The first reference to factor V Leiden (FVL) is in a letter to the journal Nature by Bertina and colleagues1 from the University of Leiden in the Netherlands. This is now a citation classic, having been cited a remarkable 3,279 times (Google Scholar - accessed 14 May 2012). The paper followed the key discovery by Dahlback of an autosomal dominantly inherited form of activated protein C resistance which was associated with a predisposition to venous thrombosis2. A point mutation in the factor V gene that causes a missense mutation in the protein (Arg506Gln, factor V Leiden) renders the molecule less susceptible to inactivation by activated protein C. The mutation is found in 3–7% of the healthy Caucasian population and is associated with a sevenfold increase in the risk of thrombosis3.
The presence of the FVL defect is associated with venous thromboembolism as well as with recurrent miscarriage and other pregnancy complications such as severe preeclampsia, growth retardation and stillbirth. Testing for FVL is fairly straightforward because in practise it is usually associated with a single mutation3. Just because a test is easy to perform however, does not mean that there is value in performing it, unless knowledge of the result alters the management of the affected individual. It is sometimes assumed that identification of a positive result is always going to be helpful but positive patients frequently suffer from psychological anxiety as a result of knowing they have a genetic disease, may suffer higher insurance premiums, and there is an actual monetary cost associated with performance of the test.
In this issue of Blood Transfusion, Franchini4 and, Favaloro and McDonald5 debate the utility of FVL testing. The clinical utility of a test is its ability to influence or alter a clinical outcome. Franchini describes the background to the development of the FVL test and supports the recommendations of the American College of Medical Genetics in selecting categories where testing for FVL is justified, but also argues for the addition of blood donors to these categories4,6. With the aim of improving blood donor safety, the Italian authorities recommend avoidance of donors who are homozygous for FVL or who have combined thrombophilia but the reference is in Italian and we do not know the precise reasoning behind this recommendation. Even if it is accepted that these thrombophilic individuals are at some risk, it must be questionable whether it is justified to screen blood donors to identify these individuals especially since the prevalence of homozygous FVL in the population would be expected to be around 1 in 1,000.
In discussing the futility of FVL testing, Favaloro and McDonald take the opposite view5. The authors observed a dramatic year on year increase in the number of requests for FVL testing in their laboratory service which was accompanied by a concomitant reduction in the number of positive tests, suggesting that tests were being requested inappropriately. Thus, despite the presence of recommendations on who to test for FVL, clinicians are not following these and continue to request the test unselectively. The authors conclude that in the majority of cases FVL testing will actually have a negative impact on identified individuals and their relatives, and clinicians should be discouraged from testing on the basis of theoretical benefits.
The issue of thrombophilia testing in general has been tackled by a number of publications including recently the British Committee for Standards in Haematology7. A common finding of many guidelines is, that although testing will identify cases, the evidence that knowledge that an individual is a carrier of a thrombophilic defect rarely influences management.
Ultimately the decision of whether to test or not comes from the definition of the term “utility”, if knowing the result will affect your management you should test, but unfortunately this is rarely followed when referring to FVL.
Footnotes
The Author declares no conflicts of interest.
References
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