Polycythemia
| Polycythemia | |
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| Packed cell volume diagram. | |
| Specialty | Hematology |
Polycythemia (also known as polycythaemia, and erythrocytosis) is a disease state in which the hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration are elevated in peripheral blood.
It can be due to an increase in the number of red blood cells[1] ("absolute polycythemia") or to a decrease in the volume of plasma ("relative polycythemia").[2] Polycythemia is sometimes called erythrocytosis, but the terms are not synonymous, because polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells.
The emergency treatment of polycythemia (e.g., in hyperviscosity or thrombosis) is by phlebotomy (removal of blood from the circulation). Depending on the underlying cause, phlebotomy may also be used on a regular basis to reduce the hematocrit. Myelosuppressive medications such as hydroxyurea are sometimes used for long-term management of polycythemia.[3]
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 >16.5g/dL in men or >16.0g/dL in women.[4] The definition is different for neonates, who can physiologically have higher Hct/HgB.[5][6]
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 net number of red blood cells or hemoglobin in the blood, but rather an artificially 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.[7] If relative polycythemia is deemed unlikely (no other signs of hemoconcentration, sustained polycythemia without clear etiology of hypovolemia), 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.[8]
- Secondary polycythemia is polycythemia that occurs in reaction to chronically low oxygen levels, medications, or, rarely, a malignancy. This is the most common cause of polycythemia.[9]
- Alternatively, additional red blood cells may have been received through another process—for example, being over-transfused (either accidentally or, as blood doping, deliberately).[citation needed]
Polycythemia in Neonates
Polycythemia in neonates is defined as hematocrit >65%. Significant polycythemia can be associated with blood hyperviscosity. Causes of neonatal polycythemia include:
- Hypoxia: Poor oxygen delivery (hypoxia) in utero resulting in compensatory increased 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.[6]
- Umbilical cord stripping: delayed cord clamping, followed by stripping the umbilical cord towards the baby can cause the residual blood in the cord/placenta to enter fetal circulation, which can increase blood volume.[6]
- The recipient twin in a pregnancy undergoing twin-to-twin transfusion syndrome can cause polycythemia.[10]
Evaluation
History and Physical Exam
The first step to evaluate new polycythemia in any individual is to conduct a detailed history and physical exam.[8] 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.[8]
Laboratory Evaluation
Polycythemia is often initially identified on a complete blood count (CBC). If an etiology of polycythemia is unclear from history or physical, additional laboratory evaluation might include:[11]
- Repeat complete blood count (CBC) to evaluate for persistence in polycythemia[8]
- Blood smear to evaluate cell morphology[3]
- Iron panel to evaluate for concurrent iron deficiency
- JAK2 mutation testing[8]
- Serum erythropoeitin (EPO) levels[11]
- Oxygen saturation (usually via pulse oximetry or blood gas tests)[8]
Additional Testing:
- Sleep studies if high suspicion for sleep apnea[8]
- Abdominal imaging, such as ultrasound[11]
- Erythropoietin receptor or von Hippel–Lindau (VHL) genetic testing, if high suspicion for familial erythrocytosis[11]
- Hemoglobin (globin-gene) sequencing or high-performance liquid chromatography to evaluate for high-affinity hemoglobin variants[8]
- Bone marrow biopsy might be considered in specific cases[11]
Absolute polycythemia
Primary polycythemia
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.[12] 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.[13] A somatic (non-hereditary) mutation (V617F) in the JAK2 gene, also present in other myeloproliferative disorders, is found in 95% of cases.[14] 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.[15]
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.[16] 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.[17]
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, 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.[citation needed]
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.[18]
- 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.[citation needed]
- 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.[citation needed]
Conditions where the secondary polycythemia is not caused by physiologic adaptation, and occurs irrespective of body needs include:[citation needed]
- 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.[19]
Altered oxygen sensing
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:[citation needed]
- 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.[20] 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.[21]
- PHD2 erythrocytosis: Heterozygosity for loss-of-function mutations of the PHD2 gene are associated with autosomal dominant erythrocytosis and increased hypoxia-inducible factors activity.[22][23]
- HIF2α erythrocytosis: Gain-of-function mutations in HIF2α are associated with autosomal dominant erythrocytosis[24] and pulmonary hypertension.[25]
Symptoms
Polycythemia is often asymptomatic. For patients with significant polycythemia (often polycythemia vera), they may not experience in any notable symptom until their red cell count is very high. While not specific, symptoms include:[5]
- A ruddy complexion, or plethora[8]
- Headache, transient blurry vision (amaurosis fugax), other signs of a transient ischemic attack (TIA)
- Dizziness, fatigue
- Unusual bleeding, nosebleeds
- Pain in abdomen, or pain in hands and feet (erythromelalgia)
- Itchiness, especially after a hot shower (aquagenic pruritis)
- Numbness or tingling in different body parts[26]
Notable people
Polycythemia is linked to increased performance in endurance sports due to the blood being able to store more oxygen.[citation needed] It can also be linked to damage from smoking.
- Eero Mäntyranta, Finnish cross-country skier
- Bob Newhart, American comedian[27]
See also
- Anemia, an increase in blood cell count
- Cytopenia, a decrease in blood cell count
- Capillary leak syndrome, another cause of hemoconcentration
References
- ^ "Absolute polycythemia" at Dorland's Medical Dictionary
- ^ "Relative polycythemia" at Dorland's Medical Dictionary
- ^ a b Spivak JL (July 2019). "How I treat polycythemia vera". Blood. 134 (4): 341–352. doi:10.1182/blood.2018834044. PMID 31151982.
