Polycythemia

Polycythemia (also known as polycythaemia or erythrocytosis) is a disease state in which the proportion of blood volume that is occupied by red blood cells increases. Blood volume proportions can be measured as hematocrit level.

It can be due to an increase in the mass of red blood cells ("absolute polycythemia") or to a decrease in the volume of plasma ("relative polycythemia").

Absolute polycythemia
The overproduction of red blood cells may be due to a primary process in the bone marrow (a so-called myeloproliferative syndrome), or it may be a reaction to chronically low oxygen levels or, rarely, a malignancy

Primary polycythemia
Primary polycythemias are due to factors intrinsic to red cell precursors. Polycythemia vera (PCV), polycythemia rubra vera (PRV), or erythremia, occurs when excess red blood cells are produced as a result of an abnormality of the bone marrow. Often, excess white blood cells and platelets are also produced. Polycythemia vera is classified as a myeloproliferative disease. Symptoms include headaches and vertigo. Signs on physical examination include an abnormally enlarged spleen and/or liver. In some cases, affected individuals may have associated conditions including high blood pressure or the formation of blood clots. Transformation to acute leukemia is rare. Phlebotomy is the mainstay of treatment. A hallmark of polycythemia is an elevated hematocrit, with Hct > 55% seen in 83% of cases. Mutations in JAK2 are found in 95% of cases, though also present in other myeloproliferative disorders.

Primary familial polycythemia, Primary familial and congenital polycythemia (PFCP) also exists as a benign hereditary condition, in contrast with malignant acquired Polycythemia vera. In some of the cases a molecular mechanism of PFCP has been identified to be a dominant mutation in the erythropoietin receptor.

Secondary polycythemia
Secondary polycythemia is caused by either natural or artificial increases in the production of erythropoietin, hence an increased production of erythrocytes. In secondary polycythemia, there may be 6 to 8 million and occasionally 9 million erythrocytes per cubic millimeter of blood. Secondary polycythemia resolves when the underlying cause is treated.

Secondary polycythemia in which the production of erythropoietin increases appropriately is called physiologic polycythemia.

Conditions which may result in a physiologically appropriate polycythemia include:

Altitude related - This physiologic (meaning normal) polycythemia is a normal adaptation to living at high altitudes (see altitude sickness). Many athletes train at high altitude to take advantage of this effect &mdash; a legal form of blood doping. Some individuals believe athletes with primary polycythemia may have a competitive advantage due to greater stamina. However, this has yet to be proven due to the multifaceted complications associated with this condition.

Hypoxic disease associated - for example in cyanotic heart disease where blood oxygen levels are reduced significantly. May also occur as a result of hypoxic lung disease and as a result of chronic obstructive sleep apnea.

Iatrogenic - Secondary polycythemia can be induced directly by phlebotomy (blood letting) to withdraw some blood, concentrate the erythrocytes, and return them to the body.

Genetic - Heritable causes of secondary polycythemia also exist and are associated with abnormalities in hemoglobin oxygen release. Patients have a special form of hemoglobin known as Hb Chesaspeake, which has a greater inherent affinity for oxygen than normal adult hemoglobin. This reduces oxygen delivery to the kidneys, causing increased erythropoietin production and a resultant polycythemia. Hemoglobin Kempsey also produces a similar clinical picture. These conditions are relatively uncommon.

Conditions where the polycythemia is not as a result of physiologic adaptation and occurs irrespective of body needs include:

Neoplasms - Renal or liver tumors, hemangioblastomas in the central nervous system, and endocrine abnormalities including pheochromocytoma and adrenal adenoma with Cushing's syndrome. People whose testosterone levels are high because of the use anabolic steroids, including athletes who abuse steroids and people whose doctors put them on doses that are too high, as well as people who take erythropoietin may develop secondary polycythemia. Polycythemia Vera is a condition that evidence suggests may be linked to radiation exposure. There are treatment options but no known cure. PV is characterized by an increase in the numbers of all types of blood cells which may reach a level of 80 - 90 on the hematocrit. Most, if not all, the blood cells are a produced by one abnormal hematopoietic stem cell. This condition usually affects individuals who are 60 – 80 years of age.***

Polycythemia caused by altered oxygen sensing
Inherited mutations in 3 genes which all result in increased stability of Hypoxia Inducible Factors (HIFs), leading to increased erythropoietin production, have been shown to cause erythrocytosis:
 * Chuvash polycythemia: An autosomal recessive form of erythrocytosis which is endemic in patients from Chuvashia. Chuvash Polycythaemia is associated with homozygosity for a C598T mutation in the von Hippel-Lindau gene (VHL) which is needed for the destruction of HIF in the presence of oxygen. Clusters of patients with Chuvash polycythemia have been found in other populations, such as on the Italian island of Ischia, located in the Bay of Naples.
 * PHD2 erythrocytosis: Heterozygosity for loss-of-function mutations of the PHD2 gene are associated with autosomal dominant erythrocytosis and increased HIF activity.
 * HIF2α erythrocytosis: Gain-of-function mutations in HIF2α are associated with autosomal dominant erythrocytosis and pulmonary hypertension.

Relative polycythemia
Relative polycythemia is an apparent rise of the erythrocyte level in the blood; however, the underlying cause is reduced blood plasma. Relative polycythemia is often caused by loss of body fluids, such as through burns, dehydration and stress. Rarely, relative polycythemia can be caused by apparent polycythemia also known as Gaisböck's syndrome. Apparent polycythemia primarily affects middle-aged obese men and is associated with smoking, increased alcohol intake and hypertension.