Polycythemia Research Articles

Evaluation of neutrophil lymphocyte ratio as a venous risk factor in patients with primary familial erythrocytosis

Evaluation of neutrophil lymphocyte ratio as a venous risk factor in patients with primary familial erythrocytosis

Increased carotid intima media thickness as an indicator of increased cardiovascular risk in patients with primary familial erythrocytosis

Increased carotid intima media thickness as an indicator of increased cardiovascular risk in patients with primary familial erythrocytosis

Analysis of mutations in EPOR, VHL, EPAS1 and EGLN1 genes associated with the familial erythrocytosis ECYT1-4 among JAK2- and CALR-negative patients with the erythrocytosis of unclear etiology

Introduction. In addition to the clonal nature of the development of erythrocytosis, there are other causes, such as germinal mutations in genes of proteins responsible for the development of familial inherited erythrocytosis (EPOR, VHL, EPAS1, EGLN1, etc.).Aim. To conduct the analysis of mutations in the EPOR, VHL, EPAS1 and EGLN1 genes associated with the familial erythrocytosis ECYT1-4 among JAK2- and CALR-negative patients.Materials and methods. The study included 50 JAK2- and CALR-negative patients of Krasnoyarsk Krai with erythrocytosis of unclear etiology. Analysis of mutations in the EPOR, VHL, EPAS1 and EGLN1 genes, responsible for the development of familial erythrocytosis was conducted with the use of the Sanger sequencing. A mass parallel sequencing study was also performed for 12 patients.Results. The Sanger sequencing analysis of EPOR, VHL, EPAS1 and EGLN1 revealed any of the genetic variants in 22 of the 50 patients studied. Of all the variants identifi ed in the coding regions of the genes surveyed that result in amino acid substitutions, the following were of biggest interest: 1) two mutations in the VHL gene (rs28940298 and rs5030821) associated with the development of Chuvash polycythemia (ECYT2); 2) rs12097901 variant in the EGLN1 gene associated with altitude adaptation and increasing haemoglobin levels, but with no pathogenetic relevance for erythrocytosis according to ClinVar; and 3) one mutation in the EPOR gene not previously described in literature. According to the results of the NGS study, 12 somatic and 4 putative germinal variants were identifi ed in 5 out of 12 patients.Conclusion. The possibility of conducting a comprehensive molecular genetic study in order to identify new mutations or those already described in the literature in genes associated with familial erythrocytosis could make a signifi cant contribution to the diagnosis of patients with absolute erythrocytosis.

MISSED OPPORTUNITIES IN PREVENTING COGNITIVE DECLINE: UNDERDIAGNOSIS OF POLYCYTHEMIA IN OLDER ADULTS

Abstract Polycythemia is a hematologic disorder characterized by an abnormally high red blood cell count which can result in serious complications. Microvascular clotting or emboli in polycythemia can reduce brain oxygenation levels with transient ischemic attacks or strokes and lead to subsequent development of vascular dementia. However, the impact of polycythemia on the brain health of older adults may be under-appreciated by primary care providers. The aim of this retrospective study was to investigate the prevalence of missed diagnoses of polycythemia in older adults with cognitive impairment. Electronic medical records (EMR) of patients with cognitive impairment, aged 60-100 years, inclusive of all races, ethnicities, and genders, seen between January 2018-January 2021, were obtained through the University of Arkansas for Medical Sciences database. Cognitive impairment included all subtypes of dementia and delirium with either primary or secondary polycythemia. A total of 9700 patients with cognitive impairment were analyzed for hemoglobin and hematocrit cut-off values for polycythemia. We found 696 instances of comorbid polycythemia of which only 88 (12.6%) had a correct polycythemia diagnosis on record. However, 608 instances (87.4%) had never been identified as having polycythemia either in the problem list or diagnosis. This study highlights the high prevalence of undiagnosed polycythemia in patients with delirium and dementia and underscores the importance of considering polycythemia as a potential etiology, when evaluating cognitive impairment. Early detection and appropriate management of polycythemia in older adults may have implications for reducing the incidence of vascular dementia and improving overall patient outcomes and quality of life.

