Jan Blatný  (born 24 March 1970) [ 1 ]  is a  Czech   physician ,  teacher [ 2 ]  and  politician . On 29 October 2020 he was named as  Minister of Health of the Czech Republic  by Prime Minister  Andrej Babiš  following the resignation of  Roman Prymula . On 7 April 2021 he was replaced by  Petr Arenberger .


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Robin Wayne Carrell  (born 5 April 1936) is a New Zealand-born haematologist.


Born in 1936, [ 1 ]  Carrell was educated at  Christchurch Boys' High School  from 1949 to 1953. [ 2 ]  He graduated  MB ChB  from the  University of Otago  in 1959, [ 3 ]  and  BSc(Hons)  in chemistry and biochemistry from the  University of Canterbury  and  Lincoln College  in 1965. [ 1 ] [ 4 ]  He completed his PhD at the  University of Cambridge  in 1967 and in 1968 he was appointed head of clinical biochemistry at  Christchurch Hospital , [ 5 ]  the department later becoming part of the  University of Otago Christchurch School of Medicine . As a spin-off from his research he co-founded biotechnology company Canterbury Scientific in 1985. [ 6 ]  He returned to Cambridge the following year as professor of haematology, retiring in 2003, but as professor emeritus he has continued his research at Cambridge. [ 5 ]  He retired from the board of directors of Canterbury Scientific in 2012. [ 7 ]


In 1986 he won the  Hector Medal , at the time the highest award in New Zealand science. [ 8 ]  He was elected a  Fellow of the Royal Society of New Zealand  in 1980, [ 9 ]  a Fellow of  Trinity College, Cambridge  in 1987, [ 10 ]  and a  Fellow of the Royal Society  in 2002. [ 11 ]


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Kathryn Elizabeth Crosier   ONZM  ( née   Barber ) is a New Zealand academic, a clinical  haematologist , and is an emeritus professor at the  University of Auckland , specialising in  molecular medicine . In 2005, she was appointed an  Officer of the New Zealand Order of Merit  for services to medicine.


Crosier completed a medical degree at the  University of Otago  followed by a  PhD  titled  The regulation of human haemopoiesis by cytokines  at the University of Auckland in 1988. [ 1 ]  Crosier then joined the faculty of the University of Auckland, rising to full professor as Professor of Molecular Medicine and Pathology. Crosier is a clinical haematologist, and her husband Philip Crosier is also an emeritus professor of the university. [ 2 ] [ 3 ]  Crosier is a  Fellow of the Royal Australasian College of Physicians  and a Fellow of the  Royal College of Pathologists of Australasia . [ 2 ]  Crosier was appointed Associate Deputy Vice-Chancellor (Research) for  PBRF  at the university in 2010. [ 4 ]


Crosier served as a member of the  New Zealand Blood Service , being appointed in 2003 for a three year term, and subsequently reappointed in 2006 for a second term. [ 5 ] [ 6 ]


Crosier's research interests include  medical genetics ,  leukaemia  and  stem cell  development. Crosier was part of a team that announced a breakthrough in understanding of the formation of  lymphatic vessels  in 2019. [ 7 ] [ 8 ]  The research, funded by the  Health Research Council , the  Marsden fund  and the Auckland Medical Research Foundation, involved a collaboration between researchers at Auckland, the  University of Münster  and the  University of Queensland . Researchers used fluorescent  zebra fish  to show that lymphatic vessels can develop through different routes, rather than from blood vessels as previously thought. [ 7 ]  The findings have relevance to the development of treatments for  lymphedoema , a common condition resulting from some cancer treatments. [ 8 ]


One of Crosier's notable doctoral students is rheumatologist  Fiona McQueen . [ 9 ]


In the  2005 New Year Honours , Crosier was appointed an  Officer of the New Zealand Order of Merit , for services to medicine. [ 10 ]


She is married to  Phil Crosier , an emeritus professor of molecular medicine and pathology at the University of Auckland. [ 11 ]


Björn Dahlbäck  (born 1949) is a Swedish physician, medical researcher, and professor of clinical chemistry, specializing in  hematology  and the molecular mechanisms of blood coagulation. [ 1 ]  He determined that  activated protein C (APC) resistance  is the most common inherited risk factor of  venous thrombosis .


Dahlbäck graduated with an M.D. from  Lund University  and then completed his medical internship and residency at  Malmö 's University Hospital, [ 2 ]  which is now merged into  Skåne University Hospital . In 1981 he received from Lund University his doctorate with dissertation  The activation of prothrombin on the platelet surface [ 3 ]  under the supervision of  Johan Stenflo . Dahlbäck was a postdoc at  La Jolla 's  Scripps Research , where his supervisor was  Hans J. Müller-Eberhard , and later was a visiting scholar at  Oklahoma Medical Research Foundation  (OMRF). In 1989 at Lund University, Dahlbäck was appointed a full professor of clinical chemistry, specializing in hematology and cardiac and cardiovascular systems. [ 2 ] [ 1 ]  He is also the director of the blood coagulation unit at Malmö General Hospital. [ 4 ]


His research was important in showing that  APC resistance  is caused by a harmful mutation in the  F5  gene corresponding to the protein  Factor V ; the specific mutation was subsequently identified by several groups of researchers and is now called  Factor V Leiden . [ 2 ]  In 2013, Dahlbäck and colleagues identified the  F5  gene mutation that causes the phenotype called "east Texas bleeding disorder". [ 5 ] [ 2 ]


He has received several honors and awards, [ 2 ]  including in 1996 the  Louis-Jeantet Prize for Medicine [ 4 ]  and in 2019  H. M. The King's Medal  ( H.M. Konungens Medalj ) of the 12th size from the  Royal Court of Sweden . [ 6 ]  He is a member of the  Royal Swedish Academy of Sciences . [ 7 ]


In 2000,  Academic Press  published  Hematology: Landmark Papers of the Twentieth Century  , which included the 1994 paper  Resistance to activated protein C as a basis for venous thrombosis  by Peter J. Svensson and Björn Dahlbäck. [ 8 ] [ 9 ]


Brian G.M. Durie  is a Scottish  hematologist  known  for his research and efforts regarding  multiple myeloma  and blood disorders, especially  his development of the multiple myeloma staging system.  He is the chairman of the board and Scientific Director for the Myeloma Foundation and a specialist in multiple myeloma and related disorders at the Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute ..


Durie was born December 1942 in  Gullane , Scotland. [ 1 ]  and graduated in 1960 from North Berwick High School. [ 1 ]  He attended the  University of Edinburgh Medical School  and graduated in 1966. After Medical and Surgical House Officer positions at the  University of Edinburgh  Royal Infirmary in 1967, [ 1 ]  he moved to the United States to complete his medical residency and subspecialty training. His training at  Mayo Clinic  in Minnesota was completed in 1972 [ 1 ]  and led to Specialty Board Certification in Internal Medicine (ABIM) in 1972 followed by his Certification in Hematology (ABIM) in 1974 [ 1 ]  and Oncology (ABIM) in 1975. [ 1 ]  Durie obtained his Medical licensure in Minnesota in 1972, [ 1 ]  Arizona in 1974 [ 1 ]  and California in 1993 [ 1 ]


Upon completing subspecialty training, Durie joined the Medical Faculty of the  University of Arizona College of Medicine - Tucson    in 1972 where he progressed to Full Professor status in the Section of Hematology/Oncology in 1981. [ 1 ]  He served as Head of the Hematology Section and Director of the Myeloma Program. [ 2 ]  In 1989, he became a professor and Head of the Department of Clinical and Laboratory Hematology at the  University of London  where he also established a myeloma program. [ 2 ]  In 1992, he returned to the United States in the Division of Hematology/Oncology at  Cedars-Sinai Medical Center  in Los Angeles. [ 3 ]  Upon   return to the United States, he  assume Directorship of the Hematological Research and Myeloma Programs for Aptium Oncology Inc. (subsequently  AMyC Myeloma Consortium) [ 4 ]  also based at Cedars-Sinai Medical Center in the Comprehensive Cancer Center Division. He currently remains as a myeloma specialist physician [ 3 ]


Durie's key research articles have focused on classifying and staging myeloma. Durie's first faculty position at the University of Arizona was with  Sydney Salmon with the assignment to develop a clinical staging system for multiple myeloma. [ 5 ]  This was based upon a new system for directly measuring the number of myeloma cells within the body, an  approach which led to the publication of a seminal paper on myeloma staging in the journal  Cancer  in 1975, [ 6 ]  which has been cited more than 3000 times by other scientists. This publication continues to be referenced as the standard way to clinically stage multiple myeloma, named the Durie-Salmon Staging System. Durie has co-authored two updates to the staging system.


Salmon and Durie  authored a paper that concluded that the pretreatment labeling index provides helpful prognostic information in addition to tumor mass staging, which was patented. [ 7 ]  Furthermore, Durie showed it was possible to stratify myeloma patients based on combinations of serum beta 2 microglobulin with both albumin and age, producing significant separation of patients into low-, intermediate-, and high-risk categories. [ 8 ]  His research concluded that serum beta 2 microglobulin is the most powerful prognostic factor currently available for multiple myeloma. [ 8 ]  In 2006, Durie and team created an international uniform response criteria for multiple myeloma, which became very substantial for use by doctors and other researchers. [ 9 ]  Durie co-authored an update to the response criteria in 2016 [ 10 ]


In 1990, Durie co-created a non-profit foundation, the  International Myeloma Foundation . Formed in conjunction with Brian Novis and Susie Lavitt. [ 11 ]  Durie has continued to serve as  chairman of the board and Scientific Director. The foundation has established myeloma patient support groups in the US and globally, created th p International Myeloma Working Group ] [ 12 ]  with 250 myeloma experts to conduct collaborative research and guideline development, and established the Black Swan Research Initiative to conduct treatment trials. [ 13 ]


Durie is a Leukemia Society of America Scholar and a U.S. Hematologic Research Foundation Annual Awardee. Hr received the 2006 Robert A. Kyle Lifetime Achievement Award, which honors a physician in myeloma research. In 2009, he received the Waldenström's Award in recognition of his contributions to that field. He was awarded an Honorary Doctorate of Medicine from the  Vrije Universiteit Brussel    in 2019.


1991	5th Annual Hematological Research Award [ 2 ]
2002	Nuclear Medicine First Prize Award [ 2 ]
2006	Robert A. Kyle Lifetime Achievement Award [ 14 ]
2009	Waldenström Award for Myeloma Research [ 15 ]
2014	Mayo Distinguished Alumni Award [ 16 ] [ 17 ]
2019	Honorary Doctorate of Medicine: Free University of Brussels [ 18 ]


Durie has   written over 600 research papers, sixteen book chapters, and five books. [ 19 ]


Robert (Robin) Sanno Fåhræus  (15 October 1888 – 18 September 1968) was a  Swedish  medical researcher noted for his contributions to  hemorheology . [ 1 ]


Fåhræus was the son of art historian  Klas Fåhraeus  and actress  Olga Björkegren . [ 2 ]  He commenced studies at  Karolinska Institute  in 1908, where he received his medical license in 1922. Before that, in 1921, he had completed his research doctorate with the title  The suspension-stability of the blood . He became associate professor of experimental  pathology  at the Karolinska Institute in 1922. He was professor of pathology at  Uppsala University  from 1928 to 1947, and professor of general pathology and pathological anatomy in Uppsala from 1947 to 1955, after his previous chair had been split in two. [ 1 ]


Fåhræus became a member of the  Royal Swedish Academy of Sciences  in 1935. [ 1 ]  In 1966, the  International Society of Hemorheology  awarded him their first Poiseuille medal, the Society's highest award. [ 3 ]


While studying at the Karolinska Institute he conducted research on  eclampsia  and observed that blood samples from pregnant women easily could be distinguished from other blood samples because the  red blood cells  descended more quickly in the test tubes, leaving a thick layer of  blood plasma  on top. [ 2 ]  This phenomenon is the  erythrocyte sedimentation rate , which can be used as a diagnostic tool.


