instance, by using a JAK2 inhibitor. A bone marrow biopsy may be required.