polycythemia

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.{{cite journal | vauthors = Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW | display-authors = 6 | title = The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia | journal = Blood | volume = 127 | issue = 20 | pages = 2391–2405 | date = May 2016 | pmid = 27069254 | doi = 10.1182/blood-2016-03-643544 | s2cid = 18338178 | doi-access = free }} The definition is different for neonates and varies by age in children.

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

Relative polycythemia, also known as pseudopolycythemia,{{cite journal |last=Kaung |first=David T. |title="Relative Polycythemia" or "Pseudopolycythemia" |journal=Archives of Internal Medicine |volume=110 |issue=4 |date=1962-10-01 |issn=0003-9926 |doi=10.1001/archinte.1962.03620220048008 |page=456}} 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.{{cn|date=December 2020}} 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.{{cite journal |vauthors=Stefanini M, Urbas JV, Urbas JE |date=July 1978 |title=Gaisböck's syndrome: its hematologic, biochemical and hormonal parameters |journal=Angiology |volume=29 |issue=7 |pages=520–533 |doi=10.1177/000331977802900703 |pmid=686487 |s2cid=42326090}} 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.{{cite journal |last1=Mithoowani |first1=Siraj |last2=Laureano |first2=Marissa |last3=Crowther |first3=Mark A. |last4=Hillis |first4=Christopher M. |title=Investigation and management of erythrocytosis |journal=Canadian Medical Association Journal |date=10 August 2020 |volume=192 |issue=32 |pages=E913–E918 |doi=10.1503/cmaj.191587|pmc=7829024 |pmid=32778603}}
• Alternatively, additional red blood cells may have been received through another process—for example, being over-transfused (either accidentally or, as blood doping, deliberately).{{cn|date=December 2020}}

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.{{cite journal | vauthors = Sarkar S, Rosenkrantz TS | title = Neonatal polycythemia and hyperviscosity | language = English | journal = Seminars in Fetal & Neonatal Medicine | volume = 13 | issue = 4 | pages = 248–255 | date = August 2008 | pmid = 18424246 | doi = 10.1016/j.siny.2008.02.003 }}
• 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.
• The recipient twin in a pregnancy undergoing twin-to-twin transfusion syndrome can have polycythemia.{{cite journal |vauthors=Couck I, Lewi L |date=June 2016 |title=The Placenta in Twin-to-Twin Transfusion Syndrome and Twin Anemia Polycythemia Sequence |url=https://lirias.kuleuven.be/handle/123456789/539893 |journal=Twin Research and Human Genetics |volume=19 |issue=3 |pages=184–190 |doi=10.1017/thg.2016.29 |pmid=27098457 |s2cid=7376104}}

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.{{cite journal | vauthors = Ebert BL, Bunn HF | title = Regulation of the erythropoietin gene | journal = Blood | volume = 94 | issue = 6 | pages = 1864–1877 | date = September 1999 | pmid = 10477715 | doi = 10.1182/blood.V94.6.1864 | url = https://ora.ox.ac.uk/objects/uuid:86a152eb-cfc8-4812-935e-c89ab48acee3 }} 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. 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. 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.{{cite journal | vauthors = Shahani S, Braga-Basaria M, Maggio M, Basaria S | title = Androgens and erythropoiesis: past and present | journal = Journal of Endocrinological Investigation | volume = 32 | issue = 8 | pages = 704–716 | date = September 2009 | pmid = 19494706 | doi = 10.1007/BF03345745 | s2cid = 30908506 }}

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.

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).{{cite journal | vauthors = Kwaan HC, Wang J | title = Hyperviscosity in polycythemia vera and other red cell abnormalities | journal = Seminars in Thrombosis and Hemostasis | volume = 29 | issue = 5 | pages = 451–458 | date = October 2003 | pmid = 14631544 | doi = 10.1055/s-2003-44552 }}

The first step to evaluate new polycythemia in any individual is to conduct a detailed history and physical exam. 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.

