Alexander Bogdanov  founded an academic institution devoted to the science of blood transfusion in  Moscow  in 1925. Bogdanov was motivated, at least in part, by a search for  eternal youth , and remarked with satisfaction on the improvement of his eyesight, suspension of balding, and other positive symptoms after receiving 11 transfusions of  whole blood . Bogdanov died in 1928 as a result of one of his experiments, when the blood of a student with  malaria  and  tuberculosis  was given to him in a transfusion. [ 113 ]  Following Bogdanov's lead, Vladimir Shamov and  Sergei Yudin  in the  USSR  pioneered the  transfusion of cadaveric blood  from recently deceased donors. Yudin performed such a transfusion successfully for the first time on March 23, 1930, and reported his first seven  clinical  transfusions with cadaveric blood at the Fourth Congress of  Ukrainian  Surgeons at Kharkiv in September. However, this method was never used widely, even in the Soviet Union. Nevertheless, the Soviet Union was the first to establish a network of facilities to collect and store blood for use in transfusions at hospitals.


Frederic Durán-Jordà  established one of the earliest blood banks during the  Spanish Civil War  in 1936. Duran joined the Transfusion Service at the  Barcelona Hospital  at the start of the conflict, but the hospital was soon overwhelmed by the demand for blood and the paucity of available donors. With support from the Department of Health of the  Spanish Republican Army , Duran established a blood bank for the use of wounded soldiers and civilians. The 300–400 mL of extracted blood was mixed with 10% citrate solution in a modified Duran Erlenmeyer flask. The blood was stored in a sterile glass enclosed under pressure at 2 °C. During 30 months of work, the Transfusion Service of Barcelona registered almost 30,000 donors, and processed 9,000 liters of blood. [ 114 ]


In 1937  Bernard Fantus , director of therapeutics at the  Cook County Hospital  in  Chicago , established the first hospital blood-bank in the  United States . In setting up a hospital laboratory that preserved, refrigerated and stored donor blood, Fantus originated the term "blood bank". Within a few years, hospital and community blood-banks were established across the United States. [ 115 ]   Until the middle of World War II, the newly established US blood banks rejected African-American donors.  During the war, Black people were allowed to donate blood, but the donated blood was labeled as being suitable only for transfusion into another person from the same race. [ 116 ]


Frederic Durán-Jordà fled to Britain in 1938 and worked with Dr  Janet Vaughan  at the  Royal Postgraduate Medical School  at Hammersmith Hospital to establish a system of national blood banks in London. [ 117 ]  With the outbreak of  war  appearing imminent in 1938, the  War Office  created the Army Blood Supply Depot (ABSD) in Bristol, headed by  Lionel Whitby  and in control of four large blood-depots around the country. British policy through the war was to supply military personnel with blood from centralized depots, in contrast to the approach taken by the Americans and Germans where troops at the front were bled to provide required blood. The British method proved more successful in adequately meeting all requirements, and over 700,000 donors were bled over the course of the war. This system evolved into the  National Blood Transfusion Service  established in 1946, the first national service to be implemented.
 [ 118 ]


Stories tell of  Nazis  in Eastern Europe during World War II using captive children as repeated involuntary blood-donors. [ 119 ]


A blood-collection program was initiated [ by whom? ]  in the US in 1940 and  Edwin Cohn  pioneered the process of  blood fractionation . He worked out the techniques for isolating the  serum albumin  fraction of  blood plasma , which is essential for maintaining the  osmotic pressure  in the  blood vessels , preventing their collapse.


Gordon R. Ward, writing in the correspondence columns of the  British Medical Journal , proposed the use of  blood plasma  as a substitute for whole blood and for transfusion purposes as early as 1918. At the onset of  World War II , liquid plasma was used in Britain. A large project, known as "Blood for Britain", began in August 1940 to collect blood in  New York City  hospitals for the export of plasma to  Britain . A  freeze-dried  plasma package was developed by the Surgeons General of the Army and Navy, working with the  National Research Council , [ 120 ]  which reduced breakage and made transportation, packaging, and storage much simpler. [ 121 ]


The resulting dried plasma package came in two tin cans containing 400 mL bottles. One bottle contained enough  distilled water  to reconstitute the dried plasma contained within the other bottle. In about three minutes, the plasma would be ready to use and could stay fresh for around four hours. [ 122 ]  Dr.  Charles R. Drew  was appointed medical supervisor, and he was able to transform the  test-tube  methods into the first successful technique for mass production.


Another important breakthrough came in 1937–40 when  Karl Landsteiner  (1868–1943), Alex Wiener, Philip Levine, and R.E. Stetson discovered the  Rhesus blood group system , which was found to be the cause of the majority of  transfusion reactions  up to that time. Three years later, the introduction by  J.F. Loutit  and Patrick L. Mollison of  acid–citrate–dextrose  (ACD) solution, which reduced the volume of anticoagulant, permitted transfusions of greater volumes of blood and allowed longer-term storage.


Carl Walter and W.P. Murphy Jr. introduced the  plastic bag  for blood collection in 1950. Replacing breakable  glass  bottles with durable plastic bags made from  PVC  allowed for the evolution of a collection system capable of safe and easy preparation of multiple blood components from a single unit of whole blood.


In the field of  cancer surgery , the replacement of massive blood-loss became a major problem. The cardiac-arrest rate was high. In 1963 C. Paul Boyan and William S. Howland discovered that the temperature of the blood and the rate of infusion greatly affected survival rates, and introduced blood warming to surgery. [ 123 ] [ 124 ]


Further extending the shelf-life of stored blood up to 42 days was an anticoagulant preservative, CPDA-1, introduced in 1979, which increased the blood supply and facilitated resource-sharing among blood banks. [ 125 ] [ 126 ]


As of 2006 [update]  about 15 million units of blood products were transfused per year in the United States. [ 127 ]  By 2013 the number had declined to about 11 million units, because of the shift towards  laparoscopic surgery  and other surgical advances and studies that have shown that many transfusions were unnecessary. For example, the standard of care reduced the amount of blood transfused in one case from 750 to 200 mL. [ 77 ]   In 2019, 10,852,000 RBC units, 2,243,000 platelet units, and 2,285,000 plasma units were transfused in the United States. [ 78 ]


To ensure the safety of blood transfusion to pediatric patients, hospitals are taking additional precautions to avoid infection and prefer to use pediatric blood units that are guaranteed "safe" from  Cytomegalovirus . Some guidelines have recommended the provision of CMV-negative blood components and not simply leukoreduced components for newborns or low birthweight infants in whom the immune system is not fully developed, [ 128 ]  but practice varies. [ 129 ]  These requirements place additional restrictions on blood donors who can donate for neonatal use, which may be impractical given the rarity of CMV seronegative donors and the preference for fresh units.


Neonatal transfusions typically fall into one of two categories:


A  massive transfusion protocol  is used when significant blood loss is present such as in  major trauma , when more than ten units of blood are needed. Packed red blood cells, fresh frozen plasma, and platelets are generally administered. [ 131 ]  Typical ratios of  fresh frozen plasma ,  platelets  and  packed red blood cells  are between 1:1:1 and 1:1:2. [ 132 ]


In some locations, blood has begun to be administered  pre-hospital  in an effort to reduce preventable deaths from significant blood loss. Earlier analyses suggested that in the US, up to 31,000 patients per year bleed to death that otherwise could have survived if pre-hospital transfusions were widely available. [ 133 ]  For example, when a mother experiences severe blood loss during pregnancy, [ 134 ]  ambulances are able to arrive with blood stored in portable, FDA listed blood refrigerators, similar to those found in blood banks. Once the infusion is given on scene, the patient and the ambulance have more time to get to a hospital for surgery and additional infusions if needed. This could be critical in rural areas or sprawling cities where patients can be far from a major hospital and the local emergency medical team may need to use blood infusions to keep that patient alive during transport.  Larger studies pointed to improvements in 24-hour mortality with pre-hospital plasma and RBC transfusions, but no difference in 30-day or long-term mortality. [ 135 ]