- ^ Arber, Daniel A.; Orazi, Attilio; Hasserjian, Robert; Thiele, Jürgen; Borowitz, Michael J.; Le Beau, Michelle M.; Bloomfield, Clara D.; Cazzola, Mario; Vardiman, James W. (2016-05-19). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. ISSN 0006-4971.
- ^ a b c d Pillai AA, Fazal S, Babiker HM (2022). "Polycythemia". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 30252337. Retrieved 2022-11-01.
- ^ a b c Sarkar, Shikha; Rosenkrantz, Ted S. (2008-08-01). "Neonatal polycythemia and hyperviscosity". Seminars in Fetal and Neonatal Medicine. 13 (4): 248–255. doi:10.1016/j.siny.2008.02.003. ISSN 1744-165X. PMID 18424246.
- ^ Stefanini M, Urbas JV, Urbas JE (July 1978). "Gaisböck's syndrome: its hematologic, biochemical and hormonal parameters". Angiology. 29 (7): 520–533. doi:10.1177/000331977802900703. PMID 686487. S2CID 42326090.
- ^ a b c d e f g h i Lee, Grace; Arcasoy, Murat O. (2015). "The clinical and laboratory evaluation of the patient with erythrocytosis". European Journal of Internal Medicine. 26 (5): 297–302. doi:10.1016/j.ejim.2015.03.007.
- ^ Mithoowani S, Laureano M, Crowther MA, Hillis CM (August 2020). "Investigation and management of erythrocytosis". CMAJ. 192 (32): E913–E918. doi:10.1503/cmaj.191587. PMC 7829024. PMID 32778603.
- ^ Couck I, Lewi L (June 2016). "The Placenta in Twin-to-Twin Transfusion Syndrome and Twin Anemia Polycythemia Sequence". Twin Research and Human Genetics. 19 (3): 184–190. doi:10.1017/thg.2016.29. PMID 27098457. S2CID 7376104.
- ^ a b c d e McMullin, Mary F.; Bareford, D.; Campbell, P.; Green, A. R.; Harrison, Claire; Hunt, Beverley; Oscier, D.; Polkey, M. I.; Reilly, J. T.; Rosenthal, E.; Ryan, Kate; Pearson, T. C.; Wilkins, Bridget; the General Haematology Task Force of the British Committee for Standards in Haematology (2005). "Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis". British Journal of Haematology. 130 (2): 174–195. doi:10.1111/j.1365-2141.2005.05535.x. ISSN 0007-1048.
- ^ MedlinePlus Encyclopedia: Polycythemia vera
- ^ Wallach JB. Interpretation of Diagnostic Tests (7th ed.). Lippencott Williams & Wilkins. ISBN 978-0-7817-3055-6.
- ^ Current Medical Diagnosis & Treatment. McGraw Hill Lange. 2008. p. 438.
- ^ Tefferi A, Vannucchi AM, Barbui T (January 2018). "Polycythemia vera treatment algorithm 2018". Blood Cancer Journal. 8 (1): 3. doi:10.1038/s41408-017-0042-7. PMC 5802495. PMID 29321547.
- ^ "Polycythemia, Primary Familial snd Congenital; PFCP". OMIM.
- ^ Burkeman O (29 Sep 2013). "Malcolm Gladwell: 'If my books appear oversimplified, then you shouldn't read them'". Guardian newspaper.
- ^ Bailey DM, Davies B (September 1997). "Physiological implications of altitude training for endurance performance at sea level: a review". British Journal of Sports Medicine. 31 (3): 183–190. doi:10.1136/bjsm.31.3.183. PMC 1332514. PMID 9298550.
- ^ Sottas PE, Robinson N, Fischetto G, Dollé G, Alonso JM, Saugy M (May 2011). "Prevalence of blood doping in samples collected from elite track and field athletes". Clinical Chemistry. 57 (5): 762–769. doi:10.1373/clinchem.2010.156067. PMID 21427381.
- ^ Ang SO, Chen H, Hirota K, Gordeuk VR, Jelinek J, Guan Y, et al. (December 2002). "Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia". Nature Genetics. 32 (4): 614–621. doi:10.1038/ng1019. PMID 12415268. S2CID 15582610.
- ^ Perrotta S, Nobili B, Ferraro M, Migliaccio C, Borriello A, Cucciolla V, et al. (January 2006). "Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster". Blood. 107 (2): 514–519. doi:10.1182/blood-2005-06-2422. PMID 16210343. S2CID 17065771.
- ^ Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, et al. (January 2006). "A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis". Proceedings of the National Academy of Sciences of the United States of America. 103 (3): 654–659. doi:10.1073/pnas.0508423103. PMC 1334658. PMID 16407130.
- ^ Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF, Lee FS (September 2007). "A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove". Blood. 110 (6): 2193–2196. doi:10.1182/blood-2007-04-084434. PMC 1976349. PMID 17579185.
- ^ Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR, McMullin MF, Lee FS (January 2008). "A gain-of-function mutation in the HIF2A gene in familial erythrocytosis". The New England Journal of Medicine. 358 (2): 162–168. doi:10.1056/NEJMoa073123. PMC 2295209. PMID 18184961.
- ^ Gale DP, Harten SK, Reid CD, Tuddenham EG, Maxwell PH (August 2008). "Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation". Blood. 112 (3): 919–921. doi:10.1182/blood-2008-04-153718. PMID 18650473. S2CID 14580718.
- ^ "Polycythemia Vera". Mayo Clinic.
{{cite web}}: CS1 maint: url-status (link) - ^ Newhart, Bob (2006). I Shouldn't Even Be Doing This!. New York: Hyperion. ISBN 1-4013-0246-7