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Research regarding the hematologic sequelae of estrogen and testosterone therapy for transgender people is an emerging area. While estrogen therapy has been widely studied in cisgender women, studies in transgender individuals are limited, revealing variable adverse effects influenced by the dose and formulation of estrogen used. Thrombotic risk factors in transgender and gender-diverse individuals are multifactorial, involving both modifiable and nonmodifiable factors. Management of venous thromboembolism (VTE) in individuals receiving gender-affirming estrogen entails standard anticoagulation therapy alongside shared decision-making regarding hormone continuation and risk factor modification. While data and guidance from cisgender women can offer a reference for managing thrombotic risk in transgender individuals on hormone therapy, fully applying these insights can be challenging. The benefits of gender-affirming hormone therapy include significantly reducing the risk of suicide and depression, highlighting the importance of a contemplative approach to the management of hormonal therapy after a VTE event. Although limited, the available data in the literature indicate a low thrombotic risk for transgender individuals undergoing gender-affirming testosterone therapy. However, polycythemia is a common adverse effect necessitating monitoring and, occasionally, adjustments to hormonal therapy. Additionally, iron deficiency may arise due to the physiological effects of testosterone or health care providers' use of phlebotomy, an aspect that remains unstudied in this population. In conclusion, while the set of clinical data is expanding, further research remains vital to refine management strategies and improve hematologic outcomes for transgender individuals undergoing gender-affirming hormone therapy., (Copyright © 2024 by The American Society of Hematology.)

Purpose: In clinical trials, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and testosterone replacement therapy (TRT) were shown to stimulate red blood cell production. Little is known if combination therapy poses risk of erythrocytosis in real world clinical practice., Methods: This was a retrospective nationwide cohort study of US Veterans with type 2 diabetes (T2D) and baseline hematocrit between 38 and 50% who were prescribed SGLT-2i and/or TRT between 3/2013 and 10/2022 and had adequate adherence based on the proportion of days covered > 80%. Patients were divided into 3 groups: SGLT-2i only, TRT only, or combination therapy. Odds Ratio (OR) of new erythrocytosis defined as hematocrit level > 54% within 365 days of therapy initiation was calculated by logistic regression model adjusted for baseline hematocrit, age, BMI, obstructive sleep apnea, diuretic use, and smoking status., Results: Of the entire cohort of 53,971 people with T2D, total of 756 (1.4%) patients developed erythrocytosis. In unadjusted analyses, the OR of new onset erythrocytosis was higher in the combined SGLT-2i and TRT group compared with the SGLT-2i or TRT group alone (4.99, 95% CI (3.10-7.71) and 2.91, 95% CI (1.87-4.31), respectively). In the models adjusted for baseline characteristics, patients on combination therapy had significantly higher odds of erythrocytosis compared to those on SGLT-2i (OR 3.80, 95% CI (2.27-6.11)) or TRT alone (OR 2.49, 95% CI (1.51-3.59)). Testosterone delivery route (topical vs injectable) did not modify increased odds of erythrocytosis., Conclusions: For the first time, we demonstrated that in large cohort of patients combined therapy with SGLT-2i and TRT is associated with increased erythrocytosis risk compared with either treatment alone. Given rising prevalence of SGLT-2i use, providers should consider periodic hematocrit assessment in persons receiving both SGLT-2i and TRT., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: In transgender individuals assigned female at birth, testosterone therapy is employed for body masculinization. Guidelines recommend close monitoring for potential side effects of hormonal therapy, especially during the first year. Erythrocytosis is a common finding during testosterone therapy and has been associated with a potential risk of thrombotic and cardiovascular events. Currently, the hematologic effects of testosterone therapy are understudied, with existing data primarily derived from the cisgender male population. The aim of this study was to comprehensively examine the hematological changes induced by testosterone therapy in the transgender population., Evidence Acquisition: A systematic search was conducted using the electronic database PubMed., Evidence Synthesis: Thirty-six manuscripts were retrieved. After screening for original studies, 19 articles were included. Selected articles were published between 2005 and 2023., Conclusions: In our systematic review, the prevalence of erythrocytosis varied from 0% to 29.3%, with severe erythrocytosis ranging from 0.5% to 2.3%. Testosterone therapy was associated with an increase in hemoglobin and hematocrit, particularly within the first year of therapy. Factors such as serum testosterone levels, along with the duration, doses, and formulation of testosterone therapy, were found to be associated with the development of erythrocytosis. Further research is crucial to provide specific recommendations for clinical practice.

Context: Studies have found a variable incidence of erythrocytosis among people using testosterone as part of gender-affirming hormone therapy (GAHT)., Objective: To examine the effect of using exogenous testosterone as GAHT on hematocrit in a large North American cohort., Methods: We conducted a cross-sectional analysis of testosterone and hematocrit laboratory values in 6670 patients who were prescribed testosterone through Plume, a national provider of GAHT. The prevalence of erythrocytosis, the mean hematocrit at predetermined testosterone thresholds and with varying routes of testosterone administration were assessed., Results: Among 6670 individuals, 560 (8.4%) had a hematocrit ≥50%, 182 ≥ 52% (2.7%), and 60 ≥ 54% (0.9%). There was significant variation (P < .001) in hematocrit between different clinically relevant testosterone thresholds (T < 50 vs T 50-299 vs T 300-999 vs T ≥ 1000 ng/dL) and when comparing serum testosterone in increments of 50 ng/dL within the target range for males (300-1000 ng/dL) (P < .001). Mean hematocrit ranged from 41.84% (T < 50 ng/dL) to 45.68% (T 900-949 ng/dL). Patients on intramuscular testosterone had a higher mean hematocrit than those on transdermal testosterone (44.96% vs 43.41%, P < .001). Both route of administration (P < .001) and testosterone level (P < .001) had statistically significant associations with hematocrit when controlling for each other., Conclusion: While the magnitude of change in hematocrit with serum level and route of administration of testosterone was statistically significant, the absolute levels were within the normal range, unlikely to be clinically meaningful. These findings, along with the low prevalence of erythrocytosis, should help allay concerns about the use of testosterone as GAHT., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: The authors have no conflicts of interest to declare.

