DoDSR inventory data and related information are stored in an  Oracle  database referred to as the  Defense Medical Surveillance System  (DMSS), [ 20 ]  which serves as the "sole link" to the DoDSR inventory. [ 21 ]  Serum specimens are identified by a unique  specimen identification number , [ 22 ]  which for the majority of specimens are linked to the  Social Security Number  of the donor, [ 21 ]  and the date the specimen was obtained.


In addition to inventory data, DMSS also integrates select medical outcomes data available through the  Military Health System  (MHS), including  International Classification of Diseases, 9th Edition, Clinical Modification  (ICD-9CM)  diagnosis  codes,  Current Procedural Terminology  (CPT) codes, and other pertinent administrating data from inpatient and outpatient encountered provided directly by the MHS or through   Tricare   managed care  services.


Active duty  component service members (unlike service members in the  Reserve components ), are entitled to free (or nearly free) health care for the duration of their military service, the details of which are captured electronically in DMSS.  The active duty component thus constitutes a cohort where health events can be assessed longitudinally with minimal  ascertainment bias . Over half of the specimens in the DoDSR are traceable to service members who have been on active duty, and 75% of active duty service members have provided three or more longitudinal specimens.


Limited additional health and personnel data linked to DoDSR specimens include records of  immunizations , overseas  deployments , military assignment data, and records from pre- and post-deployment health assessments.


Significant additional  MHS  administrative and clinical data exist which are not integrated into DMSS. These include:


Recent AFHSC solicitations have requested additional staff to address these data shortfalls. [ 19 ]


The Department of Defense, through the  Armed Forces Institute of Pathology  operates the AFIP Tissue Repository, which contains approximately 3 million case files and associated paraffin blocks, microscopic glass slides, and formalin-fixed tissue specimens from pathologic examinations occurring throughout the Military Health System. Thousands of cases are added to the repository each year. With the disestablishment of the AFIP under  Base Realignment and Closure , management of the Tissue Repository was to have been transferred to the  Uniformed Services University of the Health Sciences . [ 23 ]  However, Public Law 110-181 Section 722 [ 24 ]  directed the President to establish a Joint Pathology Center, which would subsume responsibility for the AFIP Tissue Repository. A Joint Pathology Center Working Group Concept of Operations stated that:


The JPC ... will provide maintenance/modernization of the Tissue Repository in support of the mission of the DoD and other federal agencies.


In its review of the JPC Working Group Concept of Operations, the  Defense Health Board  emphasized that:


Every effort must be pursued to guarantee that the Tissue Repository is preserved, implements world-class modernization, and is utilized appropriately. A recent independent report by  Asterand  (Detroit, MI) submitted to  Uniformed Services University of the Health Sciences  found the repository to have a commercial value of $3.0-$3.6 Billion ...


Despite the utility of linking AFIP Tissue Repository specimens to longitudinal pre-diagnostic serum available in the DoDSR, no formal linkage of the AFIP Tissue Repository inventory has yet been made to DMSS or to the DoDSR. No estimate is yet available on the potential commercial value of such a formal linkage.


Requests for access to DoDSR specimens are governed by  guidelines  developed by the Armed Forces Health Surveillance Center. According to guidelines,  " [t]he Director of the repository is solely responsible for authorizing releases of specimens from the repository." [ 25 ]


DoDSR specimens may only be released to principal investigators outside the Department of Defense for purposes of medical research if the proposed study has  "a coinvestigator who is assigned to the Department of Defense and is knowledgeable, responsible, and accountable for all aspects of the study's design and execution (including data management, analysis, interpretation, and reporting of results). " [ 26 ]


Serum from the DoDSR may be requested by clinicians within the Military Health System to aid diagnosis and guide clinical management. Serum may also be released to clinicians outside the Military Health System provided a physician in the Military Health System in the same specialty as the requestor validates the clinical relevance of the requested use prior to the release of any serum. [ 27 ]


Serum specimens from the DoDSR may be used for criminal investigations and prosecutions if directed by the  Assistant Secretary of Defense for Health Affairs . [ 28 ]


DoDSR specimens are collected without informed consent, and specimen donors are not informed of the use of their specimens in subsequent studies. Specimens retrieved by the DoDSR for use in external research studies are, with rare exceptions,  deidentified  prior to being sent to outside investigators.


A 1996  memorandum [ permanent dead link  ]  specifically stated that DoDSR specimens collected for pre- and post-deployment health surveillance  "will not be used for any genetics related testing" . [ 5 ]


As a result of clinically indicated HIV testing performed on civilians and family beneficiaries at Military Treatment Facilities (eligible for health care within the Military Health System), approximately 900,000 serum specimens from individuals not directly affiliated with the Uniformed Services through application or service are also stored in the DoDSR. [ 29 ]  In Privacy Act documentation, DoD acknowledges that the AFHSC maintains "...   specimen collections (remaining serum from blood samples) from which serologic tests can be performed   ..." from categories of individuals which include "Department of Defense military personnel (active and reserve) and their family members   ...". [ 30 ]


DoDSR guidelines are silent as to whether a mechanism exists for specimen donors to request destruction or removal of their specimens from the repository. [ 31 ]   In Privacy Act documentation, DoD states that "[r]ecords are destroyed when no longer needed for reference and for conducting business", but no formal mechanism is articulated for the destruction or specimens. [ 30 ]  This is in contrast to the  Armed Forces Institute of Pathology   DNA  Repository (also known as the Repository of Specimen Samples for the Identification of Remains) which articulates a  mechanism  for donors to request the destruction of their specimens following separation from service. [ 32 ]


On May 1, 2009, during the early stages of the  2009 H1N1 flu outbreak , an unpublished  RAND  study, originally commissioned in 2006 by  USACHPPM  was published in its entirety on  WikiLeaks . The leaked documents [ 33 ]  included a justification for the $500,000 contract cost, directly authorized by former  Surgeon General of the United States Army   Kevin C. Kiley  on August 4, 2006, which stated the study and its 12-month timetable for delivery was necessary


... to describe the current and future capabilities of the Department of Defense Serum Repository to assist with the early identification and response to an influenza pandemic. Adequate resources are not available in-house to perform these analyses in sufficient time to prepare for a pandemic ...


Despite the leaked study draft's publication date of May 2008, at the time of the leak and outbreak in May 2009, RAND listed the study as a "current project", noting in its description that "the threat of an emerging human pandemic [has] highlighted the importance of a comprehensive U.S. Armed Forces health surveillance architecture". [ 34 ]  Around the time of the leaked documents' appearance on WikiLeaks, the lead author of the unpublished  RAND  study published an op-ed piece [ 35 ]  in  The Baltimore Sun  describing the control of the outbreak a concern of "national security", and highlighting the need to "marshal the best ... institutional strengths ... to prevent, detect and respond effectively to this latest infectious disease".


The  European Hematology Association  ( EHA ) is a non-governmental and not-for-profit membership organization that is guided by its mission to promote excellence in patient care, research, and education in hematology.


The European Hematology Association (EHA) was officially established in 1992. [ 1 ]  EHA is a global platform for excellence in hematology, focusing on blood, blood cells, and blood disorders such as leukemia, lymphoma, hemophilia, anemia and thrombosis. [ citation needed ]


HemaSphere  ( ISSN   2572-9241 ) is the official open access journal of the European Hematology Association. [ 2 ]  The journal publishes basic, translational and clinical research as well as review articles with recommendations for future research and clinical applications. [ citation needed ]


The  International Council for Standardization of Hematology  (ICSH) was originally known as the International Committee for Standardization in Hematology and was initiated by the  European Society of Hematology  (ESH) in 1963, as a standardization committee [1]. In 1964 it was formally ratified as an organization during a meeting of the International Society of Hematology (ISH), in Stockholm. The ICSH is a  non-governmental organization  recognized as having formal relations with the  World Health Organization  (WHO) and is a  non-profit organization . The underlying goal of ICSH is to obtain reliable and repeatable results in the laboratory, mainly involving diagnostic haematology. All guidelines and recommendations now include the appropriate level of evidence. ICSH Working Groups review laboratory methods and tools for blood analysis, consider standardization issues, and promote and coordinate scientific work in the development of international standardized materials and guidelines.


1. McFadden S, Briggs C, Davis B, Jou J, Machin S. The reformed International Council for Standardization in Hematology (ICSH). Int Jnl Lab Hem 2008; 30: 89-90.


2. Lewis SM. International Council for Standardization in Haematology – The first 40 years. Int Jnl Lab Hem 2009; 31: 253-67.


3. Lee SH, Machin SJ. Years of the ICSH: 1964 to 2014. Int Jnl Lab Hem 2014; 36: 589-90.


4. Lewis, S. M. (24 April 2009). "Standardization and harmonization of the blood count: The role of International Committee for Standardization in Haematology (ICSH)". European Journal of Haematology. 45 (S53): 9–13. doi:10.1111/j.1600-0609.1990.tb01520.x.


5. Davis, Bruce H.; Jungerius, Bart (April 2010). "International Council for Standardization in Haematology technical report 1-2009: new reference material for haemiglobincyanide for use in standardization of blood haemoglobin measurements". International Journal of Laboratory Hematology. 32 (2): 139–141. doi:10.1111/j.1751-553x.2009.01196.x.


6. Zini G, Kern W, Brereton M, Stephens AD. ICSH: on board for new projects. Int Jnl Lab Hem 2014; 36: 306-12


7.Mackie I, Erber WN. The International Council for Standardization in Haematology: 1964-2021. Int Jnl Lab Hematol 2021; 43: 884-5.


The  International Society for Laboratory Hematology  (ISLH) is a  non-profit organization  founded in 1992. Its purpose is to provide a forum for the  dissemination  of new ideas and information related to the field of laboratory  hematology . [ 1 ]


In 1984, Dr. Berend Houwen began to organize meetings that brought together  scientists ,  manufacturers ,  clinicians , and  regulatory  representatives to exchange ideas on technical innovations in laboratory  hematology . The first meeting was held in  Banff, Alberta , Canada.


At the time of incorporation, the founding members agreed to start a new journal for the publication of research and review articles in the broadening arena of laboratory hematology. In 2003, this journal,  Laboratory Hematology , began to be officially indexed by the  National Center for Biotechnology Information . [ 2 ]  The current journal,  The International Journal of Laboratory Hematology , is the official journal of the ISLH. [ 3 ]  It provides an international forum for new developments in the practice and research of laboratory hematology and includes invited  reviews , original articles, research results, [ 4 ]  and correspondence. [ 5 ]


In 2001, the organization published the first flow-based reference method for  platelet  counting. [ 6 ]  In 2005, it published a document titled  The International Consensus Group for Hematology Review: Suggested Criteria for Action Following Automated CBC and White Blood Cell Differential Analysis . [ 3 ] [ 7 ]  This publication gathered 20 hematology laboratorians from around the globe to share their views on the slide review. After its publication, ISLH also maintains affiliation with the International Committee for Standardization in Hematology (ICSH), and sponsors review studies in its field. [ 8 ]


ISLH has also expanded its focus to include a number of sub-disciplines related to laboratory hematology, including cellular analysis,  flow cytometry ,  hemostasis  and  thrombosis ,  molecular diagnostics , hematology informatics,  hemoglobinopathies ,  hemolytic anemias ,  point-of-care testing , [ 9 ]  and standards and guidelines. ISLH addresses these with symposia, research, and journal reviews. As of 2015, the ISLH has about 900 members from more than 50 countries. [ 10 ] The society organizes annual international  scientific meetings  held in the  United States ,  Europe  or  Asia . [ citation needed ]


The meeting, held annually in the spring, brings together laboratory  hematologists  from around the world to discuss critical issues in laboratory hematology. The symposium features a combination of invited speakers, oral and  poster presentations , and commercial exhibits/workshops.


