A 44-year-old man develops a lower limb deep vein thrombosis with no apparent risk factors.
Should he be investigated for thrombophilia?
The British Committee for Standards in Haematology (1990) defines thrombophilia as ‘disorders of the haemostatic mechanisms which are likely to predispose to thrombosis’. This definition encompasses acquired and inherited thrombophilia. Acquired thrombophilic states include surgery, nephrotic syndrome, inflammatory disorders, hormone use and pregnancy. Inherited thrombophilia is a genetically determined tendency to thrombosis.
This definition is now widely used but has disadvantages. First, many individuals who carry these defects never have a thrombotic event. Secondly, despite an increasing number of thrombophilic risk factors that can be tested for, at least 50% of patients presenting with a history of thrombosis do not have an identifiable laboratory defect.1
A more clinically useful definition of thrombophilia is used in North America where the term is used to describe patients who have developed venous thrombosis either spontaneously or of a severity out of proportion to any recognized stimulus, patients who have recurrent venous thrombotic events and patients who develop venous thrombosis at an early age.
Thrombophilia screening includes measurement of the natural anticoagulants (protein C, protein S, antithrombin) and the common mutations, as shown in Table 6.1.
Table 6.1Thrombophilic defects |Favorite Table|Download (.pdf) Table 6.1 Thrombophilic defects
|Inherited ||Acquired – environmental ||Combined |
|Antithrombin deficiency ||Lupus anticoagulant ||Elevated factor VIII level |
|Protein C deficiency ||Dysfibrinogenaemia ||Elevated factor XI level |
|Protein S deficiency || ||Elevated factor IX level |
|Prothrombin gene mutation || || |
|Factor V Leiden mutation || || |
|Dysfibrinogenaemia || || |
Inherited thrombophilic defects
A small number of genetic variants are independent risk factors for venous thromboembolism (VTE). 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. Levels fluctuate and hence the finding of a low level of a natural anticoagulant on a single occasion is not diagnostic of primary deficiency and vice versa. There are no guidelines on the number of times that measurements should be repeated or on the extent of family testing required to confirm or exclude deficiencies in these anticoagulant proteins.
Activated protein C resistance and factor V Leiden
Factor V Leiden is the most common cause of inherited activated protein C (APC) resistance, defined as an impaired plasma anticoagulant response to APC added in vitro.
This impaired response is caused by a point mutation in the gene for clotting factor V (G1691A) rendering the protein more resistant to degradation. However, APC resistance may be acquired by those using an oestrogen-containing contraceptive pill, by pregnancy and by hormone replacement therapy. The effect is more ...