Direct to consumer thrombophilia testing approved–a good thing?

Approved list from FDA Press Release

On April 6, 2017, the FDA  approved marketing of 23andMe Personal Genome Service Genetic Health Risk tests for 10 diseases or conditions.(FDA Press Release 4-6-17) No prescription or physician needed. These are the first direct-to-consumer tests authorized by the FDA that provide information on an individual’s genetic predisposition to certain medical conditions.  Among them, hereditary thrombophilia.

The “hereditary thrombophilia” wording used in the FDA release is a very broad term. There are multiple genetic variants which have been shown to correlate with increased clot risk including heterozygous & homozygous Factor V Leiden, prothrombin 20210 and deficiencies of antithrombin, protein C and protein S.

So a question I posed to both the FDA and the company 23andMe was 1) Which specific thrombophilias does the panel test for and 2) to what specificity—ie do results only indicate the presence of a gene mutation or does it report whether the mutation is heterozygous or homozygous.

Two most common thrombophilias included

The company replied with the following information:

“The 23andMe PGS Genetic Health Risk Report for Hereditary Thrombophilia is indicated for reporting of the Factor V Leiden variant in the F5 gene, and the Prothrombin G20210A variant in the F2 gene. This report describes if a person has variants associated with a higher risk of developing harmful blood clots, but it does not describe a person’s overall risk of developing harmful blood clots. This report is most relevant for people of European descent.”

The FDA responded with identical wording and indicated more details may be in the de novo pathway Decision Summary for the product, which may not be publicly posted for some time due to the need for review by the Freedom of Information staff.

What does this mean?  23andMe’s genetic test will include the 2 most common thrombophilias–Factor V Leiden and Prothrombin 20210 mutations.

Factor V Leiden thrombophilia is the most common thrombophilia in the United States. “Between 3 and 8 percent of people with European ancestry carry one copy of the factor V Leiden mutation in each cell (heterozygous mutation), and about 1 in 5,000 people have two copies of the mutation (homozygous mutation). The mutation is less common in other populations.” (Source: NIH Genetics Home Reference, US National Library of Medicine)  The heterozygous mutation increases clot risk 5 fold, the homozygous mutation increases clot risk 18 fold. (see chart source below)

Prothrombin thrombophilia is the second most common inherited form of thrombophilia after factor V Leiden. “Approximately 1 in 50 people in the white population in the United States and Europe has prothrombin thrombophilia. This condition is less common in other ethnic groups, occurring in less than one percent of African American, Native American, or Asian populations.” (Source:  NIH Genetics Home Reference) The heterozygous form of the mutation increases clot risk 4 fold; no data was available on homozygous risk.(See source chart below)

Why testing may (or may not) be helpful.

First, to be clear, when we are talking about a genetic thrombophilia, what we’re truly talking about is not a disease but rather a specific gene mutation that results in an increased tendency to form abnormal blood clots known as deep venous thrombosis (DVT). DVTs are fairly common–impacting ~900,000 Americans annually–and occur most often in the legs, although they can also occur in other parts of the body such as the arm, brain or abdomen. DVTs which travel to the lungs result in pulmonary embolism (PE), which is a potentially life-threatening condition. In the US, pulmonary embolism deaths outnumber those from breast cancer, AIDS and car accidents combined.

Inherited thrombophilias are found in around half of all DVT/PE patients.

Inherited thrombophilias are found in around half of all DVT/PE patients.(Source) So what a thrombophilia test does is look for a gene mutation which is correlated with an increased risk for developing these types of deadly clots.  Sounds desirable, yes?  The rub is that not everyone with the genetic mutation will develop a blood clot.  In the most common thrombophilia, Factor V Leiden, only about 10 percent of individuals with the factor V Leiden mutation ever develop abnormal clots. (Source)  Blood clots are often the result of a combination of risk factors–such as hospitalization, cancer, long-duration travel, surgery, pregnancy, estrogen containing oral contraceptives in addition to thrombophilia.(Source)

With that said, there is a subpopulation of thrombophilia patients at very high risk for developing a blood clot.  These are the patients for whom access to thrombophilia testing would potentially be life-altering. The following chart (Source ) is helpful to illustrate:

Lim, Moll,Thrombophilia Vasular Medicine, 2015

Put into perspective

I have publicly disclosed previously that I have a high-risk thrombophilia–homozygous Factor V Leiden.  You will notice in the chart above, that means my risk for developing a blood clot is 18 times greater than someone without the mutation.  Indeed, the statistics bore out and I developed both DVT and PE in 2003 for which I was hospitalized 9 days and, without exaggeration, nearly died from my clot. I am now on life-long treatment to prevent a recurrence. Most folks would agree that’s something pretty bad to avoid if possible.

The question then is:  If I’d known I carried this high-risk mutation years earlier, could I have taken steps to reduce my risk and avoid the clot? Absolutely. Effective prevention strategies exist. For one, I would not have chosen to take an estrogen based oral contraceptive (which further increased my clot risk) and when I suffered from pregnancy complications, my physician and I would have better understood the potential cause and managed it better as a high risk pregnancy. (pregnancy and c-section both increase clot risk). So, in theory, if I’d known earlier I had a high-risk thrombophilia, it would have altered my lifestyle and medical decisions in such a way that, perhaps, my eventual DVT/PE episode as well as pregnancy complications could have been avoided.  There is of course no way to know for certain since for some people, despite best prevention efforts, clots and complications still happen.

Views from the medical community

For the past 2 years, I have served as a patient representative and voting member of a thrombophilia evidenced-based guideline panel of the American Society of Hematology.  And while I cannot disclose the group’s findings until publication, I can make some general observations.

The medical community is conflicted about when and why to do thrombophilia testing. There is inconsistency in daily practice from clinician to clinician and hospital to hospital as to when tests are orders, for what patients and how those are used to inform decisions. Research studies tend to be few, with small study size and therefore of limited quality.  Decisions based on such weak data translates into a diversity of opinions and practices. Thrombophilia testing as it correlates to outcomes is an area in which further clinical research is sorely needed.

What is clear, is that we are at a crossroads for thrombophilia testing and the FDA approval of a direct-to-consumer test reflects this change in thinking.  A decade ago, thrombophilia testing was considered rather routine following a DVT/PE.  More recently, the pendulum  swung to an opposite extreme to where few clinicians routinely test for thrombophilia. (See the ACCP guideline for current recommendations & evidence)

Based upon recent data, I suspect we will eventually end up somewhere in the middle of these two extremes—to where there will be a certain patient population in which thrombophilia testing is warranted and helpful in informing decisions, patients such as myself for example.   The challenge will be in how to screen and find those persons at high-risk for clotting, without over-testing and creating undue worry in those patients who are lower-risk for clotting.  It is the shared challenge of every screening test really–from breast cancer to PSA–how to maximize helping the most numbers of patients and minimize potential harms. In my view, this is where education of both patient and provider is essential.

Patient & provider education gaps

Unfortunately, patient education is an area of great concern and where we fail badly. Very badly. Ideally, every person who receives a genetic test would receive counseling before and after.  As this doesn’t always happen with diagnostic thrombophilia tests, it is unrealistic to expect it will happen with direct-to-consumer tests either.  I, myself, received no genetic counseling before or after my thrombophilia test–it was never offered. In fact I never even knew my clinician had ordered a genetic test until the results were given to me by a different provider who really, in hindsight, didn’t articulate accurately what the results meant.  My understanding of the impact of the test was very much a process of self-education and searching for a knowledgeable clinician, in my case a thrombosis-specialized hematologist.

A 2008 Surgeon General report found clinical gaps in thrombosis  knowledge and the inconsistent application of evidence based interventions.  My personal experience is that little has changed since the report’s release. While any provider in any specialty can order a thrombophilia panel, not every provider is skilled in interpreting them. Thrombophilia specialists are few. With direct-to-consumer testing, there is the potential for patients to have a difficult time finding a professional well-versed in thrombophilia and its implications for thrombosis risk management.