After Fåhræus had received his position at the Karolinska Institute in 1922, he sought contact with professor  Theodor Svedberg  in Uppsala and suggested that the recently built  ultracentrifuge  should be used to determine the  molecular mass  of  hemoglobin . Svedberg and Fåhræus published the result in 1926, the same year Svedberg received the  Nobel Prize in Chemistry . [ 2 ]


In Uppsala from 1928, Fåhræus started to study the flow of blood in thin blood vessels, which led to the discovery of two effects named after him. In 1929 he described the  Fåhræus effect , a decrease in the average concentration of red blood cells when blood flows in a tube of smaller diameter. In 1931 he and co-worker Torsten Lindqvist described the  Fåhræus–Lindqvist effect , the change of the  viscosity  of blood with the diameter of the tube it travels through.


Floy Agnes  " Aggie " ( Naranjo Stroud )  Lee  was a biologist who worked on the  Manhattan Project  at  Los Alamos  as a hematology technician.


Floy Agnes Lee was born July 23, 1922, at the  Albuquerque Indian School  and was the fourth of five siblings. [ 1 ] [ 2 ]  Her mother was a German-American teacher from Indiana who had traveled in the US teaching at different Indian schools including the Winnebago Indian schools in Wisconsin, in Santa Fe, and at the Albuquerque Indian School. Her father was a member of the  Santa Clara Pueblo .


Lee grew up at the Albuquerque Indian School, but was sent to St. Mary's Catholic School for her education. She then went on to graduate from  Albuquerque High School . In 1945, she graduated from the  University of New Mexico  (UNM) with a degree in biology. While there, she worked for a professor putting different solutions into each plant to see how they grew. This job made her more interested in doing research. [ 2 ]  During her college years she also learned to fly planes and worked at a grocery store to pay for flying lessons. She was one flight short of qualifying to become a member of the  Women’s Airforce Service Pilots  before the program was disbanded in 1944. [ 3 ]


In 1945, Lee was asked by professor Edward Castetter, head of UNM's biology department, to do research for him. While she was compiling and recording information on what the Indigenous people of New Mexico ate before colonization, Castetter asked her to postpone a trip that she had planned to see her mother's relatives in order to finish the research. While Lee was continuing this research, Castetter got a call from Los Alamos. They told him that they were looking for a biology student or a graduate to work in the hematology laboratory. [ 2 ]


Lee accepted this position at the hematology lab at Los Alamos in 1945. She collected and examined blood samples from Manhattan Project scientists, including  Louis Hempelmann , as well as  Louis Slotin  and  Alvin Graves  after  the criticality accident  that exposed Slotin to a fatal dose of radiation. Lee said that she learned how to take blood, read blood cell counts, and identify blood types on the job, but that she excelled at these tasks once taught. She was sent to different sites of the Manhattan Project where she would draw blood from individuals. While working in the hematology lab at Los Alamos, Lee was assigned specific scientists to monitor, including  Enrico Fermi .


Lee and Fermi became friends during this time. In Lee's oral history, conducted by the  Atomic Heritage Foundation , she elaborated on her relationship with Fermi: "We got to talking about what I liked to do and what he liked to, and we got on the subject of tennis. Now, I did not know that this was Enrico Fermi. I only knew him as a number, because they wouldn’t give names out. So we would play tennis. This was before the bomb was dropped, and then afterwards also. He was a short man, and he had a funny little hat." [ 2 ]  After the  atomic bombs  were detonated over Hiroshima and Nagasaki, Lee was told that she had been playing tennis with a Nobel Prize-winner for months. She was shocked. She said that her response was: "'Oh, I can't believe that.' Because I was beating him in tennis every time. So when we went out to play tennis later, I didn't beat him. I tried not to. We became very, very good friends." [ 2 ]


After the war ended, Fermi encouraged Lee to continue her studies at the  University of Chicago . [ 2 ]  She moved to Chicago, began her doctorate in biology, and worked at  Argonne National Laboratory . She continued to study, work at the lab and raise her child after her husband passed away from cancer. After 14 years, she received her PhD. She later worked at the  Jet Propulsion Lab  in California and returned to work at  Los Alamos National Laboratory  before she retired. Over the course of her long career, she conducted research on the impact of radiation on chromosomes. [ citation needed ]


Lee died in 2018 at the age of 95. [ 4 ]


Munib Jalal Shahid  ( Arabic :  منيب جلال شهيد ,  romanized :  Munīb Jalāl Shahīd ; 1908–1973) was Chairman of Hematology and Oncology at the Faculty of Medicine of the  American University of Beirut . [ 1 ] [ 2 ]   He built the hematology laboratory at the Faculty of Medicine, a development that increased research output significantly. [ 3 ]   The Dr. Munib Shahid Award is presented annually at the American University of Beirut to the fourth year medical student demonstrating the best performance in internal medicine and a mature character. [ 4 ]


Munib Shahid was born in 1908 in  Acre, Palestine  to a prominent  Baháʼí lineage . He was the great-grandson of  Baháʼu'lláh , the founder-prophet of the  Baháʼí Faith . His parents were Jalal, an  Afnán , and Rúḥá, a daughter of  ʻAbdu'l-Bahá . His paternal grandfather was Muhammad-Hasan, titled " King of the Martyrs ". In 1944, he married  Serene Husseini  according to the Muslim rites. She was related to the  Grand Mufti of Jerusalem , an enemy of the Baháʼís.  Shoghi Effendi , Munib's cousin and then head of the Baháʼí Faith, labeled this marriage a "treacherous act" and excommunicated Munib Shahid as a  Covenant-breaker . [ 5 ] [ 6 ]


Munib and Serene Husseini continued to live in Beirut, where he pursued his academic career, and she promoted cottage industries among  Palestinian refugees .  Serene Shahid wrote a critically acclaimed autobiography of her childhood, titled,  Jerusalem Memories. [ 7 ]   The couple had three daughters, including  Leila Shahid . [ 8 ]


Among Shahid's publications were: [ 2 ]


Ruth Lilian Spearing   CNZM  is a New Zealand  haematologist , and researches blood cancer. In 2023 Spearing was appointed a Companion of the  New Zealand Order of Merit  for services to haematology.


Spearing attended the  University of Otago . [ 1 ]  She has worked as a consultant haematologist at  Christchurch Hospital  since 1989, and is the clinical director of haematology at  Canterbury District Health Board . [ 2 ]  From 2003 until 2017 Spearing served as Chair of the Canterbury Hospitals’ Medical Staff Association. [ 2 ]  Spearing was also Canterbury Clinical Lead for the Adolescent and Young Adult Cancer Service. [ 2 ]  Spearing was also a board member of the  New Zealand Medical Association , and a trustee of the Chronic Lymphocytic Leukaemia Advocates New Zealand. [ 3 ] [ 4 ]


Spearing led the New Zealand involvement in international collaborative trials with the UK's  Medical Research Council  and the Australasian Leukaemia and Lymphoma Group. [ 2 ]  These trials have investigated treatments for a range of blood cancers including  myeloma ,  chronic lymphocytic leukaemia ,  acute lymphocytic  and  myeloid leukaemia , and have resulted in increased survival rates from 13% for acute myeloid leukaemia in the 1980s to 65 per cent. [ 2 ]


In 2008 Spearing established the Ruth Spearing Cancer Research Trust, to support haematology research in the South Island. [ 2 ]


In 2024 Spearing led calls for  Pharmac  chief executive Sarah Fitt to step down after an  Official Information Act  request revealed internal communications showing disdain for patients and their advocates. [ 5 ]  Spearing has been critical of Pharmac's approach to funding new drugs, especially drugs for blood cancers, pointing out that New Zealand funds far fewer blood cancer drugs than other countries. [ 6 ] [ 7 ]


In the  2023 King's Birthday and Coronation Honours  Spearing was appointed a Companion of the New Zealand Order of Merit for services to haematology. [ 2 ] [ 8 ]  Spearing is a Life Member of ALLG, the Australasian Leukaemia and Lymphoma Group. [ 8 ]


Swee Lay Thein  is a Malaysian haematologist and  physician-scientist  who is Senior Investigator at the  National Institutes of Health . She works on the  pathophysiology  of  haemoglobin  disorders including  sickle cell disease  and  thalassemia .


Thein was born in  Kuala Lumpur ,  Malaysia . [ 1 ]  She studied medicine in both Malaysia and the  United Kingdom . [ 2 ]  She graduated from the  University of Malaya  in 1976. [ 3 ]  She specialised in  hematology  at the  Royal Postgraduate Medical School  and the  Royal Free Hospital . She moved to  Oxford , where she worked at the  Medical Research Council  (MRC) Molecular Hematology Unit in the  Weatherall Institute of Molecular Medicine  and the  John Radcliffe Hospital . She held various positions at Oxford, including a MRC Clinical Training position, a  Wellcome Trust  senior fellowship and an honorary consultancy. [ 1 ]


In 2000 Thein joined  King's College London  as a Professor of Molecular Haematology. She was made Clinical Director of the Red Blood Cell clinic at  King's College Hospital . Her work considers the  pathophysiology  of haemoglobin disorders; which include  sickle cell disease  and  thalassemia . The only cures for sickle cell disease and thalassemia are  bone marrow  transplants, but these are not always available. Whilst both conditions can present with a variety of clinical severities, a remediating factor is the ability to produce  foetal haemoglobin  (HbF). Foetal haemoglobin is the haemoglobin that transports oxygen during  foetal  life and in infants until they are six months old. [ 4 ]  She has studied the mechanisms responsible for the formation of foetal haemoglobin.


