Thrombophilia testing: what do we think the tests mean and what should we do with the results?

Inherited thrombophilia is a genetically determined tendency to thrombosis. In 1965 the first family with antithrombin deficiency was described, and for many years this was the only identifiable cause of thrombophilia. More recently, pedigree and case–control studies have confirmed that the risk of venous thrombosis is increased by deficiencies of antithrombin, protein C, and protein S, and by resistance to activated protein C. Other candidate genetic factors are included in table 1. The value of obtaining laboratory evidence of thrombophilia is the ability to predict the likelihood of recurrence in symptomatic patients and the risk of thrombosis in their relatives. Thus thrombophilia testing would be used to optimise the benefit/risk ratio of anticoagulant treatment. Therapeutic recommendations would have to be based on a risk–benefit analysis that considers the risk of the disease, the eVectiveness of treatment, the risk of treatment, and the predictive value of the laboratory tests used to establish the diagnosis of thrombophilia. Venous thromboembolism is a common disease with a significant risk. The risk of death from recurrence in the first three months after a pulmonary embolus is 1–2%. The risk of recurrence of deep vein thrombosis is 17.5% after two years and 24.6% after five years. Treatment with oral anticoagulation is extremely eVective as long as the international normalised ratio (INR) is maintained above 2.0. 9 However, this treatment is potentially dangerous—in any one year there is a 1% chance of a major haemorrhage, and one quarter of these are fatal. Therefore the disease carries a high risk, and treatment, while eVective, is also associated with significant danger. The ability to distinguish patients at high and low risk of thrombosis would help to optimise therapeutic decisions. The identification of laboratory evidence of thrombophilia would seem a rational way to achieve this. Evidence based guidelines are currently limited to grade C recommendations. 11 12 However, level I evidence is becoming available which will form the basis of grade A recommendations. 14 How might thrombophilia testing be used to help decide when and how to treat patients? Before beginning to answer this question, consideration must be given to the accuracy of the laboratory tests used to “diagnose” thrombophilia. Potential diagnostic inaccuracy was clearly illustrated by the Leiden group in 1993, when they published a report of a series of protein C deficient symptomatic families. There was a significant overlap of protein C levels in aVected and unaVected members of families with mutations aVecting the protein C gene. Distribution curves of protein C activity indicated that unaVected family members could have levels as low as 40% while aVected members could have levels as high as 100% of normal. It is also clear that some laboratory methods produce discordance between phenotype and genotype. 17 Therefore phenotypic testing will not identify or exclude a thrombophilic genetic defect with complete accuracy. While genetic testing for the factor V Leiden or F2G20210A mutations is relatively simple, the risk of venous thrombosis associated with these defects is only modest. The highest relative risk is associated with mutations aVecting the functional plasma levels of the natural anticoagulants antithrombin, protein C, and protein S. In these cases the extent of possible mutations excludes routine genetic testing. Therefore the finding of a low level of a natural anticoagulant on a single occasion is not diagnostic of primary deficiency of a natural