Polycythemia is often initially identified on a complete blood count (CBC). The CBC is often repeated to evaluate for persistent polycythemia. If an etiology of polycythemia is unclear from history or physical, additional laboratory evaluation might include:{{cite journal | vauthors = McMullin MF, Bareford D, Campbell P, Green AR, Harrison C, Hunt B, Oscier D, Polkey MI, Reilly JT, Rosenthal E, Ryan K, Pearson TC, Wilkins B | display-authors = 6 | title = Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis | journal = British Journal of Haematology | volume = 130 | issue = 2 | pages = 174–195 | date = July 2005 | pmid = 16029446 | doi = 10.1111/j.1365-2141.2005.05535.x | s2cid = 11681060 }}

• Blood smear to evaluate cell morphology{{cite journal |vauthors=Spivak JL |date=July 2019 |title=How I treat polycythemia vera |journal=Blood |volume=134 |issue=4 |pages=341–352 |doi=10.1182/blood.2018834044 |pmid=31151982 |doi-access=free}}
• Iron panel to evaluate for concurrent iron deficiency
• JAK2 mutation testing
• Serum erythropoeitin (EPO) levels
• Oxygen saturation (usually via pulse oximetry or blood gas tests) or oxygen dissociation tests

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

{{main|Polycythemia vera}}

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.{{MedlinePlusEncyclopedia|000589|Polycythemia vera}} 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.{{cite book | vauthors = Wallach JB | title = Interpretation of Diagnostic Tests | year = 2007 | edition = 7th | publisher = Lippencott Williams & Wilkins | isbn = 978-0-7817-3055-6 }} A somatic (non-hereditary) mutation (V617F) in the JAK2 gene, also present in other myeloproliferative disorders, is found in 95% of cases.{{cite book |title=Current Medical Diagnosis & Treatment |year=2008 |page=438 |publisher= McGraw Hill Lange}} 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. Salazar Vázquez, B. Y., Cabrales, P., Tsai, A. G., Johnson, P. C., & Intaglietta, M. (2008). Lowering of blood pressure by increasing hematocrit with non nitric oxide scavenging red blood cells. American journal of respiratory cell and molecular

biology, 38(2), 135–142. https://doi.org/10.1165/rcmb.2007-0081OC 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.{{cite journal | vauthors = Tefferi A, Vannucchi AM, Barbui T | title = Polycythemia vera treatment algorithm 2018 | journal = Blood Cancer Journal | volume = 8 | issue = 1 | pages = 3 | date = January 2018 | pmid = 29321547 | pmc = 5802495 | doi = 10.1038/s41408-017-0042-7 }}

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.{{cite web | work = OMIM | url = https://www.ncbi.nlm.nih.gov/omim/133100 | title = Polycythemia, Primary Familial snd Congenital; PFCP }} 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.{{cite web | vauthors = Burkeman O | date = 29 Sep 2013 | url = https://www.theguardian.com/books/2013/sep/29/malcolm-gladwell-david-and-goliath-interview | work = Guardian newspaper | title = Malcolm Gladwell: 'If my books appear oversimplified, then you shouldn't read them' }}

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).{{cite book | vauthors = Pillai AA, Fazal S, Babiker HM | chapter = Polycythemia |date=2022 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK526081/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30252337 |access-date=2022-11-01 }} 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.{{cite journal | vauthors = Bailey DM, Davies B | title = Physiological implications of altitude training for endurance performance at sea level: a review | journal = British Journal of Sports Medicine | volume = 31 | issue = 3 | pages = 183–190 | date = September 1997 | pmid = 9298550 | pmc = 1332514 | doi = 10.1136/bjsm.31.3.183 }}
• 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; 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.{{cite journal | vauthors = Wajcman H, Galactéros F | title = Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts | journal = Hemoglobin | volume = 29 | issue = 2 | pages = 91–106 | date = 2005 | pmid = 15921161 | doi = 10.1081/HEM-58571 | s2cid = 10609812 }}
• 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.{{cite journal | vauthors = Kralovics R, Prchal JT | title = Congenital and inherited polycythemia | journal = Current Opinion in Pediatrics | volume = 12 | issue = 1 | pages = 29–34 | date = February 2000 | pmid = 10676771 | doi = 10.1097/00008480-200002000-00006 }}