Thein demonstrated that HbF levels are mainly controlled by genetics, and that majority of the genetic variance is accounted for by factors outside the  globin  locus. [ 1 ]  Thein used  linkage analysis  to identify two of the  quantitative trait loci  (QTL) for this HbF variability. These loci are involved with the control  haematopoiesis  and the production of HbF. The loci are located on the chromosomes 6q and 2p which are located within the  BCL11A  gene. Whilst it was known that BCL11A was involved with cancer, Thein was the first to show that BCL11A was associated with red blood cell disorders. [ 5 ]  The 6q QTL contains  single-nucleotide polymorphisms  distributed across three  linkage disequilibrium  blocks, in an intergenic region between  MYB  and  HBS1L . [ 1 ]  Thain showed that this interval contains regulatory sequences. She has investigated how QTL regulates the expression of MYB and HBS1L. [ 1 ]  These two QTLs (6q and 2p), and a single-nucleotide polymorphism on the  HBB  cluster account for around half of the variability in HbF levels. [ 1 ]  She established that these two variants had spread from Africa into almost all human populations. [ 6 ]


By delineating the genetics of foetal haemoglobin control in adults, she hopes to explain the trait variance in adults as well as identifying the loci and sequences of variants. She believes that by identifying the HbF QTLs she will be able to improve patient management through the development of novel therapies, more sophisticated genetic counselling and better predictions of disease severity. These therapies may include approaches to activate the BCL11A gene. [ 5 ]  By trying to find the relationships between genotypes and phenotypes, Thein has helped with  DNA  diagnostics in the  haemoglobinopathies . [ 1 ]


Sickle cell disease occurs because rigid strands form inside  red blood cells , destroying their structure and resulting in the formation of sickled cell shapes. Thein is working on therapeutic agents that can work against this polymerisation, stopping the cells changing shape. [ 5 ]  Thein has served as Chair of the  European Hematology Association  working group on red blood cells. [ 7 ]  She has been involved with the teaching of their programs on haematology. [ 7 ]


She moved to the  National Institutes of Health  as Senior Investigator and Chief of the new NIH Sickle Cell Branch in 2015. [ 8 ]


Thein is an editor for  Blood ,  Annals of Haematology ,  Hemoglobin , and the  American Journal of Hematology . [ 5 ]  She is feature editor of the  Sickle Blood Hub , an online space for the journal  Blood . [ 14 ]


Wilhelm Türk  (2 April 1871 – 20 May 1916) was an Austrian haematologist and professor of medicine at the  University of Vienna .  He coined the term "lymphatic reaction" and the Türk cell is named for him. [ 1 ] [ 2 ] [ 3 ]


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Peter Valent  (born 9 October 1962 in  Vienna ,  Austria ) is an Austrian  hematologist  and  stem cell  researcher. Since 1990 he leads a research group at the  Medical University of Vienna . From 2002 he coordinates the  European Competence Network on Mastocytosis  and since 2008 he is Scientific Director of the  Ludwig Boltzmann Institute for Hematology and Oncology  of the  Ludwig Boltzmann Society  in Austria. [ 1 ]


Valent studied medicine at the  Medical University of Vienna  and graduated in 1987. He is a specialist in  internal medicine  and  hematology  and was promoted to Assistant Professor for  Experimental Hematology  in 1992 and Associate Professor for Internal Medicine in 1995. Valent visited several universities in Germany as Guest Scientist, including the Institute of Pathology of the  University of Tübingen , the University of Schleswig-Holstein (Campus Lübeck) and the  LMU Munich . [ 2 ]


Between 1989 and 1999 Valent examined the phenotype and growth characteristics of human mast cells. [ 3 ]  He found that mast cells form a unique lineage in the hematopoietic cell system. [ 4 ] [ 5 ]  In subsequent studies, neoplastic mast cells were characterized. [ 6 ] [ 7 ]  The resulting data contributed essentially to the development of diagnostic criteria and the  WHO  classification of  mastocytosis . [ 8 ]  In 2000, Valent organized a Working Conference on Mastocytosis to implement this classification together with an international consensus group. [ 9 ]  Since 2002 Valent coordinates the  European Competence Network on Mastocytosis  that expanded rapidly and provides a useful basis for the development and conduct of studies and activities in the field of mastocytosis. [ 10 ]  In the forthcoming years, the diagnostic WHO criteria of mastocytosis were validated, adjusted and extended. [ 11 ]  To discuss these developments, Valent and his team organized additional conferences in Vienna, including a  Working Conference on Standards and Standardization of Diagnostic Criteria and Therapies in Mastocytosis [ 12 ]  and one on the  Global Classification of Mast Cell Disorders and Mast Cell Activation Syndromes  (2010). [ 13 ]


One additional focus in Valent´s research is the neoplastic stem cell, also termed cancer stem cell in the context of cancer and leukemic stem cell in leukemia contexts. Valent investigates the phenotype of these cells in various hematologic neoplasms and develops concepts predicting the step-wise development of these cells from normal stem cells. The major aim in his research is to identify molecular targets in these cells and to develop more effective (curative) therapies by eliminating these cells in various blood cell disorders, including  Acute Myeloid Leukemia ,  Chronic Myeloid Leukemia , [ 14 ]   Systemic Mastocytosis [ 15 ]  and  Myelodysplastic Syndromes . [ 16 ]  These studies are primarily conducted in the  Ludwig Boltzmann Institute for Hematology and Oncology  at the Medical University of Vienna. [ 17 ]


Valent is a member of numerous scientific organizations and has published over 850 publications since 1988, including more than 500 original papers, over 200 review articles and numerous book contributions. He also published numerous textbook chapters. In 2001, 2008 and 2016 he drew book chapters on mastocytosis as the author of the WHO. Peter Valent is one of the most frequently cited scientists from German-speaking countries in the field of immunology from 2011 to 2015. In Austria he is one of the top 5 scientists in the field of medicine (as of June 2022 -  https://research.com  /scientists-rankings/medicine/at). In total, his work has been cited more than 35,000 times by March 2019 and his h-index is 103 (as of April 2022). Peter Valent is currently ranked #777 among the world's top scientists in Biology and Biochemistry as of April 2022, and #913 among the world's top scientists in Medicine as of June 2022 -  https://research.com/scientists-  rankings/medicine).


Valent received several national and international awards, including the  Karl Landsteiner -Award  of the  Austrian Society for Allergy and Immunology , the  Paracelsus Award  of the  Austrian Society for Internal Medicine , the  Wilhelm Türk Award  of the  Austrian Society for Hematology and Oncology , the  Theodor-Billroth Medal  of the  Austrian Medical Association , the  Mac Forster Award  of the  European Society for Clinical Investigation  and the  Middle European Award for Interdisciplinary Cancer Research . [ 18 ]


Hematology  ( spelled   haematology  in  British English ) is the branch of  medicine  concerned with the study of the cause, prognosis, treatment, and prevention of diseases related to  blood . [ 1 ] [ 2 ]  It involves treating diseases that affect the production of blood and its components, such as  blood cells ,  hemoglobin ,  blood proteins ,  bone marrow ,  platelets ,  blood vessels ,  spleen , and the mechanism of  coagulation . Such diseases might include  hemophilia ,  sickle cell anemia , blood clots ( thrombus ), other bleeding disorders, and blood  cancers  such as  leukemia ,  multiple myeloma , and  lymphoma . [ 3 ]  The laboratory analysis of blood is frequently performed by a  medical technologist  or  medical laboratory scientist .


Physicians specialized in hematology are known as  hematologists  or  haematologists . [ 2 ]  Their routine work mainly includes the care and treatment of patients with hematological diseases, although some may also work at the hematology laboratory viewing  blood films  and  bone marrow  slides under the  microscope , interpreting various hematological test results and  blood clotting test  results. In some institutions, hematologists also manage the hematology laboratory. [ 3 ]  Physicians who work in hematology laboratories, and most commonly manage them, are pathologists specialized in the diagnosis of hematological diseases, referred to as  hematopathologists  or  haematopathologists . Hematologists and hematopathologists generally work in conjunction to formulate a diagnosis and deliver the most appropriate therapy if needed. Hematology is a distinct subspecialty of internal medicine, separate from but overlapping with the subspecialty of medical  oncology . Hematologists may specialize further or have special interests, for example, in:


Starting hematologists (in the US) complete a four-year medical degree followed by three or four more years in residency or internship programs. After completion, they further expand their knowledge by spending two or three more years learning how to experiment, diagnose, and treat blood disorders. [ 7 ]  Some exposure to  hematopathology  is typically included in their fellowship training. Job openings for hematologists require training in a recognized fellowship program to learn to diagnose and treat numerous blood-related benign conditions and  blood cancers . Hematologists typically work across specialties  to care for patients with complex illnesses, such as  sickle cell disease , who require complex, multidisciplinary care, and to provide consultation on cases of  disseminated intravascular coagulation ,  thrombosis  and other conditions that can occur in hospitalized patients. [ 8 ]


1q21.1  copy number variations  (CNVs) [ 1 ]  are rare aberrations of human  chromosome 1 .


In a common situation a human cell has one pair of identical chromosomes on chromosome 1. With the 1q21.1 CNVs one chromosome of the pair is not complete because a part of the sequence of the chromosome is missing, or overcomplete, because some parts of the sequence are duplicated. The result is that one chromosome is of normal length and the other one is too long or too short. [ citation needed ]


The structure of 1q21.1 is complex. The area has a size of approximately 6 Mega base  (Mb) (from 141.5 Mb to 147.9 Mb). Within 1q21.1 there are two areas where the CNVs can be found: the proximal area or TAR area (144.1 to 144.5) and the distal area (144.7 to 145.9). A 1q21.1 CNV will commonly be found in one of these areas, but an overlap with the other area or parts that are outside these areas are possible. 1q21.1 has multiple repetitions of the same structure: Only 25% of the structure is not duplicated. There are several gaps in the sequence. There is no further information available about the DNA-sequence in those areas up till now. The gaps represent approximately 700 Kilobase. New genes are expected in the gaps. The area of 1q21.1 is one of the most difficult parts of the human genome to map. [ citation needed ]


CNVs occur due to  non-allelic homologous recombination  mediated by  low copy repeats  (sequentially similar regions), commonly found in 1q21.1. [ citation needed ]


Four separate forms of 1q21.1 CNVs are mentioned in literature. [ citation needed ]


The CNVs lead to a very variable  phenotype  and the manifestations in individuals are quite variable. Some people who have a CNV can function in a normal way, while others have symptoms of mental retardation and various physical anomalies. [ citation needed ]


Meiosis  is the process of dividing cells in humans. In meiosis, the chromosome pairs splits and a representative of each pair goes to one daughter cell. In this way the number of chromosomes will be halved in each cell, while all the parts on the chromosome (genes) remain, after being randomized. Which information of the parent cell ends up in the daughter cell is purely decided by chance. Besides this random process, there is a second random process. In this second random process the DNA will be scrambled in a way that pieces are omitted ( deletion ), added ( duplication ), moved from one place to another ( translocation ) and inverted ( inversion ). This is a common process, which leads to about 0,4% variation in the DNA. It explains why even identical twins are not genetically 100% identical. [ citation needed ]


Problem of the second random process is that genetic mistakes can occur. Especially due to the deletion and duplication process, the chromosomes that come together in a new cell may be shorter or longer. The result of this spontaneous change in the structure of DNA is a so-called  copy number variation . Due to the CNV chromosomes of different sizes can be combined in a new cell. If this occurs around conception, the result will be a first cell of a human with a genetic variation. This can be either positive or negative. In positive cases this new human will be capable of a special skill that is assessed positively, for example, in sports or science. In negative cases, you have to deal with a syndrome or a severe disability, as in this case the 1q21.1 CNVs. [ citation needed ]


Based on the meiotic process, the syndrome may occur in two ways.


Due to this genetic misprint the embryo may experience problems in the development during the first months of pregnancy. Approximately 20 to 40 days after fertilization, something goes wrong in the construction of the body parts and brain, which leads to a chain reaction.


Because of the repetitions in 1q21.1, there is a larger chance on an unequal crossing-over during  meiosis .


Genes related to the proximal area are  HFE2 ,  TXNIP ,  POLR3GL ,  LIX1L ,  RBM8A ,  PEX11B ,  ITGA10 ,  ANKRD35 ,  PIAS3 ,  NUDT17 ,  POLR3C ,  RNF115 ,  CD160 ,  PDZK1 , and  GPR89A
Genes related to the distal area are  PDE4DIP ,  HYDIN2 ,  PRKAB2 ,  PDIA3P ,  FMO5 ,  CHD1L ,  BCL9 ,  ACP6 ,  GJA5 ,  GJA8 ,  NBPF10 ,  GPR89B ,  GPR89C ,  PDZK1P1  and  NBPF11 .