Aims: Sodium glucose transporter inhibitors (SGLT2i) therapy is associated with an increase in hematocrit as a class effect. There is a lack of information regarding the clinical magnitude and significance of hematocrit elevation, especially cardiovascular outcomes in patients with polycythemia and possible masking of lower hemoglobin levels as a sign of potential severe disease., Methods: A retrospective study utilizing large community healthcare provider electronic database. Hematocrit levels and variables with potential effect on hematocrit change were compared before and during SGLT2i treatment in adults with type 2 diabetes mellitus., Results: Study population included 9646 patients treated with Dapagliflozin or Empagliflozin between 01.2015 and 06.2019. Hematocrit levels were significantly higher after treatment initiation (2.1%), with higher median elevation among male vs female (2.3% vs. 1.8%). Anemia prevalence was significantly lower under treatment (20% vs. 31.6%). In multivariable model, gender, smoking status, SGLT2i type, pretreatment hematocrit, diabetes duration, body mass index and estimated glomerular filtration rate change significantly effected hematocrit change., Conclusions: In the current study SGLT2i treatment was associated with significant hematocrit elevation, polycythemia and lower anemia prevalence. Further studies are needed to determine the clinical significance and approach to patients with pretreatment or on treatment polycythemia and the approach to patients with lower-normal hemoglobin levels under SGLT2i treatment., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Purpose: Gender-affirming hormone therapy (GAHT) is safe overall, with few adverse effects. One potential effect from using testosterone for GAHT is an increase in hemoglobin and/or hematocrit, known as secondary erythrocytosis. Current guidelines recommend monitoring hemoglobin or hematocrit routinely in the first year, some as frequently as every 3 months, which can create barriers to care. Our study explored the incidence of erythrocytosis in the first 20 months of testosterone therapy among people receiving gender-affirming care., Methods: This is a descriptive fixed cohort study of hematocrit and hemoglobin data from the charts of 282 people taking testosterone for GAHT., Results: During the first 20 months of testosterone therapy, the cumulative incidence of hematocrit >50.4% was 12.6%, hematocrit >52% was 1.0%, and hematocrit >54% was 0.6%. All people were taking injectable testosterone cypionate, with a median dose of 100 mg weekly., Conclusion: Severe erythrocytosis (hematocrit >54%) is a rare outcome of gender-affirming testosterone therapy. Clinical recommendations should reconsider the need for routine frequent erythrocytosis screening within the first year of testosterone therapy for patients who prefer to minimize laboratory draws., (© 2023 Annals of Family Medicine, Inc.)

Competing Interests: Disclosures None.

Purpose: This manuscript reports on the occurrence of early and frequent erythrocytosis in advanced hepatocellular carcinoma (HCC) patients treated with lenvatinib., Methods: A cohort of 23 patients with advanced HCC, treated with this antiangiogenic drug for at least one month, was retrospectively analyzed., Results: These patients (82.7% men, median age 58.3, cirrhosis in 60.8%) were treated between October 2019 and September 2020 with lenvatinib, as first-line systemic therapy for 82.6% of them. For 20 patients (87%), an early and significant increase in hemoglobin (Hb) level, up to 1.41 g/dL (p < 0.001) was reported and remained elevated. Ten patients (43.5%), all men, reached erythrocytosis (Hb > 16.5 g/dL), 7 were treated with low-dose aspirin for primary thromboprophylaxis and 2 needed phlebotomy. None underwent thromboembolic complications. A significant Hb decrease was observed after treatment discontinuation (p < 0.05). Erythropoietin (EPO) serum levels also increased, which was attributed to HCC after immunostaining for EPO in liver biopsies. The Naranjo adverse drug reaction probability scale documented the relationship between erythrocytosis and lenvatinib and regression at treatment discontinuation. Erythrocytosis was hypothesized to be a class effect of anti-VEGF therapies, the magnitude of which might depend on the IC50 value of each molecule., Conclusion: This report documents the frequent occurrence of erythrocytosis during lenvatinib treatment for advanced HCC, likely secondary to EPO secretion by tumor cells through the antiangiogenic activity levatinib. An early and close monitoring of hematologic parameters is, thus, recommended, together with thromboprophylaxis by low-dose aspirin and phlebotomy in case of symptomatic erythrocytosis., (© 2023. The Author(s).)

