Increased CXCL10 (IP-10) is associated with advanced myeloproliferative neoplasms and its loss dampens erythrocytosis in mouse models.

Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of the disease, but the precise role of the cellular microenvironment in disease initiation and evolution remains poorly understood. In myeloproliferative neoplasms (MPNs), higher levels of specific cytokines have been previously correlated with increased disease severity (tumor necrosis factor-alpha [TNF-α], interferon gamma-induced protein-10 [IP-10 or CXCL10]) and decreased survival (interleukin 8 [IL-8]). Whereas TNF-α and IL-8 have been studied by numerous groups, there is a relative paucity of studies on IP-10 (CXCL10). Here we explore the relationship of IP-10 levels with detailed genomic and clinical data and undertake a complementary cytokine screen alongside functional assays in a wide range of MPN mouse models. Similar to patients, levels of IP-10 were increased in mice with more severe disease phenotypes (e.g., JAK2V617F/V617F TET2-/- double-mutant mice) compared with those with less severe phenotypes (e.g., CALRdel52 or JAK2+/V617F mice) and wild-type (WT) littermate controls. Although exposure to IP-10 did not directly alter proliferation or survival in single hematopoietic stem cells (HSCs) in vitro, IP-10-/- mice transplanted with disease-initiating HSCs developed an MPN phenotype more slowly, suggesting that the effect of IP-10 loss was noncell-autonomous. To explore the broader effects of IP-10 loss, we crossed IP-10-/- mice into a series of MPN mouse models and showed that its loss reduces the erythrocytosis observed in mice with the most severe phenotype. Together, these data point to a potential role for blocking IP-10 activity in the management of MPNs.

Hemangioblastoma: An Uncommon Cause of Polycythemia in a Child.

Polycythemia is a rare condition in children. Myeloproliferative neoplasms, including polycythemia vera although rare, is an important cause of childhood primary polycythemia. Secondary polycythemia is more common in children due to conditions causing hypoxia or due to pathologic erythropoietin production in malignancies like renal cell carcinoma, Wilms tumor or Hepatocellular carcinoma. Central nervous system hemangioblastoma is one of the rare causes of polycythemia. We report a 13-year-old girl with primarily neurological symptoms identified to be polycythemic during routine evaluation. Clinical examination and neuroimaging subsequently confirmed an intracranial space occupying lesion which was excised. Hemoglobin level normalized after tumor excision. This case report emphasizes the need for thorough systemic evaluation including central nervous system examination in children identified to be polycythemic. Keywords: CNS tumor; hemangioblastoma; polycythemia.

Central Retinal Artery Occlusion in Young Adults at High Altitude: Thin Air, High Stakes.

Rana, Vipin, Pradeep Kumar, Sandeepan Bandopadhyay, Vijay K. Sharma, Meenu Dangi, Dattakiran Joshi, Sanjay Kumar Mishra, Satyabrat Srikumar, and V.A. Arun. Central retinal artery occlusion in young adults at high altitude: thin air, high stakes. High Alt Med Biol. 00:000-000, 2024.-We present five cases of young security personnel who were posted at high altitude (HA) for a duration of at least 6 months and presented with a sudden decrease of vision in one eye. The diagnosis of central retinal artery occlusion (CRAO) was made in all patients. Fundus fluorescein angiography and optical coherence tomography of the macula supported the diagnosis. None of these cases had any preexisting comorbidities. Erythrocytosis was noticed in all patients, and two of them had hyperhomocysteinemia. Four out of five patients showed either middle cerebral artery or internal carotid artery (ICA) thrombosis on computed tomography angiography. The patients were managed by a team of ophthalmologist, hematologist, vascular surgeon, and neurologist. In cases of incomplete ICA occlusion, patients were managed surgically. However, in the case of complete ICA occlusion, management was conservative with antiplatelet drugs. This case series highlights HA-associated erythrocytosis and hyperhomocysteinemia as important risk factors for CRAO in young individuals stationed at HA.

A Case of High-Altitude Renal Syndrome.

