Diagnosis, Management, and Outcomes of Drug-Induced Erythrocytosis: A Systematic Review

Background: Secondary erythrocytosis refers to an elevation in hemoglobin > 160 g/L in women or > 165 g/L in men that is not due to an underlying myeloproliferative neoplasm. Medications such as testosterone and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are common causes of secondary erythrocytosis. Current guidelines on the diagnosis and management of drug-induced secondary erythrocytosis are limited, and the risks of thromboembolism, bleeding, and mortality in this population have yet to be fully described. We therefore conducted a systematic review to inform the clinical management of drug-induced erythrocytosis. Methods: Following PRISMA guidelines, we performed a systematic literature search in MEDLINE, EMBASE, CENTRAL (all via Ovid), and Google Scholar. We included adult patients, age 18 years and older, and studies published from 2005 to February 2024. We excluded case reports and case series with fewer than 5 patients. Two reviewers independently screened titles and abstracts of studies, with disagreements resolved by a third party. Data was extracted on variables pertaining to the diagnosis, management, and outcomes of drug-induced erythrocytosis, and were synthesized using descriptive analysis. (PROSPERO CRD42024508643) Results: Our systematic search identified 2,037 studies for screening. Forty-four studies were included in our review, with 35 studies on testosterone and other androgen use, four studies on SGLT-2 inhibitors, three studies on anti-angiogenic tyrosine kinase inhibitors (TKIs), and one study on erythropoiesis-stimulating agents (ESAs). Cis- and transgender men on prescription testosterone had rates of erythrocytosis up to 46.7%, with intramuscular formulations more commonly associated with erythrocytosis, compared to pellet or intranasal formulations. In cisgender men, only one study identified an increased risk of cardiovascular and thromboembolic events associated with erythrocytosis; in transgender men, one study described thromboembolic events in 2.6% of individuals with erythrocytosis while on testosterone. In individuals on SGLT-2 inhibitors, rates of erythrocytosis ranged from 10-22%, with those who discontinued therapy demonstrating improvement or resolution of erythrocytosis; only one patient had a thromboembolic event associated with erythrocytosis, post-renal transplant. Anti-angiogenic TKIs were studied in patients with cancer, with erythrocytosis developing in up to 43.5% of patients, which was managed with dose reduction, phlebotomy, or acetylsalicylic acid for primary thromboprophylaxis. One study examined erythrocytosis in patients receiving ESAs, with 38.5% of patients requiring dose reduction and 23% requiring phlebotomy; no thromboembolic events were recorded. Conclusion: Drug-induced erythrocytosis is a heterogeneous condition for which there is no clear consensus among clinicians about its diagnosis and management. Rates of thromboembolism associated with this condition are low in the existing literature. Dose reduction or discontinuation of the implicated drug appear to be effective in reversing or resolving erythrocytosis; phlebotomy is another commonly used strategy. Further studies are required to clarify the management and outcomes of drug-induced erythrocytosis.