1q21.1 deletion syndrome  is a rare aberration of  chromosome 1 . A human cell has one pair of identical chromosomes on  chromosome 1 . With the 1q21.1 deletion syndrome, one chromosome of the pair is not complete, because a part of the sequence of the chromosome is missing. One chromosome has the normal length and the other is too short.


In 1q21.1, the '1' stands for chromosome 1, the 'q' stands for the long arm of the chromosome and '21.1' stands for the part of the long arm in which the deletion is situated.


The syndrome is a form of the  1q21.1 copy number variations , and it is a deletion in the distal area of the 1q21.1 part. The  CNV  leads to a very variable  phenotype , and the manifestations in individuals are quite variable. Some people who have the syndrome can function in a normal way, while others have symptoms of intellectual impairment and various physical anomalies. [ 1 ]


1q21.1 microdeletion is a very rare chromosomal condition. Only 46 individuals with this deletion have been reported in medical literature as of August 2011. [ 3 ]


Approximately 75% of all children with a 1q21.1 microdeletion exhibit  delayed development , notably in  motor skills  such as sitting, standing, and walking. [ 1 ]  Individuals may have generalized mild  learning difficulties ;  about 30% of those diagnosed with 1q21.1 deletion syndrome are affected. [ 4 ]


Dysmorphic craniofacial  traits are common, however, they are highly varied and thus difficult to identify.  Microcephaly  has been reported in 39% of those with the 1q21.1 deletion. [ 4 ] [ 2 ]


It is not clear whether the list of symptoms is complete. Very little information is known about the syndrome. The syndrome can have completely different effects on members of the same family. [ 1 ] [ 4 ]


Genitourinary  abnormalities include  vesicoureteral reflux ,  hydronephrosis ,  inguinal hernia ,  cryptorchidism , and  genital malformations . There have been two reported cases of  Mayer-Rokitansky-Kuster-Hauser syndrome  alongside 1q21.1 deletion syndrome. [ 6 ] [ 4 ] [ 1 ]


The majority of affected people have normal  neurologic  physical examinations, however  hypotonia  and  tremors  are quite common.  Seizures  affect roughly 16% of children and typically begin during infancy. [ 1 ] [ 4 ]


Possible psychiatric and behavioral abnormalities include  autism spectrum disorder ,  attention deficit hyperactivity disorder , and  mood disorders . Furthermore, distal 1q21.1 microdeletions have been found in 0.2%-0.6% of those with  schizophrenia . [ 4 ] [ 7 ]


A common deletion is between 1.0-1.9Mb. Mefford states that the standard for a deletion is 1.35Mb. [ 8 ]


1q21.1 deletion is  autosomal dominant , with 18%-50% of deletions developing  de novo  and 50%-82%  inherited  from a parent. [ 4 ] [ 1 ]


The majority of affected individuals are missing a 1.35 million  DNA   base pair sequence , also written as 1.35  megabases  (Mb), in the q21.1 region of  chromosome 1 , though the exact size of the deleted region differs. This deletion affects one of each cell's two copies of  chromosome 1 . [ 1 ]


The symptoms caused by a 1q21.1 microdeletion are most likely due to the loss of many  genes  in this region. Researchers are attempting to determine which missing genes may contribute to 1q21.1 deletions' specific characteristics. Because some people with a 1q21.1 microdeletion have no clear associated traits, it is hypothesized that additional  genetic  and  environmental factors  influence the development of symptoms. [ 1 ]


Due to this genetic misprint, the  embryo  may experience problems in the development during the first months of pregnancy. Approximately 20 to 40 days after  fertilization , something goes wrong in the construction of the body parts and brain, which leads to a chain reaction. [ 9 ]


The recurring distal 1.35-Mb  heterozygous  deletion within the position of 145–146.35 Mb in the reference  genome  confirms the diagnosis of 1q21.1 deletion. The  copy number  of sequences can be determined using  chromosome microarrays  or targeted deletion analysis by  fluorescence in situ hybridization . [ 4 ]


22q11.2 microdeletion  shares several characteristics with 1q21.1 microdeletion including  developmental delays ,  learning disabilities ,  intellectual disability , and  behavioral deviations . Those with recurrent 1q21.1 microdeletion, on the other hand, do not have the distinctive facial traits seen in the  22q11.2  microdeletion syndrome. [ 4 ] [ 5 ]


Several examinations should be performed to determine the level of  disability  and the needs of a person with the 1q21.1 deletion. Because of the vast range of symptoms,  ophthalmologic ,  cardiac ,  developmental ,  neurological , and  psychiatric  evaluations may be helpful in identifying the manifestations of 1q21.1 deletion. Different developmental abnormalities of the  skull  and  genitourinary system  can be identified with  brain imaging  and  renal ultrasounds . Consultations with a  medical geneticist  or  genetic counselor  can aid in determining the cause of 1q21.1 deletion. [ 4 ]


Because of the variability in 1q21.1 deletion, management is dependent on specific symptoms.  Occupational  and  physical therapy , as well as special learning programs, may be used to manage symptoms. [ 4 ]


Nonallelic homologous recombination  (NAHR), mediated by  low copy repeats  (LCRs), is a well-known mechanism of  copy number alterations  in an array of  genomic diseases . Individually, these conditions are uncommon, yet collectively, they impact a significant portion of the population. 1q21.1 deletions are estimated to occur in about 0.015% of the population. However, these  CNVs  are incompletely  penetrant , therefore it is likely that the actual prevalence in the general population is greater than the current predictions. [ 5 ]


Statistical research showed that schizophrenia is more common in combination with 1q21.1 deletion syndrome. On the other side, autism is significantly more common with  1q21.1 duplication syndrome . Further research confirmed that the odds on a relation between schizophrenia and deletions at 1q21.1,  3q29 , 15q13.3, 22q11.21 en Neurexin 1 (NRXN1) and duplications at 16p11.2 are at 7.5% or higher. [ 10 ] [ 11 ]


Common variations in the BCL9 gene, which is in the distal area, confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder. [ 12 ]


Research is done on 10–12 genes on 1q21.1 that produce  DUF1220 -locations. DUF1220 is an unknown  protein , which is active in the  neurons  of the  brain  near the  neocortex . Based on research on  apes  and other  mammals , it is assumed that DUF1220 is related to cognitive development (man: 212 locations; chimpanzee: 37 locations; monkey: 30 locations; mouse: 1 location). It appears that the DUF1220-locations on 1q21.1 are in areas that are related to the size and the development of the brain. The aspect of the size and development of the brain is related to autism ( macrocephaly ) and schizophrenia ( microcephaly ). It has been proposed that a deletion or duplication of a gene that produces DUF1220-areas might cause growth and development disorders in the brain [ 13 ]


Another relation between  macrocephaly  with duplications and  microcephaly  with deletions has been seen in research on the HYDIN Paralog or HYDIN2. This part of 1q21.1 is involved in the development of the brain. It is assumed to be a dosage-sensitive gene. When this gene is not available in the 1q21.1 area, it leads to microcephaly. HYDIN2 is a recent duplication (found only in humans) of the HYDIN gene found on 16q22.2. [ 14 ]
Research on the genes  CHD1L  and  PRKAB2  within  lymphoblast  cells [ 15 ]  lead to the conclusion that anomalies appear with the 1q21.1-deletion syndrome:


GJA5 has been identified as the gene that is responsible for the phenotypes observed with congenital heart diseases on the 1q21.1 location. In case of a duplication of GJA5  tetralogy of Fallot  is more common. In case of a deletion other congenital heart diseases than tetralogy of Fallot are more common. [ 16 ]


The  partial thromboplastin time  ( PTT ), also known as the  activated partial thromboplastin time  ( aPTT  or  APTT ), is a  blood test  that characterizes  coagulation  of the  blood . A historical name for this measure is the  Kaolin-cephalin clotting time  ( KCCT ), [ 1 ]  reflecting  kaolin  and  cephalin  as materials historically used in the test. Apart from detecting abnormalities in blood clotting, [ 2 ]  partial thromboplastin time is also used to monitor the treatment effect of  heparin , a widely prescribed  drug that reduces blood's tendency to clot .


The PTT measures the overall speed at which blood clots form by means of two consecutive series of biochemical reactions known as the  intrinsic  pathway  and  common pathway  of  coagulation . The PTT indirectly measures action of the following  coagulation factors :  I (fibrinogen) ,  II (prothrombin) ,  V (proaccelerin) ,  VIII (anti-hemophilic factor) ,  X (Stuart–Prower factor) ,  XI (plasma thromboplastin antecedent) , and  XII (Hageman factor) . The PTT is often used in conjunction with another measure of how quickly blood clotting takes place called the  prothrombin time  (PT). The PT measures the speed of clotting by means of the  extrinsic  pathway  and  common pathway .


Activated partial thromboplastin time (APTT) is typically analyzed by a medical technologist or laboratory technician, either manually or using an automated instrument at 37°C, which approximates normal human body temperature.  Prothrombin time  utilizes complete  thromboplastin , a combination of  tissue factor  and  phospholipids . In contrast, APTT employs partial thromboplastin, containing only phospholipids and no tissue factor—hence the term "partial thromboplastin time." An activator is used in the APTT test to initiate the intrinsic pathway of blood coagulation. Common activators include kaolin, silica, celite, and ellagic acid. [ 3 ]


The typical  reference range  is between 25  seconds  and 33 s (depending on laboratory). Longer times of up to 50 s do apply to infants. Shortening of the PTT is considered to have little clinical relevance, but some research indicates that it might increase risk of  thromboembolism . [ 4 ]  Normal PTT requires the presence of the following coagulation factors: I, II, V, VIII, IX, X, XI and XII. Notably, deficiencies in factors VII or XIII will not be detected with the PTT test. [ citation needed ]


Prolonged aPTT may indicate: [ 5 ]


To distinguish the above causes,  mixing tests  are performed, in which the patient's plasma is mixed (initially at a 50:50 dilution) with normal plasma. If the abnormality does not disappear, the sample is said to contain an "inhibitor" (either heparin, antiphospholipid antibodies or coagulation factor specific inhibitors), while if it does disappear a factor deficiency is more likely. Deficiencies of  factors VIII ,  IX ,  XI  and  XII  and rarely  von Willebrand factor  (if causing a low factor VIII level) may lead to a prolonged aPTT correcting on mixing studies.


The aPTT is usually normal in  pregnancy  but tends to slightly decrease in late pregnancy. [ 6 ]


The aPTT-based  activated protein C  (APC) resistance test is used in the diagnosis of  APC resistance  (APCR). [ 7 ]  It involves a modified aPTT test performed in the presence and absence of APC. [ 7 ] [ 8 ]  The ratio of these aPTT values is calculated and is called the APC sensitivity ratio (APCsr) or simply APC ratio (APCr). [ 7 ] [ 8 ]  This ratio is inversely related to the degree of APC resistance. [ 9 ]  The aPTT-based APC resistance test was developed in 1993. [ 8 ]


The partial thromboplastin time was first described in 1953 by researchers at the  University of North Carolina at Chapel Hill . [ 10 ]  The initial exogenous phospholipid used in PTT testing was  Cephalin . [ 11 ]


Agglutination  is the clumping of particles.  The word  agglutination  comes from the  Latin   agglutinare  (glueing to).