Because  blood type  O negative is compatible with anyone, it is often overused and in short supply. [ 136 ]  According to the   Association for the Advancement of Blood and Biotherapies , the use of this blood should be restricted to persons with O negative blood, as nothing else is compatible with them, and women who might be pregnant and for whom it would be impossible to do blood group testing before giving them emergency treatment. [ 136 ]  Whenever possible, the AABB recommends that O negative blood be conserved by using blood type testing to identify a less scarce alternative. [ 136 ]


Jehovah's Witnesses may object to blood transfusions  because of their belief that blood is sacred. [ 137 ]


Sometimes people refuse blood transfusions because of fears about the safety of the blood supply. [ 116 ]   Generally speaking, the rules of  informed consent  allow mentally  competent  adults to refuse blood transfusions even when their objections are based on  misinformation  or  prejudice  and even when their refusal may result in serious and permanent harm, including death. [ 116 ]   For example, since  COVID-19 vaccines  became available, some people in the US have refused blood transfusions because the donor might have been vaccinated, and they fear that this would cause secondhand harm to them. [ 116 ]   This choice is based on false beliefs, but a mentally competent adult's choices are normally respected. [ 138 ]   However, if doctor's opinions are that parents and guardians are making harmful choices about children, they can be overruled (in some jurisdictions) using legal arguments based on the  harm principle ; in this case if doctors believe that refusing the blood transfusion would put the child at risk of serious injury or death. [ 138 ]   Blood banks do not collect information that is irrelevant to the transfusion process, including the donors' race, ethnicity, sexual orientation, COVID-19 vaccination status, etc., so selecting blood units based on the individual's personal objections is not practical. [ 116 ] [ 138 ]


Although there are clinical situations where transfusion with red blood cells is the only clinically appropriate option, clinicians look at whether alternatives are feasible. This can be due to several reasons, such as patient safety, economic burden or scarcity of blood. Guidelines recommend blood transfusions should be reserved for patients with or at risk of cardiovascular instability due to the degree of their anaemia. [ 139 ] [ 140 ]  In stable patients with iron deficiency anemia, oral or  parenteral iron  is recommended.


Thus far, there are no FDA-approved  oxygen-carrying   blood substitutes , which is the typical objective of a blood (RBC) transfusion. Non-blood  volume expanders  are available for cases where only volume restoration is required, but a substance with oxygen-carrying capacity would help doctors and surgeons avoid the risks of disease transmission and immune suppression, address the chronic blood donor shortage, and address the concerns of  Jehovah's Witnesses  and others who have religious objections to receiving transfused blood.


The research in this area is ongoing. A number of blood substitutes have been explored, but thus far they all have serious limitations. [ 141 ] [ 142 ]  Most attempts to find a suitable alternative to blood thus far have concentrated on cell-free hemoglobin solutions. Blood substitutes could make transfusions more readily available in  emergency medicine  and in pre-hospital  EMS  care. If successful, such a blood substitute could save many lives, particularly in trauma where massive blood loss results.  Hemopure , a hemoglobin-based therapy, is approved for use in  South Africa  and has been used in the United States on a case-by-case basis through the emergency Investigational New Drug (IND) process. [ 143 ]


Veterinarians  also administer transfusions to other animals. Various  species  require different levels of testing to ensure a compatible match. For example,  cats  have 3 known blood types, [ 144 ]   cattle  have 11, [ 144 ]   dogs  have at least 13, [ 145 ]   pigs  have 16, [ 146 ]  and  horses  over 30. [ 144 ]  However, in many species (especially horses and dogs), cross matching is not required before the  first  transfusion, as antibodies against non-self cell surface antigens are not expressed constitutively — i.e. the animal has to be sensitized before it will mount an immune response against the transfused blood. [ 147 ]


The rare and experimental practice of inter-species blood transfusions ( xenotransfusion ) is a form of  xenograft .


A  blood type  (also known as a  blood group ) is  a classification of  blood , based on the presence and absence of  antibodies  and  inherited   antigenic  substances on the surface of  red blood cells  (RBCs). These antigens may be  proteins ,  carbohydrates ,  glycoproteins , or  glycolipids , depending on the blood group system. Some of these antigens are also present on the surface of other types of  cells  of various  tissues . Several of these red blood cell surface antigens can stem from one  allele  (or an alternative version of a gene) and collectively form a blood group system. [ 1 ]


Blood types are inherited and represent contributions from both parents of an individual. As of 31 December 2023, [update]  a total of 45 [ 2 ]   human blood group systems  are recognized by the  International Society of Blood Transfusion  (ISBT). [ 3 ]  The two most important blood group systems are  ABO  and  Rh ; they determine someone's blood type (A, B, AB, and O, with + or − denoting  RhD  status) for suitability in  blood transfusion .


A complete blood type would describe each of the 45 blood groups, and an individual's blood type is one of many possible combinations of blood-group antigens. [ 3 ]  Almost always, an individual has the same blood group for life, but very rarely an individual's blood type changes through addition or suppression of an antigen in  infection ,  malignancy , or  autoimmune disease . [ 4 ] [ 5 ] [ 6 ] [ 7 ]  Another more common cause of blood type change is a  bone marrow transplant . Bone-marrow transplants are performed for many  leukemias  and  lymphomas , among other diseases. If a person receives bone marrow from someone of a different ABO type (e.g., a type O patient receives a type A bone marrow), the patient's blood type should eventually become the donor's type, as the patient's  hematopoietic stem cells  (HSCs) are destroyed, either by ablation of the bone marrow or by the donor's T-cells. Once all the patient's original red blood cells have died, they will have been fully replaced by new cells derived from the donor HSCs. Provided the donor had a different ABO type, the new cells' surface antigens will be different from those on the surface of the patient's original red blood cells. [ 8 ]


Some blood types are associated with inheritance of other diseases; for example, the  Kell antigen  is sometimes associated with  McLeod syndrome . [ 9 ] For another example,  Von Willebrand disease  may be more severe or apparent in people with blood type O.  Certain blood types may affect susceptibility to infections.  For example, people with blood type O may be less susceptible to pro-thrombotic events induced by  COVID-19  or  long covid . [ 10 ] [ 11 ]  Another example being the resistance to specific  malaria  species seen in individuals lacking the  Duffy antigen . [ 12 ]  The Duffy antigen, presumably as a result of  natural selection , is less common in population groups from areas having a high incidence of malaria. [ 13 ]


The ABO blood group system involves two antigens and two antibodies found in human blood. The two antigens are antigen A and antigen B. The two antibodies are antibody A and antibody B. The antigens are present on the red blood cells and the antibodies in the  serum . Regarding the antigen property of the blood all human beings can be classified into four groups, those with antigen A (group A), those with antigen B (group B), those with both antigen A and B (group AB) and those with neither antigen (group O). The antibodies present together with the antigens are found as follows: [ citation needed ]


There is an  agglutination  reaction between similar antigen and antibody (for example, antigen A agglutinates the antibody A and antigen B agglutinates the antibody B). Thus, transfusion can be considered safe as long as the serum of the recipient does not contain antibodies for the blood cell antigens of the donor. [ citation needed ]


The ABO system is the most important blood-group system in human-blood transfusion. The associated anti-A and anti-B antibodies are usually  immunoglobulin M , abbreviated  IgM , antibodies. It has been hypothesized that ABO IgM  antibodies  are produced in the first years of life by sensitization to environmental substances such as food,  bacteria , and  viruses , although blood group compatibility rules are applied to newborn and infants as a matter of practice. [ 14 ]  The original terminology used by  Karl Landsteiner  in 1901 for the classification was A/B/C; in later publications "C" became "O". [ 15 ]  Type O is often called  0  ( zero , or  null ) in other languages. [ 15 ] [ 16 ]


