Idiopathic Erythrocytosis: Vascular Complications

Idiopathic Erythrocytosis (IE) is a diagnosis of exclusion once primary and secondary causes have been eliminated; yet IE remains an enigmatic disorder. Published series from decades ago (Modan & Modan J. Hematol [1968] 14:375; Pearson & Wetherly-Mein, Clin.Lab Hematol. [1974] 1:189) have reported high rates of vascular complications (46%) and advise phlebotomy to keep the hematocrit to less than 45%. A More recent series (McMullin B.J. Hematol. [2005] 130:174) advise no need for phlebotomy in patients with no co-morbidities such as vascular disease, diabetes, or hypertension. In an attempt to determine some practice guidelines, we undertook a retrospective analysis of patients identified with IE within our practice and to quantify the rates of vascular complications, if any. From January 1, 2016 to December 31. 2020 99 patients were referred because of erythrocytosis. Twenty of these 99 patients had polycythemia rubra vera and 77 had secondary erythrocytosis ( 64 males, 13 females, median age 61 years). Of these 77 patients with secondary erythrocytosis, 40 had obstructive sleep apnea, 10 men abused testosterone, and 1 patient each was either post splenectomy or post kidney transplant, 1 patient had a renal cell carcinoma, and 1 patient had familial erythrocytosis. Twenty patients were identified as having IE and all 20 did not have a JAK2 mutation. There 13 males and 7 females with a median age of 63 years (range 31-76). The median hemoglobin was 17.2 gm/dl and the median hematocrit was 51.2 (range 15.0 to 18.4 and 49% to 55% respectively). The median erythropoietin level was 9.9 mu/ml (range 5-38.5). Two of the 20 patients underwent therapeutic phlebotomy and developed no vascular complications. Eighteen patients were simply followed with phlebotomy despite having comorbidities of hypertension, increased BMI, type II diabetes, and none developed vascular complications. IE remain an enigmatic disorder that requires uniform diagnostic criteria as well as uniform practice guidelines; however, given our retrospective review, we do not believe that therapeutic phlebotomy is justified. Disclosures No relevant conflicts of interest to declare.

Epidemiologic and Genetic Associations of Erythropoietin With Blood Pressure, Hypertension, and Coronary Artery Disease

While exogenous administration of recombinant erythropoietin has been associated with increased risk of hypertension, coronary artery disease, and mortality, it is not known if endogenous circulating erythropoietin level is associated with coronary artery disease and its risk factors. We measured and analyzed epidemiological and genetic associations of circulating plasma erythropoietin levels in 2 population cohorts, from China (N=4329) and the United States (N=3671). In vitro smooth muscle cell responses and in vivo murine studies of erythropoietin exposure were performed. Erythropoietin levels were positively and linearly associated with blood pressure traits and inversely associated with cholesterol levels and red cell indices. Higher erythropoietin level was associated with higher prevalence of hypertension (odds ratio, 1.20 [95% CI, 1.12–1.29], P =4.41×10 −7 ) and coronary artery disease (odds ratio, 1.16 [95% CI, 1.00–1.34], P =0.046). In a discovery stage genetic association study of erythropoietin level, we identified a previously reported locus on chromosome 6 (rs7776054 near HBS1L-MYB , P =4.86×10 −25 ) and a new locus on chromosome 4 (rs172629 near PDGFRA-KIT , P =2.1×10 −8 ), which was independently replicated. Meta-analysis of discovery and replication genetic association results identified a locus on chromosome 22 (rs855791 near TMPRSS6 , P =3.60×10 −9 ). Erythropoietin administration, within a physiological range of hematocrit achieved, induced hypertension in vivo and increased contraction of vascular smooth muscle cells in vitro. In conclusion, endogenous circulating erythropoietin level is influenced by common genetic variation and is associated with blood pressure traits, hypertension, and coronary artery disease. Vascular effects of erythropoietin demonstrated in vitro and in vivo support a newly discovered mechanism of hypertension and cardiovascular risk with potential implications for erythropoietic support in the clinic. Graphic Abstract: An online graphic abstract is available for this article.

Polycythemia

Polycythemia is a disease state in which the red blood cell numbers are increased in the blood (erythrocytosis), which in turn makes blood thicker and can cause circulatory problems. Polycythemia Vera is a stem cell disease belonged to a group of myeloproliferative neoplasm in which the erythroid progenitors are overly proliferated by acquired mutation of the JAK2 gene, resulting in excessive erythrocytosis. Secondary Polycythemia refers erythrocytosis due to underlying conditions. It is usually associated with increased blood erythropoietin levels as a compensatory reaction to tissue hypoxia, which can be seen in patients with chronic lung disease or sleep apnea or living at high altitudes. Certain tumors produce the erythropoiet ©Win and testosterestern University of Heone incralth Scienceseases the blood erythropoietin level, resulting in secondary polycythemia. Relative polycythemia is the consequence of plasma volume contraction, falsely raising the RBC count and hemoglobin/hematocrit level in CBC. Two cases of polycythemia are presented: 1) a patient with polycythemia vera and 2) a patient with secondary polycythemia. Various types of polycythemia are discussed with an updated review covering the etiology, clinical manifestation, diagnostic approach and treatment.

Predictive accuracy of the low erythropoietin level for the diagnosis of polycythemia vera.

7060 Background: A low erythropoietin (EPO) level is a minor diagnostic criterion for Polycythemia Vera (PV) based on the updated 2016 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms. The diagnostic value of EPO has been debated due to the increasing availability of advanced molecular testing. We hypothesized that EPO level below the normal range may not provide additional diagnostic information if JAK2 mutation status is positive. Methods: In this retrospective review we used Logistic regression to build a predictive model for the diagnosis of PV based on EPO value and JAK2V617F mutation status. 415 patient records were reviewed. 162 were used in the final statistical analysis. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the predictive accuracy. All statistical analysis was performed with R version 3.5.1. A p-value less than 0.05 was considered statistically significant. Results: EPO level below the normal range as a standalone diagnostic modality is significantly associated with PV (odds ratio (OR) 0.857; p-value < 0.001). When JAK2V617F mutation status is included in the prediction model, the association of the low erythropoietin level is not statistically significant (OR 0.962 and p-value 0.269). Positive JAK2V617F demonstrates a strong predictive value for PV (OR 670.5, p-value 0.006) either alone or in combination with other variables. Moreover, 34.2% of patients with the diagnosis of PV had EPO level within the normal range, which reflects it’s physiological variability. Conclusions: Results show that erythropoietin level below the normal range does not bring additional diagnostic value when JAK2V617F mutation status is positive. Additionally, erythropoietin level has a negative correlation with increased BMI and smoking status, making it not a reliable diagnostic marker.