The  Society for Hematology and Stem Cells  (formerly the  International Society for Experimental Hematology ) is a  learned society  which deals with  hematology , the study of the blood system and its diseases, including those caused by exposure to nuclear radiation. It was founded in 1950, and held its first official meeting in  Milwaukee  in 1972. [ 1 ]  Its mission statement is:  "To promote the scientific knowledge and clinical application of basic hematology, immunology, stem cell research, cell and gene therapy and related aspects of research through publications, discussions, scientific meetings and the support of young investigators." [ 2 ]


Dr.  Margaret Goodell  of the Baylor College of Medicine's Center for Cell and Gene Therapy is the current president. [ 3 ]


At the opening ceremony of the 30th annual meeting of ISEH, Emperor  Akihito  of  Japan  praised the "remarkable results obtained by the ISEH today in the treatment of radiation-related disorders", by contrast to the lack of any effective treatment for such disorders in 1945 when atomic bombs were dropped on  Hiroshima  and  Nagasaki . [ 4 ]


The society has an official journal,  Experimental Hematology , which has an  impact factor  of 2.907.


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Activated protein C–protein C inhibitor  ( APC-PCI ) is a complex of  activated protein C  (APC) and  protein C inhibitor  (PCI). [ 1 ] [ 2 ] [ 3 ]  It has been measured in  coagulation testing  to evaluate  coagulation ,  thrombosis , and other  cardiovascular complications . [ 2 ] [ 3 ] [ 4 ]  It is a  marker  of  thrombin generation  and indicates  hypercoagulability . [ 1 ] [ 5 ]  The  half-life  of APC-PCI is either 40 minutes or 140   minutes. [ 1 ]


Ethinylestradiol -containing  birth control pills  have been found to increase levels of APC-PCI to a similar degree as  thrombin–antithrombin complex  (TAT) and to a greater extent than  D-dimer . [ 5 ]  However, only APC-PCI was able to differentiate between a second- and third-generation birth control pill. [ 5 ]


Another complex related to APC-PCI is the  activated protein C–α 1 -antitrypsin  (APCAT) complex. [ 1 ]


Acute posthemorrhagic anemia  or  acute blood loss anemia  is a condition in which a person quickly loses a large volume of circulating hemoglobin. Acute blood loss is usually associated with an incident of trauma or a severe injury resulting in a large loss of blood. It can also occur during or after a surgical procedure. [ 1 ]


Bisalbuminemia  is the, sometimes inherited, condition of having two types of  serum albumin  that differ in mobility during  electrophoresis . It can be seen in  densitometry  as a bifid mountain where albumin has 2 heads. Inherited bisalbuminemia has no pathologic effects, but is of interest to researchers who study the evolution and functional changes in the protein. [ 1 ]


Jeannie Callum  is a  transfusion medicine  specialist and  hematologist  in Ontario, Canada. [ 1 ]  She is also a professor at the  University of Toronto  and  Queen's University . [ 2 ]  She was the co-principal investigator of the CONCOR [ 3 ]  trial, an international  randomized controlled trial  evaluating the use of  convalescent plasma  for the treatment of  COVID-19 infection . [ 2 ] [ 4 ]  She was lead editor for  Bloody Easy 4: Blood Transfusions, Blood Alternatives and Transfusion Reactions, fourth edition  a handbook in transfusion medicine for the province of Ontario. [ 5 ]


This biography related to medicine in Canada is a  stub . You can help Wikipedia by  expanding it .


Clotting time  is a general term for the time required for a sample of  blood  to form a clot, or, in medical terms,  coagulate . The term "clotting time" is often used when referring to tests such as the  prothrombin time (PT) , activated  partial thromboplastin time  (aPTT or PTT),  activated clotting time  (ACT),  thrombin time  (TT), or  Reptilase time . These tests are coagulation studies performed to assess the natural clotting ability of a sample of blood. In a clinical setting, healthcare providers will order one of these tests to evaluate a patient's blood for any abnormalities in the time it takes for their blood to clot. [ 1 ]  Each test involves adding a specific substance to the blood and measuring the time until the blood forms fibrin which is one of the first signs of clotted blood. [ 2 ]  Each test points to a different component of the clotting sequence which is made up of coagulation factors that help form clots. Abnormal results could be due to a number of reasons including, but, not limited to, deficiency in clotting factors, dysfunction of clotting factors, blood-thinning medications, medication side-effects, platelet deficiency, inherited bleeding or clotting disorders, liver disease, or advanced illness resulting in a medical emergency known as  disseminated intravascular coagulation  (DIC). [ 3 ]


There are various methods for determining the  clotting  time, the prototype historical method being the  capillary  tube method. [ 4 ]  It is affected by calcium ion levels and many diseases. The normal range of clotting times is 2-8 minutes.


For the measurement of clotting time by the test tube method, blood is placed in a glass test tube and kept at 37°C. The required time for the blood to clot is measured. [ 5 ]


There are several other methods, including testing for those on  blood thinners , such as  heparin  or  warfarin . Activated  partial thromboplastin time  (aPTT) is used for heparin studies and the  normal range  is 20–36 seconds, depending upon which type of activator is used in the study. [ 6 ]   Prothrombin time  (PT) is used for warfarin studies and the normal values differ for men and women. Adult male PT normal range is 9.6–11.8 seconds, while adult females' normal range is 9.5–11.3 seconds. [ 6 ]  Internationalized normalized ratio (INR) is also a warfarin study, with therapeutic ranges of 2–3 for standard warfarin and 3–4.5 for high-dose warfarin. [ 6 ]  In a  veterinary  study of  bovine animals , the mean ACT was 145 seconds with a range of 120–180 seconds. Standard deviations were 18 and 13 for the first and second sampling, respectively. Repeatability of the ACT was acceptable. [ 7 ]


Coagulation activation markers  are  biomarkers  of net activation of  coagulation  and  fibrinolysis . [ 1 ] [ 2 ]  Examples include  prothrombin fragment 1+2  (F1+2),  thrombin–antithrombin complex  (TAT),  fibrinopeptide A  (FpA),  fibrin monomers  (FMs),  plasmin-α 2 -antiplasmin complex  (PAP),  activated protein C–protein C inhibitor  (APC-PCI), and  D-dimer  (DD). [ 1 ] [ 2 ]  These compounds are markers of  thrombin generation  (F1+2, TAT, APC-PCI),  fibrin generation  (FpA, FMs), and fibrinolysis (DD, PAP). [ 1 ] [ 2 ]  Coagulation activation markers, particularly D-dimer, are useful in the  diagnosis  of acute  venous thromboembolism . [ 1 ] [ 3 ]  They may also be useful in the assessment of  hypercoagulability  and venous thromboembolism risk. [ 4 ] [ 5 ] [ 6 ]


Levels of coagulation activation markers are increased with  pregnancy , [ 7 ]  with  estrogen -containing  birth control pills , [ 8 ]  with  menopausal hormone therapy , [ 9 ] [ 6 ]  and with high-dose  parenteral   estradiol  therapy for  prostate cancer . [ 10 ] [ 11 ] [ 12 ]   Transdermal  estradiol appears to have less influence on coagulation activation markers than  oral  estrogens in menopausal hormone therapy. [ 9 ]   Birth control pills containing estradiol  or  estetrol  also appear to have less influence on coagulation activation markers than  ethinylestradiol -containing birth control pills. [ 8 ]


Markers of  platelet activation  ( primary hemostasis ) include  platelet factor 4  (PF4),  β-thromboglobulin  (β-TG), and  P-selectin . [ 13 ] [ 14 ]


The  Defense Blood Standard System  ( DBSS ) is a  FDA -regulated,  Class II Medical Device  designed to handle  blood collection , processing and tracking procedures, and automation of standards and safeguards for the  Military Health System  (MHS) blood supply. [ 1 ]  It is identified by the FDA as a Blood Establishment Software item.


The DBSS supports the Armed Services Blood Program Office, which manages the blood program for the  Department of Defense , and services more than 8.7 million MHS beneficiaries.


Hal Downey  (1877–1959) [ 1 ]  was an American  hematologist . [ 2 ]


In 1923, he contributed to the characterization of  reactive lymphocytes , which are sometimes called "Downey cells". [ 3 ]


This biographical article related to medicine in the United States is a  stub . You can help Wikipedia by  expanding it .


Gene therapy for blood diseases  is a novel field of  research  investigating ways in which components of  blood  can be  genetically modified  to treat  hematologic diseases . [ 1 ]


Source: [ 2 ]


CAR T-cell therapy is a type of personalized  cancer immunotherapy  designed to strengthen the patient’s own  immune system  to better fight cancer. The process begins by extracting  T-cells , a type of immune cell, from an individual patient’s blood. The surface of cancer cells contains unique markers called  antigens . The patient’s T-cells are genetically modified in laboratories to include chimeric antigen receptors (CARs). The CARs are designed to recognize the specific cancer antigens and bind to them, allowing T-cells to target and attack the cancer cells. The genetically modified T-cells are administered back to the patients as a treatment.


Leukemia is a group of blood cancers commonly found in children younger than 15 and elders older than 55. [ 3 ]  In 2017,  tisagenlecleucel (Kymriah™) , [ 2 ]  the first CAR-T cell therapy approved by the  FDA , became available to anyone up to the age of 25 with  acute lymphoblastic leukemia  (ALL). Until 2022, a total of six CAR-T therapies have been approved by the FDA, all of which target blood cancers. [ 4 ]  These CAR-T therapies have been shown to have high efficacy in eradicating leukemia cancer, including in patients with advanced-stage, treatment-resistant ( refractory ) or returned ( relapsed ) leukemia. [ 5 ]  They also have a high  remission  rate in comparison to other traditional  cancer treatments . [ 2 ]


Patients in the U.S. suffering from sickle cell disease can now receive targeted  gene therapies  using  hematopoietic stem cells . [ 6 ]  Hematopoietic stem cells are stem cells which differentiate and give rise to  red blood cells ,  white blood cells  and  platelets . [ 7 ]  These therapies involve removing hematopoietic stem cells from the patient and making specific edits to the genome of the hematopoietic stem cells. These edits in the genome of the hematopoietic stem cells are to reverse the effects of sickle cell disease. The cells are then re-administered into the patient. The hematopoietic stem cells are then able to produce red blood cells with the factors which promote proper red blood cell shape reducing the effects of sickle cell disease.


