You Make the Call: Would you extend anticoagulation in a patient who had a native aortic valve thrombus while on DHEA?

Yvonne H. Datta, MD
Professor of Medicine
Director, Hematology/Oncology Fellowship
Division of Hematology, Oncology, and Transplantation
University of Minnesota

CLINICAL DILEMMA

I have been referred a 41-year-old male patient who had a native aortic valve thrombus that caused a non-ST elevation myocardial infarction (NSTEMI) and a cerebrovascular accident. The thrombus was surgically removed, and he was started on warfarin. His primary care physician switched him to aspirin and clopidogrel after one year of treatment because of a labile international normalized ratio. The patient couldn’t afford apixaban. He is negative for antiphospholipid syndrome (APS), factor V Leiden, prothrombin gene mutation, and paroxysmal nocturnal hemoglobinuria, but his antithrombin was slightly low at 65%. There is no family history of thrombosis. He is obese and was on an oral body building supplement containing 25 mg dehydroepiandrosterone (DHEA) and androstane at the time of the clot. I feel he needs extended anticoagulation, but his surgeon thinks six months has been good enough. I am unaware of a strong association between the DHEA and thrombosis, so should this be considered unprovoked?

EXPERT OPINION

This is an unusual case, with several factors to consider. I will start with the question of DHEA, androstane, and thrombosis. I couldn’t find anything in the literature regarding increased thrombosis due to exogenous DHEA; in fact, one paper suggested it for post-menopausal symptoms in women with a history of thrombosis, although that was vaginal application.¹ There also is minimal literature on androstane and thrombosis. If the androstane raised the patient’s hemoglobin and hematocrit to above-normal levels, that may have contributed to thrombosis. A recent large trial of testosterone transdermal replacement in men was shown to be noninferior to placebo regarding risk of major adverse cardiovascular events.² I would be reluctant to say that the supplement was the sole cause of the thrombosis, and I would consider this unprovoked. However, stopping an unregulated supplement would be advised.

Since native valve thrombosis is so rare, I was only able to find a systematic review that summarized case reports.³ As a hematologist, I think first of APS, which has been ruled out. The case review indicated a wide variety of etiologies, of which 30% were hypercoagulable diseases. Overall, most cases used vitamin K antagonists (VKA) for long-term management. Some cases used antiplatelet agents, and there was no mention of direct oral anticoagulants (DOACs), though many of the cases predated DOACs. I would favor the ongoing use of VKA in this case. However, I understand the difficulties in using VKAs, such as food and medication interactions and time needed for clinic visits for monitoring. One could also consider rechecking the antithrombin, and if clearly persistently low, that would help solidify a recommendation for VKA. If the antithrombin is normal and if there are difficulties with the VKA management, it wouldn’t be entirely wrong to use aspirin and clopidogrel. However, I lean toward the recommendation for anticoagulation, given the severity of the outcome: stroke in a young person that was not due to atherosclerosis.

References

1. Pinkerton JV, James AH. Management of menopausal symptoms for women who are at high risk of thrombosis. Clin Obstet Gynecol. 2018;61(2):260-268.
2. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107-117.
3. Alajaji W, Hornick JM, Malek E, et al. The characteristics and outcomes of native aortic valve thrombosis: a systematic review. J Am Coll Cardiol. 2021;78(8):811-824.

NEXT MONTH'S CLINICAL DILEMMA

I have two patients whose testing of their bone marrow samples came back with abnormal next-generation sequencing (NGS) results:

• One patient has a TET2 mutation with an allele frequency close to 50%, raising the possibility of germline origin.
• The second patient has an unexplained normocytic anemia (hemoglobin was 11.2 g/dL with a mean corpuscular volume of 88 fL). Flow cytometry identified a clonal B-cell population with a nonspecific phenotype (CD5-, CD10-, CD20+), representing 1% (<5,000/uL) of the leukocytes. There was also a monoclonal paraproteinemia (IgA lambda on serum immunofixation) with 3-5% plasma cells in the bone marrow biopsy. The NGS panel was positive for unclear variant in EGF with an allele frequency close to 50%, again raising the possibility of germline origin.

Because these mutations may be germline, should I refer these patients for genetic counseling and germline testing? If they are germline, then it’s something that they were born with –presumably inherited – so can it be passed on? I’m not clear on the clinical significance, and maybe I don’t have to do anything?

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