Agglutination is a reaction in which particles (as red blood cells or bacteria) suspended in a liquid collect into clumps usually as a response to a specific antibody.


This occurs in biology in two main examples:


Hemagglutination  is the process by which  red blood cells  agglutinate, meaning clump or clog. The agglutin involved in hemagglutination is called  hemagglutinin .  In  cross-matching ,  donor  red blood cells and the recipient's serum or plasma are incubated together.  If agglutination occurs, this indicates that the donor and recipient blood types are  incompatible .


When a person produces  antibodies  against their own red blood cells, as in  cold agglutinin disease  and other  autoimmune  conditions, the cells may agglutinate spontaneously. [ 1 ]  This is called  autoagglutination  and it can interfere with laboratory tests such as  blood typing  and the  complete blood count . [ 2 ] [ 3 ]


Leukoagglutination occurs when the particles involved are  white blood cells .


An example is the PH-L form of  phytohaemagglutinin .


Agglutination is commonly used as a method of identifying specific bacterial antigens and the identity of such bacteria, and therefore is an important technique in diagnosis.


Two bacteriologists, Herbert Edward Durham (-1945) and  Max von Gruber  (1853–1927), discovered specific agglutination in 1896. The clumping became known as Gruber-Durham reaction. Gruber introduced the term agglutinin (from the Latin) for any substance that caused agglutination of cells.


French physician Fernand Widal (1862–1929) put Gruber and Durham's discovery to practical use later in 1896, using the reaction as the basis for a test for  typhoid fever . Widal found that blood serum from a typhoid carrier caused a culture of typhoid bacteria to clump, whereas serum from a typhoid-free person did not. This  Widal test  was the first example of serum diagnosis.


Austrian physician  Karl Landsteiner  found another important practical application of the agglutination reaction in 1900. Landsteiner's agglutination tests and his discovery of ABO blood groups was the start of the science of  blood transfusion  and  serology  which has made transfusion possible and safer.


Antigen-antibody interaction,  or  antigen-antibody reaction , is a specific chemical interaction between  antibodies  produced by  B cells  of the  white blood cells  and  antigens  during  immune reaction . The antigens and antibodies combine by a process called agglutination. It is the fundamental reaction in the body by which the body is protected from complex foreign molecules, such as pathogens and their chemical toxins. In the blood, the antigens are specifically and with high affinity bound by antibodies to form an antigen-antibody complex. The immune complex is then transported to cellular systems where it can be destroyed or deactivated.


The first correct description of the antigen-antibody reaction was given by Richard J. Goldberg at the  University of Wisconsin  in 1952. [ 1 ] [ 2 ]  It came to be known as "Goldberg's theory" (of antigen-antibody reaction). [ 3 ]


There are several types of antibodies and antigens, and each antibody is capable of binding only to a specific antigen. The specificity of the binding is due to specific chemical constitution of each antibody. The  antigenic determinant  or epitope is recognized by the  paratope  of the antibody, situated at the variable region of the polypeptide chain. The variable region in turn has hyper-variable regions which are unique  amino acid sequences  in each antibody. Antigens are bound to antibodies through weak and noncovalent interactions such as  electrostatic interactions ,  hydrogen bonds ,  Van der Waals forces , and  hydrophobic interactions . [ 4 ]


The principles of specificity and cross-reactivity of the antigen-antibody interaction are useful in clinical laboratory for diagnostic purposes. One basic application is determination of ABO blood group. It is also used as a molecular technique for infection with different pathogens, such as HIV, microbes, and  helminth  parasites.


Immunity developed as an individual is exposed to antigens is called adaptive or acquired immunity, in contrast to immunity developed at birth, which is innate immunity. Acquired immunity depends upon the interaction between antigens and a group of proteins called antibodies produced by B cells of the blood. There are many antibodies and each is specific for a particular type of antigen. Thus immune response in acquired immunity is due to the precise binding of antigens to antibody. Only very small area of the antigens and antibody molecules actually interact through complementary binding sites, called epitopes in antigens and paratopes in antibody. [ 5 ]


In an antibody, the  Fab (fragment, antigen-binding) region  is formed from the amino-terminal end of both the light and heavy chains of the  immunoglobulin  polypeptide. This region, called the variable (V) domain, is composed of amino acid sequences that define each type of antibody and their binding affinity to an antigen. The combined sequence of variable light chain (V L ) and variable heavy chain (V H ) creates three hypervariable regions (HV1, HV2, and HV3). In V L  these are roughly from residues 28 to 35, from 49 to 59, and from 92 to 103, respectively. HV3 is the most variable part. Thus these regions may be part of a paratope, the part of an antibody that recognizes and binds to an antigen. The rest of the V region between the hypervariable regions are called framework regions. Each V domain has four framework domains, namely  FR1, FR2, FR3, and FR4. [ 4 ] [ 6 ]


Antibodies bind antigens through weak chemical interactions, and bonding is essentially  non-covalent .  Electrostatic interactions ,  hydrogen bonds ,  van der Waals forces , and  hydrophobic interactions  are all known to be involved depending on the interaction sites. [ 7 ] [ 8 ]  Non-covalent bonds between antibody and antigen can also be mediated by interfacial water molecules. Such indirect bonds can contribute to the phenomenon of cross-reactivity, i.e. the recognition of different but related antigens by a single antibody. [ 9 ]


Antigen and antibody interact through a high affinity binding much like lock and key. [ 10 ]  A dynamic equilibrium exists for the binding. For example, the reaction is a reversible one, and can be expressed as: [ 11 ]


where [Ab] is the  antibody  concentration and [Ag] is the  antigen  concentration, either in free ([Ab],[Ag]) or bound ([AbAg]) state.


The equilibrium association constant  K a  can therefore be represented as:


where  k on  and  k off  are the association and dissociation rate constants, respectively.


Reciprocally, the equilibibrium dissociation constant  K d  will be:


The antibody-antigen binding kinetic can be described by the rate equation of a  second-order reversible reaction . However, these equations are applicable only to a single epitope binding, i.e. one antigen on one antibody. Since the antibody necessarily has two paratopes, and in many circumstances complex binding occurs, the multiple binding equilibrium can be summed up as:


where, at equilibrium, c is the concentration of free ligand, r represents the ratio of the concentration of bound ligand to total antibody concentration and n is the maximum number of binding sites per antibody molecule (the antibody valence). [ 12 ] [ 13 ]


The overall strength of the binding of an antibody to an antigen is termed its  avidity  for that antigen. Since antibodies are bivalent or polyvalent, this is the sum of the strengths of individual antibody-antigen interactions. The strength of an individual interaction between a single binding site on an antibody and its target epitope is termed the affinity of that interaction. [ 14 ]


Avidity and affinity can be judged by the  dissociation constant  for the interactions they describe. The lower the dissociation constant, the higher the avidity or affinity, and the stronger the interaction. [ 15 ] [ 16 ]


Normally antibodies can detect and differentiate molecules from outside of the body and those produced inside the body as a result of cellular activities. Self molecules as ignored by the immune system. However, in certain conditions, the antibodies recognise self molecules as antigens and triggers unexpected immune responses. This results in different  autoimmune diseases  depending on the type of antigens and antibodies involved. Such conditions are always harmful and sometimes deadly. The exact nature of antibody-antigen interaction in autoimmune disease is not yet understood. [ 17 ] [ 18 ]


Antigen-antibody interaction is used in laboratory techniques for serological test of blood compatibility and various pathogenic infections. The most basic is  ABO blood group  determination, which is useful for  blood transfusion . [ 19 ]  Sophisticated applications include  ELISA , [ 20 ]   enzyme-linked immunospot ( Elispot ),  immunofluorescence , and  immunoelectrophoresis . [ 21 ] [ 22 ] [ 23 ]


Soluble antigens combine with soluble antibodies in presence of an electrolyte at suitable temperature and pH to form insoluble visible complex. This is called a  precipitation reaction . It is used for qualitative and quantitative determination of both antigen and antibody. It involves the reaction of soluble  antigen with soluble  antibodies to form large interlocking aggravated called lattice. [ 24 ]  It occurs in two distinct stages. Firstly, the antigen and antibody rapidly form antigen-antibody complexes within few seconds and this is followed by a slower reaction in which the antibody-antigen complexes forms lattices that precipitate from the solution. [ 25 ] [ 26 ]


A special ring test is useful for diagnosis of anthrax and determination of adulteration in food. [ 27 ] [ 28 ]


It acts on antigen-antibody reaction in which the antibodies cross-link particulate antigens resulting in the visible clumping of the particle. There are two types, namely active and passive  agglutination . [ 29 ]  They are used in blood tests for diagnosis of  enteric fever . [ 30 ] [ 31 ]


Apheresis  ( ἀφαίρεσις  ( aphairesis , "a taking away")) is a  medical technology  in which the  blood  of a person is passed through an apparatus that separates out one particular  constituent  and returns the remainder to the circulation.  It is thus an  extracorporeal  therapy.


One of the uses of apheresis is for collecting  hematopoetic stem cells . [ 1 ]


Depending on the substance that is being removed, different processes are employed in apheresis. If separation by  density  is required,  centrifugation  is the most common method. Other methods involve absorption onto beads coated with an absorbent material [ 2 ]  and filtration. [ 3 ]


The centrifugation method can be divided into two basic categories: [ 4 ]


Continuous flow centrifugation (CFC) historically required two  venipunctures  as "continuous" means the blood is collected, spun, and returned simultaneously. Newer systems can use a single venipuncture by pooling blood in a vessel and cycling through drawing and returning blood though the needle while the centrifuge continuously processes blood remaining in the vessel. [ 5 ]  The main advantage of this system is the low extracorporeal volume (calculated by volume of the apheresis chamber, the donor's  hematocrit , and total blood volume of the donor) used in the procedure, which may be advantageous in the elderly and for children. [ citation needed ]


Intermittent flow centrifugation (IFC) works in cycles, taking blood, spinning/processing it and then giving back the unused parts to the donor in a  bolus . The main advantage is a single venipuncture site. It does require a larger extracorporeal volume, and takes significantly longer to perform the procedure via IFC. As such, it is less likely to be used for therapeutic reasons, and is often seen in Donation Center settings. [ 6 ]  To stop the blood from  coagulating ,  anticoagulant  is automatically mixed with the blood as it is pumped from the body into the apheresis machine. [ 7 ]


The centrifugation process itself has four variables that can be controlled to selectively remove desired components. The first is spin speed and bowl diameter, the second is "sit time" in centrifuge, the third is solutes added, and the fourth is not as easily controllable: plasma volume and cellular content of the donor. The result in most cases is the classic sedimented blood sample with the  RBCs  at the bottom, the  buffy coat  of platelets and  WBCs  ( lymphocytes ,  granulocytes ,  monocytes ) in the middle and the plasma on top. [ 8 ]


There are numerous types of apheresis.


