Evidence on the effect of long-term exposure to fine particulate matter (PM2.5) on erythrocytosis and thrombocytosis prevalence was limited. We aimed to investigate the association of PM2.5 and its constituents with the risks of erythrocytosis and thrombocytosis. The present study included a total of 33,585 participants from the Henan Rural Cohort at baseline between 2015 and 2017. A hybrid satellite-based model was employed to estimate the concentrations of PM2.5 mass and its constituents (including black carbon [BC], nitrate [NO3-], ammonium [NH4+], inorganic sulfate [SO42-], organic matter [OM], and soil particles [SOIL]). The logistic regression model was used to assess the associations of single exposure to PM2.5 and its constituents with the risks of erythrocytosis and thrombocytosis, and the quantile G-computation method was applied to evaluate their joint exposure risk. For the independent association, the odds ratios for erythrocytosis/thrombocytosis with 1 μg/m3 increase was 1.049/1.043 for PM2.5 mass, 1.596/1.610 for BC, 1.410/1.231 for NH4+, 1.205/1.139 for NO3-, 1.221/1.359 for OM, 1.300/1.143 for SO42-, and 1.197/1.313 for SOIL. Joint exposure to PM2.5 and its components was also positively associated with erythrocytosis and thrombocytosis. The estimated weight of NH4+ was found to be the largest for erythrocytosis, while OM had the largest weight for thrombocytosis. PM2.5 mass and its constituents were positively linked to prevalent erythrocytosis and thrombocytosis, both in single-exposure and joint-exposure models. Additionally, NH4+/OM was identified as a potentially responsible component for the association between PM2.5 and erythrocytosis/thrombocytosis.

The TEMPI syndrome is a novel and rare disease with five distinct clinical features: Telangiectasis, Erythrocytosis, Monoclonal gammopathy, Perinephric fluids collection, and Intrapulmonary shunting. Here, we report three cases of TEMPI syndrome and their treatment response. The three patients were presented to our department with polycythemia, abdominal distension, and dyspnea. On admission, all patients manifested telangiectasis, erythrocytosis, monoclonal gammopathy, and intrapulmonary shunting. Patient 1 and 2 manifested perinephric fluids collection. In addition, all patients had skin pigmentation, patient 1 and 2 had polyserosal effusion, two symptoms that had not been associated with TEMPI syndrome before. The three patients showed various response to plasma cell-directed therapy. We demonstrated their treatment response by measuring erythropoietin, hemoglobin, and M protein levels throughout therapy. This report suggested that TEMPI syndrome is a rare yet treatable disease. The diagnosis and treatment of it remain challenging.

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.
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.
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.
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.

BACKGROUND: Uterine myoma is the most common benign tumor among women and is often accompanied by anemia. Here, we report the case of a patient with a very large leiomyoma but with a hemoglobin level as high as 197 g/L. After undergoing hysterectomy, all her hematological parameters returned to normal. Immunohistochemical staining of her myoma for erythropoietin showed strong positivity, which suggested that erythropoietin may be the cause of her erythrocytosis. A multidisciplinary team played a significant role in treating the disease.
METHODS: A 47-year-old woman visited our department complaining that her abdomen had been continuously growing for the past 2 years. After careful examinations, she was suspected of having a very large leiomyoma. She was also diagnosed with erythrocytosis because her RBC count was 6.49 × 1012/L, hemoglobin was 197 g/L. Following a multidisciplinary team consultation, bilateral ureteral stents were placed, and 800 mL blood was removed by phlebotomy. The patient then underwent hysterectomy and bilateral salpingectomy. She recovered well from the operation, and her hemoglobin level decreased sharply following the surgery. Low-molecular-weight heparin was administered daily to prevent postoperative thrombosis. She was discharged from the hospital on the fourth postoperative day. Two months later, all her hematological parameters returned to normal. Pathological analysis of the myoma revealed that it was a benign leiomyoma, with partial hyalinization, and strong positivity for erythropoietin in immunohistochemical staining suggested that erythropoietin may be responsible for the erythrocytosis.
CONCLUSIONS: Erythropoietin ectopically produced from the myoma was responsible for the erythrocytosis in this patient. A multidisciplinary team is strongly recommended.