Why are there still gaps in thrombosis knowledge?  There is no line-item funding in the federal budget for venous blood clot education…without it and engagement of federal public health agencies, the dissemination of patient and provider education is severely hampered.  So whether a patient is able to access accurate information in interpreting a positive thrombophilia test is going to be entirely dependent upon how knowledgeable their individual provider is with interpreting such tests and his/her willingness to refer a patient with no prior thrombosis, but a positive thrombophilia home test, to a specialist for a more thorough thrombophilia evaluation and discussion.   It will also reflect the patient’s ability to pay–and insurance company’s willingness to reimburse—for such specialized consultation and additional testing in the absence of an acute clotting event.

My recommendation

To put the finding of a positive thrombophilia test into perspective,  patients need solid information and my concern is that they won’t easily get it. Yet despite this limitation, at the moment, I would recommend the 23andMe service and here’s why:

  1.  Knowledge empowers.  Everyone should know their clot risk.  I am a strong advocate that the public needs greater awareness and education of their blood clot risk.  This test will serve that goal.  Is it diagnostic?  No.  It is not meant to replace diagnostic testing. Perfect solution?  No.  But it is a start in the right direction and if it informs and empowers 1 person to take steps to reduce their clot risk such that a future clotting event is avoided…it is well worth it.
  2. Cost considerations.  A typical ‘thrombophilia panel’, consisting of 5-8 diagnostic tests, ordered by a physician costs around $3,000 in the US and would include tests for all the 5 mutations discussed above plus a few others which are considered ‘acquired’ thrombophilias.  Currently, 23andMe markets a genetic test panel of 65 genetic reports for $199 US.   That’s an incredible cost difference.  While the 23andMe is not meant to be a diagnostic test–it won’t replace the $3000 panel—it holds potential as a first line screening tool to allow for greater public screening of lower risk individuals.  Cost is one of the biggest drawbacks as to why we don’t see more public health screenings of all types of conditions, thrombophilia is no exception.
  3. Privacy and genetic discrimination.  Direct-to-consumer thrombophilia testing may provide a way for people to learn more about their thrombophilia status without it becoming part of their formal medical record. This may be most helpful to 2nd or 3rd degree relatives of those already diagnosed with thrombophilia or a DVT/PE event to where there is curiosity if they share a trait but don’t wish to, for whatever reason, undergo diagnostic thrombophilia testing.  The degree of privacy of both forms of testing is still unclear.  In the US, when a patient goes to a physician and a thrombophilia test is ordered, those results become part of the patients permanent medical record.  A positive thrombophilia test has implications far beyond clinical decisions.  The Genetic Information Nondiscrimination Act (GINA) protects individuals from discrimination based upon a genetic test result. However, it’s protections are limited.  While a person with a positive thrombophilia result cannot be denied health insurance or employment, it is still legal for a person with inherited thrombophilia to be denied life or disability insurance based upon the positive test and if they do get insurance, it is allowable to pay higher life, disability, or long-term care insurance premiums.  Existing GINA protections with respect to health insurance and employment are also under threat…several recent Congressional proposals call into question the long-term protections of one’s genetic results. Laws can always be changed.  Protections provided today may not be in place tomorrow. For that reason, patients should not treat genetic testing as a light decision, but rather be aware that both traditional clinic based testing and direct-to-consumer testing carries potential discrimination risks and these risks should be weighed with the benefits of testing.
  4. Peace of mind.  I can foresee a negative result from a direct-to-consumer test providing peace of mind without the cost and potential hassles of diagnostic testing. Any positive test will need to be followed up with a clinician and perhaps a confirmatory diagnostic test to confirm herto- or homozygous status….but this should be a smaller number of people as even the most common thrombophilia is found in less than 10 percent of the population.  In other words, the 23andMe could be used as an inexpensive, personal first step screen test for the most common thrombophilias, because statistically the majority of people will have a negative result.  Only those positive need to move on to the more expensive, diagnostic panel.

There is no 100% right or wrong answer when it comes to testing for genetic thrombophilia. In the end, it comes down to individualized patient decisions..decisions hopefully made with full information in hand.   It will be interesting to see how this new era of consumer driven thrombophilia testing evolves.

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