You Make the Call: Does this patient with diabetes and thrombocytosis need a bone marrow biopsy?

Mrinal Patnaik, MBBS
Associate professor of internal medicine and oncology, consultant, Division of Hematology, Mayo Clinic, Rochester, Minnesota

This month, Mrinal S. Patnaik, MBBS, discusses treatment of thrombocytosis in a patient with diabetes and ischemic cardiomyopathy.

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I have a 45-year-old male patient with type 1 diabetes and ischemic cardiomyopathy who was referred for thrombocytosis. The highest platelet count recorded was 504,000/mm3, and the rest of his workup was normal, aside from a hemoglobin level of 13.7 g/dL, ferritin level of 19 ug/L, and iron saturation level of 21%. Since his diabetes was well treated for most of his life and the cardiomyopathy seemed less than what I would expect (ejection fraction of 35%), and I was concerned about a myeloproliferative neoplasm (MPN), I did Tempus next-generation panel sequencing rather than single-gene sequencing for JAK2, CALR, and MPL to try to also capture DNMT3A, ASXL1, TET2, and so on. None of those were positive. He had a copy number loss in RUNX1 (but not RUNX1-EVT6 fusion) and a STAG2 loss-of-function mutation at 3.9%, a gene that I had never heard of. Does this qualify as clonal hematopoiesis of indeterminate potential (CHIP), and might it explain his early coronary artery disease? Does he need a bone marrow biopsy to look for myelodysplastic syndromes (MDS), MPNs, or for MDS/MPNs given his higher platelet count?


Clonal hematopoiesis (CH) is defined by the accumulation and expansion of somatic mutations in hematopoietic stem cells (HSCs) and is a function of aging.¹ Somatic clones can be detected with clinically available next-generation sequencing (NGS) panels in <1% of individuals under the age of 40, but they increase in frequency with each decade of life.² CH of indeterminate potential (CHIP) refers to the presence of a cancer-associated variant in the HSCs with a variant allele fraction in blood or marrow of ≥2%, yet without any detectable blood count abnormalities and in the absence of a frank malignancy or other clonal entities such as monoclonal B lymphocytosis and paroxysmal nocturnal hemoglobinuria. Common mutated genes associated with CHIP include epigenetic regulators such as DNMT3A, TET2, and ASXL1, and CHIP has been associated with an increase in all-cause mortality, especially from cardiovascular disease secondary to an inflammatory milieu and associated endothelial dysfunction.³

This patient is a 45-year-old male who has existing risk factors for cardiovascular disease, especially type 1 diabetes. He was assessed for thrombocytosis in the context of low normal iron reserves. A peripheral blood NGS assay was ordered largely to look for MPN-associated mutations such as JAK2, CALR, and MPL, but to also look for other mutations, including CHIP-associated genes. Current commercially available NGS assays are now sampling a large number of genes for mutations, and many are also able to assess gene copy number variations, depending on methodology.

In this case, the patient was found to have a copy number loss in RUNX1. RUNX1 is a critical hematopoietic transcription factor and germline deletions and mutations have been associated with a syndrome characterized by thrombocytopenia and an increased risk for myeloid malignancies (RUNX1-familial platelet disorder (FPD), while somatic aberrations have been associated with myeloid malignancies.4 STAG2 is a cohesin complex member; inactivating mutations and deletions observed in hematologic neoplasms increase HSC self-renewal and impair differentiation. STAG2 mutations have been documented in MDS (5-20% of cases) and in other cancers such as Ewing sarcoma (40-60%).5 Both RUNX1 and STAG2 mutations/aberrations have been associated with CHIP, albeit infrequently.

Although the ferritin of only 19 ng/mL indicates the patient may have reduced iron stores, an iron saturation above 20% suggests that iron deficiency may not be the cause of the thrombocytosis. By definition, given the persistent thrombocytosis and the absence of a clear reactive cause for the same, I would not label this patient as having CHIP as of yet. I would ensure a thorough workup for this thrombocytosis and concomitantly review the outside NGS report in detail; assessing the methodology, depth of sequencing, variant calling, and specifically the methods used to detect somatic copy number alterations (SCNA), especially the RUNX1 SCNA, to decide if this variant is clearly somatic or if the gene needs germline interrogation. A bone marrow biopsy with cytogenetics would be the next step to rule out a myeloid malignancy that can be associated with thrombocytosis such as chronic myeloid leukemia, MPN (JAK2/CALR/MPL-negative essential thrombocythemia or myelofibrosis), or a poorly defined MDS/MPN overlap syndrome (given the negative JAK2 and SF3B1 results).

Most of the cardiovascular and atherovascular mortality and morbidity that has been associated with CHIP has been in relationship to gene mutations that result in epigenetic deregulation and inflammation (DNTM3A, TET2, ASXL1) or in endothelial dysfunction (JAK2V617F). Given the variants seen in this patient and the presence of a clear risk factor (type 1 diabetes), it would be hard to attribute the cardiovascular risk to these genetic aberrations. Referral to a cardiology clinic that specializes in ischemic cardiomyopathy, so as to investigate other cardiac risk factors/causes, should also be contemplated.


  1. Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease. Science. 2019;366(6465).
  2. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488-2498.
  3. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111-121.
  4. Patnaik MM, Itzykson R, Lasho TL, et al. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia. 2014;28:2206-2212.
  5. Viny AD, Bowman RL, Liu Y, et al. Stag1 and Stag2 regulate cell fate decisions in hematopoiesis through non-redundant topological control. bioRxiv. 2019:581868.

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