Wang, Si-Yang, Jun Liang, and Jing-Hong Zhao. A Case of High-Altitude Renal Syndrome. High Alt Med Biol. 00:000-000, 2024.-Epidemiological studies have confirmed that high-altitude exposure increases the risk of proteinuria. The concept of high-altitude renal syndrome (HARS) was proposed in 2011. HARS is a group of clinical syndromes consisting of high-altitude polycythemia, hyperuricemia, systemic hypertension, and microalbuminuria. At present, no standardized and unified treatment methods of HARS have been proposed. We report a case of HARS without other organ involvement in a young man exposed to high altitude. Decreasing the red blood cell count and hemodynamic changes as soon as possible may be of great importance for reducing proteinuria. In addition, angiotensin receptor blockers are effective in the treatment of HARS.

Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera.

BACKGROUND: Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS: In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS: Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS: In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).

Neonatal polycythemia: prevalence, risk factors and predictors of severity.

BACKGROUND: Polycythemia is a disorder with several causes and risk factors. The clinical presentation is variable, ranging from asymptomatic newborns to cases with severe physiological changes. The aim of this study was to assess the prevalence, risk factors and predictors of severity of polycythemia in a Portuguese level III Neonatal Intensive Care Unit (NICU). METHODS: Case-control study of all term newborns with the diagnosis of polycythemia admitted to the NICU of the São João Universitary Hospital Center, Porto, Portugal, from January 1, 1999 to December 31, 2019; and who met one of the following inclusion criteria were eligible for the study: 1) Hct>65% or Hb>22 g/dL; and 2) Hb≥21 g/dL with clinical manifestations of polycythemia. RESULTS: A total of 53 newborns fulfilled the inclusion criteria and were included in the study, corresponding to a prevalence of 0.57%. Birth outside the hospital was the only risk factor with statistical significance. Of 53 cases, 51 (96.23%) had symptomatic polycythemia. The most frequent symptoms were: hyperbilirubinemia (69.81%), hypoglycemia (52.83%), thrombocytopenia (50.94%), cardiorespiratory (33.96%), and neurological symptoms (33.96%). Of the 53 newborns evaluated, 41 (77.36%) needed treatment. The only risk factors that influenced the hematocrit value were maternal diabetes and fetal growth restriction. CONCLUSIONS: The best way to improve the prognosis of polycythemia is to identify the risk factors present throughout pregnancy and make an early diagnosis and treatment. Out-of-hospital births should be avoided. The diagnosis should not be excluded, even if hemoglobin and hematocrit are within normal limits.

[How I manage polycythemia]. / Comment j'explore une polyglobulie.

Polycythemia is suspected when hemoglobin and/or hematocrit levels exceed established norms based on gender and age. This biological anomaly can arise from a myeloproliferative neoplasm known as polycythemia vera, or be secondary to excess erythropoietin (EPO) or decreased in plasma volume. Faced with polycythemia, the search for JAK2 mutations and measurement of serum EPO levels can guide toward the etiology. In polycythemia vera, thromboembolic events are the most lethal complications and unfortunately often the initial manifestation of the disease. The condition can also progress to myelofibrosis or acute leukemia. Management aims at reducing the hematocrit below 45 %, in order to limit, but not completely prevent, thrombo-embolic complications. This article elaborates on the clinical considerations around this biological anomaly, relevant complementary examinations, and briefly the therapeutic management.

La polyglobulie est suspectée lorsque le taux d'hémoglobine et/ou d'hématocrite est au-dessus des normes définies selon le sexe et l'âge. Cette anomalie biologique peut survenir à la suite d'une néoplasie myéloproliférative appelée polycythemia vera (PV), être secondaire à un excès d'érythropoïétine (EPO) ou à une diminution du volume plasmatique. Face à une polyglobulie, la recherche de mutations du gène JAK2 et un dosage d'EPO sérique permettront d'orienter vers l'étiologie. En cas de PV, les phénomènes thrombo-emboliques sont les complications les plus léthales et sont malheureusement souvent la première manifestation de la maladie. La maladie peut également évoluer en myélofibrose ou en leucémie aiguë. La prise en charge vise à réduire le taux d'hématocrite en-dessous de 45 %, afin de limiter, sans les empêcher complètement, les complications thrombo-emboliques. Dans cet article, nous développons la réflexion clinique autour de cette anomalie biologique, les examens complémentaires pertinents dans ce domaine et, brièvement, la prise en charge thérapeutique.

