Polycythemia

Different diseases or conditions can cause polycythemia in adults. These processes are discussed in more detail in their respective sections below.

Relative polycythemia is not a true increase in the number of red blood cells or hemoglobin in the blood, but rather an elevated laboratory finding caused by reduced blood plasma (hypovolemia, cf. dehydration). Relative polycythemia is often caused by loss of body fluids, such as through burns, dehydration, and stress. A specific type of relative polycythemia is Gaisböck syndrome. In this syndrome, primarily occurring in obese men, hypertension causes a reduction in plasma volume, resulting in (amongst other changes) a relative increase in red blood cell count.[11] If relative polycythemia is deemed unlikely because the patient has no other signs of hemoconcentration, and has sustained polycythemia without clear loss of body fluids, the patient likely has absolute or true polycythemia.

Absolute polycythemia can be split into two categories:

• Primary polycythemia is the overproduction of red blood cells due to a primary process in the bone marrow (a so-called myeloproliferative disease). These can be familial or congenital, or acquired later in life.[12]
• Secondary polycythemia is the most common cause of polycythemia. It occurs in reaction to chronically low oxygen levels, medications, other genetic mutations that impact the body's ability to transport or detect oxygen, or, rarely because of certain cancers.[4]
• Alternatively, additional red blood cells may have been received through another process—for example, being over-transfused (either accidentally or, as blood doping, deliberately).

Polycythemia in newborns is defined as hematocrit > 65%. Significant polycythemia can be associated with blood hyperviscosity, or thickening of the blood. Causes of neonatal polycythemia include:

• Hypoxia: Poor oxygen delivery (hypoxia) in utero resulting in compensatory increased production of red blood cells (erythropoeisis). Hypoxia can be either acute or chronic. Acute hypoxia can occur as a result of perinatal complications. Chronic fetal hypoxia is associated with maternal risk factors such as hypertension, diabetes and smoking.[10]
• Umbilical cord stripping: delayed cord clamping and the stripping of the umbilical cord towards the baby can cause the residual blood in the cord/placenta to enter fetal circulation, which can increase blood volume.[10]
• The recipient twin in a pregnancy undergoing twin-to-twin transfusion syndrome can have polycythemia.[13]

The first step to evaluate new polycythemia in any individual is to conduct a detailed history and physical exam.[12] Patients should be asked about smoking history, altitude, medication use, personal bleeding and clotting history, symptoms of sleep apnea (snoring, apneic episodes), and any family history of hematologic conditions or polycythemia. A thorough cardiopulmonary exam including auscultation of the heart and lungs can help evaluate for cardiac shunting or chronic pulmonary disease. An abdominal exam can assess for splenomegaly, which can be seen in polycythemia vera. Examination of digits for erythromelalgia, clubbing or cyanosis can help assess for chronic hypoxia.[12]

Polycythemia is often initially identified on a complete blood count (CBC). The CBC is often repeated to evaluate for persistent polycythemia.[12] If an etiology of polycythemia is unclear from history or physical, additional laboratory evaluation might include:[5]

• Blood smear to evaluate cell morphology[7]
• Iron panel to evaluate for concurrent iron deficiency
• JAK2 mutation testing[12]
• Serum erythropoeitin (EPO) levels[5]
• Oxygen saturation (usually via pulse oximetry or blood gas tests) or oxygen dissociation tests[12]

• Sleep studies if high suspicion for sleep apnea[12]
• Abdominal imaging, such as ultrasound[5]
• Erythropoietin receptor or von Hippel–Lindau (VHL) genetic testing, if high suspicion for familial erythrocytosis[5]
• Hemoglobin (globin-gene) sequencing or high-performance liquid chromatography to evaluate for high-affinity hemoglobin variants[12]
• Bone marrow biopsy might be considered in specific cases[5]

Primary polycythemias are myeloproliferative diseases affecting red blood cell precursors in the bone marrow. Polycythemia vera (PCV) (a.k.a. polycythemia rubra vera (PRV)) occurs when excess red blood cells are produced as a result of an abnormality of the bone marrow.[3] 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.[19] A somatic (non-hereditary) mutation (V617F) in the JAK2 gene, also present in other myeloproliferative disorders, is found in 95% of cases.[20] 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.[21]

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.[22] PFCP can cause an increase of up to 50% in the oxygen-carrying capacity of the blood; skier Eero Mäntyranta had PFCP, which is speculated to have given him an advantage in endurance events.[23]

Secondary polycythemia is caused by either natural or artificial increases in the production of erythropoietin, hence an increased production of erythrocytes.

Secondary polycythemia in which the production of erythropoietin increases appropriately is called physiologic polycythemia. Conditions which may result in physiologic polycythemia include:

• Altitude related – Polycythemia can be a normal adaptation to living at high altitudes (see altitude sickness).[9] 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.[24]
• 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;[9] conditions that reduce blood flow to the kidney e.g. renal artery stenosis. Chronic carbon monoxide poisoning (which can be present in heavy smokers) and rarely methemoglobinemia can also impair oxygen delivery.[25][4]
• Genetic – Heritable causes of secondary polycythemia include abnormalities in hemoglobin oxygen release, which results in a greater inherent affinity for oxygen than normal adult hemoglobin and reduces oxygen delivery to tissues.[26]

Conditions where the secondary polycythemia is not caused by physiologic adaptation, and occurs irrespective of body needs include:[4]

• Neoplasms – Renal cell carcinoma, liver tumors, Von Hippel–Lindau disease, and endocrine abnormalities including pheochromocytoma and adrenal adenoma with Cushing's syndrome.
• Anabolic steroid use - people whose testosterone levels are high, including athletes who abuse steroids, people on testosterone replacement for hypogonadism or transgender hormone replacement therapy.[17]
• Blood doping - Athletes who take erythropoietin-stimulating agents or receive blood transfusions to increase their red blood cell mass.[27]
• Post-transplant erythrocytosis - About 10-15% of patients after renal transplantation are found to have polycythemia at 24 months after transplantation, which can be associated with increased thrombotic (clotting) risk. [28]

Rare 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 secondary polycythemia:

• Chuvash erythrocytosis or Chuvash polycythemia is an autosomal recessive form of erythrocytosis 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.[15] Patients with Chuvash erythrocytosis experience a significantly elevated risk of events.[6]
• PHD2 erythrocytosis: Heterozygosity for loss-of-function mutations of the PHD2 gene are associated with autosomal dominant erythrocytosis and increased hypoxia-inducible factors activity.[29][30]
• HIF2α erythrocytosis: Gain-of-function mutations in HIF2α are associated with autosomal dominant erythrocytosis[31] and pulmonary hypertension.[32]

Polycythemia is theorized to increased performance in endurance sports due to the blood being able to store more oxygen. This idea has led to the illegal use of blood doping and transfusions among professional athletes, as well as use of altitude training or elevation training masks to simulate a low-oxygen environment. However, the benefits of altitude training for athletes to improve sea-level performance are not universally accepted, with one reason being athletes at altitude might exert less power during training.[35]