The Rh system (Rh meaning  Rhesus ) is the second most significant blood-group system in human-blood transfusion with currently 50 antigens. The most significant Rh antigen is the D antigen, because it is the most likely to provoke an immune system response of the five main Rh antigens. It is common for D-negative individuals not to have any anti-D IgG or IgM antibodies, because anti-D antibodies are not usually produced by sensitization against environmental substances. However, D-negative individuals can produce  IgG  anti-D antibodies following a sensitizing event: possibly a fetomaternal transfusion of blood from a fetus in pregnancy or occasionally a blood transfusion with D positive  RBCs . [ 17 ]   Rh disease  can develop in these cases. [ 18 ]  Rh negative blood types are much less common in Asian populations (0.3%) than they are in European populations (15%). [ 19 ]


The presence or absence of the Rh(D) antigen is signified by the + or − sign, so that, for example, the A− group is ABO type A and does not have the Rh (D) antigen. [ 20 ]


As with many other genetic traits, the distribution of ABO and Rh blood groups varies significantly between populations. [ citation needed ] [ 21 ]  While theories are still debated in the scientific community as to why blood types vary geographically and why they emerged in the first place, evidence suggests that the evolution of blood types may be driven by genetic selection for those types whose antigens confer resistance to particular diseases in certain regions – such as the prevalence of blood type O in malaria-endemic countries where individuals of blood type O exhibit the highest rates of survival. [ 22 ]


As of 31 December 2022, [update]  42 blood-group systems have been identified by the International Society for Blood Transfusion in addition to the ABO and Rh systems. [ 3 ]  Thus, in addition to the ABO antigens and Rh antigens, many other antigens are expressed on the RBC surface membrane. For example, an individual can be AB, D positive, and at the same time M and N positive ( MNS system ), K positive ( Kell system ), Le a  or Le b  negative ( Lewis system ), and so on, being positive or negative for each blood group system antigen. Many of the blood group systems were named after the patients in whom the corresponding antibodies were initially encountered. Blood group systems other than ABO and Rh pose a potential, yet relatively low, risk of complications upon mixing of blood from different people. [ 23 ]


Following is a comparison of clinically relevant characteristics of antibodies against the main human blood group systems: [ 24 ]


Transfusion medicine is a specialized branch of  hematology  that is concerned with the study of blood groups, along with the work of a  blood bank  to provide a  transfusion  service for blood and other blood products. Across the world, blood products must be prescribed by a medical doctor (licensed  physician  or  surgeon ) in a similar way as medicines. [ citation needed ]


Much of the routine work of a  blood bank  involves testing blood from both donors and recipients to ensure that every individual recipient is given blood that is compatible and as safe as possible. If a unit of incompatible blood is  transfused  between a  donor  and recipient, a severe  acute hemolytic reaction  with  hemolysis  (RBC destruction),  kidney failure  and  shock  is likely to occur, and death is a possibility. [ 27 ]  Antibodies can be highly active and can attack RBCs and bind components of the  complement system  to cause massive hemolysis of the transfused blood. [ 28 ]


Patients should ideally receive their own blood or type-specific blood products to minimize the chance of a  transfusion reaction . It is also possible to use the patient's own blood for transfusion. This is called  autotransfusion , which is always compatible with the patient. The procedure of washing a patient's own red blood cells goes as follows: The patient's lost blood is collected and washed with a saline solution. The washing procedure yields concentrated washed red blood cells. The last step is reinfusing the packed red blood cells into the patient. There are multiple ways to wash red blood cells. The two main ways are centrifugation and filtration methods. This procedure can be performed with microfiltration devices like the Hemoclear filter. Risks can be further reduced by  cross-matching  blood, but this may be skipped when blood is required for an emergency. Cross-matching involves mixing a sample of the recipient's serum with a sample of the donor's red blood cells and checking if the mixture  agglutinates , or forms clumps. If agglutination is not obvious by direct vision, blood bank technologist usually check for  agglutination  with a  microscope . If agglutination occurs, that particular donor's blood cannot be transfused to that particular recipient.  In a blood bank it is vital that all blood specimens are correctly identified, so labelling has been standardized using a  barcode  system known as  ISBT 128 .


The blood group may be included on  identification tags  or on  tattoos  worn by military personnel, in case they should need an emergency blood transfusion. Frontline German  Waffen-SS had blood group tattoos  during  World War II .


Rare blood types can cause supply problems for  blood banks  and hospitals. For example,  Duffy -negative blood occurs much more frequently in people of African origin, [ 29 ]  and the rarity of this blood type in the rest of the population can result in a shortage of Duffy-negative blood for these patients.  Similarly, for RhD negative people there is a risk associated with travelling to parts of the world where supplies of RhD negative blood are rare, particularly  East Asia , where blood services may endeavor to encourage Westerners to donate blood. [ 30 ]


A  pregnant  woman may carry a  fetus  with a blood type which is different from her own. Typically, this is an issue if a Rh- mother has a child with a Rh+ father, and the fetus ends up being Rh+ like the father. [ 31 ]  In those cases, the mother can make  IgG  blood group antibodies. This can happen if some of the fetus' blood cells pass into the mother's blood circulation (e.g. a small fetomaternal  hemorrhage  at the time of childbirth or obstetric intervention), or sometimes after a therapeutic  blood transfusion .  This can cause  Rh disease  or other forms of  hemolytic disease of the newborn  (HDN) in the current pregnancy and/or subsequent pregnancies.  Sometimes this is lethal for the fetus; in these cases it is called  hydrops fetalis . [ 32 ]  If a pregnant woman is known to have anti-D antibodies, the Rh blood type of a  fetus  can be tested by analysis of fetal DNA in maternal plasma to assess the risk to the fetus of Rh disease. [ 33 ]  One of the major advances of twentieth century medicine was to prevent this disease by stopping the formation of Anti-D antibodies by D negative mothers with an injectable medication called  Rho(D) immune globulin . [ 34 ] [ 35 ]  Antibodies associated with some blood groups can cause severe HDN, others can only cause mild HDN and others are not known to cause HDN. [ 32 ]


To provide maximum benefit from each blood donation and to extend shelf-life,  blood banks   fractionate  some whole blood into several products. The most common of these products are packed RBCs,  plasma ,  platelets ,  cryoprecipitate , and  fresh frozen plasma  (FFP).  FFP is quick-frozen to retain the labile  clotting factors   V  and  VIII , which are usually administered to patients who have a potentially fatal clotting problem caused by a condition such as advanced  liver  disease, overdose of  anticoagulant , or  disseminated intravascular coagulation  (DIC). [ citation needed ]


Units of packed red cells are made by removing as much of the plasma as possible from whole blood units.


Clotting factors  synthesized by modern  recombinant  methods are now in routine clinical use for  hemophilia , as the risks of infection transmission that occur with pooled blood products are avoided.


Table note
1. Assumes absence of atypical antibodies that would cause an incompatibility between donor and recipient blood, as is usual for blood selected by cross matching.


An Rh D-negative patient who does not have any anti-D antibodies (never being previously sensitized to D-positive RBCs) can receive a transfusion of D-positive blood once, but this would cause sensitization to the D antigen, and a female patient would become at risk for  hemolytic disease of the newborn .  If a D-negative patient has developed anti-D antibodies, a subsequent exposure to D-positive blood would lead to a potentially dangerous transfusion reaction. Rh D-positive blood should never be given to D-negative women of child-bearing age or to patients with D antibodies, so blood banks must conserve Rh-negative blood for these patients. In extreme circumstances, such as for a major bleed when stocks of D-negative blood units are very low at the blood bank, D-positive blood might be given to D-negative females above child-bearing age or to Rh-negative males, providing that they did not have anti-D antibodies, to conserve D-negative blood stock in the blood bank. The converse is not true; Rh D-positive patients do not react to D negative blood.


This same matching is done for other antigens of the Rh system as C, c, E and e and for other blood group systems with a known risk for immunization such as the Kell system in particular for females of child-bearing age or patients with known need for many transfusions.