Beta thalassemia is a heritable disorder, characterized by the inability to make  beta globin protein , and in turn reduced functioning of  hemoglobin  (which beta globin is a part of). [ 8 ]  In December 2023, the  European Medicines Agency  recommended approval for a cell based gene therapy that works through the  CRISPR/Cas9  system. The therapy known as Casgevy [ 9 ]  works through editing a dysfunctional protein that interferes with creation of  adult hemoglobin . This gene is known as the  BCL11A , and when people have Beta thalassemia, their bodies do not make enough adult hemoglobin. Casgevy uses precise gene editing of stem cells, and reduces the activity of  BCL11A . With the subsequent reduction of adult hemoglobin,  fetal hemoglobin  (HbF) genes are turned back on, allowing the cells to produce enough hemoglobin. Typically, the body stops making fetal hemoglobin around 6 months of age, and starts making adult hemoglobin. [ 10 ]  These serve similar functions, however fetal hemoglobin has a higher binding affinity for  oxygen  than adult hemoglobin, but both are functional at transporting oxygen in the body. [ 10 ]  Stem cells edited by Casgevy are then  transfused  back into the body where they can create more HbF and therefore make more functional red blood cells that have this edit. With this therapy, patients who would regularly need  blood transfusions  can now produce enough hemoglobin for themselves. [ 11 ]


Human immunodeficiency virus  (HIV) is a disease that, once contacted, attacks cells that are necessary to fight off  infections . It can be transmitted in many different ways, including through sexual contact, blood contamination, the sharing of needles, or from mother to infant. [ 12 ]  If left untreated, HIV can result in  acquired immunodeficiency syndrome  (AIDS). [ 13 ]  HIV weakens an individual’s  immune system , leading to increased risk of fatal infections and cancers. [ 14 ]  In 2023, around 40 million people globally were living with HIV. [ 15 ]  Despite options available for the treatment and management of HIV (e.g.,  highly active antiretroviral therapy ; HAART), they come with limitations including the need for indefinite daily treatment. [ 16 ]  Attempts to generate a long-term HIV-resistant immune system have been promising with results from a case report of a patient who developed  acute myeloid leukemia  after HIV infection. [ 17 ]  Previously, researchers had found a version of a  gene  (an  allele ) that was resistant to HIV. These researchers therefore found a donor who had two copies of this allele ( homozygous ) and extracted their stem cells in an attempt to produce HIV resistance in the patient with acute myeloid leukemia. After stem cell transplantation from this donor, the patient tested and remained HIV-negative at 20 months post-transplantation and was able to discontinue use of antiviral therapies. [ 17 ]


This article about  biological engineering  is a  stub . You can help Wikipedia by  expanding it .


Monocytopoiesis  is the process which leads to the production of  monocytes  (and, subsequently,  macrophages ).


It can be induced by  macrophage colony-stimulating factor . [ citation needed ]


It is a component of  myelopoiesis . [ 1 ]


In  hematology ,  myelopoiesis  in the broadest  sense  of the term is the production of  bone marrow  and of all  cells  that arise from it, namely, all  blood cells . [ 1 ]  In a narrower sense, myelopoiesis also refers specifically to the regulated formation of  myeloid  leukocytes ( myelocytes ), including  eosinophilic granulocytes ,  basophilic granulocytes ,  neutrophilic granulocytes , and  monocytes . [ 2 ]


The  common myeloid progenitor  can  differentiate  in the bone marrow into  red blood cells  and  megakaryocytes  (leading to  platelets ) as well as  mast cells  and  myeloblasts , the latter leading to the  myelocytic  line ( granulocytes ) and to  monocytes ,  macrophages , and  dendritic cells  of the  innate immune system . The granulocytes, also called polymorphonuclear leukocytes because of their multilobed nuclei, are three short lived cell types including  eosinophils ,  basophils , and  neutrophils . A granulocyte differentiates into a distinct cell type by a process called  granulopoiesis . In this process it first transforms from a common  myeloblast  (myeloid progenitor) to a common promyelocyte. This promyelocyte gives rise to a unique myelocyte that for the first time can be classified as an eosinophil, basophil, or neutrophil progenitor based on the histological staining affinity (eosinophilic, basophilic, or neutral granules). [ 3 ]  The unique myelocyte next differentiates into a metamyelocyte and then a  band cell , with a C-shaped nucleus, before becoming a mature eosinophil, basophil, or neutrophil. Macrophages come from monoblast progenitors that differentiate into  promonocytes , which mature into  monocytes . Monocytes eventually enter the tissues and become  macrophages . [ citation needed ]


Plasmin-α2-antiplasmin complex  ( PAP ) is a 1:1 irreversibly formed inactive complex of the  enzyme   plasmin  and its inhibitor  α 2 -antiplasmin . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It is a marker of the activity of the  fibrinolytic  system and a marker of net activation of  fibrinolysis . [ 5 ] [ 6 ]


PAP levels are increased with  pregnancy [ 7 ]  and by  ethinylestradiol -containing  combined birth control pills . [ 5 ]  Conversely, levels of PAP do not appear to be affected with  menopausal hormone therapy . [ 6 ]  PAP levels have been reported to be elevated in men with  prostate cancer . [ 8 ]


Bone marrow  is a semi-solid  tissue  found within the  spongy  (also known as cancellous) portions of  bones . [ 2 ]  In birds and mammals, bone marrow is the primary site of new  blood cell  production (or  haematopoiesis ). [ 3 ]  It is composed of  hematopoietic cells ,  marrow adipose tissue , and supportive  stromal cells . In adult humans, bone marrow is primarily located in the  ribs ,  vertebrae ,  sternum , and  bones of the pelvis . [ 4 ]  Bone marrow comprises approximately 5% of total body mass in healthy adult humans, such that a man weighing 73 kg (161 lbs) will have around 3.7 kg (8 lbs) of bone marrow. [ 5 ]


Human marrow produces approximately 500 billion blood cells per day, which join the  systemic circulation  via permeable  vasculature   sinusoids  within the  medullary cavity . [ 6 ]  All types of  hematopoietic cells , including both  myeloid  and  lymphoid lineages , are created in bone marrow; however, lymphoid cells must migrate to other  lymphoid organs  (e.g.  thymus ) in order to complete maturation.


Bone marrow transplants  can be conducted to treat severe diseases of the bone marrow, including certain forms of  cancer  such as  leukemia . Several types of stem cells are related to bone marrow.  Hematopoietic stem cells  in the bone marrow can give rise to hematopoietic lineage cells, and  mesenchymal stem cells , which can be isolated from the primary culture of bone marrow stroma, can give rise to bone,  adipose , and  cartilage  tissue. [ 7 ]


The composition of marrow is dynamic, as the mixture of cellular and non-cellular components (connective tissue) shifts with age and in response to systemic factors. In humans, marrow is colloquially characterized as "red" or "yellow" marrow ( Latin :  medulla ossium rubra ,  Latin :  medulla ossium flava , respectively) depending on the prevalence of hematopoietic cells vs  fat cells .  While the precise mechanisms underlying marrow regulation are not understood, [ 6 ]  compositional changes occur according to stereotypical patterns. [ 8 ]  For example, a newborn baby's bones exclusively contain hematopoietically active "red" marrow, and there is a progressive conversion towards "yellow" marrow with age. In adults, red marrow is found mainly in the  central skeleton , such as the  pelvis ,  sternum ,  cranium ,  ribs ,  vertebrae  and  scapulae , and variably found in the proximal  epiphyseal  ends of  long bones  such as the  femur  and  humerus . In circumstances of chronic hypoxia, the body can convert yellow marrow back to red marrow to increase blood cell production. [ 9 ]


At the cellular level, the main functional component of bone marrow includes the progenitor cells which are destined to mature into blood and lymphoid cells. Human marrow produces approximately 500 billion blood cells per day. [ 10 ]  Marrow contains  hematopoietic stem cells  which give rise to the three classes of blood cells that are found in circulation:  white blood cells  (leukocytes),  red blood cells  (erythrocytes), and  platelets  (thrombocytes). [ 11 ]


The  stroma  of the bone marrow includes all tissue not directly involved in the marrow's primary function of  hematopoiesis . [ 6 ]  Stromal cells may be indirectly involved in hematopoiesis, providing a microenvironment that influences the function and differentiation of hematopoietic cells. For instance, they generate  colony stimulating factors , which have a significant effect on hematopoiesis. Cell types that constitute the bone marrow stroma include:


That bone marrow is a priming site for  T-cell  responses to blood-borne  antigens  was first described in 2003. [ 13 ]  Mature circulating naïve T cells home to bone marrow sinuses after they have passed through arteries and arterioles. [ 14 ]  They transmigrate sinus endothelium and enter the parenchyma which contains  dendritic cells  (DCs). These have a capacity of antigen uptake, processing, and presentation. [ 13 ]  Cognate interactions between antigen-specific T cells and antigen-presenting DCs (APCs) in parenchyma lead to rapid T-APC cluster formation followed by T cell activation, T cell proliferation and T cell re-circulation to blood. [ 13 ]  These findings were corroborated and extended in 2013 by in situ two-photon dynamic imaging of mice skulls. [ 15 ]


Bone marrow is a nest for migratory memory T cells [ 16 ]  and a sanctuary for plasma cells. [ 17 ]  This has implications for adaptive immunity and vaccinology. [ 17 ]  Memory B and T cells persist in the parenchyma in dedicated survival niches organized by stromal cells. [ 18 ]  This memory can be maintained over long time periods in the form of quiescent cells [ 18 ]  or by repeated antigenic restimulation. [ 19 ]  Bone marrow protects and optimizes immunological memory during dietary restriction. [ 20 ]  In cancer patients, cancer-reactive memory T cells can arise in bone marrow spontaneously or after specific vaccination. [ 21 ]  Bone marrow is a center of a variety of immune activities: i) hematopoiesis, ii) osteogenesis, iii) immune responses, iv) distinction between self and non-self antigens, v) central immune regulatory function, vi) storage of memory cells, vii) immune surveillance of the central nervous system, viii) adaptation to energy crisis, ix) provision of mesenchymal stem cells for tissue repair. [ 22 ]


The bone marrow stroma contains  mesenchymal stem cells  (MSCs), [ 11 ]  which are also known as marrow stromal cells. These are  multipotent   stem cells  that can  differentiate  into a variety of cell types. MSCs have been shown to differentiate,  in vitro  or  in vivo , into  osteoblasts ,  chondrocytes ,  myocytes ,  marrow adipocytes  and  beta-pancreatic islets cells . [ citation needed ]


The  blood vessels  of the bone marrow constitute a barrier, inhibiting immature blood cells from leaving the marrow. Only mature blood cells contain the  membrane proteins , such as  aquaporin  and  glycophorin , that are required to attach to and pass the blood vessel  endothelium . [ 23 ]   Hematopoietic stem cells  may also cross the bone marrow barrier, and may thus be harvested from blood. [ citation needed ]