The most common side effect of testosterone therapy (TT) is erythrocytosis. Patient-specific factors therefore should be considered when choosing an appropriate TT dosage and modality. Providers should decrease or discontinue therapy if the patient's hematocrit exceeds 54% until the hematocrit normalizes., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: The goal of this study was to evaluate contributing factors and management strategies for polycythemia in transmasculine patients on testosterone therapy. Methods: A retrospective analysis of medical records was performed for transmasculine patients on testosterone for at least 12 months. Data collected from each patient included age, body mass index (BMI), nicotine dependence, pulmonary disease status, obstructive sleep apnea (OSA) status, oophorectomy status, and testosterone route of administration. For patients who developed polycythemia, polycythemia management strategy data were collected. Results: Five-hundred-eleven patients were evaluated and 113 (22%) experienced an episode of polycythemia. Within the polycythemia group, 77% of patients were younger than age 40, 56% had a BMI >30.0, 44% had current or former nicotine dependence, 12% had a pulmonary disease, 12% had OSA, and 47% had received an oophorectomy. The polycythemia group had a significantly higher average age, BMI, and dose of testosterone, and also had a higher proportion of patients with OSA and an oophorectomy. Conclusion: These results revealed that polycythemia is a common side effect for transmasculine patients on testosterone. Importantly, previous oophorectomy may be associated with polycythemia which appears to be a novel finding. This finding requires further research but provides the potential to be an important screening consideration for transmasculine patients after oophorectomy. Polycythemia will continue to be a major concern for patients on testosterone therapy, and this study provided important information for clinical practice and future research that will lead to improved outcomes.

Men with hypogonadism who use intranasal testosterone are less likely to develop polycythemia than men using intramuscular testosterone cypionate., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Secondary erythrocytosis is one of the most common adverse events associated with testosterone therapy (TT). Upon encountering this, clinicians will often either adjust TT dosing, stop therapy, order a phlebotomy, or recommend a combination of these. Despite this, the evidence for secondary polycythemia causing harm during TT is scarce, and the hematocrit-based cutoffs present in multiple guidelines appear to be arbritrarily chosen. In this review, we present the pathophysiology behind TT and secondary erythrocytosis, the evidence connecting TT, secondary erythrocytosis and major adverse cardiovascular events (MACE), and the data supporting varying interventions upon diagnosis of secondary erythrocytosis., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

BACKGROUND The purpose of this study was to identify the prevalence and risk factors of post-transplant erythrocytosis (PTE) and its relationship with cytomegalovirus (CMV). MATERIAL AND METHODS The study consisted of patients who received a kidney allograft and followed-up in our nephrology transplantation clinic from 2000 to 2014. Patient age, sex, length of dialysis, etiology of end-stage kidney disease, date of transplantation, medications, types of donors, the development of PTE were recorded. RESULTS Among 185 adult kidney recipients, 43 (23.2%) had PTE. The average time between transplantation and diagnosis was 36 months. PTE was more common in male patients (P<0.05) and patients with living donors and those who had been treated with ganciclovir after transplantation (P<0.05). There were 79 patients treated for CMV - 54 in the non-PTE group and 24 in the PTE group. There was no significant difference in patient age, etiology of end-stage kidney disease, and immunosuppressive therapy when comparing the PTE group and non-PTE group. Univariate analysis showed ganciclovir therapy was significantly associated with PTE. However, this was not seen in the multivariate analyses. CONCLUSIONS Treatment with ganciclovir can precipitate development of PTE. Prospective studies are needed to assess the association of between PTE and CMV infection, valganciclovir, and ganciclovir.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have proven cardiovascular benefits in patients with type 2 diabetes (T2D). This self-controlled case series study aims to evaluate whether metformin use and SGLT2i-associated erythrocytosis influence its cardiovascular benefits., Methods: T2D patients with metformin and/or SGLT2i prescriptions between 2015 and 2020 were identified from the Hong Kong population. Study outcomes were composite cardiovascular diseases (CVD), coronary heart disease (CHD), hospitalisation for heart failure (HHF), stroke, and erythrocytosis. Risk periods were patient-time divided into four mutually exclusive windows: (i) 'baseline period' of metformin use without SGLT2i; (ii) pre-SGLT2i period; (iii) exposure to SGLT2i without metformin; and (iv) exposure to the drug combination. Another SCCS model was applied to evaluate the association between erythrocytosis and cardiovascular outcomes regarding SGLT2i exposure. Four mutually exclusive risk periods included (i) SGLT2i exposure with erythrocytosis; (ii) SGLT2i exposure without erythrocytosis; (iii) absence of SGLT2i exposure with erythrocytosis; and (iv) absence of SGLT2i exposure without erythrocytosis. Incidence rate ratios (IRR) of events at different risk periods were estimated using conditional Poisson regression model., Results: Among 20,861 patients with metformin and/or SGLT2i prescriptions, 2575 and 1700 patients with events of composite CVD and erythrocytosis were identified, respectively. Compared to metformin use without SGLT2i, SGLT2i initiation was associated with lower risks of composite CVD, CHD, and HHF-regardless of the presence (CVD: IRR = 0.43, 95% CI 0.37-0.51; CHD: IRR = 0.44, 95% CI 0.37-0.53; HHF: IRR = 0.29, 95% CI 0.22-0.40; all p < 0.001) and absence of concomitant metformin (CVD: IRR = 0.31, 95% CI 0.20-0.48; CHD: IRR = 0.38, 95% CI 0.25-0.59; HHF: IRR = 0.17, 95% CI 0.09-0.31; all p < 0.001); while SGLT2i was neutral on stroke risk. Compared to metformin-SGLT2i combination, exposure to SGLT2i alone was associated with comparable risks of all cardiovascular outcomes (all p > 0.05). Incidence rates of erythrocytosis at baseline, SGLT2i without and with metformin use periods were 0.75, 3.06 and 3.27 per 100 person-years, respectively. SGLT2i users who developed erythrocytosis had lower risk of HHF (IRR = 0.38, 95% CI 0.14-0.99, p = 0.049) than those who did not., Conclusions: Our real-world data suggested that SGLT2i-associated cardiovascular benefits were not attenuated by metformin use. Further studies will delineate the role of erythrocytosis as a surrogate marker of SGLT2i-associated cardiovascular benefit in reducing HHF., (© 2022. The Author(s).)