Blood plasma  compatibility is the inverse of red blood cell compatibility. [ 39 ]  Type AB plasma carries neither anti-A nor anti-B antibodies and can be transfused to individuals of any blood group; but type AB patients can only receive type AB plasma. Type O carries both antibodies, so individuals of blood group O can receive plasma from any blood group, but type O plasma can be used only by type O recipients.


Table note
1. Assuming absence of strong atypical antibodies in donor plasma


Rh D antibodies are uncommon, so generally neither D negative nor D positive blood contain anti-D antibodies.  If a potential donor is found to have anti-D antibodies or any strong atypical blood group antibody by antibody screening in the blood bank, they would not be accepted as a donor (or in some blood banks the blood would be drawn but the product would need to be appropriately labeled); therefore, donor blood plasma issued by a blood bank can be selected to be free of D antibodies and free of other atypical antibodies, and such donor plasma issued from a blood bank would be suitable for a recipient who may be D positive or D negative, as long as blood plasma and the recipient are ABO compatible. [ citation needed ]


In transfusions of packed red blood cells, individuals with type O Rh D negative blood are often called universal donors. Those with type AB Rh D positive blood are called universal recipients. However, these terms are only generally true with respect to possible reactions of the recipient's anti-A and anti-B antibodies to transfused red blood cells, and also possible sensitization to Rh D antigens. One exception is individuals with  hh antigen system  (also known as the Bombay phenotype) who can only receive blood safely from other hh donors, because they form antibodies against the H antigen present on all red blood cells. [ 41 ] [ 42 ]


Blood donors with exceptionally strong anti-A, anti-B or any atypical blood group antibody may be excluded from blood donation. In general, while the plasma fraction of a blood transfusion may carry donor antibodies not found in the recipient, a significant reaction is unlikely because of dilution.


Additionally, red blood cell surface antigens other than A, B and Rh D, might cause adverse reactions and sensitization, if they can bind to the corresponding antibodies to generate an immune response.  Transfusions are further complicated because  platelets  and  white blood cells  (WBCs) have their own systems of surface antigens, and sensitization to platelet or WBC antigens can occur as a result of transfusion.


For transfusions of  plasma , this situation is reversed.  Type O plasma, containing both anti-A and anti-B antibodies, can only be given to O recipients.  The antibodies will attack the antigens on any other blood type.  Conversely, AB plasma can be given to patients of any ABO blood group, because it does not contain any anti-A or anti-B antibodies.


Typically, blood type tests are performed through addition of a blood sample to a solution containing antibodies corresponding to each antigen. The presence of an antigen on the surface of the blood cells is indicated by  agglutination .


In addition to the current practice of serologic testing of blood types, the progress in molecular diagnostics allows the increasing use of blood group genotyping. In contrast to serologic tests reporting a direct blood type phenotype, genotyping allows the prediction of a phenotype based on the knowledge of the molecular basis of the currently known antigens. This allows a more detailed determination of the blood type and therefore a better match for transfusion, which can be crucial in particular for patients with needs for many transfusions to prevent allo-immunization. [ 43 ] [ 44 ]


Blood types were first discovered by an Austrian physician,  Karl Landsteiner , working at the Pathological-Anatomical Institute of the University of Vienna (now  Medical University of Vienna ). In 1900, he found that blood sera from different persons would clump together (agglutinate) when mixed in test tubes, and not only that, some human blood also agglutinated with animal blood. [ 45 ]  He wrote a two-sentence footnote:


The serum of healthy human beings not only agglutinates animal red cells, but also often those of human origin, from other individuals. It remains to be seen whether this appearance is related to inborn differences between individuals or it is the result of some damage of bacterial kind. [ 46 ]


This was the first evidence that blood variation exists in humans. The next year, in 1901, he made a definitive observation that blood serum of an individual would agglutinate with only those of certain individuals. Based on this he classified human bloods into three groups, namely group A, group B, and group C. He defined that group A blood agglutinates with group B, but never with its own type. Similarly, group B blood agglutinates with group A. Group C blood is different in that it agglutinates with both A and B. [ 47 ]  This was the discovery of blood groups for which Landsteiner was awarded the Nobel Prize in Physiology or Medicine in 1930. (C was later renamed to O after the German  Ohne , meaning without, or zero, or null. [ 48 ] ) Another group (later named AB) was discovered a year later by Landsteiner's students Adriano Sturli and Alfred von Decastello without designating the name (simply referring it to as "no particular type"). [ 49 ] [ 50 ]  Thus, after Landsteiner, three blood types were initially recognised, namely A, B, and C. [ 50 ]


Czech serologist  Jan Janský  was the first to recognise and designate four blood types in 1907 that he published in a local journal, [ 51 ]  using the Roman numerical I, II, III, and IV (corresponding to modern O, A, B, and AB respectively). [ 52 ]  Unknown to Janský, American physician  William L. Moss  introduced an almost identical classification in 1910, [ 53 ]  but with Moss's I and IV corresponding to Janský's IV and I. [ 54 ]  Thus the existence of two systems immediately created confusion and potential danger in medical practice. Moss's system was adopted in Britain, France, and the US, while Janský's was preferred in most other European countries and some parts of the US. It was reported that "The practically universal use of the Moss classification at that time was completely and purposely cast aside. Therefore in place of bringing order out of chaos, chaos was increased in the larger cities." [ 55 ]  To resolve the confusion, the  American Association of Immunologists , the  Society of American Bacteriologists , and the Association of Pathologists and Bacteriologists made a joint recommendation in 1921 that the Jansky classification be adopted based on priority. [ 56 ]  But it was not followed particularly where Moss's system had been used. [ 57 ]


In 1927, Landsteiner, who had moved to the  Rockefeller Institute for Medical Research  in New York, and as a member of a committee of the  National Research Council  concerned with blood grouping suggested to substitute Janský's and Moss's systems with the letters O, A, B, and AB, first instroduced by Polish physician  Ludwik Hirszfeld  and German physician  Emil von Dungern . [ 58 ]  There was another confusion on the use of O which was introduced in 1910. [ 59 ]  It was never clear whether it was meant for the figure 0, German  null  for zero or the upper case letter O for  ohne , meaning without; Landsteiner chose the latter. [ 60 ]


In 1928 the Permanent Commission on Biological Standardization adopted Landsteiner's proposal and stated:


The Commission learns with satisfaction that, on the initiative of the Health Organization of the League of Nations, the nomenclature proposed by von Dungern and Hirszfeld for the classification of blood groups has been generally accepted, and recommends that this nomenclature shall be adopted for international use as follows: 0 A B AB. To facilitate the change from the nomenclature hitherto employed the following is suggested:


This classification became widely accepted and after the early 1950s it was universally followed. [ 62 ]


Hirszfeld and Dungern discovered the inheritance of blood types as  Mendelian genetics  in 1910 and the existence of sub-types of A in 1911. [ 59 ] [ 63 ]  In 1927, Landsteiner, with  Philip Levine , discovered the  MN blood group system , [ 64 ]  and the  P system . [ 65 ]  Development of the  Coombs test  in 1945, [ 66 ]  the advent of  transfusion medicine , and the understanding of  ABO hemolytic disease of the newborn  led to discovery of more blood groups. As of October 2024 [update] , the International Society of Blood Transfusion (ISBT) recognizes 47 blood groups. [ 3 ]


A popular  pseudoscientific  belief in Eastern Asian countries (especially in  Japan  and  South Korea [ 67 ] ) known as 血液型  ketsuekigata / hyeoraekhyeong  is that a person's ABO blood type is predictive of their  personality ,  character , and  compatibility with others . [ 68 ]  Researchers have established no scientific basis exists for blood type personality categorization, and studies have found no "significant relationship between personality and blood type, rendering the theory 'obsolete' and concluding that no basis exists to assume that personality is anything more than randomly associated with blood type." [ 67 ]


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Bone marrow examination  refers to the  pathologic  analysis of samples of  bone marrow  obtained by  bone marrow biopsy  (often called  trephine  biopsy) and  bone marrow aspiration . Bone marrow examination is used in the diagnosis of a number of conditions, including  leukemia ,  multiple myeloma ,  lymphoma ,  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.


