TEMPI syndrome is a rare, acquired disorder with multisystemic manifestations. It is classified as a plasma cell disorder and is characterized by telangiectasias, erythrocytosis, monoclonal gammopathy, perinephric fluid collections and intrapulmonary shunt. Even though TEMPI\'s pathophysiology remains elusive, it responds to anti-myeloma therapy indicating that the monoclonal protein or clone plays a key role. We present a challenging case of a 73-year-old man with erythrocytosis and deteriorating renal function with nephrotic-range proteinuria in whom after extensive work up, the diagnosis of TEMPI syndrome was made. He was received treatment with daratumumab-bortezomib-cyclophosphamide and dexamethasone (Dara-VCD) and achieved a hematological and clinical response. We also report preliminary data on a multiplex assay for cytokines and growth factors for two patients with TEMPI syndrome and note lower levels for non-specific innate immunity related cytokines. A direct link between renal impairment and TEMPI syndrome is not currently established; cytokine deregulation could potentially be involved in the ischemic changes observed in the renal biopsy of our patient.

BACKGROUND: Approximately, 11% of trans men experience erythrocytosis diagnosis due to testosterone administration during the first year of the gender-affirming hormone treatment (GAHT).
OBJECTIVE: To identify and compare the effect of different testosterone formulations on hematocrit (Hct) and diagnose erythrocytosis in trans men.
METHODS: This systematic review was based on PRISMA guidelines. We performed an electronic search of PubMed, Embase, and Web of Science in January 2024. The Newcastle-Ottawa scale was used to evaluate the quality of evidence in the observational studies.
RESULTS: Of the 152 records retrieved, 18 met the eligibility criteria. Studies observed an increase of up to 5% in Hct in trans men using injectable testosterone undecanoate (TU), and up to 6.9% in trans men using intermediate injectable testosterone esters (TE). Trans men using TE experience a larger increase in serum Hct levels compared to those receiving TU. Erythrocytosis prevalence varies according to the cutoff used (50%, 52%, and 54%). Erythrocytosis was also associated with tobacco use, age at initiation of hormone therapy, body mass index (BMI), and pulmonary conditions. Studies that evaluated the effect of testosterone formulation on erythrocytosis diagnosis present conflicting result. Trans men have a hazard ratio of 7.4 (95% CI: 4.1, 13.4) of developing erythrocytosis compared to cisgender men, using a 52% hematocrit cutoff.
CONCLUSIONS: All testosterone formulations result in an increase in Hct, irrespective of dose, formulation, and administration method. Smoking, higher age at initiation of the testosterone therapy, higher BMI, and a predisposing medical history are associated with this increase in Hct. The difference in effect of TE and TU on Hct is conflicting, although it is important to point out that these data come from observational studies, retrospective, and with a small-sample size.

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There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to mitigate thrombotic risks and control blood counts and symptoms. There is now increased focus on disease modification through progressive attrition of JAK2-mutant stem/progenitor cells. The approval of ropeginterferon, a novel monoPEGylated interferon, coupled with findings from LOW-PV and longer-term data from CONTINUATION-PV that strongly support a disease-modifying effect for interferon therapy, have transformed the treatment paradigm for this disorder. Results from MAJIC-PV demonstrate that disease modification can also be induced with JAK inhibitors, suggesting an urgent need to incorporate prospective molecular monitoring into PV trials. Novel agents, such as hepcidin mimetics, aim to help patients with PV restore normal hematocrit levels and become phlebotomy-free. In this review, we will summarize past, current and future approaches to PV management and highlight findings from key clinical studies.

Methemoglobinemia secondary to administration of hydroxyurea is only reported in veterinary medicine as a result of accidental ingestion of high doses, and once at therapeutic dose in human medicine. A 2.5-year-old female spayed mixed breed dog was presented for acute signs of neurologic disease and diagnosed with severe erythrocytosis without an identified underlying cause, leading to suspicion of polycythemia vera. The dog was managed with phlebotomies, supportive care, and administration of hydroxyurea. Within 2 h of administration of hydroxyurea (37 mg/kg) administration, respiratory distress with cyanosis, and methemoglobinemia developed. Signs resolved within 24 h but recurred after a second administration of lower dosage of hydroxyurea (17 mg/kg) 20 days later. The dog remained asymptomatic except for mild cyanosis but was humanely euthanized for lack of relevant improvement of signs of neurologic disease. This case report documents the repeated occurrence of methemoglobinemia in a dog after administration of hydroxyurea at therapeutic doses.

Erythrocytosis, a rare adverse effect associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i), has been reported in diabetic patients, but its occurrence in those with chronic kidney disease (CKD) remains underrecognized. Here, we present two cases of dapagliflozin-related erythrocytosis in diabetic patients with CKD, highlighting the need for increased awareness among clinicians. Despite the established efficacy of SGLT2i in managing type 2 diabetes mellitus (T2DM) and its cardiovascular benefits, erythrocytosis poses a potential complication, necessitating thorough understanding and monitoring. While the precise mechanism of SGLT2i-induced erythrocytosis remains unclear, hypotheses include hemoconcentration and modulation of iron metabolism. Notably, our cases demonstrate a rapid onset of erythrocytosis, possibly exacerbated by CKD, emphasizing the importance of vigilant hemoglobin monitoring, especially in CKD patients on SGLT2i therapy. Timely discontinuation of dapagliflozin resulted in a significant reduction in hemoglobin levels, underscoring the critical role of early intervention in preventing erythrocytosis-related complications. This report advocates for routine hematological evaluation in CKD patients treated with SGLT2i to promptly detect and manage erythrocytosis, enhancing patient safety and improving clinical outcomes.

