November 2nd, 2009
Genetic Testing in Unexplained Thrombosis – Part I
Harlan M. Krumholz, MD, SM
The case. (For an expert’s response, see Part II)
A very healthy 44-year-old man who engaged in daily vigorous physical activity suddenly developed shortness of breath and pleuritic chest pain. He was quickly diagnosed with multiple pulmonary emboli. He was not overweight and had no recent history of long trips, injuries, periods of bed rest, or weight loss. Genetic testing revealed two polymorphisms that might be related to risk for thrombosis: prothrombin gene mutation (homozygous) and PAI-I (plasminogen activator inhibitor type I) 4G/4G polymorphism. No other tests revealed underlying causes of the thrombosis.
- How should the genetic test results affect his treatment?
- Should his children and siblings be tested? If they have these polymorphisms, what should they do?
- Was screening for these polymorphisms useful for this patient?
3 Responses to “Genetic Testing in Unexplained Thrombosis – Part I”
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Thombophilia screening
While it wascertainly reasonable to test for major factor deficiencies associated with unexplained VTE (i.e., ATIII, Proteins S & C, there remains no compelling evidence that, in isolation, other genetic variants (e.g., prothrombin G20210A, MTHFR, heteroozygous FVL, PAI-I) are, by themselves, strong predispositions to VTE. Thus, based upon current knowledge, these tests add essentially nothing to treatment or evaluation of this patient and his family should not be tested. He should receive standard anticoagulant therapy for presumptively unprovoked VTE.
Unfortunately physicians are now primed to search for thrombophilia in nearly every patient who presents with DVT or PE and the battery of expensive genetic tests are ordered even in elderly patients with clear precipitating factors.
Testing for thrombophilia
I wonder if many physicians are primed to search for thrombophilia based on what they were taught in training. As a fellow in training, it still remains unclear to me which tests are the highest versus lowest yield based on the existing evidence — and perhaps this is because the evidence is still evolving. Are there up-to-date guidelines that you would recommend? Or perhaps a top 3 or 5 tests that you think should always be considered in a young person with otherwise unexplained VTE?
Should this patient receive just six months or a year of anticoagulant therapy or should he get lifelong anticoagulation?
Thanks in advance.
More questions than answers…
I agree with what’s been posted before. From a practical standpoint, it is difficult to even know what to order. I often wonder if it would be better to organize a lot of these tests as a “panel”, so that clinicians a little distanced from this field would be able to easily discern factors with the best evidence from those with little data to support them. I think the presence of risk factors could make a difference – maybe even recommendations about life-long anticoagulation, which is no small issue in an active 44 year-old.
About family members, I’m equally confused especially about what to do after you find something. I recently put a stent in an elderly patient in his 70s who told us he had Factor V Leiden, but had never had a VTE. In this case, we struggled with what to do about this potential “thrombophilia” and his dual antiplatelet therapy regimen.