Polycythemia

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Polycythemia
1901 Composition of Blood.jpg
Diagram illustrating normal composition of blood compared to anemia and polycythemia
Specialty Hematology

Polycythemia (also known as polycythaemia) is a laboratory finding in which the hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.[ citation needed ]

Contents

Polycythemia has many causes. It can describe an increase in the number of red blood cells [1] ("absolute polycythemia") or to a decrease in the volume of plasma ("relative polycythemia"). [2] Absolute polycythemia can be due to genetic mutations in the bone marrow ("primary polycythemia"), physiologic adaptations to one's environment, medications, and/or other health conditions. [3] [4] Laboratory studies such as serum erythropoeitin levels and genetic testing might be helpful to clarify the cause of polycythemia if the physical exam and patient history do not reveal a likely cause. [5]

Mild polycythemia on its own is often asymptomatic. Treatment for polycythemia varies, and typically involves treating its underlying cause. [6] Treatment of primary polycythemia (see polycythemia vera) could involve phlebotomy, antiplatelet therapy to reduce risk of blood clots, and additional cytoreductive therapy to reduce the number of red blood cells produced in the bone marrow. [7]

Definition

Polycythemia is defined as serum hematocrit (Hct) or hemoglobin (HgB) exceeding normal ranges expected for age and sex, typically Hct >49% in healthy adult men and >48% in women, or HgB >16.5 g/dL in men or >16.0 g/dL in women. [8] The definition is different for neonates and varies by age in children. [9] [10]

Differential diagnoses

Polycythemia in adults

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.[ citation needed ] 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:

Polycythemia in neonates

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:

Pathophysiology

The pathophysiology of polycythemia varies based on its cause. The production of red blood cells (or erythropoeisis) in the body is regulated by erythropoietin, which is a protein produced by the kidneys in response to poor oxygen delivery. [14] As a result, more erythropoeitin is produced to encourage red blood cell production and increase oxygen-carrying capacity. This results in secondary polycythemia, which can be an appropriate response to hypoxic conditions such as chronic smoking, obstructive sleep apnea, and high altitude. [4] Furthermore, certain genetic conditions can impair the body's accurate detection of oxygen levels in the serum, which leads to excess erythropoeitin production even without hypoxia or impaired oxygen delivery to tissues. [15] [16] Alternatively, certain types of cancers, most notably renal cell carcinoma, and medications such as testosterone use can cause inappropriate erythropoeitin production that stimulates red cell production despite adequate oxygen delivery. [17]

Primary polycythemia, on the other hand, is caused by genetic mutations or defects of the red cell progenitors within the bone marrow, leading to overgrowth and hyperproliferation of red blood cells regardless of erythropoeitin levels. [3]

Increased hematocrit and red cell mass with polycythemia increases the viscosity of blood, leading to impaired blood flow and contributing to an increased risk of clotting (thrombosis). [18]

Evaluation

History and physical exam

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]

Laboratory evaluation

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]

Additional testing

Absolute polycythemia

Primary polycythemia

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. Studies suggest that mean arterial pressure (MAP) only increases when hematocrit levels are 20% over baseline. When hematocrit levels are lower than that percentage, the MAP decreases in response, which may be due, in part, to the increase in viscosity and the decrease in plasma layer width. [21] Furthermore, affected individuals may have other associated conditions alongside high blood pressure, including formation of blood clots. Transformation to acute leukemia is rare. Phlebotomy is the mainstay of treatment. [22]

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. [23] 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. [24]

Secondary polycythemia

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:

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

Altered oxygen sensing

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. [30] [31]
  • HIF2α erythrocytosis: Gain-of-function mutations in HIF2α are associated with autosomal dominant erythrocytosis [32] and pulmonary hypertension. [33]

Symptoms

Polycythemia is often asymptomatic; patients may not experience any notable symptoms until their red cell count is very high. For patients with significant elevations in hemoglobin or hematocrit (often from polycythemia vera), some non-specific symptoms include: [9]

Epidemiology

The prevalence of primary polycythemia (polycythemia vera) was estimated to be approximately 44–57 per 100,000 individuals in the United States. [29] Secondary polycythemia is considered to be more common, but its exact prevalence is unknown. [29] In one study using the NHANES dataset, the prevalence of unexplained erythrocytosis is 35.1 per 100,000, and was higher among males and among individuals between ages 50–59 and 60–69. [35]

Management

The management of polycythemia varies based on its etiology:

Relation to athletic performance

Polycythemia is theorized to increased performance in endurance sports due to the blood being able to store more oxygen.[ citation needed ] 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. [36]

See also

Related Research Articles

<span class="mw-page-title-main">Hypoxia (medicine)</span> Medical condition of lack of oxygen in the tissues

Hypoxia is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body. Although hypoxia is often a pathological condition, variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise.

<span class="mw-page-title-main">Hemoglobin</span> Metalloprotein that binds with oxygen

Hemoglobin is a protein containing iron that facilitates the transport of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin in the blood carries oxygen from the respiratory organs to the other tissues of the body, where it releases the oxygen to enable aerobic respiration which powers the animal's metabolism. A healthy human has 12 to 20 grams of hemoglobin in every 100 mL of blood. Hemoglobin is a metalloprotein, a chromoprotein, and globulin.

<span class="mw-page-title-main">Hemoglobinopathy</span> Any of various genetic disorders of blood

Hemoglobinopathy is the medical term for a group of inherited blood disorders involving the hemoglobin, the protein of red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.