Blood taken from a healthy donor can be separated into its component parts during  blood donation , where the needed component is collected and the unharvested components are returned to the donor.  Fluid replacement  is usually not needed in this type of collection.  In many countries, apheresis donors can donate platelets more often than those donating whole blood. There are several categories of component collections:


Two apheresis kit recalls were:


People who do not use a drug that may prevent blood donation, who do not have the risk of the carrier of a disease, and who have suitable vascular structure may be apheresis donors. For apheresis platelet donation the donor's pre platelet count should be above 150 x 10^9/L. For apheresis plasma donation, the donor's total protein level should be greater than 60 g/L. For double red cell apheresis, donors of either gender require a minimum hemoglobin level of 14.0 g/dl. [ 16 ]


Apheresis uses plastics and tubing, which come into contact with the blood. The plastics are made of  PVC  in addition to additives such as a  plasticizer , often  DEHP . DEHP leaches from the plastic into the blood, and people have begun to study the possible effects of this leached DEHP on donors as well as transfusion recipients. [ 17 ]


The various apheresis techniques may be used whenever the removed constituent is causing severe symptoms of disease. Generally, apheresis has to be performed fairly often, and is an invasive process. It is therefore only employed if other means to control a particular disease have failed, or the symptoms are of such a nature that waiting for medication to become effective would cause suffering or risk of complications.  For autoimmune diseases in which apheresis is effective, it is used not as a standalone treatment, but rather in conjunction with therapies that reduce production of autoantibodies.


In 2023, [ 22 ]  the  American Society for Apheresis  published the 9th Special Edition of  evidence based guidelines  for the practice of Apheresis Medicine.  These guidelines are based upon a systematic review of available scientific literature.  Clinical utility for a given disease is denoted by assignment of an  ASFA Category  (I – IV).  The quality and strength of evidence are denoted by standard  GRADE  recommendations. ASFA Categories are defined as follows:


Only diseases (or mentioned special conditions thereof) with ASFA category I or II are displayed in  bold , with category I being  underlined  in addition.


When an apheresis system is used for therapy, the system is removing relatively small amounts of fluid (not more than 10.5 mL/kg body weight). That fluid must be replaced to keep correct intravascular volume. The fluid replaced is different at different institutions. If a  crystalloid  like  normal saline  (NS) is used, the infusion amount should be triple what is removed as the 3:1 ratio of normal saline for plasma is needed to keep up  oncotic pressure . Some institutions use  human serum albumin , but it is costly and can be difficult to find. Routine use of  fresh frozen plasma  (FFP) is not generally appropriate because of the dangers including citrate toxicity (from the anticoagulant),  ABO incompatibility ,  infection , and allergic reactions.  However, FFP should be used in cases of  thrombotic thrombocytopenic purpura  or patients at high risk of bleeding.


Arterial blood  is the oxygenated blood in the  circulatory system  found in the  pulmonary vein , the left chambers of the  heart , and in the  arteries . [ 1 ]  It is bright red in color, while  venous blood  is dark red in color (but looks purple through the translucent skin). It is the  contralateral  term to  venous blood . [ citation needed ]


Framed in the  cardiac cycle , often historically accredited to the  Wiggers diagram , arterial blood has just passed through the lungs and is ready to boost  oxygen  to sustain the peripheral organs. The essential difference between venous and arterial blood is the curve of the oxygen saturation of  haemoglobin . The difference in the oxygen content of the blood between the arterial blood and the venous blood is known as the  arteriovenous oxygen difference . [ citation needed ]


The  Ashby technique  is a method for determining the volume and life span of red blood cells in humans, first published by  Dr. Winifred Ashby  in 1919. [ 1 ]  The technique involves injection of compatible donor red blood cells of a different  blood group  into a recipient, followed by blood testing periodically afterwards. Differential  agglutination  of the red cells is then used to determine the number of remaining donor cells, allowing the survival rate to be determined. It does not involve  radioisotope  technology, and was the first technique to successfully establish the correct red blood cell life span. In particular,  Type O blood  is first transfused into  Type A or B  subjects. In subsequent blood samples, the patient's own A and B blood cells are removed by agglutination with either anti-A or anti-B  serum . The number of remaining nonagglutinated Type O cells as a function of time defines the survival rate of blood cells. [ 2 ]  This technique was used extensively during World War II and shortly after but has more recently been replaced by techniques that label one's own blood, due to the dangers of using donor blood. [ 3 ]


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In  hematology ,  atypical localization of immature precursors  ( ALIP ) refers to finding of atypically localized precursors ( myeloblasts  and  promyelocytes ) on  bone marrow biopsy . In healthy humans, precursors are rare and are found localized near the endosteum, and consist of 1–2 cells. In some cases of  myelodysplastic syndromes  (MDS), immature precursors might be located in the intertrabecular region and occasionally aggregate as clusters of 3–5 cells. The presence of ALIPs is associated with worse prognosis of MDS. [ 1 ]  Recently, in bone marrow sections of patients with  acute myeloid leukemia  cells similar to ALIPs were defined as ALIP-like clusters. The presence of ALIP-like clusters in AML patients within remission was reported to be associated with  early relapse of the disease. [ 2 ]


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An  azurophilic granule  is a cellular object readily  stainable  with a  Romanowsky stain .  In  white blood cells  and  hyperchromatin , staining imparts a  burgundy  or merlot coloration.  Neutrophils  in particular are known for containing azurophils loaded with a wide variety of anti-microbial  defensins  that fuse with  phagocytic   vacuoles .  Azurophils may contain  myeloperoxidase ,  phospholipase A2 ,  acid hydrolases ,  elastase , defensins, neutral  serine proteases ,  bactericidal permeability-increasing protein , [ 1 ]   lysozyme ,  cathepsin G ,  proteinase 3 , and  proteoglycans . [ citation needed ]


Azurophil granules are also known as "primary granules". [ 2 ]


Furthermore, the term "azurophils" may refer to a unique type of cells, identified only in  reptiles .  These cells are similar in size to so-called  heterophils  with abundant  cytoplasm  that is finely to coarsely granular and may sometimes contain vacuoles.  Granules may impart a purplish hue to the cytoplasm, particularly to the outer region.  Occasionally, azurophils are observed with vacuolated cytoplasm. [ 3 ]


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4U0Q ,  3B5H ,  3I84 ,  3I85 ,  3QQN ,  3QR2


NM_001728 NM_198589 NM_198590 NM_198591 NM_001322243


NM_001077184 NM_009768


NP_001309172 NP_001719 NP_940991 NP_940992 NP_940993


NP_001070652 NP_033898


Basigin  ( BSG ) also known as  extracellular matrix metalloproteinase inducer  ( EMMPRIN ) or  cluster of differentiation 147  ( CD147 ) is a  protein  that in humans is encoded by the  BSG   gene . [ 5 ] [ 6 ] [ 7 ]  This protein is a determinant for the Ok  blood group system . There are three known antigens in the Ok system; the most common being Ok a  (also called OK1), OK2 and OK3. Basigin has been shown to be an essential receptor on red blood cells for the human malaria parasite,  Plasmodium falciparum . [ 8 ]  The common isoform of basigin (basigin-2) has two immunoglobulin domains, and the extended form basigin-1 has three. [ 9 ]


Basigin is a member of the  immunoglobulin superfamily , with a structure related to the putative primordial form of the family. As members of the immunoglobulin superfamily play fundamental roles in intercellular recognition involved in various immunologic phenomena, differentiation, and development, basigin is thought also to play a role in intercellular recognition (Miyauchi et al., 1991; Kanekura et al., 1991). [ 10 ] [ 11 ]


It has a variety of functions. In addition to its metalloproteinase-inducing ability, basigin also regulates several distinct functions, such as  spermatogenesis , expression of the  monocarboxylate transporter  and the responsiveness of  lymphocytes . [ 6 ]
Basigin is a type I  integral membrane receptor  that has many  ligands , including the  cyclophilin  (CyP) proteins Cyp-A and CyP-B and certain  integrins . [ 12 ] [ 13 ] [ 14 ]  Basigin also serves as a receptor for S100A9 and platelet glycoprotein VI, and basigin-1 acts as a receptor for the rod-derived cone viability factor. [ 9 ]  It is expressed by many cell types, including  epithelial cells ,  endothelial cells , neural progenitor cells [ 15 ]  and  leukocytes . The human basigin protein contains 269 amino acids that form two heavily  glycosylated   C2 type immunoglobulin-like domains  at the N-terminal extracellular portion. A second form of basigin has also been characterized that contains one additional immunoglobulin-like domain in its extracellular portion. [ 6 ]


Basigin has been shown to  interact  with  Ubiquitin C . [ 16 ]


Basigin has been shown to form a complex with  monocarboxylate transporters  in the retina of mice. Basigin appears to be required for proper placement of MCTs in the membrane.  In the Basigin  null mouse , the failure of MCTs to integrate with the membrane may be directly linked to a failure of nutrient transfer in the retinal pigmented epithelium (the lactates transported by MCTs 1, 3, and 4 are essential nutrients for the developing RPE), resulting in loss of sight in the null animal. [ 17 ]


Basigin interacts with the fourth  C-type lectin [ circular reference ]  domain in the receptor  Endo180 [ 18 ]  to form a molecular  epithelial-mesenchymal transition [ citation needed ]  suppressor complex that if disrupted results in the induction of invasive prostate epithelial cell behavior associated with poor prostate cancer survival. [ 19 ]


It have been shown that  Atorvastatin  suppresses CD147 and  MMP-3  expression. [ 20 ] [ 21 ]


It has recently (November 2011) been found that basigin is a receptor that is essential to erythrocyte invasion by most strains of  Plasmodium falciparum , the most virulent species of the  plasmodium  parasites that cause human  malaria .  It is hoped that by developing antibodies to the parasite ligand for Basigin,  Rh5 , a better vaccine for malaria might be found. [ 8 ]  Basigin is bound by the PfRh5 protein on the surface of the malaria parasite. [ citation needed ]


Meplazumab , an anti-CD147 antibody, was tested in patients with SARS-CoV-2 pneumonia. [ 22 ]


Some of these claims have been challenged by another group of scientists who found no evidence of a direct role for basigin in either binding the viral spike protein or promoting lung cell infection. [ 23 ]


More recent studies suggests CD147 as SARS-CoV-2 entry receptor of  platelets  and  megakaryocytes , leading to hyperactivation and thrombosis, that differs from common cold coronavirus  CoV-OC43 . Incubation of megakaryocyte cells with SARS-CoV-2 resulted in a significant increase in the proinflammatory transcripts  LGALS3BP  and  S100A9 . Notably, CD147 antibody-mediated blocking significantly reduced the expression of  S100A9 , and  S100A8  on megakaryocytes following incubation with SARS-CoV-2. These data indicate that megakaryocytes and platelets actively take up SARS-CoV-2 virions, likely via an  ACE-2 -independent mechanism. [ 24 ]


Another study states that platelets challenged with SARS-CoV-2 undergo activation, dependent on the CD147 receptor. [ 25 ]  Yet SARS-CoV-2 does not replicate in human platelets, but initiates cell death. [ 26 ]


Yet another study describes high-interaction coupling of N-RBD of SARS-CoV-2 and CD147 as the main way of infecting  lymphocytes  allegedly leading to  Acquired Immune Deficiency Syndrome . [ 27 ]


Bence Jones protein  is a monoclonal  globulin   protein  or  immunoglobulin light chain  found in the  urine , with a molecular weight of 22–24  kDa . [ 1 ]    Detection of Bence Jones protein may be suggestive of  multiple myeloma , [ 2 ]  or  Waldenström's macroglobulinemia . [ citation needed ]