BACKGROUND: Double outlet right ventricle (DORV) is a rare and complex congenital heart defect, and the surgical repairs vary with type and pathophysiology consequences. Due to prolonged progressive hypoxemia, severe polycythemia is common in patients with DORV, which ultimately leads to coagulation dysfunction and increases the risk of thrombosis and infarction. Consequently, the anesthetic management is challenging and how to manage severe polycythemia and avoid hypoxia-related complications in such patients is of great significance.
METHODS: Herein, we report the anesthetic management of a 10-year-old female patient with a DORV. She lived in the low-oxygen Qinghai-Tibet Plateau, and presented with severe polycythemia (hemoglobin, 24.8 g/dL; hematocrit, 75%). She underwent a modified Fontan surgery, which was satisfactory and without any perioperative complications. Our anesthetic management highlights the importance of perioperative hemodilution in decreasing the risk of thromboembolism and the importance of correcting coagulopathy in preventing hemorrhage.
CONCLUSIONS: Anesthetic management is challenging in rare cyanotic congenital heart disease patients with severe polycythemia. It is important to adopt perioperative hemodilution and correction of coagulopathy in preventing thrombosis and hemorrhage.

BACKGROUND: Pheochromocytoma is a rare catecholamines-secreting tumor arising from chromaffin cells in the adrenal medulla. It classically presents with paroxysmal hypertension, headaches, palpitations, sweating, and metabolic disorders. Atypical presentations such as acute myocardial infarction, heart failure, cardiomyopathy, stroke, and transient erythrocytosis have been infrequently documented.
METHODS: We describe the case of a 72-year-old man diagnosed with pheochromocytoma presenting with non-ST segment elevation myocardial infarction, heart failure, and transient erythrocytosis with nonobstructed coronary arteries. This was his second heart attack. The patient was previously diagnosed with myocardial infarction, and an immense mass was found on the left adrenal gland 3 years prior. Based on clinical and laboratory findings, a diagnosis of pheochromocytoma was confirmed. His coronary angiogram showed nonobstructed coronary arteries except for a myocardial bridge in the left anterior descending branch. This was a form of type-2 myocardial infarction. The myocardial cell lesions were caused by sudden secretion of catecholamines by the pheochromocytoma. Even more atypically, his hemoglobin level was obviously elevated at admission, but after a few days of treatment with an alpha-adrenergic receptor blocker, it dropped to normal levels without additional treatment.
CONCLUSIONS: Pheochromocytoma may be a cause of acute myocardial infarction, heart failure, and transient erythrocytosis.

OBJECTIVE: Hypoxia-inducible factors (HIFs) play important roles in the pathogenesis of erythrocytosis in chronic mountain sickness (CMS). von Hippel-Lindau (VHL) is a key regulator of hypoxia that can direct the poly-ubiquitylation and degradation of HIFs. Epigenetic mechanisms are believed to contribute toward adaption to chronic hypoxia. Here, we investigated the contribution and mechanism of VHL methylation in rats with erythrocytosis in CMS.
METHODS: The methylation status of VHL was measured via bisulfite sequencing PCR, while VHL, DNMT1, DNMT3α, and DNMT3β expression were assessed using real-time reverse transcription PCR and western blotting. HIF-2α and EPO expression levels in bone marrow were determined via immunohistochemical staining, and erythroid hyperplasia in bone marrow sections were observed with hematoxylin and eosin staining.
RESULTS: We found that chronic hypoxia triggered erythroid hyperplasia in the bone marrow and increased the quantity of peripheral red blood cells in CMS rats. Chronic hypoxia significantly induced methylation at the CpG site in the VHL promoter, decreased VHL expression, and increased HIF-2α and EPO expression. Chronic hypoxia increased DNMT3α and DNMT3β expression, consistent with the decrease in VHL expression. The DNA methyltransferase inhibitor 5-azacytidine reduced chronic hypoxia-induced erythroid proliferation in the bone marrow of rats with CMS by suppressing VHL methylation and DNMTs expression.
CONCLUSIONS: Our study suggests that VHL methylation contributes toward excessive erythrocytosis in CMS by upregulating the HIF-2α/EPO pathway in the bone marrow of rats. We demonstrated that the DNMT inhibitor 5-azacytidine can attenuate erythroid hyperplasia in the bone marrow by demethylating the VHL promoter.