Polycythemia Vera with Elevated Erythropoietin Level: A Review

According to the 2016 World Health Organization (WHO) recommendations, polycythemia vera (PV) should be suspected at hemoglobin levels of 16.5 gm/dl in males and 16 gm/dl in females. Depending on the underlying driving factor, polycythemia is classified to primary and secondary. Secondary polycythemia is driven by erythropoietin (EPO), which can be released due to hypoxemia, as seen in people living at high altitudes, those with chronic lung diseases, obstructive sleep apnea (OSA) and smoking. It can also be directly released by an underlying EPO secreting tumor, such as renal cell carcinoma. On the other hand, primary polycythemia or polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) in which erythrocytosis is driven by an acquired activating mutation that increases sensitivity to EPO or causes EPO independent erythroid colony formation. Manifestations of PV include fatigue, excessive itching, abdominal pain, weight loss, and fever. However, the most critical complications of PV, which impact survival, are thrombotic complications such as stroke and venous thromboembolism and leukemic transformation. The risk for leukemic transformation in patients with PV is about 2-5% over 15 years and is more common in individuals older than 60. History and physical examination should focus on smoking history and signs and symptoms of cardiopulmonary diseases causing chronic or intermittent hypoxemia, as seen in OSA. On the other hand, findings of abdominal pain, early satiety, weight loss, erythromelalgia, and hepatosplenomegaly would be suggestive of PV. Laboratory workup classically starts with measuring EPO level which further directs workup toward PV or secondary polycythemia. If workup is suggestive of PV, the following steps would be testing for activating Janus Kinase 2 (JAK2) mutation (V617F), which has a sensitivity of 97% for PV, and bone marrow biopsy which shows hypercellularity with trilineage growth (panmyelosis) in cases of PV. EPO measurement constitutes an essential step in polycythemia workup. It is widely accepted that elevated EPO levels are associated with secondary polycythemia; and suppressed EPO level was considered a criterion to diagnose PV, according to the WHO 2016 diagnostic criteria for PV. We conducted a systematic review searching the entity of PV with elevated EPO to study the clinical significance and outcomes. Our search yielded 4 cases summarized in Table 1. The cases were of three males and one female, with a mean age of 50. Two of them were healthy, with two with comorbid diseases, and as seen in the table; only one was a smoker. The most common symptom was headache, followed by erythromelalgia. Thrombotic phenomena happened in a single case in the form of Budd Chiari syndrome. Hepatosplenomegaly was found in a single case, and splenomegaly was found in two cases. The mean Hb level was 20.2 gm/dl, and the mean EPO level was 213. EPO is a glycoprotein hormone that is mainly produced by the kidneys. However, it is also produced in small amounts in the liver, spleen, bone marrow, lungs, and brain. The primary regulator of EPO production is the partial pressure of oxygen (PaO2). Multiple case reports and case series suggested an association between PV with elevated EPO and Budd Chiari Syndrome. Thumures et al. described four patients that were diagnosed with Budd Chiari Syndrome with elevated red cell mass and were found to have elevated serum erythropoietin levels. PV was confirmed with JAK2 mutation assay and bone marrow biopsy examination. It is speculated that liver hypoxia with subsequent hepatocyte injury and necrosis caused by Budd Chiari Syndrome leads to EPO level elevation. Accordingly, we assume that patients with PV and elevated EPO have some degree of organ injury that results in the release of EPO into circulation. This highlights the importance of a systematic approach in medicine, where signs and symptoms remain the cornerstone in diagnosis and where lab tests should be taken in their appropriate clinical context. Thus, we recommend testing for JAK2 mutation in the proper clinical scenario regardless of the EPO levels. It still remains to be clarified whether there are any prognostic importance of the elevated EPO level in these patients and whether it would alter the management.

Secondary Polycythemia Associated with COVID-19 Is Associated with Higher Mortality but Does Not Seem to Affect Thrombotic Risk

Introduction Reactive polycythemia (without presence of a chronic myeloproliferative neoplasm (MPN)) is commonly observed among patients with chronic pulmonary disease, whereas its significance in the context of COVID-19 is less well known. We aimed to investigate to what extent might polycythemia at the time of hospital admission affect outcomes of acutely ill COVID-19 patients. Methods We retrospectively evaluated a total of 5872 consecutive hospitalized COVID-19 patients treated in a tertiary referral center, UH Dubrava Zagreb, Croatia, in period 3/2020-6/2021. All patients were of white race and adults. All patients were tested positive for SARS-CoV-2 with either PCR or antigen test in the presence of compatible clinical symptoms. Patients with missing laboratory or clinical information or with prior or subsequently proven MPN were excluded from analysis. Hemoglobin threshold levels defined by the World health organization (WHO) criteria for diagnosis of anemia and the 2008 and 2016 WHO criteria for diagnosis of polycythemia vera (PV) were used to stratify patients into four subgroups (anemia, normal hemoglobin values, 2016 but not 2008 WHO polycythemia vera (PV), and 2008 WHO PV hemoglobin criteria fulfilling patients). Patients were evaluated in regard to baseline clinical characteristics, in hospital mortality, venous (VTE), arterial thrombosis and major bleeding. Due to non-normal distribution, numerical variables were presented as median and interquartile range (IQR). The Kruskal Wallis ANOVA, the chi squared test and the logistic regression were used. P values <0.05 were considered statistically significant. All analyses were performed using the MedCalc statistical software version 22.007 (MedCalc Software Ltd, Ostend, Belgium). Results A total of 5872 COVID-19 patients were analyzed. There were 2575 (43.9%) female and 3297 (56.1%) male patients. Median age was 72 years, median Charlson comorbidity index was 4 points. A total of 4166 (70.9%) patients presented with severe and 897 (15.3%) with critical intensity of COVID-19 symptoms. Median hemoglobin level at the time of admission was 128 g/L, IQR (114-141). A total of 3082 (52.5%) patients presented with normal hemoglobin levels, 2607 (44.4%) with anemia, 158 (2.7%) fulfilled 2016 but not 2008 WHO PV hemoglobin criteria and 25 (0.4%) fulfilled 2008 WHO PV hemoglobin criteria. Patients presenting with polycythemia in comparison to those with normal hemoglobin values were significantly older, were more likely to be of male sex, had higher Charlson comorbidity index, higher leukocytes, lower platelets, higher intensity of COVID-19 symptoms, required higher intensity of oxygen supplementation both at the admission and later during hospitalization (P<0.05 for all analyses). Figure 1 depicts the relationship of belonging to different hemoglobin categories with clinical outcomes. Patients presenting with anemia (OR 1.42, P<0.001), WHO 2016 grade (OR 1.63, P=0.003) and WHO 2008 grade polycythemia (OR 4.98, P<0.001) had increased risk of mortality in comparison to patients presenting with normal hemoglobin values. Anemia was associated with higher VTE (OR 1.34, P<0.006) and major bleeding risk (OR 2.27, P<0.001) in comparison to normal hemoglobin values, whereas no significant association of polycythemia with venous or arterial thrombotic or major bleeding risk was observed. Relationship of anemia, WHO 2016 and WHO 2008 grade polycythemia with increased mortality remained significant after adjusting analyses for age, sex, Charlson comorbidity index, COVID-19 severity and need for mechanical ventilation, all independently predicting inferior outcome (P<0.05 for all analyses). Conclusion Secondary polycythemia in non-MPN COVID-19 patients is associated with high mortality, increasing with higher degree of polycythemia, but does not seem to affect thrombotic or major bleeding risk in comparison to normal hemoglobin values. These observations might help in understanding risks associated with polycythemia and increased blood viscosity in the context of other respiratory diseases. These findings might also translate into the context of MPN and COVID-19, suggesting that blood cells other than erythrocytes might play a more important role regarding thrombotic risk. Future studies are warranted.