Although polycythemia vera (PV) is a chronic and incurable disease, effective management can allow most patients to maintain functional lives with near-normal life expectancy. However, there remain several inter-related factors that contribute to many ongoing challenges associated with the management of PV, which this review aims to explore. First, as a disease hallmarked by constitutive activation of the JAK/STAT pathway, PV is often accompanied by inflammatory symptoms that negatively impact quality of life. Next, patients often require recurrent therapeutic phlebotomies to maintain their hematocrit below the 45% threshold that has been associated with a decreased risk of thrombotic events. The need to closely monitor hematocrit and perform conditional therapeutic phlebotomies ties patients to the healthcare system, thereby limiting their autonomy. Furthermore, many patients describe therapeutic phlebotomies as burdensome and the procedure is often poorly tolerated, further contributing to quality-of-life decline. Phlebotomy needs can be reduced by utilizing cytoreductive therapy; however, standard first-line cytoreductive options (i.e., hydroxyurea and interferon) have not been shown to significantly improve symptom burden. Collectively, current PV management, while reducing thrombotic risk, often has a negative impact on patient quality of life. As researchers continue to advance towards the goal of developing a disease-modifying therapy for patients with PV, pursuit of nearer-term opportunities to shift the current treatment paradigm towards improving symptoms without compromising quality of life is also warranted, for example, by reducing or eliminating the frequent use of phlebotomy.

An absolute erythrocytosis is present when the red cell mass is greater than 125% of the predicted. This is suspected when the hemoglobin or hematocrit is above the normal range. An erythrocytosis can be classified as primary or secondary and congenital or acquired. The commonest primary acquired disorder is polycythemia vera. The diagnostic criteria for PV have evolved over time and this is the main diagnosis managed in hematology clinics. There are a variety of rare congenital causes both primary and secondary. In particular in young patients and/or those with a family history a congenital cause is suspected. There remains a larger cohort with acquired erythrocytosis mainly with non-hematological pathology. In order to explore for a cause of erythrocytosis, measurement of the erythropoietin level is a first step. A low erythropoietin level indicates a primary cause and a normal or elevated level indicates a secondary etiology. Further investigation is then dictated by initial findings and includes mutational testing with PCR and NGS for those in whom a congenital cause is suspected. Following this possibly bone marrow biopsy, scans, and further investigation as indicated by history and initial findings. Investigation is directed toward the identification of those with a hematological disorder which would be best managed following guidelines in hematology clinics and referral elsewhere in those for whom there are non-hematological reasons for the elevated hemoglobin.

The identification of the hormone erythropoietin (EPO), which regulates red blood cell production, and its development into a pharmaceutical-grade product to treat anemia has been not only a herculean task but it has also been the first of its kind. As with all the successes, it had \"winners\" and \"losers\", but its history is mostly told by the winners who, over the years, have published excellent scientific and divulgate summaries on the subject, some of which are cited in this review. In addition, \"success\" is also due to the superb and dedicated work of numerous \"crew\" members, who often are under-represented and under-recognized when the story is told and often have several \"dark sides\" that are not told in the polished context of most reviews, but which raised the need for the development of the current legislation on biotherapeutics. Although I was marginally involved in the clinical development of erythropoietin, I have known on a personal basis most, if not all, the protagonists of the saga and had multiple opportunities to talk with them on the drive that supported their activities. Here, I will summarize the major steps in the development of erythropoietin as the first bioproduct to enter the clinic. Some of the \"dark sides\" will also be mentioned to emphasize what a beautiful achievement of humankind this process has been and how the various unforeseen challenges that emerged were progressively addressed in the interest of science and of the patient\'s wellbeing.

Erythrocytosis or polycythemia is defined as an increase in red blood cell concentration above the age- and sex-specific normal levels. Unlike anemia, which is very common in patients with chronic kidney disease (CKD), erythrocytosis is less frequent but requires specific understanding by health care professionals in order to provide the best care. Erythrocytosis, especially when undiagnosed and untreated, can lead to serious thrombotic events and higher mortality. Classic causes of erythrocytosis associated with CKD include cystic kidney diseases, kidney or other erythropoietin-secreting neoplasms, high-altitude renal syndrome, overdosage of erythropoietin-stimulating agents, androgen therapy, heavy smoking, chronic lung disease, obstructive sleep apnea, IgA nephropathy, post-kidney transplant erythrocytosis, renal artery stenosis, and congenital etiologies. After ruling out the common acquired causes of erythrocytosis and/or in the presence of suggestive parameters, primary erythrocytosis or polycythemia vera (PV) should be considered, and patients should be screened for JAK2V617F somatic mutation. The newest entity inducing erythrocytosis is linked to the use of sodium/glucose cotransporter 2 (SGLT2) inhibitors that hypothetically activate hypoxia-inducible factor 2α (HIF-2α) and in some cases unmask PV. This Review focuses on the pathogenesis, renal manifestations and management of PV, the pathophysiology of erythrocytosis induced by SGLT2 inhibitors and the relevance of timely JAK2 mutation screening in these patients.