The red bone marrow is a key element of the  lymphatic system , being one of the  primary lymphoid organs  that generate  lymphocytes  from immature hematopoietic  progenitor cells . [ 24 ]  The bone marrow and  thymus  constitute the primary lymphoid tissues involved in the production and early selection of lymphocytes. Furthermore, bone marrow performs a  valve -like function to prevent the backflow of  lymphatic fluid  in the lymphatic system. [ citation needed ]


Biological compartmentalization  is evident within the bone marrow, in that certain cell types tend to aggregate in specific areas. For instance,  erythrocytes ,  macrophages , and their  precursors  tend to gather around  blood vessels , while  granulocytes  gather at the borders of the bone marrow. [ 11 ]


People have used animal bone-marrow in cuisine worldwide for millennia, as in the famed  Milanese   Ossobuco . [ 25 ]


The normal bone marrow architecture can be damaged or displaced by  aplastic anemia ,  malignancies  such as  multiple myeloma , or infections such as  tuberculosis , leading to a decrease in the production of blood cells and blood platelets. The bone marrow can also be affected by various forms of  leukemia , which attacks its hematologic progenitor cells. [ 26 ]  Furthermore, exposure to  radiation  or  chemotherapy  will kill many of the rapidly dividing cells of the bone marrow, and will therefore result in a depressed  immune system . Many of the symptoms of  radiation poisoning  are due to damage sustained by the bone marrow cells. [ citation needed ]


To diagnose diseases involving the bone marrow, a  bone marrow aspiration  is sometimes performed. This typically involves using a hollow needle to acquire a sample of red bone marrow from the  crest of the ilium  under general or  local anesthesia . [ 27 ]


Medical imaging may provide a limited amount of information regarding bone marrow.  Plain film x-rays  pass through soft tissues such as marrow and do not provide visualization, although any changes in the structure of the associated bone may be detected. [ 28 ]   CT  imaging has somewhat better capacity for assessing the marrow cavity of bones, although with low sensitivity and specificity. For example, normal fatty "yellow" marrow in adult long bones is of low density (-30 to -100 Hounsfield units), between subcutaneous fat and soft tissue. Tissue with increased cellular composition, such as normal "red" marrow or cancer cells within the medullary cavity will measure variably higher in density. [ 29 ]


MRI  is more sensitive and specific for assessing bone composition. MRI enables assessment of the average molecular composition of soft tissues and thus provides information regarding the relative fat content of marrow. In adult humans, "yellow" fatty marrow is the dominant tissue in bones, particularly in the (peripheral)  appendicular skeleton . Because fat molecules have a high  T1-relaxivity , T1-weighted imaging sequences show "yellow" fatty marrow as bright (hyperintense). Furthermore, normal fatty marrow loses signal on fat-saturation sequences, in a similar pattern to subcutaneous fat. [ citation needed ]


When "yellow" fatty marrow becomes replaced by tissue with more cellular composition, this change is apparent as decreased brightness on T1-weighted sequences. Both normal "red" marrow and pathologic marrow lesions (such as cancer) are darker than "yellow" marrow on T1-weight sequences, although can often be distinguished by comparison with the MR signal intensity of adjacent soft tissues. Normal "red" marrow is typically equivalent or brighter than skeletal muscle or intervertebral disc on T1-weighted sequences. [ 8 ] [ 30 ]


Fatty marrow change, the inverse of red marrow  hyperplasia , can occur with normal aging, [ 31 ]  though it can also be seen with certain treatments such as  radiation therapy . Diffuse marrow T1 hypointensity without contrast enhancement or cortical discontinuity suggests red marrow conversion or  myelofibrosis . Falsely normal marrow on T1 can be seen with diffuse  multiple myeloma  or  leukemic  infiltration when the water to fat ratio is not sufficiently altered, as may be seen with lower grade tumors or earlier in the disease process. [ 32 ]


Bone marrow examination is the pathologic analysis of samples of bone marrow obtained via  biopsy  and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma,  anemia , and  pancytopenia . The bone marrow produces the cellular elements of the blood, including  platelets ,  red blood cells  and  white blood cells . While much information can be gleaned by testing the blood itself (drawn from a vein by  phlebotomy ), it is sometimes necessary to examine the source of the blood cells in the bone marrow to obtain more information on hematopoiesis; this is the role of bone marrow aspiration and biopsy. [ citation needed ]


The ratio between  myeloid series  and  erythroid  cells is relevant to bone marrow function, and also to diseases of the bone marrow and  peripheral blood , such as leukemia and anemia. The normal myeloid-to-erythroid ratio is around 3:1; this ratio may increase in  myelogenous leukemias , decrease in  polycythemias , and reverse in cases of  thalassemia . [ 33 ]


In a  bone marrow transplant , hematopoietic stem cells are removed from a person and infused into another person ( allogenic ) or into the same person at a later time ( autologous ). If the donor and recipient are compatible, these infused cells will then travel to the bone marrow and initiate blood cell production. Transplantation from one person to another is conducted for the treatment of severe bone marrow diseases, such as congenital defects, autoimmune diseases or malignancies. The patient's own marrow is first killed off with drugs or  radiation , and then the new stem cells are introduced. Before radiation therapy or  chemotherapy  in cases of  cancer , some of the patient's hematopoietic stem cells are sometimes harvested and later infused back when the therapy is finished to restore the immune system. [ 34 ]


Bone marrow stem cells can be induced to become neural cells to treat neurological illnesses, [ 35 ]  and can also potentially be used for the treatment of other illnesses, such as  inflammatory bowel disease . [ 36 ]  In 2013, following a clinical trial, scientists proposed that bone marrow transplantation could be used to treat  HIV  in conjunction with  antiretroviral  drugs; [ 37 ] [ 38 ]  however, it was later found that HIV remained in the bodies of the test subjects. [ 39 ]


The stem cells are typically harvested directly from the red marrow in the  iliac crest , often under  general anesthesia . The procedure is minimally invasive and does not require stitches afterwards. Depending on the donor's health and reaction to the procedure, the actual harvesting can be an  outpatient procedure , or can require 1–2 days of recovery in the hospital. [ 40 ]


Another option is to administer certain drugs that stimulate the release of stem cells from the bone marrow into circulating blood. [ 41 ]  An  intravenous   catheter  is inserted into the donor's arm, and the stem cells are then filtered out of the blood. This procedure is similar to that used in blood or platelet donation. In adults, bone marrow may also be taken from the  sternum , while the  tibia  is often used when taking samples from infants. [ 27 ]  In newborns, stem cells may be retrieved from the  umbilical cord . [ 42 ]


One of the most damaged areas of the body following chemotherapy is typically the uterus. Following uterine damage due to cancer treatment, follicle damage makes it difficult for individuals to get pregnant even if viable ova are present. With bone marrow stem cell transplants, chemotherapy patients have been able to increase their fertility as follicle damage is repaired. [ 43 ]  As follicles are necessary for ovum attachment to the  endometrium , it is important for these areas to be repaired in order to increase fertility. For individuals who have sustained egg and follicle damage, IVF has been found to be more effective following bone marrow stem cell transplantation. [ 44 ]


One human clinical case has shown improvements of uterine lining thickness and overall endometrium repair following bone marrow stem cell transplantation. [ 45 ]  This repair allowed for the patient to successfully become pregnant and carry to term.


Additional repairs following bone marrow stem cell transplant to the endometrium include increased vascularity and iron levels, with egg implantation clustering around areas with high blood flow. [ 44 ] [ 46 ]


Using quantitative polymerase chain reaction (qPCR) and next-generation sequencing (NGS) a maximum of five DNA viruses per individual have been identified. Included were several herpesviruses, hepatitis B virus, Merkel cell polyomavirus, and human papillomavirus 31. Given the reactivation and/or oncogenic potential of these viruses, their repercussion on hematopoietic and malignant disorders calls for further studies. [ 47 ]


The earliest fossilised evidence of bone marrow was discovered in 2014 in  Eusthenopteron , a  lobe-finned fish  which lived during the  Devonian  period approximately 370 million years ago. [ 48 ]  Scientists from  Uppsala University  and the  European Synchrotron Radiation Facility  used  X-ray synchrotron microtomography  to study the fossilised interior of the skeleton's  humerus , finding organised tubular structures akin to modern vertebrate bone marrow. [ 48 ]   Eusthenopteron  is closely related to the early  tetrapods , which ultimately evolved into the land-dwelling  mammals  and  lizards  of the present day. [ 48 ]


Erythropoiesis  (from Greek 'erythro' meaning "red" and 'poiesis' "to make") is the process which produces  red blood cells  (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell. [ 1 ]


It is stimulated by decreased O 2  in circulation, which is detected by the  kidneys , which then secrete the hormone  erythropoietin . [ 2 ]  This hormone stimulates proliferation and differentiation of red cell precursors, which activates increased erythropoiesis in the  hemopoietic  tissues, ultimately producing  red blood cells  (erythrocytes). [ 2 ]  In  postnatal   birds  and  mammals  (including  humans ), this usually occurs within the  red bone marrow . [ 2 ]  In the early  fetus , erythropoiesis takes place in the mesodermal cells of the  yolk sac . By the third or fourth month, erythropoiesis moves to the liver. [ 3 ]  After seven months, erythropoiesis occurs in the bone marrow. Increased levels of physical activity can cause an increase in erythropoiesis. [ 4 ]  However, in  humans  with certain  diseases  and in some  animals , erythropoiesis also occurs outside the  bone marrow , within the  spleen  or  liver . This is termed  extramedullary erythropoiesis .


The  bone marrow  of essentially all the  bones  produces red blood cells until a person is around five  years  old. The  tibia  and  femur  cease to be important sites of  hematopoiesis  by about age 25; the  vertebrae ,  sternum ,  pelvis  and  ribs , and  cranial bones  continue to produce red blood cells throughout life. Up to the age of 20 years, RBCs are produced from red bone marrow of all the bones (long bones and all the flat bones). After the age of 20 years, RBCs are produced from membranous bones such as vertebrae, the sternum, ribs, scapulas, and the iliac bones. After 20 years of age, the shaft of the long bones becomes yellow bone marrow because of fat deposition and loses the erythropoietic function. [ 5 ]


Comparison of erythrocyte production by marrow stem cell lines from old and young adult donors shows no significant differences. [ 6 ]  This finding implies that little or none of the proliferative capacity of the erythropoietic stem cells is exhausted by a lifetime of normal functioning. [ 6 ]


In the process of red blood corpuscle maturation, a cell undergoes a series of  differentiations . The following stages of development all occur within the  bone marrow :


The cell is released from the bone marrow after Stage 7, and so in newly circulating red blood cells there are about 1% reticulocytes. After one to two days, these ultimately become "erythrocytes" or mature red blood cells.


These stages correspond to specific appearances of the cell when stained with  Wright's stain  and examined by light microscopy, and correspond to other biochemical changes.