Purpose: An unsafe hematocrit threshold for men receiving testosterone therapy (TT) has never been tested. This study seeks to determine whether secondary polycythemia among men receiving TT confers an increased risk of major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE)., Materials and Methods: Using a multi-institutional database of 74 million patients, we identified 2 cohorts of men with low testosterone (total testosterone <350 ng/dl) who received TT and subsequently either developed polycythemia (5,887) or did not (4,2784). Polycythemia was defined as hematocrit ≥52%. As a secondary objective, we identified 2 cohorts of hypogonadal men without polycythemia, who either did (26,880) or did not (27,430) receive TT. Our primary outcome was the incidence of MACE and VTE in the first year after starting TT. We conducted a Kaplan-Meier survival analysis to assess differences in MACE and VTE survival time, and measured associations following propensity score matching., Results: A total of 5,842 men who received TT and developed polycythemia were matched and compared to 5,842 men who did not develop polycythemia. Men with polycythemia had a higher risk of MACE/VTE (number of outcomes: 301, 5.15%) than men who had normal hematocrit (226, 3.87%) while on TT (OR 1.35, 95% CI 1.13-1.61, p <0.001). In hypogonadal men who received testosterone, no increased risk of MACE and VTE was identified as compared to hypogonadal men naïve to TT., Conclusions: Developing polycythemia while on TT is an independent risk factor for MACE and VTE in the first year of therapy. Future research on the safety of TT should include hematocrit as an independent variable.

Androgen abuse is associated with unfavourable changes in blood pressure, lipid metabolism and erythrocytosis. Most knowledge is based on cross-sectional studies sensitive to bias. We assessed the magnitude of these effects and their recovery in a prospective cohort study which included 100 men (≥18 years) performing an androgen cycle. Clinic visits took place before the cycle, at the end, 3 months after and 1 year after start of the cycle and included measurement of blood pressure, lipid parameters and haematocrit. During androgen use, systolic and diastolic blood pressure increased 6.87 (95% CI 4.34-9.40) and 3.17 mmHg (1.29-5.04) compared to baseline respectively. LDL cholesterol and ApoB increased 0.45 mmol/L (0.29-0.61) and 18.2 mg/dl (13.5-22.8) respectively, whereas HDL cholesterol, ApoA and Lp(a) decreased with 0.40 mmol/L (-0.45 to 0.35), 36.6 mg/dl (30.2-42.9) and 37.6% (13.9-61.3). ANGPTL3 increased 20.3% (7.38-33.2). Mean haematocrit increased 0.03 L/L (0.02-0.03). Three months after the cycle, and 1 year after the start, these parameters returned to baseline. In conclusion, androgen abuse induces small but clinically relevant adverse changes in blood pressure, lipid metabolism and erythrocytosis which are rapidly reversible after cessation. As follow-up was limited to 1 year, the impact of androgen abuse on cardiovascular disease remains uncertain., (© 2022 Wiley-VCH GmbH.)

Introduction: Tyrosine kinase inhibitors have become the mainstay of treatment for many malignancies, but their use can be accompanied by unusual and often puzzling side effects., Case Report: We describe herein a 64-year-old patient who developed a robust and sustained erythrocytosis shortly after starting treatment with lenvatinib. Our patient also experienced elevated blood pressure, mucositis, and hand-foot syndrome that are not uncommonly seen with this agent. The clinico-laboratory work-up suggested that lenvatinib was the likely culprit in this case., Management & Outcome: Lenvatinib had to be discontinued due to suboptimal tolerance and a short-lived response. With the discontinuation of lenvatinib, hemoglobin trended downwards and subsequently resolved. A score of 6 on the Naranjo nomogram supported a probable causality relationship between lenvatinib and the observed erythrocytosis., Discussion: Erythrocytosis has previously been described with sunitinub, sorafenib and pazopanib. The exact mechanism of this phenomenon is not known. It might increase the risk of venous and arterial thromboses in cancer patients that are already in a hypercoagulable state due to cancer itself. In addition, laboratory work-up for polycythemia may prove extensive and costly. Therefore, clinicians need to be aware of this important side effect of tyrosine kinase inhibitors.

In clinical trials, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) use alone in persons with type 2 diabetes (T2D) or testosterone replacement therapy (TRT) prescription alone in men with hypogonadism was shown to lead to a modest but significant increase in red blood cell mass. Recent evidence indicates that combined use of TRT and SGLT-2i in persons with T2D may be associated with risk of erythrocytosis. However, factor(s) that may lead to the development of erythrocytosis in these patients is unknown. We describe here 5 consecutive patients with hypogonadism on chronic TRT who developed erythrocytosis following addition of SGLT-2i empagliflozin for optimization of T2D management. In addition to the careful review of medical history, all patients underwent genetic screening for hereditary hemochromatosis. We have found that none of the patients had C282Y mutation in the HFE (Homeostatic Iron Regulator) gene and 4 out of 5 patients had heterozygosity in the H63D allele. Upon TRT discontinuation or its dose reduction or referral for scheduled phlebotomy, patients showed resolution of erythrocytosis. Our study reaffirms that practitioners should monitor for changes in hematocrit following the initiation of SGLT-2i in persons with T2D and hypogonadism on chronic TRT. Also, for the first time, we showed that in some of the patients receiving combined TRT and SGLT-2i H63D heterozygosity in the HFE gene may mediate the development of new-onset erythrocytosis.