Bence Jones proteins are particularly diagnostic of multiple myeloma in the context of target organ manifestations such as  kidney failure , lytic (or "punched out") bone lesions,  anemia , or large numbers of  plasma cells  in the  bone marrow .  Bence Jones proteins are present in 2/3 of multiple myeloma cases. [ 3 ]


The proteins are  immunoglobulin light chains  ( paraproteins ) and are produced by  neoplastic  plasma cells. They can be kappa (most of the time) or lambda. [ 3 ]  The light chains can be immunoglobulin fragments or single homogeneous immunoglobulins. They are found in urine as a result of decreased kidney filtration capabilities due to  kidney failure , sometimes induced by  hypercalcemia  from the calcium released as the bones are destroyed, dehydration due to polyuria, amyloidosis or from the light chains themselves. [ citation needed ]  The light chains were historically detected by heating a  urine  specimen (which causes the protein to precipitate) and nowadays by  electrophoresis  of concentrated urine. [ 4 ]   More recently,  serum free light chain assays  have been utilised in a number of published studies which have indicated superiority over the urine tests, particularly for patients producing low levels of monoclonal free light chains, as seen in nonsecretory multiple myeloma [ 5 ] [ 6 ] [ 7 ]  and  amyloid light chain amyloidosis (AL amyloidosis) . [ 7 ] [ 8 ] [ 9 ] [ 10 ]


The Bence Jones protein was described by the English physician  Henry Bence Jones  in 1847 and published in 1848. [ 11 ]


β-Thromboglobulin  ( β-TG ), or  beta-thromboglobulin , is a  chemokine   protein  secreted by  platelets . [ 1 ] [ 2 ]  It is a type of  chemokine (C-X-C motif) ligand 7 . [ 3 ]  Along with  platelet factor 4  (PF4), β-TG is one of the best-characterized platelet-specific proteins. [ 4 ]  β-TG and PF4 are stored in  platelet alpha granules  and are released during  platelet activation . [ 1 ] [ 4 ] [ 5 ]  As a result, they are useful markers of platelet activation. [ 1 ] [ 4 ]  β-TG also has multiple  biological activities , for instance being involved in maturation of  megakaryocytes . [ 6 ]


β-TG is a  chemoattractant , strongly for  fibroblasts  and weakly for  neutrophils . It is a stimulator of  mitogenesis ,  extracellular matrix  synthesis,  glucose metabolism , and  plasminogen activator  synthesis in human fibroblasts. [ 5 ]


β-TG also affects  megakaryocyte  maturation, and thus helps in regulating  platelet  production. [ 5 ]


Levels of β-TG is used to index platelet activation. It is measured by  ELISA  in  blood plasma  or urine, and often in conjunction with PF4. [ 5 ]


β-TG levels may increase with age. [ 7 ]  It is elevated in  diabetes mellitus . [ 8 ]


β-TG levels have been found to be increased by treatment with the  synthetic   estrogen   ethinylestradiol , though were not significantly increased by the  natural  estrogen  estradiol valerate . [ 9 ] [ 10 ] [ 11 ] [ 12 ]  Levels of β-TG have also been found to be increased or unchanged during normal  pregnancy . [ 13 ]


This  biochemistry  article is a  stub . You can help Wikipedia by  expanding it .


Bilirubin glucuronide  is a water-soluble  reaction intermediate  over the process of  conjugation  of indirect  bilirubin . [ 1 ]  Bilirubin  glucuronide  itself belongs to the category of conjugated bilirubin along with  bilirubin di-glucuronide . [ 2 ]  However, only the latter one is primarily excreted into the bile in the normal setting. [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 1 ]


Upon  macrophages  spot and  phagocytize  the effete  Red Blood Corpuscles  containing  hemoglobin , [ 6 ]  unconjugated bilirubin is discharged from macrophages into the blood plasma. [ 7 ] [ 8 ]  Most often, the free and water-insoluble unconjugated bilirubin which has an internal hydrodren [ clarification needed ]  bonding [ 9 ]  will bind to  albumin  and, to a much lesser extent, high density  lipoprotein  in order to decrease its  hydrophobicity  and to limit the probability of unnecessary contact with other tissues [ 1 ] [ 9 ]  and keep bilirubin in the vascular space from traversing to extravascular space including  brain , and from ending up increasing  glomerular filtration . [ 9 ]  Nevertheless, there is still a little portion of indirect bilirubins stays free-of-bound. [ 9 ]  Free unconjugated bilirubin can poison the  cerebrum . [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ]


Finally, albumin leads the indirect bilirubin to the  liver . [ 1 ] [ 9 ]  In the  liver sinusoid , albumin disassociates with the indirect bilirubin and returns to the circulation while the  hepatocyte  transfers the indirect bilirubin to  ligandin  and  glucuronide  conjugates the indirect bilirubin in the  endoplasmic reticulum  by disrupting unconjugated bilirubin's internal  hydrogen bonding , which is the thing that makes indirect bilirubin having the property of eternal half-elimination life and insoluble in water, [ 20 ] [ 9 ] [ 1 ] [ 21 ] [ 22 ]  and by attaching two molecules of  glucuronic acid  to it in a two step process. [ 23 ]  The reaction is  a transfer of two glucuronic acid groups  including  UDP glucuronic acid  sequentially to the  propionic acid  groups of the bilirubin, primarily catalyzed by  UGT1A1 . [ 23 ] [ 24 ] [ 5 ]  In greater detail about this reaction, a glucuronosyl moiety is conjugated to one of the  propionic acid  side chains, located on the C8 and C12 carbons of the two central  pyrrole rings  of bilirubin. [ 25 ]


When the first step is completely done, the  substrate  bilirubin glucuronide (also known as mono- glucuronide [ 26 ] ) is born at this stage and is water-soluble and readily excreted in  bile . [ 24 ] [ 9 ]  Thereafter, so long as the second step of attachment of the other glucuronic acid to it succeeds (officially called "re- glucuronidated " [ 26 ] ), the substrate bilirubin glucuronide will turn into bilirubin  di -glucuronide (8,12-diglucuronide [ 26 ] ) and be excreted into  bile canaliculi  by way of  C-MOAT [ note 1 ]   [ 27 ] [ 28 ] [ 29 ] [ 30 ]  and  MRP2 [ 5 ] [ 31 ]  as normal human bile along with a little amount of unconjugated bilirubin as much as only 1 to 4 percent of total  pigments  in normal bile. [ 9 ] [ 32 ]  That means up to 96%-99% of bilirubin in the bile are conjugated. [ 9 ] [ 1 ]


Normally, there is just a little conjugated bilirubin escapes into the general circulation. [ 1 ]  Nonetheless, in the setting of severe  liver disease , a significantly greater number of conjugated bilirubin will leak into circulation and then dissolve into the  blood [ note 2 ]  and thereby filtered by the  kidney , and only a part of the leaked conjugated bilirubin will be re-absorbed in the  renal tubules , the remainder will be present in the  urine  making it dark-colored. [ 1 ] [ 3 ]


The clinical significance of bilirubin glucuronide is involved in many conditions. Drugs that inhibit the activities of the components involved in bilirubin metabolism can give rise to accumulation of bilirubin in the blood. [ 5 ]  In comparison, conjugation of some drugs is also usually impaired if the liver cannot normally  metabolize  indirect bilirubin. [ 5 ]


When  excretion of bilirubin glucuronide by the kidney  is detected in the  urine  through urine examination, meaning that a conspicuous amount of conjugated bilirubin is present and circulating in the blood. [ 3 ]


In  Dubin–Johnson syndrome , impaired biliary excretion of bilirubin glucuronide is due to a mutation in the canalicular  multiple drug-resistance protein 2 (MRP2) . A darkly pigmented liver is due to polymerized  epinephrine   metabolites , not bilirubin. [ 33 ]


If it is the liver that cannot effectively transfer the indirect bilirubin into bilirubin glucuronide and further into bilirubin di-glucuronide, the consequence will be  hyperbilirubinemia  or  intrahepatic (or hepatocellular) jaundice . [ 3 ]


Moreover, the  unconjugated hyperbilirubinemia  arises in case the components of liver transfer the indirect bilirubin into bilirubin glucuronide in the rate  slower  than they should be. [ 3 ]  This condition is associated with either decreased uptake of bilirubin into  hepatocytes  ( Rotor syndrome [ 34 ] ) or defective intracellular protein binding. [ 3 ]


In similar fashion, the  conjugated hyperbilirubinemia  emerges in case the components of the liver have difficulty turning bilirubin glucuronide into bilirubin di-glucuronide. [ 3 ]  Note that  biliary duct blockage  can also lead to  conjugated hyperbilirubinemia  but the pathophysiology is that backflow of bilirubin di-glucuronide with little indirect bilirubin and bilirubin glucuronide from bile duct through liver into blood plasma. [ 3 ] [ 35 ]  These conditions are associated with either defective intracellular protein binding (for the second time) or disturbed secretion into the  bile canaliculi  ( Dubin–Johnson syndrome [ 34 ] ). [ 3 ]


Liver failure  and  hepatitis  are the most etiological in liver-genesis  hyperbilirubinemia . [ 3 ]  In case of hyperbilirubinemia due to  intrahepatic  or  extrahepatic   bile ducts  blockage, e.g.  gallstone , the name is given as  Post-hepatic (or obstructive)  jaundice . [ 3 ]


Bilirubin concentration is not a sensitive early indicator of  liver diseases  as the liver may have reserved its capacity in removal of bilirubin to save energy and unreserved the previously reserved capacity when encountering a sudden rise of unconjugated bilirubin. [ 36 ]  In short, there is still a chance for an ill liver to get rid of excessive unconjugated bilirubin in the blood plasma, displaying a total bilirubin level that is within normal reference range. [ 36 ]


In  Crigler Najjar disease , there is an inherited deficiency of  glucuronyl transferase  resulting in high concentrations of unconjugated bilirubin appear in the plasma. [ 3 ]  Furthermore, those affected may develop  kernicterus  (deposits of pigment in the brain) that can cause  nerve degeneration . [ 3 ]


In  Gilbert's syndrome ,  glucuronyl transferase  activity is reduced by approximately 70%, leading to mild accumulation of unconjugated bilirubin in the plasma. [ 3 ]


At birth, infants don't develop enough ability to conjugate bilirubin. [ 37 ]  Up to 8% to 11% neonates will develop  hyperbilirubinemia  in the first week of their lives. [ 37 ] [ 19 ]


In  jaundice  owing to  hemolysis  (prehepatic, or  hemolytic , jaundice), the  pathophysiology  is that overproduction of bilirubin from the extravascular or intravascular hemolysis overwhelms the capacity of the liver to excrete it. [ 3 ]  The bilirubin present in the plasma is largely unconjugated in this setting as they haven't been taken up and conjugated by the liver. [ 3 ]  In this case, total serum bilirubin increases while the ratio of direct bilirubin to indirect bilirubin remains 96 to 4 as up to 96%-99% of bilirubin in the bile are conjugated mentioned above. [ 9 ] [ 1 ]


Although there were some studies that showed an  inverse correlation  between  serum  bilirubin level and prevalences of  ischemic   coronary artery disease , [ 38 ]   cancer  mortality, [ 39 ]  or  colorectal cancer [ 40 ]  in general population, the potential benefits of the chemopreventive function of bilirubin and their causative relations haven't been proved. [ 40 ] [ 9 ] [ 10 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ] [ excessive citations ]


Blood  is a  body fluid  in the  circulatory system  of  humans  and other  vertebrates  that delivers necessary substances such as  nutrients  and  oxygen  to the  cells , and transports  metabolic waste products  away from those same cells. [ 1 ]


Blood is composed of blood cells suspended in  blood plasma . Plasma, which constitutes 55% of blood fluid, is mostly  water  (92% by volume), [ 2 ]  and contains  proteins ,  glucose , mineral  ions , and  hormones . The blood cells are mainly  red blood cells  (erythrocytes),  white blood cells  (leukocytes), and (in mammals)  platelets  (thrombocytes). [ 3 ]  The most abundant cells are red blood cells. [ 4 ]  These contain  hemoglobin , which facilitates oxygen transport by reversibly binding to it, increasing its solubility. [ 5 ]   Jawed vertebrates  have an  adaptive immune system , based largely on white blood cells. White blood cells help to resist infections and parasites. Platelets are important in the  clotting  of blood.