In the process of maturation, a basophilic pronormoblast is converted from a cell with a large  nucleus  and a volume of 900  fL  to an  enucleated  disc with a volume of 95 fL. By the reticulocyte stage, the cell has extruded its nucleus, but is still capable of producing hemoglobin.


Essential for the maturation of red blood cells are  Vitamin B 12  (cobalamin) and  Vitamin B 9  (folate). Lack of either causes maturation failure in the process of erythropoiesis, which manifests clinically as  reticulocytopenia , an abnormally low amount of reticulocytes.


As they mature, a number of erythrocyte characteristics change:


The production of all blood cells begins with the haemocytoblast, a multipotent haematopoietic stem cell. Haemocytoblasts have the greatest powers of self-renewal of any adult cell. They are found in the bone marrow and can be mobilised into the circulating blood when needed.
Some haemocytoblasts differentiate into common myeloid progenitor cells, which go on to produce erythrocytes, as well as mast cells, megakaryocytes and myeloblasts.
The process by which common myeloid progenitor cells become fully mature red blood cells involves several stages. First, they become normoblasts (aka eryhthroblasts), which are normally present in the bone marrow only.
Then, they lose their nucleus as they mature into reticulocytes, which can be thought of as immature red blood cells. Some of these are released into the peripheral circulation.
Finally, reticulocytes lose their remaining organelles as they mature into erythrocytes-which are fully mature red blood cells. The average lifespan of a red blood cell is approximately 120 days.
During this maturation process, there is nuclear extrusion – i.e. mature erythrocytes have no nucleus. Nucleated red blood cells present in a sample of bone marrow can indicate the release of incompletely developed cells. This can occur in pathology such as thalassaemia, severe anaemia or haematological malignancy.


A feedback loop involving  erythropoietin  helps regulate the process of erythropoiesis so that, in non-disease states, the production of red blood cells is equal to the destruction of red blood cells and the red blood cell number is sufficient to sustain adequate tissue oxygen levels but not so high as to cause sludging,  thrombosis , or  stroke . Erythropoietin is produced in the kidney and liver in response to low oxygen levels. In addition, erythropoietin is bound by circulating red blood cells; low circulating numbers lead to a relatively high level of unbound erythropoietin, which stimulates production in the bone marrow.


Recent studies have also shown that the peptide hormone  hepcidin  may play a role in the regulation of hemoglobin production, and thus affect erythropoiesis. The liver produces hepcidin. Hepcidin controls iron absorption in the gastrointestinal tract and iron release from reticuloendothelial tissue. Iron must be released from  macrophages  in the bone marrow to be incorporated into the heme group of  hemoglobin  in erythrocytes. There are colony forming units that the cells follow during their formation. These cells are referred to as the committed cells including the granulocyte monocyte colony forming units.


The secretion of hepcidin is inhibited by another hormone,  erythroferrone , produced by erythroblasts in response to erythropoietin, and identified in 2014. [ 8 ] [ 9 ]   It appears that this links erythropoietin-driven eyrthropoiesis with the iron mobilization needed for hemoglobin synthesis.


Loss of function of the erythropoietin receptor or JAK2 in mice cells causes failure in erythropoiesis, so production of red blood cells in embryos and growth is disrupted. If there is no systemic feedback inhibition, for example, the diminishment or absence of suppressors of cytokine signaling proteins,  giantism  may result as shown in  mice  models. [ 10 ] [ 11 ]


In addition to the steady state erythropoiesis, acute anemia probably stimulates another response which results in rapid development of new red blood cells. This has been studied in rats and happens in the liver through the activation of the BMP4-dependent stress erythropoiesis pathway. [ 12 ]


Extramedullary hematopoiesis  ( EMH  or sometimes  EH [ 1 ] ) refers to  hematopoiesis  occurring outside of the medulla of the bone ( bone marrow ). [ 2 ]  It can be physiologic or pathologic.


Physiologic EMH occurs during  embryonic  and  fetal  development; during this time the main site of fetal hematopoiesis are liver and the spleen.


Pathologic EMH can occur during adulthood when physiologic hematopoiesis can't work properly in the bone marrow and the  hematopoietic stem cells (HSC)  have to migrate to other tissues in order to continue with the formation of  blood cellular components . Pathologic EMH can be caused by  myelofibrosis , [ 3 ]   thalassemias  or disorders caused in the hematopoietic system.


During fetal development, hematopoiesis occurs mainly in the  fetal liver  and in the  spleen  followed by localization to the bone marrow. [ 4 ]  Hematopoiesis also takes place in many other tissues or organs such as the  yolk sac , the  aorta-gonad mesonephros (AGM)  region, and  lymph nodes . During development, vertebrates go through a primitive and a definitive phase of hematopoiesis. The lungs also play a role in platelet production in adults. [ 5 ]


Primitive hematopoiesis  occurs in the yolk sac during early embryonic development. It is characterized by the production of primitive nucleated erythroid cells, which is thought to originate from endothelial cells or hemangioblasts, which are capable of forming both endothelium and primitive blood cells. The main objective of the production of these cells will be the facilitation of tissue oxygenation to support rapid embryonic growth. This primitive phase is transitory and the cells that are produced express embryonic hemoglobins (HBZ and HBE1 genes produce the alpha and beta chains, respectively) aren't  pluripotent , and aren't capable of self-renewal. [ 6 ] [ 7 ]


Definitive hematopoiesis  differs from the primitive phase through the production of  hematopoietic stem cells . [ 8 ]  The formation of these cells occurs in the AGM (aorta-gonad-mesonephros) later in development. This occurs by conversion of endothelial cells to hematopoietic stem and progenitor cells (HPSCs) - a process called endothelial-to-hematopoietic transition or EHT. These hematopoietic stem cells are further closely associated with endothelial cells throughout human life. Later, they migrate to the fetal liver where the majority of physiologic EMH (extra-medullary hematopoiesis) takes place. They can also migrate to the spleen and lymph nodes where hematopoiesis can occur, but to a lesser degree. Finally, once the bone marrow has developed, they migrate there. [ 9 ]


Pulmonary hematopoiesis  also appears to play an important role in adults. [ 5 ]  In comparison to the bone marrow, where trilineage hematopoiesis occurs, the lungs preferentially contribute to the production of platelets through a resident population of  megakaryocytes . This is supported by studies showing that blood leaving the lungs has more platelets and fewer progenitor cells than blood entering the lungs. It has been seen that in cases of severe  thrombocytopenia , pulmonary megakaryocytes migrate out of lungs into the bone marrow, where they help to replenish the depleted bone marrow population. [ citation needed ]


In adults, the majority of hematopoiesis occurs in the bone marrow. Significant production in any other organ is usually the result of a pathological process. When  red blood cell (RBC)  numbers are low, the body induces a homeostatic mechanism aimed to increase the synthesis of RBCs, typically via the production of erythropoietin. If the loss of RBCs becomes severe, hematopoiesis will occur in the extramedullary spaces outside the bone. [ 10 ]


The cause of pathologic EMH can be one of many hematological diseases, such as  myelofibrosis , or as a result of bone marrow irradiation.  Thalassemia  and its resultant  hemolytic anemia  is another important cause of pathologic EMH. EMH has been observed in numerous other benign hematological disorders such as sickle cell anemia, hereditary spherocytosis, congenital dyserythroblastic anemia and idiopathic thrombocytopenic purpura. [ 10 ]  EMH can also be seen as part of the response to  systemic inflammation  or  infection .


Sites of EMH can be widespread however, most common localizations are in the spleen, liver, and lymph nodes. Other manifestations occur in the thymus, heart, breast, prostate, broad ligaments, kidneys, adrenal glands, pleura, retroperitoneal tissue, skin, peripheral and cranial nerves, and the spinal canal. [ 10 ] [ 11 ]


During the postnatal period, the spleen becomes a frequent site of EMH whereas, during the embryonic stages of hematopoiesis, it is only a minor factor. Despite the hypoxic/acidic conditions of the splenic microenvironment, supplied with a legion of macrophages making it inhospitable for HSCs, EMH usually occurs within the red pulp. Among the various organs associated with EMH, the spleen offers a unique site for evaluation of hematopoietic stem cell (HSC)/niche interactions. [ 12 ] [ 11 ]


It is normal for infants have hepatic EMH as they are developing up until roughly 5 weeks of age. [ 13 ]  On the other hand, hepatic EMH in adults can indicate a pathological state. This includes transplantation, hepatic tumors, hepatic disorders, or sepsis. Hepatoblastoma, adenomas and hepatocellular carcinomas can also lead to EMH in adults. [ 14 ] [ 15 ]  Additionally, EMH is often observed within the hepatic sinusoids.


EMH in the lymph nodes is usually associated with underlying hematopoietic neoplasms. Myeloproliferative neoplasms (MPNs) tend to result in EMH. [ 16 ]  If EMH is identified in the lymph nodes of an adult or infant, a hematologic evaluation, including blood cell counts, peripheral blood smear and potentially a bone marrow biopsy should be performed. [ 11 ]


The following tissues may also be associated with EMH:  thymus ,  heart ,  breast ,  prostate ,  fatty tissue ,  adrenal glands ,  kidney ,  periosteum ,  pleural cavity , para-vertebral regions, intra-spinal tissue, retroperitoneal tissue, skin, peripheral and cranial nerves, the spinal canal, pre-sacral region, nasopharyngeal region, para-nasal sinuses and numerous types of benign/malignant neoplasms. The most common sites of EMH associated with neoplastic disorder are the spleen, lymph nodes, skin, bone, small intestine, orbit, breast, cervix, nasal sinus, mediastinum and brain. [ 11 ] [ 17 ] [ 18 ] [ 19 ]


Of the various organs associated with EMH, the spleen offers a unique site for evaluating HSC/niche interactions as it is one of the most common sites of EMH, however it does not play a major role in embryonic/developmental hematopoiesis. [ 11 ]  High expression levels of  CXCL12  were found in the human spleens of EMH-positive patients compared to those who were EMH-negative. The high expression of CXCL12, a candidate marker of bone marrow niche-constituting in cells, indicates HSC/niche interactions in the spleen. [ 20 ]  Studies have shown that CXCL12 localizes in the sinus endothelial cells of the red pulp in EMH-positive spleens; whereas, CXCL12 was expressed throughout the vascular endothelial cells of the white pulp in spleens of EMH-negative and -positive cases. [ 20 ]  The fact that EMH frequently occurs in the red pulp, is supported by current data that suggests that splenic sinus endothelial cells expressing CXCL12 may contribute to the attachment and recruitment of circulating hematopoietic precursor cells, forming bone marrow niche-like regions of EMH in the human spleen. [ 20 ]


Granulopoiesis  (or  granulocytopoiesis ) is a part of  haematopoiesis , that leads to the production of  granulocytes . A  granulocyte , also referred to as a polymorphonuclear leukocyte (PMN), is a type of  white blood cell  that has multi lobed  nuclei , usually containing three lobes, and has a significant amount of cytoplasmic  granules  within the cell. [ 1 ]  Granulopoiesis takes place in the  bone marrow . [ 2 ]  It leads to the production of three types of mature  granulocytes :  neutrophils  (most abundant, making up to 60% of all  white blood cells ),  eosinophils  (up to 4%) and  basophils  (up to 1%). [ 3 ]


Granulopoiesis is often divided into two parts;


1) Granulocyte lineage determination and


2) Committed granulopoiesis.