Hematologic Derangements among Children with Unoperated Cyanotic Congenital Heart Disease in Ethiopia.

Background: Surgical treatment has transformed the course and outcome of congenital heart defects in high-income countries, but children with congenital heart diseases in sub-Saharan Africa, where access to cardiac surgery is limited, often experience the natural course of untreated lesions and their complications. The objective of this study was to determine the prevalence of hematologic derangements among Ethiopian children with unoperated cyanoticcongenital heart diseases, to identify factors associated with coagulopathy in this population, and to describe how these complications are managed in this setting. Methods: In this single-center cross-sectional study, we prospectively collected clinical and demographic data from children (<18 years) with cyanotic congenital heart diseases. Blood samples were collected to measure hematologic parameters. Polycythemia was defined as hematocrit >50% and thrombocytopenia as <150,000 per microliter. Results: Among 70 children recruited, the overall prevalence of polycythemia and thrombocytopenia was 63% (n=44) and 26% (n=18), respectively. On multivariate logistic regression analysis, hematocrit ≥65% (p-value=.024), and oxygen saturation <85% (p-value=.018) were independently associated with moderate or severe thrombocytopenia. Thirty-one (44%) patients had undergone therapeutic phlebotomy, and 84% (26/31) of these patients received iron supplementation. Conclusion: We report a high prevalence of polycythemia and thrombocytopenia in Ethiopian children with untreated cyanotic congenital heart diseases. There was variable implementation of iron supplementation and therapeutic phlebotomy, highlighting the need to optimize supportive management strategies in this population to mitigate the risk of life-threatening complications.

Hidronefrosis como causa de poliglobulia secundaria / Hydronephrosis as a cause of secondary polyglobulia

La policitemia primaria es producida por una mutación adquirida o heredada en las células progenitoras de los glóbulos rojos, mientras que la poliglobulia secundaria está relacionada con un aumento de la eritropoyetina sérica como respuesta a la hipoxia tisular o a la producción autónoma tumoral. Hace más de medio siglo que se conoce que la hidronefrosis puede actuar como una rara causa de eritrocitosis debido al aumento de producción de eritropoyetina por un riñón que censa una disminución de oxígeno, mecanismo también observado en la estenosis de la arteria renal y en los quistes renales. Se describe a continuación el caso de un paciente de 38 años con poliglobulia atendido en el Hospital Italiano de San Justo (Argentina), que presenta como hallazgo una hidronefrosis unilateral severa y cuya resolución quirúrgica a través de una nefrectomía revierte el cuadro hematológico de base. (AU)

Primary polycythemia is produced by an acquired or inherited mutation in progenitor cells of red blood cells, while secondary polyglobulia is related to an increase in serum erythropoietin in response to tissue hypoxia or autonomous tumor production. Since the middle of the twentieth century, the hydronephrosis is known to be a rare etiology of secondary polycythemia, with increased erythropoietin production caused by diminished oxygen sensing by the kidney, also seen in renal artery stenosis and kidney cysts. We describe a case of a 38 year old patient with polycythemia studied in the "Hospital Italiano de San Justo" (Argentina) that presented an incidental severe unilateral hydronephrosis, and nephrectomy was carried out as a final resolution of the hematological disorder. (AU)

Resultados perinatales en el síndrome de transfusión feto fetal manejados con la técnica de Solomon: revisión de la literatura / Perinatal outcomes in fetal-fetal transfusion syndrome managed with the Solomon technique: literature review