Bone marrow samples can be obtained by aspiration and trephine biopsy.  Sometimes, a bone marrow examination will include both an aspirate and a biopsy.  The aspirate yields semi-liquid bone marrow, which can be examined by a  pathologist  under a  light microscope  and analyzed by  flow cytometry ,  chromosome analysis , or  polymerase chain reaction  (PCR). Frequently, a trephine biopsy is also obtained, which yields a narrow, cylindrically shaped solid piece of bone marrow, 2 mm wide and 2 cm long (80 μL), which is examined microscopically (sometimes with the aid of  immunohistochemistry ) for cellularity and infiltrative processes. An aspiration, using a 20 mL syringe, yields approximately 300 μL of bone marrow. [ 1 ]  A volume greater than 300 μL is not recommended, since it may dilute the sample with peripheral blood. [ 1 ]


Aspiration does not always represent all cells since some such as  lymphoma  stick to the  trabecula , and would thus be missed by a simple aspiration. [ citation needed ]


Bone marrow aspiration and trephine biopsy are usually performed on the back of the hipbone, or posterior  iliac crest .  An  aspirate  can also be obtained from the  sternum  (breastbone).  For the sternal aspirate, the patient lies on their back, with a pillow under the shoulder to raise the chest. A  trephine biopsy  should never be performed on the sternum, due to the risk of injury to  blood vessels ,  lungs  or the  heart .  Bone marrow aspiration may also be performed on the tibial (shinbone) site in children up to 2 years of age while spinous process aspiration is frequently done in a lumbar puncture position and on the L3-L4 vertebrae. [ citation needed ]


Anesthesia is used to reduce surface pain at the spot where the needle is inserted.  Pain may result from the procedure's insult to the marrow, which cannot be anesthetized, as well as short periods of pain from the anesthetic process itself.  The experience is not uniform; different patients report different levels of pain, and some do not report any pain at certain expected points. [ 2 ]


A bone marrow biopsy may be done in a health care provider's office or in a hospital.  Informed consent  for the procedure is typically required. The patient is asked to lie on their abdomen ( prone position ) or on their side (lateral  decubitus  position). The skin is cleansed, and a  local anesthetic  such as  lidocaine  or  procaine  is injected to numb the area. Patients may also be pretreated with  analgesics  and/or  anti-anxiety medications , although this is not a routine practice.


Typically, the aspirate is performed first. An aspirate needle is inserted through the skin using manual pressure and force until it hits the  bone . Then, with a twisting motion of clinician's hand and wrist, the needle is advanced through the  bony cortex  (the hard outer layer of the bone) and into the marrow cavity. Once the needle is in the marrow cavity, a syringe is attached and used to aspirate ("suck out") liquid bone marrow. A twisting motion is performed during the aspiration to avoid excess content of blood in the sample, which might be the case if an excessively large sample from one single point is taken. Subsequently, the biopsy is performed if indicated.  A different, larger  trephine  needle is inserted and anchored in the bony cortex. The needle is then advanced with a twisting motion and rotated to obtain a solid piece of bone marrow. This piece is then removed along with the needle. The entire procedure, once preparation is complete, typically takes 10–15 minutes.


If several samples are taken, the needle is removed between the samples to avoid blood coagulation.


After the procedure is complete, the patient is typically asked to lie flat for 5–10 minutes to provide pressure over the procedure site. After that, assuming no bleeding is observed, the patient can get up and go about their normal activities.  Paracetamol  (aka acetaminophen) or other simple analgesics can be used to ease soreness, which is common for 2–3 days after the procedure. Any worsening pain, redness, fever, bleeding or swelling may suggest a complication. Patients are also advised to avoid washing the procedure site for at least 24 hours after the procedure is completed.


There are few  contraindications  to bone marrow examination. It is important to note that thrombocytopenia or bleeding disorders are  not  contraindications as long as the procedure is performed by a skilled clinician. [ 3 ]  Bone marrow aspiration and biopsy can be safely performed even in the setting of extreme  thrombocytopenia  (low  platelet  count). If there is a skin or soft tissue infection over the hip, a different site should be chosen for bone marrow examination. [ citation needed ]


While mild soreness lasting 12–24 hours is common after a bone marrow examination, serious  complications  are extremely rare. In a large review, an estimated 55,000 bone marrow examinations were performed, with 26  serious adverse events  (0.05%), including one fatality. [ 4 ]  The same author collected data on over 19,000 bone marrow examinations performed in the  United Kingdom  in 2003, and found 16  adverse events  (0.08% of total procedures), the most common of which was bleeding. In this report, complications, while rare, were serious in individual cases. [ 5 ]


Bone marrow failure  occurs in individuals who produce an insufficient amount of  red blood cells ,  white blood cells  or  platelets .  Red blood cells  transport oxygen to be distributed throughout the body's tissue.  White blood cells  fight off infections that enter the body. Bone marrow progenitor cells known as  megakaryocytes  produce  platelets , which trigger  clotting , and thus help stop the blood flow when a wound occurs. [ 1 ]


The two most common signs and symptoms of bone marrow failure are bleeding and bruising. Blood may be seen throughout the gums, nose or the skin, and bleeding tends to last longer than normal. Children have a greater chance of seeing blood in their urine or stools, which results in digestive problems with an unpleasant scent. Individuals with this condition may also encounter tooth loss or tooth decay. Chronic fatigue, shortness of breath, and recurrent infections can also be symptoms of bone marrow failure. [ 2 ]


Bone marrow failure in both children and adults can be either inherited or acquired. Inherited bone marrow failure is often the cause in young children, while older children and adults may acquire the disease later in life. [ 3 ]   Acquired bone marrow failure may be due to  aplastic anemia [ 4 ]  or  myelodysplastic syndrome .


Inherited marrow failure syndromes include:


Fanconi anemia  is an inherited blood disorder due to abnormal breakages in DNA genes. It is linked to hyperpigmentation, which is the darkening of an area of skin or nails caused by increased melanin, though in about 30% of FA patients no physical abnormalities are found. [ 6 ]


Dyskeratosis congenita  often affects multiple parts of the body. Individuals with this disorder usually show changes in skin pigmentations, unusual fingernail growth, and mucosa leukoplakia; the inner part of the mouth is encased with white patches. [ 6 ]


Inherited bone marrow failure syndromes represent a kind of premature aging of the bone marrow. In patients with these syndromes, as in elderly patients, mutations associated with  clonal hematopoiesis  may arise as an adaptive response to a progressively deteriorating hematopoietic niche, i.e., a depleting pool of  Hematopoietic stem cells . The mutated stem cells then acquire a self-renewal advantage. [ 7 ]


Aplastic anemia  is an acquired autoimmune disease in which  T cells  attack and destroy bone marrow precursor cells. [ 8 ]


Myelodysplastic syndrome  (MDS) is a form of blood cancer in which the bone marrow no longer produces enough healthy, normal blood cells. [ 9 ]  MDS are a frequently unrecognized and rare group of bone marrow failure disorders, yet the incidence rate has rose from 143 reported cases in 1973 to approximately 15,000 cases in the United States each year.  MDS is likely under-diagnosed, with the believed actual incidence rate estimated at 35,000 to 55,000 new cases annually. [ 10 ]  One in three people with MDS progress to acute myeloid leukemia. [ 9 ]  For lower risk patients, those who do not undergo a bone marrow transplant have an average survival rate of up to six years. [ 9 ]  However, high-risk patients have a survival rate of approximately five months. [ 9 ]


Cytopenias may be noted in the peripheral blood.  Bone marrow examination is required to assess erythroid, myeloid and  megakaryocytic precursors, identify genetic abnormalities, and rule out other entities such as leukemia. [ 11 ]   B-cell lymphopenia has been observed in some patients with MECOM deficiency but is not a definitive indicator. [ 12 ]