Granulopoiesis, as well as the rest of  haematopoiesis , begins from a  haematopoietic stem cells . These are  multipotent  cells that reside in the  bone marrow niche  and have the ability to give rise to all haematopoietic cells, as well as the ability of self renewal. [ 4 ]  They give rise to either a  common lymphoid progenitor  (CLP, a progenitor for all  lymphoid cells ) or a  common myeloid progenitor , CMP, an  oligopotent  progenitor cell, that gives rise to the myeloid part of the haematopoietic tree. [ 1 ]  The first stage of the myeloid lineage is a granulocyte - monocyte progenitor (GMP), still an oligopotent progenitor, which then develops into  unipotent  cells that will later on form a population of  granulocytes , as well as a population of  monocytes . The first unipotent cell in granulopoiesis is a  myeloblast . [ 5 ]


Committed granulopoiesis consists of maturation stages of unipotent cells. The first cell that starts to resemble a granulocyte is a  myeloblast . It is characterized by large oval nucleus that takes up most of the space in the cell and very little cytoplasm. The next developmental stage, a  promyelocyte , still has a large oval nucleus, but there is more cytoplasm in the cell at this point, also cytoplasmic granules are beginning to form. The development of granules continues with the next stage, a  myelocyte . At this point, the nucleus is starting to shrink. At the stage of a  metamyelocyte  the cell nucleus is becoming kidney-shaped and it becomes even more bent in the stage of a  band cell . The maturation is finished with the emergence of a segmented nucleus that is specific for a  mature granulocyte . [ 1 ] [ 5 ] [ 6 ]


The maturation of granulocytic precursors is tightly regulated at transcriptional level. Granulocyte lineage determination is regulated by expression of  C/EBPα , which is necessary for the transition from  CMPs  to GMPs and levels of PU.1, that drive the differentation from GMPs to  monocytes  (high PU.1 levels) or to  granulocytes  (low PU.1 levels). [ 1 ] [ 7 ]  Committed granulopoiesis is regulated by  C/EBPε  and GFI-1, these two transcriptional factors are important for terminal granulocyte differentiation. Other transcriptional factors that regulate granulopoiesis are:  CBF ,  MYB ,  SMAD4  and  HOX genes . [ 1 ] [ 8 ] [ 9 ]


Granulopoiesis is also regulated by  cytokines  to a certain extent. The main cytokines driving granulopoiesis are:  GM-CSF  (formation of GMPs from CMPs),  G-CSF  (commitment to the granulocyte lineage, formation of myeloblasts from GMPs),  IL-3  (enhances the production of  GM-CSF  and  G-CSF ) and  SCF . [ 10 ] [ 11 ]  These are secreted by other haematopoietic cells in the bone marrow or at the site of  inflammation  as well as  epithelial  and  endothelial cells . [ 2 ] [ 12 ]


Steady state granulopoiesis is a term used to describe the normal daily production of granulocytes. Granulocytes are short lived cells (their lifespan is between 6 and 8 hours) with a high cell turnover. The number of granulocytes produced every day is between 5 and 10 x 10 10 . [ 13 ]  The master regulator of steady state granulopoiesis is C/EBPα. It restricts the cell cycle of immature cells by inhibition of  CDK2  and  CDK4  and promotes granulocytic differentiation. [ 14 ]  Steady state production of granulocytes is activated after the engulfment of apoptotic granulocytes by  tissue macrophages . [ 15 ]


Emergency granulopoiesis is a fundamental hematopoietic mechanism activated during acute infections or inflammatory conditions, leading to a swift increase in granulocyte production, especially neutrophils, in the bone marrow. This process is essential for enhancing the innate immune system's capability to confront pathogen invasions effectively. [ 16 ] [ 17 ] [ 18 ]  Hematopoietic stem cells (HSCs) undergo significant transcriptional reprogramming in response to emergency conditions, transitioning from a lymphoid-biased state towards a myeloid-biased identity, thereby aligning the hematopoietic system's output with the urgent demand for granulocytes. [ 19 ]


Under normal conditions, steady-state granulopoiesis maintains granulocyte levels to meet physiological needs. However, after a major insult, typically a bacterial infection, the hematopoietic program switches from steady-state to emergency granulopoiesis. This switch is mediated by a transition from C/EBPα to C/EBPβ, the primary transcriptional regulator of emergency granulopoiesis. C/EBPβ enhances the production of granulocytes by promoting the progression of the cell cycle of myeloid progenitors at an accelerated rate, thereby generating a sufficient amount of new granulocytes to combat the insult. [ 20 ] [ 14 ]


The transcription factor CCAAT/enhancer binding protein β (C/EBPβ) is a critical regulator in this context, significantly influencing granulocyte lineage commitment and proliferation, especially noted during candidemia-induced scenarios. [ 21 ]


The genetic backdrop plays a crucial role in the dynamics of emergency granulopoiesis, as demonstrated by studies in TP53 haploinsufficient models, particularly in FANCC−/− mice, highlighting the intricate interplay between genetic predispositions and the granulopoietic response. [ 22 ]  Additionally, recent advances have highlighted the importance of both direct and indirect pathogen sensing mechanisms. HSPCs are equipped with pathogen recognition receptors (PRRs) like Toll-like receptors (TLRs), enabling them to initiate myeloid differentiation and proliferation upon detecting pathogen-associated molecular patterns (PAMPs). [ 18 ]


Neutrophils, as primary effector cells of the innate immune defense, originate from HSCs through a series of differentiation stages. The emergency granulopoiesis significantly accelerates this differentiation process, ensuring a rapid replenishment of neutrophil populations in response to systemic inflammatory stimuli, thus maintaining immune homeostasis. [ 23 ]


The clinical significance of understanding emergency granulopoiesis extends beyond basic science, influencing therapeutic strategies against infectious diseases and immune deficiencies. Balancing rapid neutrophil mobilization against the risk of immune dysregulation is critical, as imbalances can lead to severe conditions like acute respiratory distress syndrome and sepsis-induced organ dysfunctions. [ 23 ] [ 14 ]


Haematopoiesis  ( / h ɪ ˌ m æ t ə p ɔɪ ˈ iː s ɪ s ,   ˌ h iː m ə t oʊ -,   ˌ h ɛ m ə -/ ; [ 1 ] [ 2 ]  from  Ancient Greek     αἷμα  ( haîma )  'blood' and    ποιεῖν  ( poieîn )  'to make'; also  hematopoiesis  in  American English , sometimes  h(a)emopoiesis ) is the formation of  blood  cellular components. All cellular blood components are derived from  haematopoietic stem cells . [ 3 ]  In a healthy adult human, roughly ten billion (10 10 ) to a hundred billion (10 11 ) new blood cells are produced per day, in order to maintain steady state levels in the peripheral circulation. [ 4 ] [ 5 ] [ page needed ]


Haematopoietic stem cells  (HSCs) reside in the medulla of the bone ( bone marrow ) and have the unique ability to give rise to all of the different mature blood cell types and tissues. [ 3 ]  HSCs are self-renewing cells: when they differentiate, at least some of their daughter cells remain as HSCs so the pool of stem cells is not depleted. [ 6 ]  This phenomenon is called  asymmetric division. [ 7 ]  The other daughters of HSCs ( myeloid  and  lymphoid  progenitor cells) can follow any of the other differentiation pathways that lead to the production of one or more specific types of blood cell, but cannot renew themselves. The pool of progenitors is  heterogeneous  and can be divided into two groups; long-term self-renewing HSC and only transiently self-renewing HSC, also called short-terms. [ 8 ]  This is one of the main vital processes in the body. [ citation needed ]


All blood cells are divided into three lineages. [ 9 ]


Granulopoiesis  (or granulocytopoiesis) is haematopoiesis of granulocytes, except  mast cells  which are granulocytes but with an extramedullar maturation. [ 10 ]


Thrombopoiesis  is haematopoiesis of  thrombocytes (platelets) .


Between 1948 and 1950, the Committee for Clarification of the Nomenclature of Cells and Diseases of the Blood and Blood-forming Organs issued reports on the nomenclature of blood cells. [ 11 ] [ 12 ]  An overview of the terminology is shown below, from earliest to final stage of development: [ citation needed ]


The root for erythrocyte colony-forming units (CFU-E) is "rubri", for granulocyte-monocyte colony-forming units (CFU-GM) is "granulo" or "myelo" and "mono", for lymphocyte colony-forming units (CFU-L) is "lympho" and for megakaryocyte colony-forming units (CFU-Meg) is "megakaryo". According to this terminology, the stages of red blood cell formation would be: rubriblast, prorubricyte, rubricyte, metarubricyte, and erythrocyte. However, the following nomenclature seems to be, at present, the most prevalent:


Osteoclasts  also arise from hemopoietic cells of the monocyte/neutrophil lineage, specifically CFU-GM.


In developing embryos, blood formation occurs in aggregates of blood cells in the yolk sac, called  blood islands . As development progresses, blood formation occurs in the  spleen ,  liver  and  lymph nodes . [ 13 ]  When  bone marrow  develops, it eventually assumes the task of forming most of the blood cells for the entire organism. [ 3 ]  However, maturation, activation, and some proliferation of lymphoid cells occurs in the spleen,  thymus , and lymph nodes. In children, haematopoiesis occurs in the marrow of the long bones such as the femur and tibia. In adults, it occurs mainly in the pelvis, cranium, vertebrae, and sternum. [ 14 ]


In some cases, the liver, thymus, and spleen may resume their haematopoietic function, if necessary. This is called  extramedullary haematopoiesis . It may cause these organs to increase in size substantially. During fetal development, since bones and thus the bone marrow develop later, the liver functions as the main haematopoietic organ. Therefore, the liver is enlarged during development. [ 15 ]  Extramedullary haematopoiesis and myelopoiesis may supply  leukocytes  in  cardiovascular disease  and inflammation during adulthood. [ 16 ] [ 17 ]  Splenic  macrophages  and  adhesion molecules  may be involved in regulation of extramedullary myeloid cell generation in  cardiovascular disease . [ 18 ] [ 19 ]


As a stem cell matures it undergoes changes in  gene expression  that limit the cell types that it can become and moves it closer to a specific cell type ( cellular differentiation ). These changes can often be tracked by monitoring the presence of proteins on the surface of the cell. Each successive change moves the cell closer to the final cell type and further limits its potential to become a different cell type. [ citation needed ]