INTRODUCCIÓN: Entre 15-20% de los embarazos gemelares monocoriales biamnióticos se complican con el síndrome de transfusión feto/fetal el cual se asocia con mortalidad superior a 90% y morbilidad significativa en el 50% del gemelo sobreviviente. La técnica láser que coagula la superficie de la placa coriónica entre los principales canales a lo largo del ecuador (técnica de Solomon), se ha sugerido para disminuir la recurrencia, prevenir complicaciones secundarias sin incrementar resultados adversos. Métodos: REVISIÓN de la literatura existente en las bases de datos MEDLINE, EBSCO, OVID, PROQUEST, COCHRANE, Lilacs, SciELO, desde el año 2000 al 2015. Se incluyeron los artículos de revisión e investigaciones originales que compararon la técnica estándar de fotocoagulación secuencial con láser y la técnica de Solomon, el resultado primario fue la reducción de la incidencia Secuencia Anemia Policitemia, recurrencia del síndrome de transfusión feto/fetal, mortalidad perinatal y morbilidad neonatal severa. RESULTADOS: Se encontraron 200 artículos, se seleccionaron seis: 1 ensayo clínico y su análisis secundario, 2 estudios de cohorte retrospectivos, 1 revisión sistemática y un estudio que compara los resultados del neurodesarrollo. Los estudios sugieren una mejoría en la sobrevida de algunos de los fetos con la técnica Solomon, menor recurrencia del síndrome de transfusión feto/fetal y Secuencia Anemia Policitemia, sin la presencia de eventos adversos. CONCLUSIÓN: La técnica de Solomon mejora la sobrevida de algunos gemelos, sin embargo no puede concluirse que haya mejoría en la mortalidad pues los estudios no tienen el suficiente poder para determinarlo.

INTRODUCTION: Between 15 to 20% of monochorionic diamniotic twin pregnancies are complicated by the twin-twin transfusion syndrome. It has a mortality greater than 90% and a significant morbidity, 50% in the surviving twin. The Solomon technique (laser photocoagulation of the main vascular channels of the chorio-nic plate surface along the entire vascular equator) has been suggested to reduce the recurrence, and pre-vent secondary complications without increasing adverse results. METHODS: Systematic review of electronic searches of the literature from 2000 to 2015 (MEDLINE, EBSCO, OVID, PROQUEST, COCHRANE, Lilacs, and SciELO). We included review articles and original investigations comparing the standard photocoagulation technique with laser ablation against the Solomon technique. The primary results were reduction of Anemia Polycythemia Sequence incidence, twin-twin transfusion syndrome recurrence, perinatal mortality and severe neonatal morbidity. RESULTS: Of 200 articles, we selected six: one clinical essay and its secondary analysis, two retrospective cohort studies, one systematic review and a study comparing neurodeve-lopmental outcomes. The studies suggested a survival improvement in some fetuses using the Solomon technique, less twin-twin transfusion syndrome recurrence and Anemia Polycythemia Sequence without the presence of adverse effects. CONCLUSION: Solomon technique improves the survival of some twins, although we cannot conclude there is mortality improvement, because the studies do not have enough power to determine that.

Complicaciones tardías de la terapia láser como tratamiento de la transfusión feto-fetal: caso clínico / Late complications of laser therapy as a treatment for feto-fetal transfusion: clinical case

Presentamos la descripción del diagnóstico y manejo de una secuencia anemia-policitemia (SAP) que se presenta como complicación de una terapia láser exitosa en un embarazo gemelar monocorial cursando una transfusión feto-fetal (TFF) severa. Describimos la manifestación de esta complicación tardía de la terapia láser de la TFF severa y realizamos una revisión de la literatura internacional al respecto. A pesar del éxito de la introducción de la terapia láser en cuanto a la sobrevida y secuelas neonatales, recientemente se han descrito una serie de complicaciones de presentación tempranas o tardías. Entre las tardías, destacan la muerte de uno o ambos gemelos, recidiva de la TFF, y aparición de una SAP. Varios autores han descrito que la SAP sería secundaria a la presencia, o persistencia, de comunicaciones vasculares extremadamente pequeñas de flujo lento, las cuales llevan a una discordancia en los niveles de hemoglobina entre ambos gemelos, sin diferencias en sus volúmenes sanguíneos.