<span class="mw-page-title-main">Anemia</span> Reduced ability of blood to carry oxygen

Anemia or anaemia is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin available for oxygen transport, or abnormalities in hemoglobin that impair its function.

<span class="mw-page-title-main">Erythropoietin</span> Protein that stimulates red blood cell production

Erythropoietin, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO include any anemia, and hypoxemia due to chronic lung disease and mouth disease.

<span class="mw-page-title-main">Complete blood count</span> Routine laboratory test of blood cells

A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and platelets, the concentration of hemoglobin, and the hematocrit. The red blood cell indices, which indicate the average size and hemoglobin content of red blood cells, are also reported, and a white blood cell differential, which counts the different types of white blood cells, may be included.

<span class="mw-page-title-main">Hematocrit</span> Volume percentage of red blood cells in blood

The hematocrit, also known by several other names, is the volume percentage (vol%) of red blood cells (RBCs) in blood, measured as part of a blood test. The measurement depends on the number and size of red blood cells. It is normally 40.7–50.3% for males and 36.1–44.3% for females. It is a part of a person's complete blood count results, along with hemoglobin concentration, white blood cell count and platelet count.

<span class="mw-page-title-main">Polycythemia vera</span> Overproduction of red blood cells by the bone marrow

In oncology, polycythemia vera (PV) is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. The majority of cases are caused by mutations in the JAK2 gene, most commonly resulting in a single amino acid change in its protein product from valine to phenylalanine at position 617.

<span class="mw-page-title-main">Essential thrombocythemia</span> Overproduction of platelets in the bone marrow

In hematology, essential thrombocythemia (ET) is a rare chronic blood cancer characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid leukemia or myelofibrosis. It is one of the blood cancers wherein the bone marrow produces too many white or red blood cells, or platelets.

<span class="mw-page-title-main">Altitude training</span> Athletic training at high elevations

Altitude training is the practice by some endurance athletes of training for several weeks at high altitude, preferably over 2,400 metres (8,000 ft) above sea level, though more commonly at intermediate altitudes due to the shortage of suitable high-altitude locations. At intermediate altitudes, the air still contains approximately 20.9% oxygen, but the barometric pressure and thus the partial pressure of oxygen is reduced.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

<span class="mw-page-title-main">Myeloproliferative neoplasm</span> Overproduction of blood cells in the bone marrow

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.

Blood doping is a form of doping in which the number of red blood cells in the bloodstream is boosted in order to enhance athletic performance. Because such blood cells carry oxygen from the lungs to the muscles, a higher concentration in the blood can improve an athlete's aerobic capacity (VO2 max) and endurance. Blood doping can be achieved by making the body produce more red blood cells itself using drugs, giving blood transfusions either from another person or back to the same individual, or by using blood substitutes.

Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver. Hepcidin production and release shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells. As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, or anemia of inflammatory response.

<span class="mw-page-title-main">Eero Mäntyranta</span> Finnish cross-country skier

Eero Antero Mäntyranta was one of the most successful Finnish cross-country skiers. He competed in four Winter Olympics (1960–1972) winning seven medals at three of them. His performance at the 1964 Winter Olympics earned him the nickname "Mister Seefeld", referring to the venue where the cross-country skiing and biathlon competitions took place. The Finnish Ministry of Education endowed him with the Pro Urheilu letter of recognition in 2000. There is also a museum centered on Mäntyranta in his birthplace of Pello.

<span class="mw-page-title-main">2,3-Bisphosphoglyceric acid</span> Chemical compound

2,3-Bisphosphoglyceric acid (2,3-BPG), also known as 2,3-diphosphoglyceric acid (2,3-DPG), is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid (1,3-BPG).

<span class="mw-page-title-main">EPAS1</span> Protein-coding gene in the species Homo sapiens

Endothelial PAS domain-containing protein 1 is a protein that is encoded by the EPAS1 gene in mammals. It is a type of hypoxia-inducible factor, a group of transcription factors involved in the physiological response to oxygen concentration. The gene is active under hypoxic conditions. It is also important in the development of the heart, and for maintaining the catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.

<span class="mw-page-title-main">Basophilia</span> Medical condition

Basophilia is the condition of having greater than 200 basophils/μL in the venous blood. Basophils are the least numerous of the myelogenous cells, and it is rare for their numbers to be abnormally high without changes to other blood components. Rather, basophilia is most often coupled with other white blood cell conditions such as eosinophilia, high levels of eosinophils in the blood. Basophils are easily identifiable by a blue coloration of the granules within each cell, marking them as granulocytes, in addition to segmented nuclei.

<span class="mw-page-title-main">Hemoglobinemia</span> Abnormally increased hemoglobin in blood plasma

Hemoglobinemia is a medical condition in which there is an excess of hemoglobin in the blood plasma. This is an effect of intravascular hemolysis, in which hemoglobin separates from red blood cells, a form of anemia.

Myomatous erythrocytosis syndrome(MES) is an uncommon gynecological disorder associated with isolated polycythemia and uterine fibroids. The primary feature of myomatous erythrocytosis syndrome is that hemoglobin goes back to its baseline level following the removal of the myoma. There have only been 50 cases of myomatous erythrocytosis syndrome documented as of 2023. Thomsen and Marson published the first case in 1953.

References

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  2. ↑ "Relative polycythemia" at Dorland's Medical Dictionary
  3. 1 2 3 MedlinePlus Encyclopedia : Polycythemia vera
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