Two models for haematopoiesis have been proposed: determinism and stochastic theory. [ 20 ]  For the stem cells and other undifferentiated blood cells in the bone marrow, the determination is generally explained by the  determinism  theory of haematopoiesis, saying that colony stimulating factors and other factors of the haematopoietic microenvironment determine the cells to follow a certain path of cell differentiation. [ 3 ]  This is the classical way of describing haematopoiesis. In  stochastic   theory,  undifferentiated blood cells differentiate to specific cell types by randomness. This theory has been supported by experiments showing that within a population of mouse haematopoietic progenitor cells, underlying stochastic variability in the distribution of  Sca-1 , a  stem cell  factor, subdivides the population into groups exhibiting variable rates of  cellular differentiation . For example, under the influence of  erythropoietin  (an erythrocyte-differentiation factor), a subpopulation of cells (as defined by the levels of Sca-1) differentiated into  erythrocytes  at a sevenfold higher rate than the rest of the population. [ 21 ]  Furthermore, it was shown that if allowed to grow, this subpopulation re-established the original subpopulation of cells, supporting the theory that this is a stochastic, reversible process. Another level at which stochasticity may be important is in the process of apoptosis and self-renewal. In this case, the haematopoietic microenvironment prevails upon some of the cells to survive and some, on the other hand, to perform  apoptosis  and die. [ 3 ]  By regulating this balance between different cell types, the bone marrow can alter the quantity of different cells to ultimately be produced. [ 22 ]


Red and white blood cell production is regulated with great precision in healthy humans, and the production of leukocytes is rapidly increased during infection. The proliferation and self-renewal of these cells depend on growth factors. One of the key players in self-renewal and development of haematopoietic cells is  stem cell factor  (SCF), [ 25 ]  which binds to the c-kit receptor on the HSC. Absence of SCF is lethal. There are other important  glycoprotein  growth factors which regulate the proliferation and maturation, such as  interleukins   IL-2 ,  IL-3 ,  IL-6 ,  IL-7 . Other factors, termed  colony-stimulating factors  (CSFs), specifically stimulate the production of committed cells. Three CSFs are  granulocyte-macrophage CSF  (GM-CSF),  granulocyte CSF  (G-CSF) and  macrophage CSF  (M-CSF). [ 26 ]  These stimulate  granulocyte  formation and are active on either  progenitor cells  or end product cells. [ citation needed ]


Erythropoietin  is required for a myeloid progenitor cell to become an erythrocyte. [ 23 ]  On the other hand,  thrombopoietin  makes myeloid progenitor cells differentiate to  megakaryocytes  ( thrombocyte -forming cells). [ 23 ]  The diagram to the right provides examples of cytokines and the differentiated blood cells they give rise to. [ 27 ]


Growth factors initiate  signal transduction  pathways, which lead to activation of  transcription factors . Growth factors elicit different outcomes depending on the combination of factors and the cell's stage of differentiation. For example, long-term expression of  PU.1  results in myeloid commitment, and short-term induction of PU.1 activity leads to the formation of immature eosinophils. [ 28 ]  Recently, it was reported that transcription factors such as  NF-κB  can be regulated by  microRNAs  (e.g., miR-125b) in haematopoiesis. [ 29 ]


The first key player of differentiation from HSC to a multipotent progenitor (MPP) is transcription factor CCAAT-enhancer binding protein α ( C/EBP α). Mutations in C/EBPα are associated with  acute myeloid leukaemia . [ 30 ]  From this point, cells can either differentiate along the Erythroid-megakaryocyte lineage or lymphoid and myeloid lineage, which have common progenitor, called lymphoid-primed multipotent progenitor. There are two main transcription factors. PU.1 for Erythroid-megakaryocyte lineage and  GATA-1 , which leads to a lymphoid-primed multipotent progenitor. [ 31 ]


Other transcription factors include Ikaros [ 32 ]  ( B cell  development), and  Gfi1 [ 33 ]  (promotes  Th2  development and inhibits Th1) or  IRF8 [ 34 ]  ( basophils  and  mast cells ). Significantly, certain factors elicit different responses at different stages in the haematopoiesis. For example, CEBPα in neutrophil development or  PU.1  in monocytes and dendritic cell development. It is important to note that processes are not unidirectional: differentiated cells may regain attributes of progenitor cells. [ 1 ]


An example is  PAX5  factor, which is important in B cell development and associated with lymphomas. [ 35 ]  Surprisingly, pax5 conditional knock out mice allowed peripheral mature B cells to de-differentiate to early bone marrow progenitors. These findings show that transcription factors act as caretakers of differentiation level and not only as initiators. [ 36 ]


Mutations  in transcription factors are tightly connected to blood cancers, as  acute myeloid leukemia  (AML) or  acute lymphoblastic leukemia  (ALL). For example, Ikaros is known to be regulator of numerous biological events. Mice with no Ikaros lack  B cells ,  Natural killer  and  T cells . [ 37 ]  Ikaros has six  zinc fingers  domains, four are conserved  DNA-binding domain  and two are for  dimerization . [ 38 ]  Very important finding is, that different zinc fingers are involved in binding to different place in DNA and this is the reason for pleiotropic effect of Ikaros and different involvement in cancer, but mainly are mutations associated with  BCR-Abl  patients and it is bad prognostic marker. [ 39 ]


In some  vertebrates , haematopoiesis can occur wherever there is a loose  stroma  of connective tissue and slow blood supply, such as the  gut ,  spleen  or  kidney . [ 40 ]


Unlike eutherian mammals, the liver of newborn marsupials is actively haematopoietic. [ 41 ] [ 42 ] [ 43 ] [ 44 ]


Hemogenic endothelium  or   haemogenic endothelium [ 1 ]  is a special subset of endothelial cells scattered within blood vessels that can differentiate into  haematopoietic  cells. [ 2 ]


The development of hematopoietic cells in the embryo proceeds sequentially from  mesoderm  through the  hemangioblast  to the hemogenic endothelium and hematopoietic progenitors. [ 3 ]  The relationship between the hemogenic endothelium and the hemangioblast is not clearly understood. [ 1 ]


This  molecular  or  cell biology  article is a  stub . You can help Wikipedia by  expanding it .


Hemopoietic growth factors  regulate the differentiation and proliferation of particular  progenitor cells . Made available through recombinant  DNA  technology, they hold tremendous potential for medical uses when a person's natural ability to form  blood cells  is diminished or defective.  Recombinant  erythropoietin  (EPO) is very effective in treating the diminished red blood cell production that accompanies end-stage kidney disease.   Erythropoietin is a sialoglycoprotein hormone produced by peritubular cells of kidney.


Granulocyte -macrophage colony-stimulating factor and granulocyte CSF are given to stimulate white blood cell formation in cancer patients who are receiving  chemotherapy , which tends to kill their red bone marrow cells as well as the cancer cells.   Thrombopoietin  shows great promise for preventing  platelet  depletion during chemotherapy.  CSFs and thrombopoietin also improve the outcome of patients who receive bone marrow transplants.


Leukopoiesis  is a form of  hematopoiesis  in which white blood cells (WBC, or  leukocytes ) are formed in  bone marrow  located in bones in adults and hematopoietic organs in the fetus. White blood cells, indeed all blood cells, are formed from the differentiation of pluripotent hematopoietic  stem cells  which give rise to several cell lines with unlimited differentiation potential. These immediate cell lines, or colonies, are progenitors of red blood cells ( erythrocytes ), platelets ( megakaryocytes ), and the two main groups of WBCs,  myelocytes  and  lymphocytes .


Lymphopoiesis  (lĭm'fō-poi-ē'sĭs) (or  lymphocytopoiesis ) is the generation of  lymphocytes , one of the five types of  white blood cells  (WBCs). [ 1 ] [ page needed ]  It is more formally known as  lymphoid   hematopoiesis .


Disruption in lymphopoiesis can lead to a number of  lymphoproliferative disorders , such as  lymphomas  and  lymphoid leukemias .


Lymphocytes  are blood cells of  lymphoid  (rather than the  myeloid  or  erythroid ) lineage.


Lymphocytes are found in the  bloodstream  and originate in the  bone marrow , however, they principally belong to the separate  lymphatic system , which interacts with the blood circulation. [ citation needed ]


Lymphopoiesis is now usually used interchangeably with the term "lymphocytopoiesis" – the making of lymphocytes, but some sources distinguish between the two, stating that "lymphopoiesis" additionally refers to creating  lymphatic tissue , while "lymphocytopoiesis" refers only to the creation of cells in that tissue. It is rare now for lymphopoiesis to refer to the creation of lymphatic tissues. [ citation needed ]


Myelopoiesis  refers to the "generation of cells of the myeloid lineage" and  erythropoiesis  refers to the "generation of cells of the erythroid lineage", so parallel usage has evolved in which lymphopoiesis refers to the "generation of cells of the lymphoid lineage". [ citation needed ]


The two classes of WBCs in mice originate from cells with strong  stem cell  properties –  myeloids  from the  common myeloid progenitor  (CMP), and  lymphoids  from the common lymphoid progenitor (CLP). [ 1 ] [ page needed ]  It was eventually found these  progenitors  were not unique, and that the myeloid and lymphoid classes were not disjoint, but rather two partially interwoven family trees. [ citation needed ]


Mature lymphocytes are a critical part of the immune system that, with the exception of  memory B  and  T cells , have short lives measured in days or weeks and must be continuously generated throughout life by cell division and  differentiation  from cells such as common lymphoid  progenitors  (CLPs) in mice. [ citation needed ]


The set comprising CLP cells and similar progenitors are themselves descendants of the  pluripotential hemopoietic stem cell  (pHSC), which is capable of generating all of the cell types of the complete blood cell system. [ 2 ]  Despite their ability to generate the complete suite of  lymphocytes , most progenitors are not true stem cells, and must be continually renewed by differentiation from the pHSC stem cell. [ 1 ] [ page needed ]


Many progenitor cells are also referred to as  transit cells , [ 3 ]  sometimes also called  transit amplifying cells , the meaning of this term being that the transit cell may find a new sub-lineage but the number of resultant cells is strictly limited (although possibly very large, even trillions yet finite) and the lineage is terminated by cells that die off (by  apoptosis ) or remain as  cells that can no longer divide . Examples of such cells are CFUs (Colony-forming units – referred to as such because of their ability to form colonies in vitro in artificial media) such as CFU-T. [ 4 ]


Transplantation of a single pHSC cell can reconstitute a sub-lethally irradiated host (i.e. a mouse that has been irradiated so that all leukocytes are killed) with all these lineages of cells, including all types of lymphocytes via CLPs.


Lymphopoiesis continues throughout life and so progenitor cells and their parent  stem cells  must always be present. [ 1 ] [ page needed ]


In the case of  mammals  such as humans ( Homo sapiens ), lymphopoiesis begins with limited passive provision from the mother.  This includes lymphocytes and  immunoglobulin G  that cross the  placenta  and enter the fetus to provide some protection against  pathogens , as well as leukocytes that come from breast milk and enter circulation via the digestive tract. [ 5 ]  It is often not effective in preventing  infections  in the newborn. [ 6 ]


However, early in  gestation , the developing embryo has begun its own lymphopoiesis from the  fetal liver . Lymphopoiesis also arises from the  yolk sac . [ 7 ]  This is in contrast to the adult where all  lymphocytes  originate in the bone marrow. [ 8 ]


There are four major types of lymphocytes, along with many sub-types. Scientists have identified hundreds or thousands of  lymphocyte  cell types, all of which are generated by normal or abnormal lymphopoiesis, except for certain artificial strains created in laboratories through the development of existing strains. Although lymphocytes are usually considered mature, as seen in blood tests, they are certainly not inert. Lymphocytes can travel around the body wherever there is a need. When such needs arise, new rounds of downstream lymphopoiesis, such as cell multiplication and differentiation, may occur, accompanied by intense  mitotic  and  metabolic activity .