Blood is circulated around the body through  blood vessels  by the pumping action of the  heart . In animals with  lungs ,  arterial  blood carries oxygen from inhaled air to the tissues of the body, and  venous  blood carries carbon dioxide, a waste product of  metabolism  produced by cells, from the tissues to the lungs to be exhaled. Blood is bright red when its hemoglobin is oxygenated and dark red when it is  deoxygenated . [ 6 ] [ 7 ]


Medical terms related to blood often begin with  hemo- ,  hemato- ,  haemo-  or  haemato-  from the Greek word  αἷμα  ( haima ) for "blood". In terms of  anatomy  and  histology , blood is considered a specialized form of  connective tissue , [ 8 ]  given its origin in the bones and the presence of potential molecular fibers in the form of  fibrinogen . [ citation needed ]


Blood performs many important functions within the body, including:


Blood accounts for 7% of the human body weight, [ 9 ] [ 10 ]  with an average density around 1060 kg/m 3 , very close to pure water's density of 1000 kg/m 3 . [ 11 ]  The average adult has a  blood volume  of roughly 5  litres  (11 US pt) or 1.3 gallons, [ 10 ]  which is composed of plasma and  formed elements . The formed elements are the two types of blood cell or  corpuscle  – the  red blood cells , (erythrocytes) and  white blood cells  (leukocytes), and the cell fragments called  platelets [ 12 ]  that are involved in clotting. By volume, the red blood cells constitute about 45% of whole blood, the plasma about 54.3%, and white cells about 0.7%.


Whole blood (plasma and cells) exhibits  non-Newtonian   fluid dynamics . [ specify ]


One microliter of blood contains:


45 ± 7 (38–52%) for males
42 ± 5 (37–47%) for females


Oxygenated: 98–99%
Deoxygenated: 75%


About 55% of blood is  blood plasma , a fluid that is the blood's liquid medium, which by itself is straw-yellow in color. The blood plasma volume totals of 2.7–3.0 liters (2.8–3.2 quarts) in an average human. It is essentially an  aqueous  solution containing 92% water, 8% blood plasma  proteins , and trace amounts of other materials. Plasma circulates dissolved nutrients, such as  glucose ,  amino acids , and  fatty acids  (dissolved in the blood or bound to plasma proteins), and removes waste products, such as  carbon dioxide ,  urea , and  lactic acid .


Other important  components  include:


The term  serum  refers to plasma from which the clotting proteins have been removed. Most of the proteins remaining are albumin and  immunoglobulins .


Blood pH  is regulated to stay within the narrow range of 7.35 to 7.45, making it slightly  basic  (compensation). [ 17 ] [ 18 ]  Extra-cellular fluid in blood that has a pH below 7.35 is too  acidic , whereas blood pH above 7.45 is too basic. [ 16 ]  A pH below 6.9 or above 7.8 is usually lethal. [ 16 ]  Blood pH,  partial pressure of oxygen (pO 2 ) ,  partial pressure of carbon dioxide (pCO 2 ) , and  bicarbonate  (HCO 3 − ) are carefully regulated by a number of  homeostatic mechanisms , which exert their influence principally through the  respiratory system  and the  urinary system  to control the  acid–base balance  and respiration, which is called compensation. [ 16 ]  An  arterial blood gas test  measures these. Plasma also circulates  hormones  transmitting their messages to various tissues. The list of normal  reference ranges  for various blood electrolytes is extensive.


Human blood is typical of that of mammals, although the precise details concerning cell numbers, size,  protein structure , and so on, vary somewhat between species. In non-mammalian vertebrates, however, there are some key differences: [ 19 ]


Blood is circulated around the body through  blood vessels  by the pumping action of the  heart . In humans, blood is pumped from the strong  left ventricle  of the heart through  arteries  to peripheral  tissues  and returns to the right  atrium of the heart  through  veins . It then enters the right  ventricle  and is pumped through the  pulmonary artery  to the  lungs  and returns to the left atrium through the  pulmonary veins . Blood then enters the left ventricle to be circulated again. Arterial blood carries oxygen from inhaled air to all of the cells of the body, and  venous blood  carries carbon dioxide, a waste product of  metabolism  by  cells , to the lungs to be exhaled. However, one exception includes pulmonary arteries, which contain the most deoxygenated blood in the body, while the pulmonary veins contain oxygenated blood.


Additional return flow may be generated by the movement of  skeletal muscles , which can compress veins and push blood through the valves in veins toward the  right atrium .


The blood circulation was famously described by  William Harvey  in 1628. [ 20 ]


In vertebrates, the various cells of blood are made in the  bone marrow  in a process called  hematopoiesis , which includes  erythropoiesis , the production of red blood cells; and  myelopoiesis , the production of white blood cells and platelets. During childhood, almost every human bone produces red blood cells; as adults, red blood cell production is limited to the larger bones: the bodies of the vertebrae, the breastbone (sternum), the ribcage, the pelvic bones, and the bones of the upper arms and legs. In addition, during childhood, the  thymus  gland, found in the  mediastinum , is an important source of  T lymphocytes . [ 21 ]
The proteinaceous component of blood (including clotting proteins) is produced predominantly by the  liver , while hormones are produced by the  endocrine glands  and the watery fraction is regulated by the  hypothalamus  and maintained by the  kidney .


Healthy  erythrocytes  have a plasma life of about 120 days before they are degraded by the  spleen , and the  Kupffer cells  in the liver. The liver also clears some proteins, lipids, and amino acids. The kidney actively secretes waste products into the  urine .


About 98.5% [ 22 ]  of the  oxygen  in a sample of arterial blood in a healthy human breathing air at sea-level pressure is chemically combined with the  hemoglobin . About 1.5% is physically dissolved in the other blood liquids and not connected to hemoglobin. The hemoglobin molecule is the primary transporter of oxygen in  mammals  and many other species. Hemoglobin has an oxygen binding capacity between 1.36 and 1.40 ml O 2  per gram hemoglobin, [ 23 ]  which increases the total  blood oxygen capacity  seventyfold, [ 24 ]  compared to if oxygen solely were carried by its solubility of 0.03 ml O 2  per liter blood per mm Hg partial pressure of oxygen (about 100 mm Hg in arteries). [ 24 ]


With the exception of pulmonary and  umbilical arteries  and their corresponding veins, arteries carry  oxygenated blood  away from the heart and deliver it to the body via  arterioles  and  capillaries , where the oxygen is consumed; afterwards,  venules  and veins carry  deoxygenated blood  back to the heart.


Under normal conditions in adult humans at rest, hemoglobin in blood leaving the lungs is about 98–99%  saturated with oxygen , achieving an oxygen delivery between 950 and 1150 ml/min [ 25 ]  to the body. In a healthy adult at rest, oxygen consumption is approximately 200–250 ml/min, [ 25 ]  and deoxygenated blood returning to the lungs is still roughly 75% [ 26 ] [ 27 ]  (70 to 78%) [ 25 ]  saturated. Increased oxygen consumption during sustained exercise reduces the oxygen saturation of venous blood, which can reach less than 15% in a trained athlete; although breathing rate and blood flow increase to compensate, oxygen saturation in arterial blood can drop to 95% or less under these conditions. [ 28 ]  Oxygen saturation this low is considered dangerous in an individual at rest (for instance, during surgery under anesthesia). Sustained hypoxia (oxygenation less than 90%), is dangerous to health, and severe hypoxia (saturations less than 30%) may be rapidly fatal. [ 29 ]


A  fetus , receiving oxygen via the  placenta , is exposed to much lower oxygen pressures (about 21% of the level found in an adult's lungs), so fetuses produce another form of hemoglobin with a much higher affinity for oxygen ( hemoglobin F ) to function under these conditions. [ 30 ]


CO 2  is carried in blood in three different ways. (The exact percentages vary depending whether it is arterial or venous blood). Most of it (about 70%) is converted to bicarbonate ions  HCO − 3  by the enzyme  carbonic anhydrase  in the red blood cells by the reaction  CO 2  + H 2 O  →  H 2 CO 3   →  H +  + HCO − 3 ; about 7% is dissolved in the plasma; and about 23% is bound to hemoglobin as  carbamino  compounds. [ 31 ] [ 32 ]


Hemoglobin, the main oxygen-carrying molecule in red blood cells, carries both oxygen and carbon dioxide. However, the CO 2  bound to hemoglobin does not bind to the same site as oxygen. Instead, it combines with the N-terminal groups on the four globin chains. However, because of  allosteric  effects on the hemoglobin molecule, the binding of CO 2  decreases the amount of oxygen that is bound for a given partial pressure of oxygen. The decreased binding to carbon dioxide in the blood due to increased oxygen levels is known as the  Haldane effect , and is important in the transport of carbon dioxide from the tissues to the lungs. A rise in the partial pressure of CO 2  or a lower pH will cause offloading of oxygen from hemoglobin, which is known as the  Bohr effect .


Some oxyhemoglobin loses oxygen and becomes deoxyhemoglobin. Deoxyhemoglobin binds most of the hydrogen ions as it has a much greater affinity for more hydrogen than does oxyhemoglobin.


In mammals, blood is in equilibrium with  lymph , which is continuously formed in tissues from blood by capillary ultrafiltration. Lymph is collected by a system of small lymphatic vessels and directed to the  thoracic duct , which drains into the left  subclavian vein , where lymph rejoins the systemic blood circulation.


Blood circulation transports heat throughout the body, and adjustments to this flow are an important part of  thermoregulation . Increasing blood flow to the surface (e.g., during warm weather or strenuous exercise) causes warmer skin, resulting in faster heat loss. In contrast, when the external temperature is low, blood flow to the extremities and surface of the skin is reduced and to prevent heat loss and is circulated to the important organs of the body, preferentially.


Rate of blood flow varies greatly between different organs. Liver has the most abundant blood supply with an approximate flow of 1350 ml/min. Kidney and brain are the second and the third most supplied organs, with 1100 ml/min and ~700 ml/min, respectively. [ 33 ]


Relative rates of blood flow per 100 g of tissue are different, with kidney, adrenal gland and thyroid being the first, second and third most supplied tissues, respectively. [ 33 ]


The restriction of blood flow can also be used in specialized tissues to cause engorgement, resulting in an  erection  of that tissue; examples are the  erectile tissue  in the  penis  and  clitoris .


Another example of a hydraulic function is the  jumping spider , in which blood forced into the legs under pressure causes them to straighten for a powerful jump, without the need for bulky muscular legs. [ 34 ]