Congenital erythrocytosis is a rare and hereditary disorder of red blood cell (RBC) production that can be caused by high oxygen affinity hemoglobin (Hb) variants. We applied a genetic approach including whole exome sequencing and Sanger sequencing. We identified a heterozygous β-globin gene (Hb San Diego or HBB: c.328G>A) in exon 3 as a causative germline mutation in a Chinese family with congenital erythrocytosis. We concluded that in erythrocytosis with a dominant inheritance and normal or inappropriately high erythropoietin (EPO) levels, the high oxygen affinity Hb variants should be considered. In addition, as a tool for identification of mutations in congenital erythrocytosis, whole exome sequencing improves diagnostic accuracy and provides the opportunity for discovery of novel variants.

TEMPI (telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal gammopathy, perinephric fluid collections, intrapulmonary shunting) syndrome is a newly described clinical entity that is generally considered a plasma cell dyscrasia with multiple system involvement. The etiology and pathophysiology of this condition remains elusive. Nevertheless, clonal plasma cells and monoclonal protein appear to be major contributors. The early diagnosis of TEMPI syndrome is essential because therapies targeting the underlying plasma cells can lead to a dramatic response. Bortezomib-based chemotherapy, daratumumab monotherapy, and autologous hematopoietic stem cell transplantation can result in reversal of most manifestations. Nevertheless, the diagnosis of TEMPI syndrome remains a substantial challenge owing to its rarity and the complexity of clinical presentations. TEMPI syndrome is often misdiagnosed as other causes of erythrocytosis, resulting in a delayed diagnosis and further clinical deterioration. The aim of the present review was to present the clinical and biologic features of TEMPI syndrome, highlighting the differential diagnosis and outlining the present understanding of its pathophysiology and treatment.

Background: Because the pathogenesis of high altitude polycythemia (HAPC) is unclear, the aim of the present study was to explore whether abnormal iron metabolism is involved in the pathogenesis of HAPC and the possible cause. Methods: We examined the serum levels of iron, total iron binding capacity, soluble transferrin receptor (sTfR), ferritin, and hepcidin as well as erythropoietin (EPO) and inflammation-related cytokines in 20 healthy volunteers at sea level, 36 healthy high-altitude migrants, and 33 patients with HAPC. Mice that were exposed to a simulated hypoxic environment at an altitude of 5,000 m for 4 weeks received exogenous iron or intervention on cytokines, and the iron-related and hematological indices of peripheral blood and bone marrow were detected. The in vitro effects of some cytokines on hematopoietic cells were also observed. Results: Iron mobilization and utilization were enhanced in people who had lived at high altitudes for a long time. Notably, both the iron storage in ferritin and the available iron in the blood were elevated in patients with HAPC compared with the healthy high-altitude migrants. The correlation analysis indicated that the decreased hepcidin may have contributed to enhanced iron availability in HAPC, and decreased interleukin (IL)-10 and IL-22 were significantly associated with decreased hepcidin. The results of the animal experiments confirmed that a certain degree of iron redundancy may promote bone marrow erythropoiesis and peripheral red blood cell production in hypoxic mice and that decreased IL-10 and IL-22 stimulated iron mobilization during hypoxia by affecting hepcidin expression. Conclusion: These data demonstrated, for the first time, that an excess of obtainable iron caused by disordered IL-10 and IL-22 was involved in the pathogenesis of some HAPC patients. The potential benefits of iron removal and immunoregulation for the prevention and treatment of HAPC deserve further research.