This is hardly a simple topic. In his 1976 text  Immunology, Aging and Cancer  immunologist and Nobel Prize winner Sir Frank Macfarlane Burnet speculated that the immune system might one day be found to be as complex as the  nervous system . As the production of lymphocytes is so close to the central role of the  immune response  it is wise to approach the study of it with some humility in the face of the task. However, there are general principles that help in understanding.


Lymphopoiesis can be viewed in a  mathematical  sense as a recursive process of cell division and also as a process of differentiation, measured by changes to the properties of cells.


Considering the P as the ‘mother’ cell, but not a true stem cell, it may divide into two new cells, which are themselves identical, but differ to some degree from the mother. Or the mother cell P may divide unequally into two new daughter cells both of which differ from each other and also from the mother.


Any daughter cell will usually have new specialized abilities and if it is able to divide it will form a new sub-lineage. The difference of a daughter cell from the mother may be great, but it could also be much less, even subtle. What the P mother cell does  not  do is divide into two new P mother cells or a mother and a daughter; this is a matter of observation as such limited progenitor cells are known to not self-renew.


T and B lymphocytes are indistinguishable  under the microscope . The inactive B and T cells are so featureless with few cytoplasmic  organelles  and mostly inactive  chromatin  that until the 1960s textbooks could describe these cells, now the central focus of immunology, as having no known function! [ 11 ]


However, T and B lymphocytes are very distinct cell lineages and they ‘grow up’ in different places in the body. They perform quite different (although co-operative) functions in the body. No evidence has ever been found that T and B cells can ever interconvert. T and B cells are  biochemically  distinct and this is reflected in the differing markers and receptors they possess on their cell surfaces. This seems to be true in all vertebrates, although there are many differences in the details between the species.


T cells are formed in  bone marrow  and then migrate to the cortex of the  thymus  to undergo maturation in an antigen-free environment for about one week where a mere 2–4% of the T cells succeed. The remaining 96–98% of T cells die by  apoptosis  and are  phagocytosed  by  macrophages  in the thymus. So many thymocytes (T cells) die during the maturation process because there is intensive screening to make sure each thymocyte can recognize  self-peptide:self-MHC complex [ 12 ]  and for  self-tolerance . Having experienced apoptosis, the thymocyte dies and is quickly recycled.


Upon maturity, there are several forms of thymocytes including  [ 13 ]


When T cells become  activated  they undergo a further series of developments. A small, resting T lymphocyte rapidly undergoes  blastogenic transformation  into a large lymphocyte (13–15  μm ).  This large lymphocyte (known in this context as a  lymphoblast ) then divides several times to produce an expanded population of medium (9–12 μm) and small lymphocytes (5–8 μm) with the same   antigenic specificity . [ 14 ]  Final activated and differentiated T lymphocytes are once again  morphologically  indistinguishable from a small, resting lymphocyte. Thus the following developmental states may be noticed in sequence in blood tests:


Basic Map of T Cell lymphopoiesis


This basic map of T Cell formation in sequence, is simplified and is akin to textbook descriptions, and may not reflect latest research. (Medical Immunology, p. 119)


In the thymus


In the  Periphery


Unlike other lymphoid lineages, T cell development occurs almost exclusively in the thymus. T-lymphopoiesis does not occur automatically but requires signals generated from the thymus  stromal  cells. Several stages at which specific regulators and growth factors are required for T cell development to proceed have been defined. Later in T cell development and its maturation, these same regulatory factors again are used to influence T cell specialization. [ citation needed ]


T cells are unique among the lymphocyte populations in their ability to further specialize as mature cells and become yet more mature. T cells come in many flavors, for example: the conventional TcRαβ T cells; the so-called unconventional TcRγδ T cells; NKT cells; and T regulatory cells (T reg ).  Details regarding the developmental and life cycle of the unconventional T cells are less well-described measured to the conventional T cells. [ citation needed ]


Stages of T cell maturation


Stage One:  Thymus Migration


Multi-potent lymphoid progenitors (MLP) enter the T cell pathway as they immigrate to the thymus. The most primitive cells in the thymus are the early thymocyte progenitors (ETP), which retain all lymphoid and myeloid potential but exist only transiently, rapidly differentiating into T and NK lineages. (Medical Immunology, p. 118)


Stage Two:  Proliferative Expansion and T Lineage Commitment


Final commitment to the T cell lineage occurs within the thymus microenvironment, the microscopic structures of the thymus where T cells are nurtured. The most primitive T cells retain multipotential ability and can differentiate into cells of the myeloid or lymphoid lineages (B cells, DC, T cells, or NK cells).


More differentiated double negative T cells (DN2 cells) have more limited potentiality but are not yet fully restricted to the T cell lineage (they can still develop into DC, T cells, or NK cells). Later on, they are fully committed to the T cell lineage- when thymocytes expressing Notch1 receptors engage thymus stromal cells expressing Notch1 ligands, the thymocytes become finally committed to the T-cell lineage. See Gallery Image "Double Negatives"


With the commitment to the T cell lineage, begins a very complex process known as  TCR  gene rearrangement. This creates an enormous diversity of T cells bearing antigen receptors. Afterward some T cells leave the thymus to migrate to the skin and  mucosae .


Stage Three:  β-Selection


Stage Four:  T Cell Receptors Selection


Only 2% to 3% of the differentiating thymocytes, those that express TcR capable of interaction with MHC molecules, but tolerant to self-peptides,  [ further explanation needed ]  survive the Stage Four selection process.


Stage Five:  Continuing Differentiation in the Periphery


It was previously believed that the human thymus remained active as the site of T cell differentiation only until early adulthood and that later in adult life the thymus  atrophies , perhaps even vanishing. Recent reports indicate that the human thymus is active throughout adult life. Thus, several factors may contribute to the supply of T cells in adult life: generation in the thymus, extra-thymic differentiation, and the fact that memory T cells are long-lived and survive for decades.


The thymus also gives rise to the so-called ‘unconventional T cells’ such at γδ T cells, natural killer T cells (NKT) and regulatory T cells (T reg ). [ citation needed ]


γδT cells represent only 1% to 5% of the circulating T cells but are abundant in the mucosal immune system and the skin, where they represent the dominant T cell population. These ‘non-MHC restricted T cells’ are involved in specific primary immune responses, tumor surveillance, immune regulation and wound healing. [ 15 ]


Several differences between αβ and γδ T cell development have been described. They emigrate from the thymus in "waves" of clonal populations, which home to discrete tissues. For example, one kind is found in the peripheral blood while another predominates in the intestinal tract.


Human NKT cells are a unique population and are thought to play an important role in tumor immunity [ 16 ]   and  immunoregulation .


T reg  cells are considered as naturally occurring regulatory T cells. Tregs comprised about 5% of the circulating  CD4 +  T cells. These cells are thought to possess an important autoimmunity property by regulating 'autoreactive' T cells in the  periphery . (Medical Immunology, p. 117-122)


B cells are formed and mature in bone marrow (and spleen).


It is a good mnemonic aide that B cells are formed in the bone marrow, but it is a mere coincidence since B cells were first studied in the chicken's  bursa of Fabricius  and it is from this bursa that B cells get their name. [ citation needed ]


These B cells then leave the bone marrow and migrate via bloodstream and the lymph to peripheral lymphoid tissues, such as a spleen, lymph nodes, tonsils and mucosal tissues. Once in a secondary lymphoid organ the B cell can be introduced to an antigen that it is able to recognize. [ citation needed ]


Through this antigen recognition and other cell interactions the B cell becomes activated and then divides and differentiates to become a plasma cell. The plasma cell, a B cell end product, is a very active  antibody -secreting cell that helps protect the body by attacking and binding to antigen.


Even after many decades of research, some controversy remains as to where B cells mature and 'complete their education', with the possibility remaining that the site may also partially be  peri-intestinal lymphoid tissues . [ 17 ]


B lymphopoiesis occurs exclusively in the bone marrow and B lymphocytes are made continuously throughout life there in a 'microenvironment' composed of  stromal cells ,  extracellular matrix , cytokines and growth factors, which are critical for proliferation, differentiation, and survival of early lymphocyte and B-lineage precursors.


The relative proportion of precursor B cells in the bone marrow remains rather constant throughout the life span of an organism. There are stages such as Pre-B-I cells (5% to 10% of the total); Pre-B-II cells (60% to 70%) while the remaining 20% to 25% are immature B cells.  Most textbooks say that B Cells mature in the bone marrow but, generally, immature B cells migrate to the spleen for 'higher education' of some sort where they go through transitional stages before final maturation. (Medical Immunology, p. 136)


B lymphocytes are identified by the presence of soluble  immunoglobulin G  (IgG). This is the most common protective immunoglobulin in the adult body. After antigenic stimulation, B cells differentiate into plasma cells that secrete large quantities of soluble IgG. This is the final stage of B lymphopoiesis, but it is the clincher because the plasma cells must either issue antibody close to a source of infection or disseminate it in the blood to fight an infection at a distance or in an inaccessible part of the body.


Basic map of B cell lymphopoiesis


A generally regarded valid map of B cell lymphopoiesis is as follows in sequence, in two parts with the first being in the bone marrow and the second in the spleen:. [ 18 ]  The development process in the bone marrow occurs in  germinal centers


In the bone marrow


In the spleen


NK cells, which lack antigen specific receptors, develop in the bone marrow. After maturation and release from the marrow they circulate in the blood through their lifetime seeking opportunity. The opportunity they seek is to encounter and recognize and then kill abnormal cells such as  cancer  or virally infected cells. It is well known that lymphocytes never have granules or at least not granules that are readily visible even upon  staining . However, NK cells are the exception. They do have numerous granules which provide their ability to  kill cells  and these granules are why NK cells have an alternate name- Large Granular Lymphocytes (LGLs). [ citation needed ]


NK cells are the only lymphocytes considered part of the  innate immune system  (in contrast to the  adaptive immune system . Yet they are much more closely related to T cells (part of the  adaptive immune system ) than to other cells of the innate immune system. NK cells not only share many surface markers, functions and activities in common with T Cells, they also arise from a common T/NK progenitor.  The T/NK precursor is also believed to be the source of a subpopulation of lymphoid DC. (Medical Immunology, p. 121)


NK cells have a definition 'barcode' as CD3, CD16+, CD56t lymphocytes. (See Barcode Section of this article). NK progenitors can be found mainly in the thymus (mouse), but the thymus is not absolutely required for NK development.  Probably NK cells can develop in a variety of organs, but the major site of NK cell development is not known. [ citation needed ]