Prevalence of Second Cancers in Patients with Polycythemia Vera (PV): A Retrospective Analysis of US Real-World Claims Data

Background:Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) associated with risk of leukemic or fibrotic progression (Tefferi and Barbui. Am J Hematol. 2017;92;94-108). In addition to the known risk of disease transformation, patients with MPNs have a 60% higher risk of developing second non-hematologic cancers compared to matched controls. Skin cancers are among the most prevalent second cancers, with a reported 2.8-fold increase in risk of non-melanoma skin cancer (NMSC) (Landtblom et al., Leukemia. 2018;32:2203-10). The inherent risk associated with MPNs is exacerbated by cytoreductive treatments, as patients treated with hydroxyurea (HU) were found to have a two-fold higher risk of NMSC compared to patients who were not treated with HU (Barbui et al., Leukemia. 2019;33:1996-2005). Previous studies examined fewer than 2000 patients; the study populations may have included patients with other MPNs and PV. Our objective was to evaluate the frequency of second cancers in patients with a primary PV diagnosis who were treated with HU compared to phlebotomy only using a large US real-world claims database. Methods:This real-world, retrospective cohort study used Optum's deidentified Market Clarity Data consisting of electronic health records (EHR) on 105 million US patients and linked medical and prescription claims between 1/1/2007 to 12/31/2019. More than 82,000 patients with ≥1 PV diagnosis at any time were identified within the extracted dataset. For this analysis, eligible patients were ≥18 years old and required ≥2 PV diagnosis codes with ≥60 days between the first and last diagnosis code in the data period. Patients were indexed at the first diagnosis code of PV preceded by ≥1 year of EHR data (“index”) and required ≥1 year of post-index data or death prior to data period end. Patients with a pre-index diagnosis of secondary polycythemia, leukemia, myelodysplastic syndrome, myelofibrosis, or stem cell transplant were excluded. Second cancers were identified at first occurrence of a diagnosis code for a defined cancer in EHR during specified time periods. Analysis of post-treatment cancer rates used a subset of patients with pre-index medication data and excluded cancer types identified prior to treatment. Results:The total study cohort included 20,089 patients with PV (mean age, 63.0 years; 57.8% male; 88.6% Caucasian). Some patients (15.5%; n=3112) had evidence of a pre-index cancer. Median duration of follow-up was 4.3 years (IQR, 2.4-5.9). Among the total cohort, 35.7% (7181 patients) reported at least one second cancer in the post-index period (“post-index period prevalence”). The rate of second cancers in the post-index period was 109.7 events per 1000 patient years (PY). The most common non-hematologic malignancies were skin cancers (22.1/1000 PY) followed by prostate cancer (8.1/1000 PY) and breast cancer (6.7/1000 PY) (Figure 1). Within the total cohort, 9.1% (1830 patients) reported at least one skin cancer in the post-index period, with 8.3% (1659 patients) experiencing NMSC and 1.4% (286 patients) experiencing melanoma (Figure 1). The post-index period prevalence rate of NMSC was 6 times higher vs. the rate of melanoma (19.8 vs. 3.3/1000 PY). Among NMSCs, the rate of basal cell carcinoma was higher than the rate of squamous cell carcinoma (8.7 vs. 6.9/1000 PY). However, the highest rate was observed for non-specific or unspecified malignant neoplasms (8.9/1000 PY). Within a subset of 17,402 patients with pre-index medication data, 20.2% (n=3512) were exposed to at least 4 weeks of HU (without ruxolitinib) at any time; 19.0% (n=3314) were treated with phlebotomy (PHL) only. The rate of any second malignancy subsequent to treatment was >2.5-times higher in the HU vs. PHL group (140.4 vs. 55.3/1000 PY) (Table 1). Rates of skin cancers were nearly two times higher in the HU vs. PHL group for any skin cancer (31.6 vs. 17.7/1000 PY), NMSC (28.9 vs. 15.7/1000 PY), and melanoma (4.5 vs. 2.9/1000 PY). Conclusion:To our knowledge, this is the largest retrospective study evaluating the frequency of second cancers in a cohort of US patients with PV to-date. We found that patients with PV had high rates of malignancies associated with their primary PV diagnosis. The highest rates were observed for skin cancers, driven by the frequency of NMSC. Patients treated with HU had nearly twice the rate of skin cancers (including NMSC and melanoma) compared to PHL-only treated patients.