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

• 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.
• Blood doping – Athletes who take erythropoietin-stimulating agents or receive blood transfusions to increase their red blood cell mass.{{cite journal | vauthors = Sottas PE, Robinson N, Fischetto G, Dollé G, Alonso JM, Saugy M | title = Prevalence of blood doping in samples collected from elite track and field athletes | journal = Clinical Chemistry | volume = 57 | issue = 5 | pages = 762–769 | date = May 2011 | pmid = 21427381 | doi = 10.1373/clinchem.2010.156067 | doi-access = free }}
• 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. {{cite journal | vauthors = Keohane C, McMullin MF, Harrison C | title = The diagnosis and management of erythrocytosis | journal = BMJ | volume = 347 | issue = nov18 1 | pages = f6667 | date = November 2013 | pmid = 24246666 | doi = 10.1136/bmj.f6667 | s2cid = 1490914 | url = https://pureadmin.qub.ac.uk/ws/files/129485931/The_diagnosis_and_management_of_erythrocytosis.pdf }}

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.{{cite journal | vauthors = Ang SO, Chen H, Hirota K, Gordeuk VR, Jelinek J, Guan Y, Liu E, Sergueeva AI, Miasnikova GY, Mole D, Maxwell PH, Stockton DW, Semenza GL, Prchal JT | display-authors = 6 | title = Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia | journal = Nature Genetics | volume = 32 | issue = 4 | pages = 614–621 | date = December 2002 | pmid = 12415268 | doi = 10.1038/ng1019 | s2cid = 15582610 }} 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.{{cite journal | vauthors = Perrotta S, Nobili B, Ferraro M, Migliaccio C, Borriello A, Cucciolla V, Martinelli V, Rossi F, Punzo F, Cirillo P, Parisi G, Zappia V, Rotoli B, Della Ragione F | display-authors = 6 | title = Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster | journal = Blood | volume = 107 | issue = 2 | pages = 514–519 | date = January 2006 | pmid = 16210343 | doi = 10.1182/blood-2005-06-2422 | s2cid = 17065771 | doi-access = free }} Patients with Chuvash erythrocytosis experience a significantly elevated risk of events.{{cite journal | vauthors = Gangat N, Szuber N, Pardanani A, Tefferi A | title = JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views | journal = Leukemia | volume = 35 | issue = 8 | pages = 2166–2181 | date = August 2021 | pmid = 34021251 | pmc = 8324477 | doi = 10.1038/s41375-021-01290-6 }}
• PHD2 erythrocytosis: Heterozygosity for loss-of-function mutations of the PHD2 gene are associated with autosomal dominant erythrocytosis and increased hypoxia-inducible factors activity.{{cite journal | vauthors = Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, McMullin MF, Lee FS | display-authors = 6 | title = A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 3 | pages = 654–659 | date = January 2006 | pmid = 16407130 | pmc = 1334658 | doi = 10.1073/pnas.0508423103 | doi-access = free }}{{cite journal | vauthors = Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF, Lee FS | title = A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove | journal = Blood | volume = 110 | issue = 6 | pages = 2193–2196 | date = September 2007 | pmid = 17579185 | pmc = 1976349 | doi = 10.1182/blood-2007-04-084434 }}
• HIF2α erythrocytosis: Gain-of-function mutations in HIF2α are associated with autosomal dominant erythrocytosis{{cite journal | vauthors = Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR, McMullin MF, Lee FS | title = A gain-of-function mutation in the HIF2A gene in familial erythrocytosis | journal = The New England Journal of Medicine | volume = 358 | issue = 2 | pages = 162–168 | date = January 2008 | pmid = 18184961 | pmc = 2295209 | doi = 10.1056/NEJMoa073123 }} and pulmonary hypertension.{{cite journal | vauthors = Gale DP, Harten SK, Reid CD, Tuddenham EG, Maxwell PH | title = Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation | journal = Blood | volume = 112 | issue = 3 | pages = 919–921 | date = August 2008 | pmid = 18650473 | doi = 10.1182/blood-2008-04-153718 | s2cid = 14580718 | doi-access = free }}

