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Practice EssentialsIn secondary polycythemia, the number of red blood cells (RBCs) is increased as a result of an underlying condition. Secondary polycythemia would more accurately be called secondary erythrocytosis or erythrocythemia, as those terms specifically denote increased red blood cells. The term polycythemia is used appropriately in the myeloproliferative disorder called polycythemia vera, in which there are elevated levels of all three peripheral blood cell lines—RBCs, white blood cells, and platelets. [1, 2] Secondary polycythemia most often develops as a response to chronic hypoxemia, which triggers increased production of erythropoietin by the kidneys. The most common causes of secondary polycythemia include obstructive sleep apnea, obesity hypoventilation syndrome, and chronic obstructive pulmonary disease (COPD). [3] Other causes include testosterone replacement therapy [4] and heavy cigarette smoking. Patients who have arteriovenous or intracardiac shunting can present with polycythemia without hypoxemia. Erythropoietin-secreting tumors (eg, hepatocellular carcinoma, renal cell carcinoma, adrenal adenoma) cause some cases. Secondary polycythemia must be differentiated from primary polycythemia and relative polycythemia (in which RBC numbers are normal but plasma volume is contracted. The reduction in plasma volume may be due to dehydration or to reduced venous compliance; the latter is also termed stress polycythemia or Gaisböck syndrome, and is typically seen in obese middle-aged men who are receiving a diuretic for treatment of hypertension. See Presentation and Workup. To the extent that the increased RBCs alleviate tissue hypoxia, secondary polycythemia may in fact be beneficial. However, treatment with phlebotomy is indicated for patients with hematocrits higher than 60%-65%, who may experience symptoms such as impaired alertness, dizziness, headaches, and compromised exercise tolerance, and who may face increased risk for thrombosis, strokes, myocardial infarction, and deep venous thrombosis. Otherwise, secondary polycythemia is addressed by treating the underlying condition. See Treatment.  PathophysiologyIncreased hemoglobin and hematocrit values reflect an increase in the ratio of red blood cell mass to plasma volume. Any change in either the hemoglobin or the hematocrit can alter test results. Relative polycythemia, or erythrocythemia, results from decreased plasma volume. A true polycythemia or erythrocythemia results from increased red blood cell mass. Therefore, hemoglobin and hematocrit levels alone cannot accurately help make this distinction. Direct measurement of red blood cell mass is necessary to differentiate these conditions. In primary polycythemia, the disorder results from a mutation expressed within the hematopoietic stem cell or progenitor cells, which drives the overproduction and accumulation of red blood cells. The secondary polycythemic disorders may be acquired or congenital; however, they are driven by factors that are independent of the function of hematopoietic stem cells. Elevated hemoglobin levels due to chronic hypoxia in patients with chronic lung disorders such as COPD or sleep apnea are the result of an increased production of erythropoietin, which in turn causes increased production of red blood cells. EtiologySecondary polycythemia is defined as an absolute increase in red blood cell mass that is caused by enhanced stimulation of red blood cell production. In contrast, polycythemia vera is characterized by bone marrow with an inherent increased proliferative activity. [1, 2, 5, 6, 7] Approximately two thirds of patients with polycythemia vera have elevated white blood cell (granulocyte, not lymphocyte) counts and platelet counts. [8] No other causes of polycythemia/erythrocytosis are associated with elevated granulocyte or platelet counts. Enhanced erythroid stimulation can be a physiologic response to generalized or localized tissue hypoxia, [9] as in the following settings:
Impaired perfusion of the kidneys, which may lead to stimulation of erythropoietin [EPO] production, is usually due to local renal hypoxia in the absence of systemic hypoxia. Conditions include the following:
Inappropriate stimulation of EPO productionInappropriate stimulation of EPO production may occur in the following settings:
Congenital causesHemoglobin mutants associated with tight binding to oxygen and a failure to deliver oxygen in the venous blood can cause high EPO levels. The high level of EPO is compensatory to elevate hemoglobin levels to deliver an optimal amount of oxygen to the tissues. Hypoxia-inducible factor 1-alpha (HIF1-alpha) binds to the hypoxia-responsive element, which is downstream of the gene for EPO. The activity of HIF1-alpha is increased by a lowered oxygen tension. A von Hippel-Lindau gene mutation results in polycythemia by altering the von Hippel-Lindau protein, which plays an important role in sensing hypoxia and binds to hydroxylated HIF1-alpha to serve as a recognition site of an E3-ubiquitin ligase complex. In this condition, and in hypoxia, the undegraded HIF1-alpha forms a heterodimer with HIF-beta and leads to increased transcriptions of the gene for EPO. Chuvash polycythemia is caused by an autosomal recessive gene mutation on the von Hippel-Lindau gene, which results in the upregulation of the HIF1-alpha target gene and causes elevations in EPO levels. [14] Low EPO-dependent polycythemiasThese are called primary familial and congenital polycythemias. [15] The EPO receptor mutation results in a gain of function, and patients have normal-to-high hematocrit values and low EPO levels. [16] These conditions can be acquired from (1) insulinlike growth factor-1 (IGF-1), a well-known stimulator of erythropoiesis, and (2) cobalt toxicity, which can induce erythropoiesis. Testosterone-associated polycythemiaThe administration of androgen esters to hypogonadal men can lead to polycythemia. However, the incidence of testosterone-associated polycythemia may be lower in men receiving pharmacokinetically steady-state delivery of testosterone formulations, as occurs following the subcutaneous implantation of testosterone pellets, than it is in men receiving intramuscular injections of shorter-acting androgen esters. Ip and colleagues found that in men receiving long-acting depot testosterone treatment, the development of polycythemia (hematocrit >50%) was predicted by higher trough serum testosterone concentrations but not by the duration of treatment. [17] OtherSecondary polycythemia has been reported as a paraneoplastic phenomenon in patients with testicular cancer. The mechanism is not clear. A case of pazopanib-related secondary polycythemia has been reported in a patient receiving treatment for myxofibrosarcoma. [18] EpidemiologyThe frequency of secondary polycythemia depends on the underlying disease. The mortality and morbidity of secondary polycythemia depend on the underlying condition. PrognosisThe prognosis of patients with secondary polycythemia is driven by the underlying disorder. The polycythemia itself, when physiologic and not sufficiently extreme to cause significant hyperviscosity, generally has no effect on life span. However, patients with secondary polycythemia generally have a shorter survival following diagnosis than patients with polycythemia vera. This is believed to reflect the dire conditions that underlie many cases of secondary polycythemia. At extreme levels of secondary polycythemia, patients can be at risk for thrombosis. Excessive polycythemia, usually defined as hematocrit levels higher than 65-70%, may result in increased whole blood viscosity. This, in turn, may lead to impaired blood flow locally, resulting in thrombosis. The risk is lower than with primary erythrocytosis but data are too sparse for accurate quantification. Hyperviscosity may also lead to generalized sluggish blood flow, resulting in impaired tissue oxygenation in multiple organs, which may lead to decreased mentation, fatigue, generalized weakness, and poor exercise tolerance.
Author Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine Srikanth Nagalla, MD, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion; Sanofi; Dova; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel. Coauthor(s) Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences Disclosure: Nothing to disclose. Specialty Editor Board Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Received salary from Medscape for employment. for: Medscape. Ronald A Sacher, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center Ronald A Sacher, MD, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada Disclosure: Nothing to disclose. Chief Editor Sara J Grethlein, MD, MBA, FACP Executive Medical Director and Medical Oncologist, Swedish Cancer Institute Sara J Grethlein, MD, MBA, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Women's Association, American Society of Clinical Oncology, American Society of Hematology, Gold Humanism Honor Society, Leukemia and Lymphoma Society Disclosure: Nothing to disclose. Additional Contributors Is polycythemia is an abnormal increase in the number of white blood cells in the blood?Polycythemia vera (PV) is a bone marrow disease that leads to an abnormal increase in the number of blood cells.
What is polycythemia mean?Polycythaemia, also known as erythrocytosis, means having a high concentration of red blood cells in your blood. This makes the blood thicker and less able to travel through blood vessels and organs.
What causes polycythemia?Polycythemia vera occurs when a mutation in a gene causes a problem with blood cell production. Normally, your body regulates the number of each of the three types of blood cells you have — red blood cells, white blood cells and platelets.
What are the most common symptoms of polycythemia?Symptoms include lack of energy (fatigue) or weakness, headaches, dizziness, shortness of breath, visual disturbances, nose bleeds, bleeding gums, heavy menstrual periods, and bruising.
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Polycythemia is an abnormal increase in the number of white blood cells in the blood. true or false
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