Background: Multidrug-resistant tuberculosis (MDR-TB) drugs have never been associated with erythrocytosis. In Eritrea, however, several cases of incident erythrocytosis had been observed in the MDR-TB hospital. This study was aimed at exploring the association between MDR-TB drugs and secondary erythrocytosis, characterising the cases, and identifying other possible risk factors., Methods: A retrospective cohort study was conducted in Merhano National Referral MDR-TB hospital. Data were extracted from physically available clinical cards and laboratory results collected longitudinally between 23 June 2011 and 17 January 2021. Initially, univariate descriptive statistics (frequency, mean (SD), median (IQR) and range) were used as appropriate. Then, χ 2 or Fisher χ 2 test, and bivariate and/or multivariate Cox proportional hazard model were used to identify the predictors of incident erythrocytosis. All statistical analyses were conducted using R, and a two-sided alpha 0.05 was used to determine the statistical significance., Results: A total of 257 patients' medical cards were screened, and 219 were eligible for further analysis. The median age of the patients was 38 years (range: 13-90 years) and 54.8% were males. During the follow-up time, 31 (14.2%) patients developed secondary erythrocytosis yielding an incidence rate of 7.8 cases per 1000 person-months. On average, the median time to onset of the event was found to be 5-months (range: 1-24 months). Males were more likely to develop the event than females (adjusted HR=7.13, 95% CI=1.66 to 30.53), and as body weight increases by 1 kg, the likelihood of developing secondary erythrocytosis was found to increase by 7% (adjusted HR=1.07, 95% CI=1.03 to 1.10). Moreover, all cases of secondary erythrocytosis were found to be possibly associated with the MDR-TB drugs., Conclusion: The authors hypothesised that the incident erythrocytosis is possibly be associated with MDR-TB drugs, and further studies are required to substantiate this finding., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

BACKGROUND Osimertinib is an oral third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) approved as first-line therapy for advanced non-small cell lung cancer (NSCLC) with positive EGFR mutation. Rashes, nail toxicity, and diarrhea are common adverse events. Hematological adverse effects, including anemia, thrombocytopenia, and lymphocytopenia, have been reported. However, erythrocytosis has not been reported as an adverse event. To the best of our knowledge, we report the first case of acute lower extremity thrombosis presumably caused by osimertinib-induced erythrocytosis. CASE REPORT A 70-year-old man with epidermal EGFR-mutant advanced NSCLC presented with acute left sural pain. The patient's left foot was cold, and peripheral arterial Doppler signals were absent. He had developed erythrocytosis of unknown etiology during osimertinib therapy. Hemoglobin (Hb) and hematocrit were 22.6 g/dL and 62.5%, respectively. Contrast-enhanced computed tomography showed thrombotic occlusion of the popliteal artery. Other than erythrocytosis, there was no possible cause of arterial thrombosis. Osimertinib was discontinued immediately because the NSCLC started to resist treatment and was presumed to be the cause of erythrocytosis. He received endovascular treatment (EVT). Following serial EVT and debridement, his fourth toe was amputated for necrosis. Erythrocytosis persisted 8 months during osimertinib therapy. Hb levels decreased to 15.4 mg/dL due to blood loss complicated with catheter thrombectomy and remained normal for 20 months after osimertinib discontinuation. The patient died of cancer progression. CONCLUSIONS This case suggests the erythrocytosis was possibly caused by osimertinib. We may need to monitor Hb levels during osimertinib therapy and be alert to thrombosis once Hb starts to rise.

Context: Erythrocytosis is a known side effect of testosterone therapy that can increase the risk of thromboembolic events., Objectives: To study the prevalence and determinants in the development of erythrocytosis in trans men using testosterone., Methods: A 20-year follow-up study in adult trans men who started testosterone therapy and had monitoring of hematocrit at our center (n = 1073)., Results: Erythrocytosis occurred in 11% (hematocrit > 0.50 L/L), 3.7% (hematocrit > 0.52 L/L), and 0.5% (hematocrit > 0.54 L/L) of trans men. Tobacco use (odds ratio [OR] 2.2; 95% CI, 1.6-3.3), long-acting undecanoate injections (OR 2.9; 95% CI, 1.7-5.0), age at initiation of hormone therapy (OR 5.9; 95% CI, 2.8-12.3), body mass index (BMI) (OR 3.7; 95% CI, 2.2-6.2), and pulmonary conditions associated with erythrocytosis and polycythemia vera (OR 2.5; 95% CI, 1.4-4.4) were associated with hematocrit > 0.50 L/L. In the first year of testosterone therapy hematocrit increased most: 0.39 L/L at baseline to 0.45 L/L after 1 year. Although there was only a slight continuation of this increase in the following 20 years, the probability of developing erythrocytosis still increased (10% after 1 year, 38% after 10 years)., Conclusion: Erythrocytosis occurs in trans men using testosterone. The largest increase in hematocrit was seen in the first year, but also after the first years a substantial number of people present with hematocrit > 0.50 L/L. A reasonable first step in the care for trans men with erythrocytosis while on testosterone is to advise them to quit smoking, to switch to a transdermal administration route, and if BMI is high, to lose weight., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Pazopanib, a tyrosine kinase inhibitor (TKI), is a standard treatment for various tumours, including metastatic non-adipocytic soft-tissue sarcomas. In literature, erythrocytosis has been described as a TKI-related condition., Case Report: A 59-year-old man underwent surgical removal of a sub-scapular mass consistent with myxofibrosarcoma. After distant relapse, he first started chemotherapy, and then Pazopanib. He was found to have increased levels of hemoglobin (Hb) and hematocrit (Hct). He was asymphtomatic, with no history of pulmonary disease nor smoking habit. Erythropoietin (EPO) level was higher than normal. A polycythemia vera was ruled out. Management & outcome: The patient started a prophylactic therapy with lysine acetylsalicylate, and we observed a reduction of Hb, but not Hct. Due to disease progression, we interrupted Pazopanib. After a week from drug discontinuation, Hb levels got back to the normal range, Hct was lowering. We decided not to perform phlebotomy, considering the declining trend in Hb and Hct values and the absence of symptoms., Discussion: We postulated a Pazopanib-related secondary erythrocytosis, since Hb and Hct levels increased from baseline during treatment, then normalized when Pazopanib was discontinued. We used the Naranjo Nomogram to assess the correlation between the adverse effect and Pazopanib, the correlation was "Probable", a score of 5. To the best of our knowledge, this is the first case report of Pazopanib-related secondary polycythemia in a patient with sarcoma. It is important to pay attention to blood count and to any symptoms potentially related to erythrocytosis in patients treated with TKIs.

