What is thrombophilia testing?

Thrombophilia testing is a set of blood tests to look for inherited conditions that are associated with an increased risk of venous thromboembolism (blood clots).

The tests should include testing for Factor V Leiden, prothrombin G20210A gene mutation, and deficiency of antithrombin and Protein C and Protein S.

Who should be tested for inherited thrombophilia?

Those patients who have had an unprovoked venous thromboembolism and have a family history of blood clots that have occurred below the age of 50 should be included. Other situations are controversial.

At World Thrombosis Day, we are concerned that testing for methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms continues to be ordered as part of thrombophilia testing, despite hard evidence showing this is not associated with an increased risk of clots. Unfortunately, if ordered by non-thrombosis experts who are not up-to-date, there is a risk of causing misinterpretation. This misinformation creates stress and confusion in patients and can lead to taking anticoagulants when there is no need.

The technical explanation of what went wrong:

The MTHFR story began in the 1990s when it was recognized that children born with the inherited metabolic defect homocystinuria and high blood levels of homocysteine had an increased risk for clots as well as multiple other problems. This led to a theory that mild increases of homocysteine might predispose to clots. It was also recognized that changes in the MTHFR gene could, if the patient had not taken enough folic acid, result in increased levels of homocysteine. We also learned that the MTHFR polymorphisms are very common, present in 60-70% of the population. Just under 50% of the population have one gene defect (a heterozygous defect), and over 10% were found to have two defects (a homozygous polymorphism).

Several very small studies in the 1990s did indeed suggest (but did not prove) that those with MTHFR changes had an increased risk of venous thromboembolism, and so MTHFR joined the list of assays on thrombophilia testing along with the “classic tests” such as antithrombin activity and genetic testing for Factor V Leiden that have been definitively associated with an increased risk of VTE. It was a compelling story – a common polymorphism leading to higher levels of homocysteine leading to thrombosis.

However, a few years later the results from large randomized clinical trials disproved this hypothesis, finding no difference in thrombotic rates in those with and without MTHFR polymorphisms. In fact, we now know that high levels of homocysteine may be a marker of other vascular risk factors, such as renal disease. The final piece of information to prove that MTHFR polymorphisms were not important, were multiple large clinical trials showing giving folate supplements (to remove the effects of MTHFR polymorphisms) showed no benefit. Given all of this scientific work, it is very clear MTHFR polymorphisms do not meet the criteria to be called an inherited thrombophilia and should be removed from thrombophilia panels.

And now all the guidelines agree! Multiple guidelines from professional society such as the American College of Medical Genetics 5, American College of Obstetricians and Gynecologists, British Society of Haematology, Society for Maternal-Fetal Medicine and the Choosing Wisely initiative of the American Board of Internal Medicine, all agree that MTHFR testing should not be part of thrombophilia testing.

While some laboratories have removed this test from thrombophilia panels, many are not up-to-date and still include MTHFR polymorphisms in their standard thrombophilia testing, which adds greatly to the costs to those paying for the tests, without bringing any benefit at all.

In summary:

MTHFR polymorphisms are not an inherited thrombophilia so they should not be included as part of a thrombophilia panel. Furthermore, patients who have these polymorphism should be reassured that this common finding does not place them at increased thrombotic risk and they do not, in fact, carry a thrombophilia. It is time for thrombosis experts to partner with patients and their laboratories and remove MTHFR polymorphism testing from existing thrombophilia panels, as is recommended by multiple professional societies and leading institutions. This will prevent unnecessary anxiety for patients and reduce healthcare spending.

World Thrombosis Day has created a number of resources for healthcare professionals and patients on thrombophilia testing and MTHFR. Click to view the Ask the Expert video featuring Beverley Hunt, M.D. and Jean Connors, M.D.

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