For those with severe bone marrow failure, the cumulative incidence of resulting stem cell transplantation or death was greater than 70% by individuals 60 years of age. [ 13 ]  The incidence of bone marrow failure is triphasic: one peak at two to five years during childhood (due to inherited causes), and two peaks in adulthood, between 20 and 25 years old and after 60 years old (from acquired causes). [ 14 ]


One in ten individuals with bone marrow failure have unsuspected Fanconi anemia (FA). [ 14 ]  FA is the most common inherited bone marrow failure with an incidence of one to five episodes per million individuals. [ 14 ]  The carrier frequency for FA is 1 in 200 to 300, however this differs by ethnicity. [ 14 ]  In Europe and North America, the incidence of acquired aplastic anemia is rare with two episodes per million people each year, yet in Asia rises with 3.9 to 7.4 episodes per million people each year. [ 15 ]  While acquired aplastic anemia with an unknown cause is rare, it is commonly permanent and life-threatening as half of those with this condition die within the first six months. [ 10 ]


The prevalence of bone marrow failure is over three times higher in Japan and East Asia than in the United States and Europe. [ 10 ]  When one's body fails to produce blood cell lines, the morbidity and mortality rate increases. [ 10 ]


Supportive care with  blood transfusions  including  platelets  should be provided for symptoms of anemia and bleeding. Inherited bone marrow failure syndromes may require  hematopoietic stem cell transplantation .  Depending on severity,  aplastic anemia  may be treated with T-cell suppression in the form of  cyclosporine  and  anti-thymocyte globulin , or may require  hematopoietic stem cell transplantation .


Bone marrow suppression  also known as  myelotoxicity  or  myelosuppression , is the decrease in production of cells responsible for providing immunity ( leukocytes ), carrying oxygen ( erythrocytes ), and/or those responsible for normal blood clotting ( thrombocytes ). [ 1 ]   Bone marrow  suppression is a serious  side effect  of  chemotherapy  and certain drugs affecting the  immune system  such as  azathioprine . [ 2 ]  The risk is especially high in cytotoxic chemotherapy for  leukemia . In the case of  non-small-cell lung cancer , myelosuppression predisposition was shown to be modulated by  enhancer  mutations. [ 3 ]


Nonsteroidal anti-inflammatory drugs  (NSAIDs), in some rare instances, may also cause bone marrow suppression. The decrease in blood cell counts does not occur right at the start of chemotherapy because the drugs do not destroy the cells already in the bloodstream (these are not dividing rapidly). Instead, the drugs affect new blood cells that are being made by the bone marrow. [ 4 ]  When myelosuppression is severe, it is called myeloablation. [ 5 ]


Many other drugs including common antibiotics may cause bone marrow suppression. Unlike chemotherapy the effects may not be due to direct destruction of stem cells but the results may be equally serious. The treatment may mirror that of chemotherapy-induced myelosuppression or may be to change to an alternate drug or to temporarily suspend treatment.


Because the bone marrow is the manufacturing center of blood cells, the suppression of bone marrow activity causes a deficiency of blood cells. This condition can rapidly lead to life-threatening  infection , as the body cannot produce  leukocytes  in response to invading  bacteria  and  viruses , as well as leading to  anaemia  due to a lack of  red blood cells  and spontaneous severe bleeding due to deficiency of  platelets .


Parvovirus B19  inhibits  erythropoiesis  by lytically infecting RBC precursors in the bone marrow and is associated with a number of different diseases ranging from benign to severe. In  immunocompromised  patients, B19 infection may persist for months, leading to chronic  anemia  with B19 viremia due to chronic marrow suppression. [ 6 ]


Bone marrow suppression due to  azathioprine  can be treated by changing to another medication such as  mycophenolate mofetil  (for organ transplants) or other disease-modifying drugs in  rheumatoid arthritis  or  Crohn's disease .


Bone marrow suppression due to anti-cancer chemotherapy is much harder to treat and often involves hospital admission, strict infection control, and aggressive use of intravenous  antibiotics  at the first sign of infection. [ 7 ]


G-CSF  is used clinically (see  Neutropenia ) but tests in mice suggest it may lead to bone loss. [ 8 ] [ 9 ]


GM-CSF  has been compared to G-CSF as a treatment of chemotherapy-induced myelosuppression/ Neutropenia . [ 10 ]


Trilaciclib (COSELA) , a  CDK4/6 inhibitor , is administered before  chemotherapy  in  small cell lung cancer  to control chemotherapy-induced myelosuppression.  [ 11 ]


In developing new chemotherapeutics, the efficacy of the drug against the disease is often balanced against the likely level of myelotoxicity the drug will cause. In-vitro colony forming cell (CFC) assays using normal human bone marrow grown in appropriate semi-solid media such as ColonyGEL have been shown to be useful in predicting the level of clinical myelotoxicity a certain compound might cause if administered to humans. [ 12 ]  These predictive in-vitro assays reveal effects the administered compounds have on the bone marrow progenitor cells that produce the various mature cells in the blood and can be used to test the effects of single drugs or the effects of drugs administered in combination with others.


A  bruise , also known as a  contusion , is a type of  hematoma  of  tissue , [ 3 ]  the most common cause being  capillaries  damaged by  trauma , causing localized bleeding that  extravasates  into the surrounding  interstitial  tissues. Most bruises occur close enough to the epidermis such that the bleeding causes a visible discoloration. The bruise then remains visible until the blood is either absorbed by tissues or cleared by  immune system  action. Bruises which do not  blanch  under pressure can involve capillaries at the level of skin,  subcutaneous tissue , muscle, or bone. [ 4 ] [ 5 ]


Bruises are not to be confused with other similar-looking  lesions . Such lesions include  petechia  (less than 3 mm (0.12 in), resulting from numerous and diverse etiologies such as adverse reactions from medications such as warfarin, straining, asphyxiation,  platelet  disorders and diseases such as  cytomegalovirus ); [ 6 ]  and  purpura  (3–10 mm (0.12–0.39 in)), classified as palpable purpura or non-palpable purpura and indicating various pathologic conditions such as  thrombocytopenia . [ 7 ]  Additionally, although many  terminology  schemas treat an  ecchymosis  (plural, ecchymoses) (over 1 cm (0.39 in)) as synonymous with a bruise, [ 1 ]  in some other schemas, an ecchymosis is differentiated by its remoteness from the source and cause of bleeding, with blood dissecting through tissue planes and settling in an area remote from the site of trauma or even nontraumatic pathology, such as in  periorbital  ecchymosis (" raccoon eyes "), arising from a  basilar skull fracture  or from a  neuroblastoma . [ 8 ]


As a type of hematoma, a bruise is always caused by internal bleeding into the interstitial tissues which does not break through the skin, usually initiated by  blunt trauma , which causes damage through  physical compression  and  deceleration  forces. Trauma sufficient to cause bruising can occur from a wide variety of situations including accidents, falls, and surgeries. Disease states such as insufficient or malfunctioning  platelets , other  coagulation  deficiencies, or vascular disorders, such as venous blockage associated with severe  allergies [ 9 ]  can lead to the formation of purpura which is not to be confused with trauma-related bruising/contusion. [ 10 ]  If the trauma is sufficient to break the skin and allow blood to escape the interstitial tissues, the injury is not a bruise but bleeding, a different variety of hemorrhage. Such injuries may be accompanied by bruising elsewhere. [ 11 ]


Bruises often induce pain immediately after the trauma that results in their formation, but small bruises are not normally dangerous alone. Sometimes bruises can be serious, leading to other more life-threatening forms of hematoma, such as when associated with serious injuries, including  fractures  and more severe  internal bleeding .  The likelihood and severity of bruising depends on many factors, including type and healthiness of affected tissues. Minor bruises may be easily recognized in people with light skin color by characteristic blue or purple appearance (idiomatically described as "black and blue") in the days following the injury.