Real-World Analysis of Thromboembolic Event Rates in Patients in the United States with Polycythemia Vera

Background:Polycythemia vera (PV) is a myeloproliferative neoplasm associated with an increased risk of thromboembolic events (TEs). PV patients are characterized based on their risk for TEs as low-risk (age <60 without prior history of TE) or high-risk (age ≥60 and/or prior history of TE). Observational studies have shown higher rates of TEs in PV patients compared to matched controls (14.3 vs 4.9/1000 patient years, or PY), with rates as high as 40% in patients with PV (Goyal et al., Blood. 2014;124:4840; Griesshammer et al., Ann Hematol. 2019;98:1071-82; Pemmaraju et al., Leuk Res. 2022;115:106809). We assessed the rate of arterial and venous TEs in a large cohort of low- and high-risk PV patients. Methods:We conducted a real-world, retrospective cohort study using Optum's de-identified Market Clarity Data, which includes electronic health records (EHR) on 105 million US patients between 2007-2019. Eligible patients were ≥18 years [yrs] old and required ≥2 PV diagnosis codes with ≥60 days between the first and last diagnosis code in the data period. Patients were indexed at the first diagnosis code of PV preceded by ≥1 year of EHR data (“index”) and required ≥1 year of post-index data or death prior to data period end (12/31/2019). Patients with a pre-index diagnosis of secondary polycythemia, leukemia, myelodysplastic syndrome, myelofibrosis, or stem cell transplant were excluded. Patients were stratified into three groups based on risk status at index: low-risk (age <60 without prior history of TE), age-based high-risk (age >60 without prior history of TE) and event-based high-risk (prior history of TE). As outcomes, TEs were identified at the first occurrence of a diagnosis code for a TE in EHR during the post-index period. Descriptive statistics were used to characterize the proportion of patients with TEs and event rates per 1000 PY. Kaplan-Meier analysis was used to evaluate the probability of TE-free survival among patients in the three risk groups at various time points. Patients were censored at death or last engagement date. Results:The total study cohort included 20,089 PV patients (mean age, 63.0 yrs; 57.8% male; 88.6% Caucasian). Approximately one-third (34.4%; 6909 patients) were low-risk, 49.4% (9924 patients) were age-based high-risk, and 16.2% (3256 patients) were event-based high-risk. Among 17,402 patients with pre-index medication data, 16.0% (n=2777) received hydroxyurea (HU) pre-index. HU usage was highest in age-based high-risk patients (21.8%) followed by event-based high-risk (20.0%) and low-risk patients (5.8%). Median follow-up period was 4.3 yrs (IQR, 2.4-5.9). Incidence of TEs was assessed within patient groups (Table 1). Overall, 25.1% (5035/20,089) of patients with PV experienced at least one TE during the post-index period. Incidence of TEs was highest among event-based high-risk patients (50.2%; 1634/3256), followed by age-based high-risk (25.0%; 2480/9924) and low-risk patients (13.3%; 921/6909). The rate of post-index TEs was more than triple for event-based high-risk patients vs. age-based high-risk patients (206 vs. 68/1000 PY) and nearly 7 times higher vs. low-risk patients (206 vs. 31/1000 PY). The rate of TEs was more than double for age-based high-risk patients vs. low-risk patients (68 vs. 31/1000 PY). Incidence of arterial and venous TEs was assessed across the total cohort (Table 1). The most common arterial events were stroke (7.1%) and MI/ACS (6.4%). The most common venous events were DVT/deep thrombophlebitis (8.1%) and pulmonary embolism (4.5%). Kaplan-Meier analysis indicated that at ≈2.5 yrs (1000 days) post-index, TE-free survival was ≈90% for low-risk, ≈80% for age-based high-risk, and ≈55% for event-based high-risk patients (Figure 1). At ≈5.5 yrs (2000 days) post-index, TE-free survival had fallen to ≈85% for low-risk, ≈70% for age-based high-risk, and ≈40% for event-based high-risk patients. The downward trend continued until the end of the data period. Conclusion: Findings from this real-world analysis indicate that PV patients experience high rates of arterial and venous TEs. Event-based high-risk patients have a substantially lower probability of TE-free survival compared with age-based high-risk and low-risk patients. While patients with a prior history of TE have the highest thromboembolic risk, all patients with PV are at high risk of TE, indicating an unmet need for reduction of thromboembolic risks.