Introduction: We present a case of a patient with a chronic carbon monoxide (CO) intoxication with facial plethora due to secondary erythrocytosis., Case Details: A 22-year-old male was referred by the dermatologist to our outpatient clinic for evaluation of polycythaemia. Laboratory results showed secondary erythrocytosis. After an extensive diagnostic evaluation, we diagnosed a chronic CO intoxication (carboxyhaemoglobin (COHb) level of 21%) without apparent complaints and facial plethora as the only clinical sign. The patient denied smoking tobacco or use of illicit drugs. On inspection of his house by the fire department, a waterpipe was found in his bedroom, which he used daily, according to his father. CO measurements in the house were normal. We treated the patient with high flow oxygen and advised him to quit smoking the waterpipe. Within a few weeks, the erythrocytosis normalised., Discussion: We propose to test for the presence of an elevated COHb in all patients with a normal or high erythropoietin level. The test is not expensive and can easily be included as part of an examination, since CO intoxication has potentially disastrous consequences, and, as is illustrated with this case, chronic CO poisoning can be virtually asymptomatic. Not all individuals consider smoking a waterpipe the same as smoking or drugs, and therefore physicians need to specifically ask for its use.

Objectives: To evaluate therapeutic phlebotomy (TP) requests for testosterone replacement therapy (TRT) and to highlight the impact to a blood center (BC) or service that provides TP for individuals on TRT., Methods: Review of TP requests for individuals on TRT at our BC over a 3-year period from 2014 through 2016, as well as the total number of TP collections., Results: Total TPs during 2014, 2015, and 2016 were 475, 500, and 569, respectively. Annual TP collections for patients on TRT were 193, 212, and 239, respectively. TRT patients with TP orders increased 71.4% during this period. After discontinuation of TP services for TRT at our BC, 32% continued to donate as volunteer blood donors at our BC., Conclusions: Our BC observed increased TP requests for patients on TRT from 2014 through 2016. Our findings suggest that individuals on TRT may be presenting to BCs as volunteer blood donors to avoid charges for TP., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Clear cell renal cell carcinoma is characterized by mutation or inactivation of Von Hippel-Lindau suppressor gene. The mutation of Von Hippel-Lindau mechanism is associated with the upregulation of the hypoxia-inducible factor protein, inducing the overexpression of proteins including erythropoietin and vascular endothelial growth factor. Vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitors are widely used in treatment of metastatic renal cell carcinoma. In paradoxical hematological effect with tyrosine kinase inhibitor therapies, hemoglobin level may be increased, but polycythemia requiring phlebotomy is very rare., Case Description: We present here a case of renal cell carcinoma who received successive treatment with sunitinib, everolimus, and axitinib. While he had a normal hemoglobin level with prior sunitinib treatment, on the sixth week of axitinib treatment, he developed polycythemia and treatment response was seen after axitinib-associated polycythemia., Conclusion: Progression-free survival (PFS) was 30 months in our case with third-line treatment axitinib. Higher hemoglobin levels may be associated with longer survival. Polycythemia was the first response to treatment of axitinib in our patient. It may be an indicator of persistent treatment response.

Anabolic steroid use is prevalent among athletes and bodybuilders. There are known cardiovascular, reproductive, musculoskeletal and neuropsychiatric risks associated with their prolonged use. Although there have been very few documented cases of strokes associated with anabolic steroid use, cardiomyopathy and secondary erythropoiesis can increase the risk of strokes in users with no other risk factors. We present a 49-year-old man with left parietal ischaemic stroke with haemorrhagic conversion resulting in Gerstmann syndrome secondary to a hypercoagulable state from chronic anabolic steroid use., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Erythrocytosis is one of the most common side effects occurring during testosterone replacement therapy (TRT) in male hypogonadism. It is well known that all testosterone formulations may cause Hb and hematocrit increase, especially with short-acting injectable formulations. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a new class of glucose-lowering agents that reduce hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by inhibition of renal glucose reabsorption, leading to increased urinary glucose excretion. The co-occurrence of T2DM and hypogonadism is known to be increasingly frequent. However, to date, no adverse events with the concomitant use of TRT and SGLT2is are reported., Case Description: We report two cases of erythrocytosis during testosterone treatment and SGLT2i in patients with hypogonadism and T2DM., Conclusion: Considering that hypogonadism and T2DM are frequently associated, clinicians should carefully monitor the risk of occurrence of erythrocytosis when prescribing TRT and SGLT2i together.

Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

A variety of methods for testosterone replacement therapy (TRT) exist, and the major potential risks of TRT have been well established. The risk of developing polycythemia secondary to exogenous testosterone (T) has been reported to range from 0.4% to 40%. Implantable T pellets have been used since 1972, and secondary polycythemia has been reported to be as low as 0.4% with this administration modality. However, our experience has suggested a higher rate. We conducted an institutional review board-approved, single-institution, retrospective chart review (2009-2013) to determine the rate of secondary polycythemia in 228 men treated with subcutaneously implanted testosterone pellets. Kaplan-Meyer failure curves were used to estimate time until the development of polycythemia (hematocrit >50%). The mean number of pellets administered was 12 (range: 6-16). The mean follow-up was 566 days. The median time to development of polycythemia whereby 50% of patients developed polycythemia was 50 months. The estimated rate of polycythemia at 6 months was 10.4%, 12 months was 17.3%, and 24 months was 30.2%. We concluded that the incidence of secondary polycythemia while on T pellet therapy may be higher than previously established.

Introduction: A rapid increase in awareness of androgen deficiency has led to substantial increases in prescribing of testosterone therapy (TTh), with benefits of improvements in mood, libido, bone density, muscle mass, body composition, energy, and cognition. However, TTh can be limited by its side effects, particularly erythrocytosis. This review examines the literature on testosterone-induced erythrocytosis and polycythemia., Aim: To review the available literature on testosterone-induced erythrocytosis, discuss possible mechanisms for pathophysiology, determine the significance of formulation, and elucidate potential thromboembolic risk., Methods: A literature review was performed using PubMed for articles addressing TTh, erythrocytosis, and polycythemia., Main Outcome Measures: Mechanism, pharmacologic contribution, and risk of testosterone-induced erythrocytosis., Results: For men undergoing TTh, the risk of developing erythrocytosis compared with controls is well established, with short-acting injectable formulations having the highest associated incidence. Potential mechanisms explaining the relation between TTh and erythrocytosis include the role of hepcidin, iron sequestration and turnover, erythropoietin production, bone marrow stimulation, and genetic factors. High blood viscosity increases the risk for potential vascular complications involving the coronary, cerebrovascular, and peripheral vascular circulations, although there is limited evidence supporting a relation between TTh and vascular complications., Conclusion: Short-acting injectable testosterone is associated with greater risk of erythrocytosis compared with other formulations. The mechanism of the pathophysiology and its role on thromboembolic events remain unclear, although some data support an increased risk of cardiovascular events resulting from testosterone-induced erythrocytosis. Ohlander SJ, Varghese B, Pastuszak AW. Erythrocytosis Following Testosterone Therapy. Sex Med Rev 2018;6:77-85., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Competing Interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: none.

Competing Interests: Competing interests: None declared.

Background: Axitinib is used after failure of first line treatment for metastatic renal cell carcinoma (mRCC). A known side effect is the increase of haemoglobin level (HbL) during treatment with a suspected correlation with better outcome. Our objective was to examine whether HbL increase during the first three months of axitinib treatment is associated with better prognosis., Methods: Retrospective multicentre analysis including patients with mRCC treated with axitinib for at least three months from 2012 to 2014. Progression-free survival (PFS) was analysed by a Cox model according to gender, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score, high blood pressure (hBP), and maximum increase in HbL within the first three months of treatment., Results: Ninety-eight patients were analysed (71% men; median age at treatment initiation: 62 years; IMDC: 24%, 50%, and 26% in the favourable, intermediate, and poor-risk group, respectively). Patients received axitinib for a median of 8 months. During the first three months, the median increase of HbL was +2.3 g/dL (-1.1; 7.2). Fifty-six (57%) patients developed hBP. In multivariate analysis, after adjustment for performance status (P < 0.0001) and gender (P = 0.0041), the combination of HbL increase ≥2.3 g/dL and any grade hBP was significantly associated with longer PFS (HR = 0.40, 95%CI [0.24; 0.68])., Conclusions: Early HbL increase during axitinib treatment combined with hBP is an independent predictive factor of PFS. These results require validation in a prospective setting.

Purpose: We evaluated the relative prevalence of secondary polycythemia in hypogonadal men treated with clomiphene citrate or testosterone replacement therapy., Materials and Methods: In this retrospective, multi-institutional study, we included 188 men who received clomiphene citrate and 175 who received testosterone replacement therapy with symptomatic hypogonadism. The overall prevalence and ORs of secondary polycythemia for clomiphene citrate treatment vs testosterone replacement were primarily measured, as were baseline characteristics. Subset analysis included polycythemia rates for different types of testosterone replacement therapy., Results: Overall, men on testosterone replacement therapy were older than clomiphene citrate treated men (age 51.5 vs 38 years). Men on testosterone replacement had longer treatment duration than clomiphene citrate treated men (19.6 vs 9.2 months). For testosterone replacement therapy and clomiphene citrate the mean change in hematocrit was 3.0% and 0.6%, and the mean change in serum testosterone was 333.1 and 367.6 ng/dl, respectively. The prevalence of polycythemia in men on testosterone replacement was 11.2% vs 1.7% in men on clomiphene citrate (p = 0.0003). This significance remained on logistic regression after correcting for age, site, smoking history and pretreatment hematocrit., Conclusions: The prevalence of polycythemia in men treated with clomiphene citrate was markedly lower than that in men on testosterone replacement therapy. The improvement in absolute serum testosterone levels was similar to that in men on testosterone replacement. There is no significant risk of polycythemia in men treated with clomiphene citrate for hypogonadism., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

A 55-year-old male patient under permanent testosterone therapy for hypogonadism presented with abdominal pain and increased blood pressure values. In the physical examination a plethora was noted and laboratory examinations revealed polyglobulia. In the subsequent diagnostic process polycythemia vera and cancer could be excluded as the cause. A secondary polyglobulia due to testosterone substitution was diagnosed. Unphysiologically high testosterone levels represent a rare cause of secondary polyglobulia and with an appropriate medical history should be taken into account at an early stage.