Hematomas can be subdivided by size. By definition, ecchymoses are 1 centimetres in size or larger, and are therefore larger than  petechiae  (less than 3 millimetres in diameter) [ 12 ]  or  purpura  (3 to 10 millimetres in diameter). [ 13 ]  Ecchymoses also have a more diffuse border than other purpura. [ 14 ]  A broader definition of ecchymosis is the escape of blood into the tissues from ruptured blood vessels. [ 15 ] [ 16 ]  The term also applies to the subcutaneous discoloration resulting from seepage of blood within the injured tissue.


Bruise colors vary from red, blue, or almost black, depending on the severity of broken capillaries or blood vessels within the bruise site. Broken  venules  or  arterioles  often result in a deep blue or dark red bruise, respectively. Darker colored bruises may result from a more severe bleeding from both blood vessels. Older bruises may appear yellow, green or brown. [ 11 ] [ 17 ]


There are many causes of subcutaneous hematomas including ecchymoses.  Coagulopathies  such as  hemophilia A  may cause ecchymosis formation in children. [ 18 ]  The medication  betamethasone  can have the adverse effect of causing ecchymosis. [ 19 ]


The presence of bruises may be seen in patients with  platelet  or  coagulation  disorders, or those who are being treated with an  anticoagulant . Unexplained bruising may be a warning sign of  child abuse ,  domestic abuse , or serious medical problems such as  leukemia  or  meningoccocal  infection. Unexplained bruising can also indicate internal bleeding or certain types of cancer. Long-term glucocorticoid therapy can cause easy bruising. Bruising present around the  navel  (belly button) with severe abdominal pain suggests acute  pancreatitis . Connective tissue disorders such as  Ehlers–Danlos syndrome  may cause relatively easy or spontaneous bruising depending on the severity. Spontaneous bruising or bruising with minimal trauma in the absence of other explanations and together with other minor or major criteria suggestive of vascular Ehlers–Danlos Syndrome (vEDS) suggests  genetic testing  for the condition. [ 20 ]


During an  autopsy , bruises accompanying  abrasions  indicate the abrasions occurred while the individual was alive, as opposed to damage incurred post mortem.


Bruise shapes may correspond directly to the instrument of injury or be modified by additional factors. Bruises often become more prominent as time lapses, resulting in additional size and swelling, and may grow to a large size over the course of the hours after the injury that caused the bruise was inflicted.


Bruises can be scored on a scale from 0–5 to categorize the severity and danger of the injury.


The harm score is determined by the extent and severity of the injuries to the organs and tissues causing the bruising, in turn depending on multiple factors.  For example, a  contracted  muscle will bruise more severely, as will tissues crushed against underlying bone.   Capillaries  vary in strength, stiffness and toughness, which can also vary by age and medical conditions.


Low levels of damaging forces produce small bruises and generally cause the individual to feel minor pain straight away. Repeated impacts worsen bruises, increasing the harm level. Normally, light bruises heal nearly completely within two weeks, although duration is affected by variation in severity and individual healing processes; [ 22 ]  generally, more severe or deeper bruises take somewhat longer.


Severe bruising (harm score 2–3) may be dangerous or cause serious complications.  Further bleeding and excess fluid may accumulate causing a hard, fluctuating lump or swelling hematoma.  This has the potential to cause  compartment syndrome  in which the swelling cuts off blood flow to the tissues.  The trauma that induced the bruise may also have caused other severe and potentially fatal harm to internal  organs .  For example, impacts to the head can cause  traumatic brain injury : bleeding, bruising and massive swelling of the brain with the potential to cause  concussion ,  coma  and death.  Treatment for brain bruising may involve emergency surgery to relieve the pressure on the brain.


Damage that causes bruising can also cause bones to be  broken ,  tendons  or muscles to be  strained ,  ligaments  to be  sprained , or other tissue to be damaged.  The symptoms and signs of these injuries may initially appear to be those of simple bruising. Abdominal bruising or severe injuries that cause difficulty in moving a limb or the feeling of liquid under the skin may indicate life-threatening injury and require the attention of a physician.


Increased distress to tissue causes  capillaries  to break under the skin, allowing blood to escape and build up. As time progresses, blood seeps into the surrounding tissues, causing the bruise to darken and spread.  Nerve  endings within the affected tissue detect the increased pressure, which, depending on severity and location, may be perceived as pain or pressure or be  asymptomatic . The damaged capillary  endothelium  releases  endothelin , a  hormone  that causes  narrowing of the blood vessel  to minimize bleeding. As the endothelium is destroyed, the underlying  von Willebrand factor  is exposed and initiates  coagulation , which creates a temporary  clot  to plug the wound and eventually leads to restoration of normal tissue.


During this time, larger bruises may change color due to the breakdown of  hemoglobin  from within escaped  red blood cells  in the extracellular space. The striking colors of a bruise are caused by the  phagocytosis  and sequential degradation of hemoglobin to  biliverdin  to  bilirubin  to  hemosiderin , with hemoglobin itself producing a red-blue color, biliverdin producing a green color, bilirubin producing a yellow color, and hemosiderin producing a golden-brown color. [ 11 ]  As these products are cleared from the area, the bruise disappears. Often the underlying tissue damage has been repaired long before this process is complete.


Treatment for light bruises is minimal and may include  RICE  ( rest ,  ice ,  compression , and  elevation ),  painkillers  (particularly  NSAIDs ) and, later in recovery, light stretching exercises. Particularly, immediate application of ice while elevating the area may reduce or completely prevent swelling by restricting blood flow to the area and preventing internal bleeding. Rest and preventing re-injury is essential for rapid recovery.


Very gently massaging the area and applying heat may encourage blood flow and relieve pain according to the  Gate control theory  of pain, although causing additional pain may indicate the massage is exacerbating the injury. [ 23 ]  As for most injuries, these techniques should not be applied until at least three days following the initial damage to ensure all internal bleeding has stopped, because although increasing blood flow will allow more healing factors into the area and encourage drainage, if the injury is still bleeding this will allow more blood to seep out of the wound and cause the bruise to become worse.


Folk medicine , including ancient medicine of Egyptians, Greeks, Celts, Turks, Slavs, Maya, Aztecs and Chinese, has used bruising as a treatment for some health problems. The methods vary widely and include cupping, scraping, and slapping.  Fire cupping  uses suction which causes bruising in patients. Scraping ( gua sha ) uses a small hand device with a rounded edge to gently scrape the scalp or the skin. Another ancient device that creates mild bruising is a  strigil , used by Greeks and Romans in the bath. Archaeologically there is no precedent for scraping tools before Greek archaeological evidence, not Chinese or Egyptian. [ 24 ]


The word  ecchymosis  ( / ˌ ɛ k ɪ ˈ m oʊ s ɪ s / ; plural  ecchymoses ,  / ˌ ɛ k ɪ ˈ m oʊ s iː s / ), comes to English from  Neo-Latin , based on  Greek   ἐκχύμωσις ,  ekchymōsis , from  ἐκχυμοῦσθαι ,  ekchymousthai , 'to extravasate blood', from  ἐκ- ,  ek-  (elided to  ἐ- ,  e- ) and  χυμός ,  chymos , 'juice'. [ 25 ]  Compare  enchyma , "tissue infused with organic juice"; elaboration from chyme, the formative juice of tissues.


α-Naphthyl butyrate esterase , also referred to as  naphthyl butyrate esterase  or  butyrate esterase , is a  histological stain  specific for  white blood cells  of the  monocytic  proliferation line. [ 1 ]


Cauterization  (or  cauterisation , or  cautery ) is a medical practice or technique of  burning  a part of a body to remove or close off a part of it. It destroys some tissue in an attempt to mitigate  bleeding  and damage, remove an undesired growth, or minimize other potential medical harm, such as  infections  when  antibiotics  are unavailable. [ 1 ]


The practice was once widespread for treatment of wounds. Its utility before the advent of antibiotics was said to be effective at more than one level:


Cautery was historically believed to prevent infection, but current research shows that cautery actually increases the risk for infection by causing more tissue damage and providing a more hospitable environment for bacterial growth. [ 2 ]   Actual cautery  refers to the metal device, generally heated to a dull red glow, that a physician applies to produce  blisters , to stop  bleeding  of a  blood vessel , and for other similar purposes. [ 3 ]


The main forms of cauterization used today are  electrocautery  and  chemical cautery —both are, for example, prevalent in cosmetic removal of  warts  and stopping  nosebleeds . Cautery can also mean the  branding of a human .