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:

• A ruddy (red) complexion, or plethora
• Headache, transient blurry vision (amaurosis fugax), other signs of a transient ischemic attack (TIA) or stroke
• Dizziness, fatigue
• Unusual bleeding, nosebleeds
• Pain in abdomen from enlarged spleen in polycythemia vera
• Pain in hands and feet (erythromelalgia)
• Itchiness, especially after a hot shower (aquagenic pruritis)
• Numbness or tingling in different body parts{{Cite web|title=Polycythemia Vera|url=https://www.mayoclinic.org/diseases-conditions/polycythemia-vera/symptoms-causes/syc-20355850|website=Mayo Clinic}}

The prevalence of primary polycythemia (polycythemia vera) was estimated to be approximately 44–57 per 100,000 individuals in the United States. Secondary polycythemia is considered to be more common, but its exact prevalence is unknown. 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.{{cite journal | vauthors = Tremblay D, Alpert N, Taioli E, Mascarenhas J | title = Prevalence of unexplained erythrocytosis and thrombocytosis - an NHANES analysis | journal = Leukemia & Lymphoma | volume = 62 | issue = 8 | pages = 2030–2033 | date = August 2021 | pmid = 33645402 | doi = 10.1080/10428194.2021.1888377 | s2cid = 232078345 }}

The management of polycythemia varies based on its etiology:

• See polycythemia vera for management of primary polycythemia, which involves reducing thrombotic risk, symptom amelioration and monitoring for further hematologic complications. Treatment can include phlebotomy, aspirin, and myelosuppressive or cytoreductive medications based on risk stratification.
• For secondary polycythemia, management involves addressing the underlying etiology of increased erythropoeitin production, such as smoking cessation, CPAP for sleep apnea, or removing any EPO-producing tumours. Phlebotomy is not typically recommended for patients with physiologic polycythemia, who rely on additional red cell mass for necessary oxygen delivery, unless the patient is clearly symptomatic and experiences relief from phlebotomy. It is unclear if patients with secondary polycythemia are at elevated thrombotic risk, but aspirin can be considered for patients at elevated cardiovascular risk or for patients with Chuvash polycythemia. The first-line treatment for post-transplant erythrocytosis specificity is angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers.

Polycythemia is theorized to increased performance in endurance sports due to the blood being able to store more oxygen.{{cn|date=December 2020}} 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.{{Cite journal |last1=Fulco |first1=C. S. |last2=Rock |first2=P. B. |last3=Cymerman |first3=A. |date=2000 |title=Improving athletic performance: is altitude residence or altitude training helpful? |url=https://pubmed.ncbi.nlm.nih.gov/10685591 |journal=Aviation, Space, and Environmental Medicine |volume=71 |issue=2 |pages=162–171 |issn=0095-6562 |pmid=10685591}}

• Anemia, a decrease in red blood cell count
• Cytopenia, a decrease in blood cell count
• Capillary leak syndrome, another cause of hemoconcentration

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{{Medical resources

| DiseasesDB = 10295

| ICD11 = {{ICD11|3A80}}, {{ICD11|3A81}}, {{ICD11|2A20.4}}, {{ICD11|KA8A}}

| ICD10 = {{ICD10|D|75|1|d|70}}, {{ICD10|P|61|1|p|50}}

| ICD9 = {{ICD9|289.0}}, {{ICD9|776.4}}

| ICDO =

| OMIM =

| MedlinePlus =

| eMedicineSubj = Ped

| eMedicineTopic = 1848

| MeshID = D011086

| Orphanet = 729

}}

{{Diseases of RBCs}}

{{Pediatric conditions originating in the perinatal period}}

Category:Red blood cell disorders

Category:Haemorrhagic and haematological disorders of fetus and newborn

Category:Hematopathology