Exploring Sleep Study As a Potential Diagnostic Tool for Polycythemia: An Indian Perspective

Introduction Polycythemia, characterized by elevated red blood cell count and hematocrit levels, affects approximately 3.4% of the population based on WHO 2016 criteria. However, existing studies predominantly focus on Caucasian populations, leaving a knowledge gap in Indian population data. Moreover, the emphasis on JAK2 mutation as a diagnostic marker has overlooked other potential risk factors like hypoxia induced sleep disturbances as causes for secondary Polycythemia. This study aims to fill these gaps by exploring the impact of overlooked risk factors and their association with polycythemia incidence. Methods Clinical data from patients evaluated for Polycythemia at two tertiary care centers in south India between January 2021 and May 2023 were collected with Institutional Research Board approval (n=316). From all the Polycythemia patients who attended Hematology out patient department, two cohorts were identified: patients who underwent JAK2 mutation study and those who underwent a sleep study. Baseline characteristics, risk factors (e.g., smoking, snoring), comorbidities (diabetes, hypertension, dyslipidemia), constitutional symptoms (pruritus, headache, blackouts, or dizziness), and vascular complications (coronary artery disease or cerebrovascular events) were recorded. Additional details such as apnoea-hypopnea index (AHI) and nocturnal desaturation were documented for those patients who had undergone sleep study. Patients who were having moderate and severe AHI were considered as sleep study positive. As many were home sleep test and due to other patient related factors, using oxygen desaturation index for hypoxemia was not relied upon. Statistical analysis was conducted using Chi-square test and t-test for equality of means. Results A retrospective analysis of 316 patients with a diagnosis of erythrocytosis as per the WHO 2016 criteria (Figure-1) was done. Among them, 278 underwent JAK2 mutation study, with 32 testing positive. Meanwhile, out of the 98 patients who underwent sleep study, 30 tested positive. The probability of testing positive in a sleep study was higher than testing JAK2 mutation positive. Patients in the sleep study-positive group were significantly younger (mean age 45.93±12.1 years) compared to the JAK2-positive group (mean age 56.72±14.8 years) (p=0.003). The sleep study-positive group comprised of only males, while the JAK2-positive group included both males (71.8%) and females (21.9%) (p<0.05). In the sleep study group, most patients were diagnosed incidentally during routine blood investigations, while the majority in the JAK2-positive group presented with symptoms (p<0.001).There was a higher percentage of overweight (46.7%) or obese (20%) patients in the sleep study group, while the majority in the JAK2-positive group had a normal BMI (58.1%) (p=0.05). Co-morbidities were similar in the two groups leading to no significant statistical difference. Both groups required venesection without significant differences (Table -1). Conclusion Sleep study shows promise as a relevant diagnostic tool for certain cases of erythrocytosis. Patients who test positive for sleep study may differ from those with a positive JAK2 mutation in terms of age, gender distribution, BMI, and presentation. However, both groups share similar co-morbidities and initiation of venesection rates. The low incidence of JAK2 mutation in polycythemia patients necessitates the consideration of sleep study as an additional evaluation tool. Our study was limited by its retrospective nature. Moreover, many patients who had performed sleep studies had not done a JAK2 mutation test. Further research is needed to validate these findings and enhance the understanding of causative role of sleep apnoea in JAK2 unmutated polycythemia in Indian population.

Diagnostic Performance of Red Blood Cell Indices, Serum Erythropoietin, and JAK2 Mutation Testing for the Evaluation of Polycythemia Vera at High Altitude