Background: Polycythemia is the most common adverse effect of testosterone replacement therapy (TRT) and may predispose patients to adverse vascular events. Current Canadian guidelines recommend regular laboratory monitoring and discontinuing TRT or reducing the dose if the hematocrit exceeds 54% (hemoglobin ≥180 g/L). This threshold has been interpreted by some physicians and patients to indicate the need for phlebotomy or blood donation while on TRT., Study Design and Methods: We reviewed all male blood donors in Southwestern Ontario at Canadian Blood Services from December 2013 to March 2016 who self-identified or were found on donor screening to be on TRT. Hemoglobin concentration was measured at the time of donation or clinic visit and with each subsequent appointment in repeat donors., Results: We identified 39 patients on TRT who presented for blood donation over a 2-year period. The mean hemoglobin level at all clinic visits was 173 g/L (range, 134-205 g/L; n = 108). Hemoglobin concentrations of 180 g/L or more (calculated hematocrit, ≥54%) were measured at 25% of appointments. Of the 27 repeat donors, 12 (44%) had persistently elevated hemoglobin levels (≥180 g/L) at subsequent donations., Conclusion: Hemoglobin concentrations were elevated in donors on TRT, and significant numbers had hemoglobin levels above those recommended by current guidelines. These data also suggest that repeat blood donation was insufficient to maintain a hematocrit below 54%. Our findings raise concerns about the persistent risk of vascular events in these donors, particularly when coupled with the misperception by patients and health care providers that donation has reduced or eliminated the risks of TRT-induced polycythemia., (© 2017 AABB.)

Purpose: We studied the incidence and risk factors for the development of erythrocytosis with implantable testosterone pellets., Materials and Methods: A multi-institutional retrospective database analysis was used to evaluate men treated with testosterone pellets between 2009 and 2014. Inclusion criteria consisted of adult, hypogonadal males who had a full complement of pretreatment and posttreatment surveillance studies. Pretreatment and posttreatment values were compared with Wilcoxon signed rank tests. Multiple linear regression was used to identify potential risk factors for significant hematocrit elevation., Results: A total of 97 patients were included in the study. The average age of the cohort was 52 years (range 24 to 80). Mean hematocrit before and after pellet implantation was 43.9% and 46.1%, respectively, corresponding to an increase of 2.2% (CI 1.4-2.9, p <0.001). The average increase in testosterone was 145.3 ng/dl from an initial mean of 278.9 ng/dl (CI 105.7-184.9, p <0.001). Multiple linear regression demonstrated that pretreatment hematocrit was inversely related to the expected change in hematocrit. Pretreatment comorbidity status (ie the presence of hypertension, hyperlipidemia, obesity or diabetes) was not associated with a significant increase in posttreatment hematocrit., Conclusions: Although the data demonstrate a statistically significant increase in hematocrit, an increment of 2.2% is unlikely to translate into clinical relevance. Thus, for this cohort of patients implantable testosterone pellets appear safe in terms of the risk of polycythemia. Pretreatment hematocrit may serve as a predictor of a significant hematocrit increase after the initiation of therapy., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Our aim was to study the effect of a broad range of recombinant human erythropoietin (rHuEPO) doses on hematological and biochemical parameters, blood pressure (BP), renal function and damage in the rat, focusing on endothelial nitric oxide synthase (eNOS) and hypoxia-inducible factors (HIFs). Male Wistar rats were divided in 5 groups receiving different doses of rHuEPO (100, 200, 400 and 600IU/kg body weight (BW)/week) and saline solution (control), during 3weeks. Blood and 24h urine were collected to perform hematological and biochemical analysis. BP was measured by the tail-cuff method. Kidney tissue was collected to mRNA and protein expression assays and to characterize renal lesions. A dose-dependent increase in red blood cells count, hematocrit and hemoglobin levels was found with rHuEPO therapy, in rHuEPO200, rHuEPO400 and rHuEPO600 groups. Increased reticulocyte count was found in rHuEPO400 and rHuEPO600 groups. BP raised in all groups receiving rHuEPO. The rHuEPO200 and rHuEPO600 groups presented increased kidney protein levels of HIF2α, a reduction in kidney protein levels of eNOS, and the highest grade of vascular and tubular renal lesions. Our study showed that rHuEPO-induced hypertension is present before significant hematological changes occur and, therefore, might involve direct (renal) and indirect (hematological) effects, which varies according to the dose used. The presence of renal hypoxia reduces eNOS activity. Excessive erythrocytosis increases blood hyperviscosity, which can be modulated by an increase in reticulocytes. Hypertension leads to early renal damage without alterations in traditional markers of renal function, thus underestimating the serious adverse effects and risks., (Copyright © 2016 Elsevier Inc. All rights reserved.)