Polycythemia

The overproduction of red blood cells may be due to a primary process in the bone marrow (a so-called myeloproliferative disease, or primary polycythemia), or it may be secondary to chronically low oxygen levels, medications, or, rarely, a malignancy (i.e secondary polycythemia).[6] Alternatively, additional red blood cells may have been received through another process—for example, being over-transfused (either accidentally or, as blood doping, deliberately).

The recipient twin in a pregnancy undergoing twin-to-twin transfusion syndrome can cause polycythemia.[7]

Primary polycythemias are myeloproliferative diseases typically due to mutations affecting red blood cell precursors in the bone marrow. 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.[8] Often, excess white blood cells and platelets are also produced. A hallmark of polycythemia vera is an elevated hematocrit, with Hct > 55% seen in 83% of cases.[9] A somatic (non-hereditary) mutation (V617F) in the JAK2 gene, also present in other myeloproliferative disorders, is found in 95% of cases.[10] Symptoms include headaches and vertigo, and 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 formation of blood clots. Transformation to acute leukemia is rare. Phlebotomy is the mainstay of treatment.[11]

Primary familial polycythemia, also known as primary familial and congenital polycythemia (PFCP), exists as a benign hereditary condition, in contrast with the myeloproliferative changes associated with acquired PCV. In many families, PFCP is due to an autosomal dominant mutation in the EPOR erythropoietin receptor gene.[12] PFCP can cause an increase of up to 50% in the oxygen-carrying capacity of the blood; skier Eero Mäntyranta had PFCP, which is considered to have given him a large advantage in endurance events.[13]

Secondary polycythemia is caused by either natural or artificial increases in the production of erythropoietin, hence an increased production of erythrocytes. In secondary polycythemia, 6 to 8 million and occasionally 9 million erythrocytes may occur 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 polycythemia is a normal adaptation to living at high altitudes (see altitude sickness).[5] Many athletes train at high altitude to take advantage of this effect, which can be considered a legal form of blood doping, although the efficacy of this strategy is unclear.[14]
• Hypoxic disease-associated – for example, in cyanotic heart disease where blood oxygen levels are reduced significantly; in hypoxic lung disease such as COPD; in chronic obstructive sleep apnea.[5]
• 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. This includes patients who have a special form of hemoglobin known as Hb Chesapeake, 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 secondary polycythemia is not caused by physiologic adaptation, and occurs irrespective of body needs include:

• Neoplasms – Renal cell carcinoma or liver tumors, Von Hippel–Lindau disease, and endocrine abnormalities including pheochromocytoma and adrenal adenoma with Cushing's syndrome.
• People whose testosterone levels are high because of the use of anabolic steroids, including athletes who abuse steroids, or people on testosterone replacement for hypogonadism or transgender hormone replacement therapy, may develop secondary polycythemia.
• Blood doping - Secondary polycythemia can be induced by endurance athletes that take erythropoietin-stimulating agents, receive blood transfusions, and take other measures to increase their red blood cell mass in an effort to increase oxygen transport capacity.[15]

Inherited mutations in three genes which all result in increased stability of hypoxia-inducible factors, leading to increased erythropoietin production, have been shown to cause erythrocytosis:

• Chuvash erythrocytosis is an autosomal recessive form of erythrocytosis which is endemic in patients from the Chuvash Republic in Russia. Chuvash erythrocytosis is associated with homozygosity for a C598T mutation in the von Hippel–Lindau gene (VHL), which is needed for the destruction of hypoxia-inducible factors in the presence of oxygen.[16] Clusters of patients with Chuvash erythrocytosis have been found in other populations, such as on the Italian island of Ischia, located in the Bay of Naples.[17]
• PHD2 erythrocytosis: Heterozygosity for loss-of-function mutations of the PHD2 gene are associated with autosomal dominant erythrocytosis and increased hypoxia-inducible factors activity.[18][19]
• HIF2α erythrocytosis: Gain-of-function mutations in HIF2α are associated with autosomal dominant erythrocytosis[20] and pulmonary hypertension.[21]