Introduction: Polycythemia vera (PV) is a clonal myeloproliferative neoplasm associated with mutation of Janus kinase 2 ( JAK2) in virtually all patients. Patients with PV typically present with constitutional symptoms and thrombotic complications related to myeloproliferation but can present with only mild or no symptoms. In 2016, the World Health Organization (WHO) diagnostic criteria for PV were revised to use lower hemoglobin and hematocrit cut-off levels in order to avoid missing masked polycythemia. Accordingly, a hemoglobin concentration of more than 16 g/dL (HCT>48%) for females and 16.5 g/dL (HCT>49%) for males can be considered for PV evaluation (previously >18.5 g/dL for men and >16.5 g/dL for women). In conjunction, concerns arise about the unnecessary evaluation of individuals with otherwise high-normal hemoglobin levels, more so for those living at high altitude. Altitude exposure, amongst others, decreases plasma volume to increase [Hb] which may accordingly muddle the diagnosis of PV at altitude. Nonetheless, Red Cell Mass (RCM) is seldom assessed in clinical practice. In addition, red blood cell count, related indices, and serum erythropoietin may also be affected by high altitude, and their diagnostic performance in the evaluation of PV at altitude has not been prospectively assessed. Method: We collected lab records for all JAK2 requests over three years (2020-2022) in two referral hospitals serving a population residing at an altitude of 2,270-3,000 meters above sea level. Indications for requests, as well as laboratory data and imaging, were gathered. Complete blood count (CBC) and other laboratory values were collected when ordered within one week of JAK2 testing. For CBC, EDTA anticoagulated samples were processed using Sysmex XN-3100. For JAK2 testing, RNA isolated from peripheral blood samples (using the MagNA Pure System) was reverse-transcribed, amplified, and sequenced for any mutations involving exons 12, 13, 14, or 15 using an ABI 3730 XL genetic analyzer. For serum EPO, frozen serum samples were outsourced to Bio Scientia Labs, Germany. Reference values for serum erythropoietin were lab generated at 4.3-29 mIU/ml and were not validated for our altitude. . Results:Of the 208 JAK2 tests performed during the reviewed period, 132 (63.4%) were for polycythemia (Table 1). The JAK2 V617F mutation was found in 22 (16.7%) patients, with 10 (45.5%) of them being men. No JAK2 mutation other than the exon 14 V617F substitution was found. JAK2-positive patients had a median age of 61 years, while JAK2-unmutated patients had a median age of 47 years. Overt polycythemia, according to the WHO 2016 classification, was identified in 15 (68.2%) , while the remainder had masked PV ( defined as increased RBCs with normal hemoglobin/ HCT). Patients with PV had significantly higher RBCs and lower MCV/MCH/MCHC compared to those with JAK2-unmutated polycythemia. They also exhibited significant elevation of RDW-CW and significant neutrophilia, basophilia, thrombocytosis, and splenomegaly. All PV patients with available serum EPO tests had low values (median 2 mIU/ml). Conclusion: At altitude, patients with PV show the same age and sex characteristics as those living at low elevations. Patients with PV have higher RBCs and lower MCV/MCH/MCHC compared to those with JAK-unmutated (secondary) polycythemia. RDW is significantly increased in patients with PV, reflecting an associated iron deficiency. Serum EPO performed well at altitude to suggest the presence of PV. The low rate of positive JAK2 mutation in our high-altitude cohort may reflect poor selection of subjects and over-workup of otherwise altitude-associated erythrocytosis. Isolated mild polycythemia at altitude remains common. Using hemoglobin/hematocrit alone to select patients for PV evaluation has a low positive predictive value and may be associated with unnecessary workup. RBC indices and RDW, along with an evaluation for iron status, might help select those more likely to have PV and could decrease unnecessary workups.

Analysis of Therapeutic Phlebotomy in Patients of Polycythemia: A Single Center Study

Introduction: Polycythemia is increased red cell mass according to age and sex of the individual. It could be primary (Polycythemia Vera), or secondary, due to chronic hypoxia or increased erythropoietic drive. Polycythemia is managed with therapeutic phlebotomy along with treating the underlying cause if determined. Phlebotomy of one unit whole blood should result in fall of Hb of at least 1g/dl. This study was conducted to see the effect of phlebotomy on fall in Hb level.Different parameters which can affect Hb levels in polycythemia patients, like age, JAK-2 mutation status and underlying cause were also studied.Methodology: A cross sectional study was conducted at blood bank of Pakistan Atomic Energy Commission (PAEC) General Hospital, Islamabad Pakistan January 2020 to December 2020. Data were collected from 121 patients of Polycythemia vera who reported in blood bank for phlebotomy.Results: The average pre phlebotomy hemoglobin of the patients was 17.45g/dl, which dropped to 15.97g/dl after phlebotomy. In total, 89 (73.5%) patients who underwent phlebotomy had a fall in Hb of greater than or equal to 1g/dl, while in 32 (26.4%) patients, Hb drop was less than 1g/dl. One hundred and five patients underwent multiple therapeutic phlebotomies to maintain their hemoglobin within normal range.Conclusion: This study has shown that there is fall in Hb as result of recommended phlebotomy leading to relief in symptoms due to Polycythemia. Phlebotomy is the basis of treating polycythemia, although in secondary polycythemia the underlying cause should also be diagnosed and treated.

The complex relation between obstructive sleep apnoea syndrome, hypogonadism and testosterone replacement therapy.

Obstructive sleep apnoea syndrome (OSAS) is an under-recognized medical disease. The main risk factors for OSAS are male sex, older age, obesity, and metabolic syndrome, that are also associated with male hypogonadism (MH). Therefore, obesity has been classically identified as the most evident link between OSAS and MH. However, OSAS is per se linked to the development of MH by a combined effect of hypoxia, increased night-time awakenings, reduced sleep efficiency and fragmented sleep. Similarly, MH might represent a risk factor for OSAS, mainly related to sleep disturbances that are frequently associated with low testosterone. Data on testosterone replacement therapy (TRT) in patients with OSAS are limited. Nevertheless, TRT is generally contraindicated by guidelines in the presence of untreated or severe OSAS. TRT might in fact worse OSAS symptoms in different ways. Furthermore, OSAS has been proposed to be a risk factor for secondary polycythaemia and TRT might exacerbate polycythaemia. Therefore, TRT in hypogonadal men affected by untreated OSAS or severe OSAS should be considered with caution and in a personalised way. Nevertheless, the type and dosage of TRT should be considered, as short-term high-dose TRT might worsen OSAS, whereas long-term lower doses could eventually determine a clinical improvement of symptoms of OSAS. Here we reviewed the data on the association between OSAS, MH and TRT, including the opportunity of assessment of patients who develop signs and symptoms of OSAS during TRT by polysomnography.

