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Review

Investigation and management of erythrocytosis

Siraj Mithoowani, Marissa Laureano, Mark A. Crowther and Christopher M. Hillis
CMAJ August 10, 2020 192 (32) E913-E918; DOI: https://doi.org/10.1503/cmaj.191587
Siraj Mithoowani
Departments of Medicine (Mithoowani, Laureano, Crowther) and Oncology (Hillis), McMaster University, Hamilton, Ont.
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Marissa Laureano
Departments of Medicine (Mithoowani, Laureano, Crowther) and Oncology (Hillis), McMaster University, Hamilton, Ont.
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Mark A. Crowther
Departments of Medicine (Mithoowani, Laureano, Crowther) and Oncology (Hillis), McMaster University, Hamilton, Ont.
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Christopher M. Hillis
Departments of Medicine (Mithoowani, Laureano, Crowther) and Oncology (Hillis), McMaster University, Hamilton, Ont.
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  • RE: CMAJ August 10, 2020 192 (32) E913-E918
    David M Conrad [BSc, MD, PhD]
    Posted on: 22 January 2021
  • RE: SGLT2 Inhibitor-Induced Erythrocytosis
    Benjamin Chin-Yee [MD MA], Ziad Solh [MD MSc] and Cyrus Hsia [MD]
    Posted on: 21 August 2020
  • Posted on: (22 January 2021)
    Page navigation anchor for RE: CMAJ August 10, 2020 192 (32) E913-E918
    RE: CMAJ August 10, 2020 192 (32) E913-E918
    • David M Conrad [BSc, MD, PhD], Hematopathologist, QEII Health Sciences Centre

    Figure 1 indicates that Polycythemia Vera can be diagnosed without a bone marrow biopsy. Per Swerdlow et al., (2017), a bone marrow biopsy showing age-adjusted hypercellularity and panymyelosis is required for a diagonsis of Polycythemia Vera to be made.

    Competing Interests: None declared.

    References

    • Siraj Mithoowani, Marissa Laureano, Mark A. Crowther, et al. Investigation and management of erythrocytosis. CMAJ 2020;192:E913-E918.
    • Swerdlow, SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (Eds): WHO Classificatio nof Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition). IARC: Lyon 2017
  • Posted on: (21 August 2020)
    Page navigation anchor for RE: SGLT2 Inhibitor-Induced Erythrocytosis
    RE: SGLT2 Inhibitor-Induced Erythrocytosis
    • Benjamin Chin-Yee [MD MA], Clinical Fellow, Division of Hematology, Department of Medicine, Western University
    • Other Contributors:
      • Ziad Solh, Assistant Professor
      • Cyrus Hsia, Associate Professor

    We thank Dr. Mithoowani and colleagues for their excellent review on the investigation and management of erythrocytosis (1), which provides a comprehensive overview and approach to a common presentation encountered by hematologists and general practitioners alike.

    One additional drug-associated cause of secondary erythrocytosis of increasing relevance in general practice is the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors. With the growing use of this class of medications in Canada, on the basis of mounting evidence for improved cardiovascular outcomes in type 2 diabetes and heart failure, SGLT2 inhibitors are worth including in the already extensive differential for secondary erythrocytosis offered by Mithoowani et al. in their article (1).

    At our centre, we have noted an increase in the number of referrals of patients with erythrocytosis on SGLT2 inhibitors, which often resolves following discontinuation of these medications. Increases in hematocrit were noted in initial clinical trials of SGLT2 inhibitors, and were thought to account in part for the cardioprotective effects of these medications. The physiology of SGLT2 inhibitor-induced erythrocytosis is complex and remains to be fully elucidated but postulated mechanisms include hemoconcentration, modulation of iron metabolism, and increased erythropoietin production, as recently demonstrated in a Canadian study (2).

    To date, we are aware of a total of five cases of severe erythrocytos...

    Show More

    We thank Dr. Mithoowani and colleagues for their excellent review on the investigation and management of erythrocytosis (1), which provides a comprehensive overview and approach to a common presentation encountered by hematologists and general practitioners alike.

    One additional drug-associated cause of secondary erythrocytosis of increasing relevance in general practice is the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors. With the growing use of this class of medications in Canada, on the basis of mounting evidence for improved cardiovascular outcomes in type 2 diabetes and heart failure, SGLT2 inhibitors are worth including in the already extensive differential for secondary erythrocytosis offered by Mithoowani et al. in their article (1).

    At our centre, we have noted an increase in the number of referrals of patients with erythrocytosis on SGLT2 inhibitors, which often resolves following discontinuation of these medications. Increases in hematocrit were noted in initial clinical trials of SGLT2 inhibitors, and were thought to account in part for the cardioprotective effects of these medications. The physiology of SGLT2 inhibitor-induced erythrocytosis is complex and remains to be fully elucidated but postulated mechanisms include hemoconcentration, modulation of iron metabolism, and increased erythropoietin production, as recently demonstrated in a Canadian study (2).

    To date, we are aware of a total of five cases of severe erythrocytosis (hematocrit >0.53) attributed to SGLT2 inhibitors reported in the literature (3-5), although anecdotally we suspect this number to be much higher and indeed rising. Two cases were associated with concomitant use of SGLT2 inhibitors and testosterone replacement therapy (4), a well-known cause of secondary erythrocytosis. Another report detailed an SGLT2 inhibitor ‘unmasking’ underlying polycythemia vera (PV) (3). To prevent over-utilization of laboratory resources, we would caution against routine investigation for PV in patients with erythrocytosis on SGLT2 inhibitors. The stepwise approach advocated by Mithoowani et al. (1) will help mitigate over-investigation. Where possible, and if alternate agents are available, we would consider discontinuing SGLT2 inhibitors in cases of severe erythrocytosis in consultation with other members of the medical team as an important diagnostic and therapeutic step in the approach to erythrocytosis.

    Show Less
    Competing Interests: None declared.

    References

    • 1. Siraj Mithoowani, Marissa Laureano, Mark A. Crowther, et al. Investigation and management of erythrocytosis. CMAJ 2020;192:E913-E918.
    • 2. Mazer CD, Hare GMT, Connelly PW et al. Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease. Circulation 2020;141(8):704-707.
    • 3. Das L, Bhansali A, Walia R. Unmasking and aggravation of polycythemia vera by canagliflozin. Diabet Med. 2018;35:1613-1616.
    • 4. Motta G, Zavattaro M, Romeo F, Lanfranco F, Broglio F. Risk of Erythrocytosis During Concomitant Testosterone and SGLT2-Inhibitor Treatment: A Warning From Two Clinical Cases. J Clin Endocrinol Metab. 2019;104:819-822.
    • 5. Gupta R, Gupta A, Shrikhande M, Tyagi K, Ghosh A, Misra A. Marked erythrocytosis during treatment with sodium glucose cotransporter-2 inhibitors-report of two cases. Diabetes Res Clin Pract. 2020;162:108127.
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Canadian Medical Association Journal: 192 (32)
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Vol. 192, Issue 32
10 Aug 2020
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Investigation and management of erythrocytosis
Siraj Mithoowani, Marissa Laureano, Mark A. Crowther, Christopher M. Hillis
CMAJ Aug 2020, 192 (32) E913-E918; DOI: 10.1503/cmaj.191587

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Investigation and management of erythrocytosis
Siraj Mithoowani, Marissa Laureano, Mark A. Crowther, Christopher M. Hillis
CMAJ Aug 2020, 192 (32) E913-E918; DOI: 10.1503/cmaj.191587
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    • What is the differential diagnosis for erythrocytosis?
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