We describe the diagnosis and management of twin anemia-polycythemia sequence (TAPS), which occurs as a late complication of successful laser therapy in twin monochorionic pregnancies developing severetwin to twin transfusion syndrome (TTTS). We offer a description of this late complication of laser therapy in this condition and a review of the related medical literature. Despite the successful introduction of laser therapy on the survival and neonatal sequelae, various early and late complications related to this procedure have been recently described. Among the late, stands out the death of one or both twins, recurrence of TTTS, and the appearance of TAPS. With regards TAPS, several authors have reported that it would be secondary to the presence, o persistence, of extremely small slow flow vascular communications, which lead to discre-pancies in the hemoglobin levéis between the twins, with no differences in blood volume.

Eritrocitosis post-transplante renal / Post-renal transplantation erythrocytosis

La eritrocitosis post-transplante es una entidad caracterizada por un hematocrito superior al 51 por ciento, tiene una prevalencia del 10 al 15 por ciento en los pacientes transplantados renales, y puede manifestarse en cualquier momento post-transplante. La eritrocitosis post-transplante se asocia a hipertensión arterial, por aumento de la volemia, y es un factor predisponente a la trombosis vascular, por aumento de la viscosidad sanguínea. Tanto la angiotensina II como el Insulin Growth Factor I y otros compuestos han sido postulados como posibles mediadores del aumento de la eritropoyesis. La eritropoyetina se encuentra en valores aumentados en esta entidad, aunque existen casos en los cuales la misma se encuentra en valores normales o disminuídos. Independientemente de estos niveles, los inhibidores de la enzima convertidora de angiotensina, o recientemente los inhibidores del receptor de angiotensina II, son las drogas de elección para tratar en forma efectiva y segura la eritrocitosis post-trasnplante.

Erythropoietin assay in mice made polycythemic by transfusion of heterologous red cells

A simple in vivo bioassay suitable testing of quality control of recombinant human erythropoietin (rHu-EPO) analogues was developed. Mice made polycythemic by intraperitoneal injection of 1.2 ml of a 80 per cent suspension of heterologous (rat) red cells were used as assay animals and splenic 59 Fe uptke as expression of the response to rHu-EPO. The assay took three days and the following schedule is propose: 1)intraperitoneal injection of 1.2 ml of washed packed red cells obtained from donor rats, 2) subcutaneous injection of test material 4-5 h after transfusion, 3) intravenous administration of 59 Fe tracer 48 h later, and 4) determination of splenic isotope uptake 6 h after injection. This method for the in vivo biossay of rHu-EPO analogues is an economical and reliable alternative to the existing bioassays of the hormone

Diagnostico etiologico y manejo de la policitemia de origen respiratorio / Etiologic diagnosis and management of polycitemia of respiratory origin

Se estudian prospectivamente dos grupos de pacientes policitemicos diagnosticados en 1990: 24 pacientes (grupo I) con diagnostico etiologico y tratamiento específico y 16 (grupo II) sin diagnostico etiologico. El objetivo del trabajo fue estudiar la etiologia, conocer la relacion hipoxemia-policitemia y valorar el tratamiento. Los resultados revelan que el 95 por ciento de pacientes policitemicos corresponden a patologia respiratoria y solo 5 por ciento (2 Pacientes) a otras etiopatogenias. En 2/3 del grupo I la etiologia fue enfermedad pulmonar obstructiva cronica y/o tromboembolismo pulmonar, presentaron insuficiencia respiratoria hipoxemica 23/24 pacientes, todos fueron sometidos a rehabilitacion respiratoria incluyendo tratamiento acorde a su etiologia. El seguimiento durante dos años reveló una mortalidad en el grupo I tratado de 32 por ciento frente a 44 por ciento del grupo II de evolucion natural (NS), estabilidad clinico funcional deambulatoria de 64 por ciento frente a 19 por ciento (p<0.02), así como menos frecuencia y duración de hospitalización del grupo I respecto al II aunque sin significación estadística.

Policitemias de origen renal / Policitemia of renal cause

Se describe el mecanismo de producción y las principales causas de policitemia secundaria fisiologicamente inadecuada,destacando las enfermedades renales caracterizadas por un aumento en la producción de eritropoyetina, incluyendo el transplante renal. Se mencionan los mecanismos íntimos de la producción de eritropoyetina y las opciones terapéuticas recientemente sugeridas a la luz de los conocimientos actuales.