Brief update on systemic therapies in myeloproliferative neoplasms

SummaryOver the past years we have gained considerable insights into the biology and consequent therapeutic options in myeloproliferative neoplasms. In this review we aim to highlight the most relevant recent developments in this field with special focus on primary as well as secondary myelofibrosis and polycythemia vera.

Association of the EPAS1 rs7557402 Polymorphism with Hemodynamically Significant Patent Ductus Arteriosus Closure Failure in Premature Newborns under Pharmacological Treatment with Ibuprofen.

Patent ductus arteriosus (PDA) is frequent in preterm newborns, and its incidence is inversely associated with the degree of prematurity. The first choice of pharmacological treatment is ibuprofen. Several genes, including EPAS1, have been proposed as probable markers associated with a genetic predisposition for the development of PDA in preterm infants. EPAS 1 NG_016000.1:g.84131C>G or rs7557402 has been reported to be probably benign and associated with familial erythrocytosis by the Illumina Clinical Services Laboratory. Other variants of EPAS1 have been previously reported to be benign for familial erythrocytosis because they decrease gene function and are positive for familial erythrocytosis because the overexpression of EPAS1 is a key factor in uncontrolled erythrocyte proliferation. However, this could be inconvenient for ductal closure, since for this process to occur, cell proliferation, migration, and differentiation should take place, and a decrease in EPAS1 gene activity would negatively affect these processes. Single-nucleotide polymorphisms (SNPs) in EPAS1 and TFAP2B genes were searched with high-resolution melting and Sanger sequencing in blood samples of preterm infants with hemodynamically significant PDA treated with ibuprofen at the National Institute of Perinatology. The variant rs7557402, present in the EPAS1 gene eighth intron, was associated with a decreased response to treatment (p = 0.007, OR = 3.53). The SNP rs7557402 was associated with an increased risk of pharmacological treatment failure. A probable mechanism involved could be the decreased activity of the product of the EPAS1 gene.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as new possible minor criteria for diagnosis of polycythemia vera.

The role of inflammation in the pathophysiology of polycythemia vera (PV) is important. The presence of JAK2 mutations is important in the diagnosis of PV, and serum levels of erythropoietin (EPO) also play a supporting role. However, serum EPO levels show some limitations. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are a readily available marker of inflammation. Thus, we examined whether NLR & PLR might diagnose PV in erythrocytosis patients. We compared NLR & PLR and EPO diagnostic values. We retrospectively reviewed clinical and laboratory data from two referral hospitals. Two hundred and eighty-five patients with erythrocytosis who underwent a test for the JAK2 mutation were included. It wac classified as the PV group and the secondary polycythemia (SP) group. The median NLR & PLR in the PV group (n = 70) was significantly higher than that in the SP group (n = 170) (NLR: 6.04 vs. 1.77, PLR: 283.18 vs. 101.56, respectively, p < 0.001). In the receiver operating characteristic analysis, the area under the curve of NLR & PLR was significantly higher than that of serum EPO (NLR vs EPO: 0.921 vs. 0.827, p = 0.003; PLR vs EPO: 0.917 vs 0.827, p = 0.003). In conclusion, NLR & PLR were higher in PV than in SP and showed better diagnostic value than serum EPO level, highlighting their potential as minor diagnostic criteria in patients with PV.

Secondary polycythemia and venous thromboembolism: a systematic review

Background Secondary polycythemia is an acquired condition characterized by an elevation in red blood cell (RBC) mass either in response to tissue hypoxia or inappropriate erythropoietin (EPO) secretion. It is proposed that the elevation of RBC mass in secondary polycythemia can lead to hyperviscosity and VTE. This systematic review aims to assess the relationship between secondary polycythemia and venous thromboembolism and discuss diagnostic strategies and management of secondary polycythemia and VTE. Methods This systematic review was conducted on September 2, 2022, and followed PRISMA guidelines to select and analyze relevant articles using the following databases: PubMed, ScienceDirect, and CINAHL. The queries used were “secondary polycythemia AND venous thromboembolism,” “secondary polycythemia AND deep vein thrombosis,” “secondary polycythemia AND pulmonary embolism,” “chronic obstructive pulmonary disease AND venous thromboembolism,” “chronic obstructive pulmonary disease AND deep vein thrombosis,” “chronic obstructive pulmonary disease AND pulmonary embolism,” “high altitude AND venous thromboembolism,” “high altitude AND deep vein thrombosis,” “high altitude AND pulmonary embolism,” “smoking AND venous thromboembolism,” “smoking AND deep vein thrombosis”, “smoking AND pulmonary embolism”, “hypoventilation AND venous thromboembolism”, “hypoventilation AND deep vein thrombosis”, “hypoventilation AND pulmonary embolism”, “testosterone AND venous thromboembolism”, “testosterone AND deep vein thrombosis”, and “testosterone AND pulmonary embolism.” The search duration was set from 2012–2022. Relevant publications were selected based on the inclusion and exclusion criteria. Results The initial search generated 5,946 articles. After narrowing the search based on inclusion and exclusion criteria, 30 articles were selected for this systematic review. Conclusion We found evidence to support the relationship between secondary polycythemia and VTE. Therapies targeting the factors that lead to secondary polycythemia can correct it and prevent VTE progression. If VTE occurs as a result of secondary polycythemia, anticoagulation therapy is recommended or inferior vena cava filters if contraindicated.

Secondary polycythaemia from chronic hypoxia is a risk for cerebral thrombosis: a case report

BackgroundSecondary polycythemia is considered the usual complication of chronic hypoxia. It can theoretically increase the oxygen-carrying capacity, but this adaptive trait has a deleterious effect because the blood viscosity increases, which can induce significant morbidity and mortality, such as stroke and myocardial infarction.Case presentationA 55-year-old man with a history of a congenitally small main pulmonary artery presented to the emergency department with sustained unsteady walking, dizziness and vertigo. Evaluation revealed elevated hemoglobin and superior posterior circulation cerebral artery thrombosis. The patient was treated with high flux inhalation of oxygen and anti-platelet aggregation.ConclusionsThe involvement of cerebral vessels has rarely been reported in chronic hypoxia cases. The present case is the first case of superior posterior circulation cerebral artery thrombosis due to chronic hypoxia in a patient with a congenitally small main pulmonary artery. This case demonstrates the importance of recognizing some chronic diseases that can lead to hypoxia and secondary polycythemia thereby leading to hypercoagulable state and subsequent thrombosis.

Thrombotic Events and Risk Factors for Thrombosis in Polycythemia in Senegal, West Africa

Objectives: We aim to identify thrombotic events and risk factors for thrombosis (RFT) comparing polycythemia vera (PV) and secondary polycythemia (SP) patients. Methods: We carried out a retrospective study of a cohort of 59 patients with PV (n=34) and SP (n=25) followed for a period of 14 years. Variables studied were the frequency and type of thrombosis, sociodemographic, clinical, and biological RFT. Statistical analysis was performed using SPSS software version 18. Multivariate analysis was performed to identify RFT. Results: Mean age in PV was 53 years (33 - 79) and 44.5 years (5 - 78) in SP (p=0.74). The sex ratio in PV was 1.12 and 2.57 in PS (p=0.52). Sixteen patients had thrombotic events (27.1%) including 12 PV (35.3%) versus 4 SP (16%) (p=0.09). Twenty-two thrombotic events were identified; 14 (63.7%) of arterial thrombosis and 8 (36.3%) of venous thrombosis. There were 18 thrombotic events (81.8%) in PV versus 4 (18.2%) in SP (p=0.02). Arterial thrombosis was more frequent in PV (55.6%). Thrombosis events were more frequent in female patients (59.1%). RFT in PV were age (40-59 years), hematocrit &gt;45% and thrombocytosis ≥ 600 G/L and in SP, RFT were hematocrit &gt;45% and hypercholesterolemia. After multivariate analysis, hematocrit &gt;45% was the only RFT independently associated with thrombosis occurrence. Conclusion: We show through this study, a frequent occurrence of arterial thrombosis in polycythemia. Main RFT is the high hematocrit level (&gt;45%). We insist on the interest of therapeutic bloodletting, sometimes associated with cytoreductive treatment in order to maintain a hematocrit level &lt;45%.

0990 Obstructive Sleep Apnea in Patient with White-Sutton Syndrome Presenting with Secondary Polycythemia

Abstract Introduction White-Sutton syndrome is a rare autosomal dominant genetic disorder associated with POGZ de novo genetic variants. Patients with White-Sutton syndrome experience a wide spectrum of disease most common being neurocognitive delays, however various sleep disturbances have also been reported. The incidence of obstructive sleep apnea in patients with White-Sutton syndrome has been previously only defined in cohort studies utilizing subjective screening questionnaires. Report of case(s) We present a case of a 14-year-old male with past medical history of White-Sutton Syndrome who was referred to the sleep clinic by Pediatric Hematology-Oncology for an evaluation of sleep disordered breathing as part of a secondary polycythemia work-up. Patient’s height was 173.6 cm, weight was 111.8 kg, and BMI was 37.1. Patient’s prior laboratory work-up was remarkable for polycythemia with hematocrit of 50.5% and hemoglobin of 16.8 g/dL. He also had a reassuring bicarbonate level of 22 and no documented daytime oxygen desaturations. The PSG was scored using adult criteria due to the patient’s height and weight. He was diagnosed with moderate obstructive sleep apnea with an apnea-hypopnea index (AHI) of 15.5 per hour and a nadir oxygenation saturation of 89%. Conclusion To the author’s knowledge, this is the first case report of a pediatric patient with White-Sutton syndrome with diagnosed obstructive sleep apnea via polysomnography. This is also the first case report of a pediatric patient undergoing polycythemia work-up who was subsequently diagnosed with obstructive sleep apnea. Support (if any)

A Screening Approach for Inherited Erythrocytosis due to the VHL:c.598C > T Mutation (Chuvash Polycythemia).

The online version contains supplementary material available at 10.1007/s12288-023-01668-9.