Cauterize is a  Middle English  word borrowed from the Old French  cauteriser , from Late Latin  cauterizare  "to burn or brand with a hot iron", from Ancient Greek  καυτηριάζειν  ( kauteriazein ), from  καυτήρ  ( kauter ), "burning or branding iron", and  καίειν  ( kaiein ) "to burn" (of caustic). [ 4 ]


Cauterization has been used to stop heavy bleeding since antiquity. The process was described in the  Edwin Smith Papyrus [ 5 ]  and  Hippocratic Corpus . [ 6 ]  It was primarily used to control hemorrhages, especially those resulting from surgery, in  ancient Greece .  Archigenes  recommended cauterization in the event of hemorrhaging wounds, and  Leonides of Alexandria  described excising breast tumors and cauterizing the resulting wound in order to control bleeding. [ 7 ]  The Chinese  Su wen  recommends cauterization as a treatment for various ailments, including dog bites. [ 8 ]   Indigenous peoples of the Americas ,  ancient Arabs , and Persians also used the technique. [ 9 ]


Tools used in the ancient cauterization process ranged from heated lances to cauterizing knives. The piece of metal was heated over fire and applied to the wound. [ 10 ]


Cauterization continued to be used as a common treatment in medieval times. The  Babylonian Talmud  (redacted in 500 AD), alluding to the practice, states: "...and the effect of the hot iron comes and removes the traces of the stroke." [ 11 ]  While mainly employed to stop blood loss, it was also used in cases of tooth extraction and as a treatment for mental illness. In the  Muslim world , scholars  Al-Zahrawi  and  Avicenna  wrote about techniques and instruments used for cauterization. [ 12 ]


As late as the 20th-century,  Bedouins  of the  Negev  in Israel had it as their practice to take the root of the Shaggy sparrow-wort ( Thymelaea hirsuta ), cut splinters lengthwise in the root, burn the splinter in fire, and then apply the red-hot tip of a splinter to the forehead of a person who was ill with ringworm ( Dermatophytosis ). [ 13 ]


The technique of  ligature  of the arteries as an alternative to cauterization was later improved and used more effectively by  Ambroise Paré .


Electrocauterization is the process of destroying tissue (or cutting through soft tissue) using  heat conduction  from a metal probe heated by electric current. The procedure stops bleeding from small vessels (larger vessels being  ligated ). Electrocautery applies high frequency alternating current by a  unipolar  or  bipolar  method. It can be a continuous  waveform  to cut tissue, or intermittent to coagulate tissue.


The electrically produced heat in this process inherently can do numerous things to the tissue, depending on the waveform and power level, including cauterize, coagulate, cut, and dry (desiccate). Thus electrocautery, electrocoagulation, electrodesiccation, and electrocurettage are closely related and can co-occur in the same procedure when desired.  Electrodesiccation and curettage  is a common procedure.


In unipolar cauterization, the physician contacts the tissue with a single small electrode. The circuit's exit point is a large surface area, such as the buttocks, to prevent electrical burns. The amount of heat generated depends on the size of contact area, power setting or frequency of current, duration of application, and waveform. A constant waveform generates more heat than intermittent. The frequency used in cutting the tissue is higher than in coagulation mode.


Bipolar electrocautery passes the current between two tips of a forceps-like tool. It has the advantage of not disturbing other electrical body rhythms (such as the heart) and also coagulates tissue by pressure. Lateral thermal injury is greater in unipolar than bipolar devices. [ 14 ]


Electrocauterization is preferable to chemical cauterization, because chemicals can leach into neighbouring tissue and cauterize outside of intended boundaries. [ 15 ]  Concern has also been raised regarding toxicity of the  surgical smoke  electrocautery produces. This contains chemicals that, through inhalation, may harm patients or medical staff. [ 16 ]


Ultrasonic  coagulation and ablation systems are also available.


Many chemical reactions can destroy tissue, and some are used routinely in medicine, most commonly to remove small skin lesions such as  warts  or necrotized tissue, or for  hemostasis . [ 17 ]  Because chemicals can leach into areas not intended for cauterization, laser and electrical methods are preferable where practical. [ 18 ]  Some cauterizing agents are:


Frequent  nosebleeds  are most likely caused by an exposed blood vessel in the nose, usually one in  Kiesselbach's plexus .


Even if the nose is not bleeding at the time, a physician may cauterize it to prevent future bleeding. Cauterization methods include burning the affected area with acid, hot metal, or lasers. Such a procedure is naturally quite painful. Sometimes, a physician uses  liquid nitrogen  as a less painful alternative, though it is less effective. A physician may apply  cocaine  in the few countries that allow it for medical use. Cocaine is the only  local anesthetic  that also produces  vasoconstriction , [ 23 ]  making it ideal for controlling nosebleeds.


More modern treatment applies  silver nitrate  after a local anesthetic. The procedure is generally painless, but after the anesthetic wears off, there may be pain for several days, and the nose may run for up to a week after this treatment.


Nasal cauterization can cause  empty nose syndrome . [ 24 ] [ 25 ] [ 26 ]


Cauterization has been used for the  circumcision  of infants in the  United States  and  Canada . The  College of Physicians and Surgeons of Manitoba  advises against its use in neonatal circumcision. [ 27 ]  This method of circumcision resulted in several infants having their  penises  severely burned. [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ] [ 33 ]


Chromatography  is a physical method of separation that distributes the components you want to separate between two phases, one stationary (stationary phase), the other (the mobile phase) moving in a definite direction. Cold ethanol precipitation, developed by Cohn in 1946, manipulates pH, ionic strength, ethanol concentration and temperature to precipitate different protein fractions from plasma. Chromatographic techniques utilise ion exchange, gel filtration and affinity resins to separate proteins. Since the 1980s it has emerged as an effective method of purifying blood components for therapeutic use.


Blood plasma  is the liquid component of blood, which contains dissolved proteins, nutrients, ions, and other soluble components. In whole blood,  red blood cells ,  white blood cells , and  platelets  are suspended within the plasma. The goal of  plasma purification and processing  is to extract specific materials that are present in blood, and use them for restoration and repair.  There are several components that make up blood plasma, one of which is the protein  albumin . Albumin is a highly water-soluble protein with considerable structural stability. It serves as a transportation device for materials such as hormones, enzymes, fatty acids, metal ions, and medicinal products.  It is also used for therapeutic purposes, being essential in restoration and maintenance of circulating blood volume in imperative situations such as severe trauma or surgery.  With little room for error, extremely pure samples that are lacking impurities needs to be at hand in good amount. Human blood plasma is important for the body so the nutrients etc. can be stored.


Traditionally, the  Cohn process  incorporating cold ethanol fractionation has been used for albumin purification.  However,  chromatographic methods  for separation started being adopted in the early 1980s.  Developments were ongoing in the time period between when Cohn fractionation started being used, in 1946, and when chromatography started being used, in 1983.  In 1962, the Kistler & Nistchmann process was created which was a spinoff of the Cohn process. Chromatographic processes began to take shape in 1983. In the 1990s, the Zenalb and the CSL Albumex processes were created which incorporated chromatography with a few variations.


The general approach to using chromatography for plasma fractionation for albumin is: recovery of supernatant I, delipidation,  anion exchange chromatography , cation exchange chromatography, and gel filtration chromatography.


The recovered purified material is formulated with combinations of sodium octanoate and sodium N-acetyl tryptophanate and then subjected to viral inactivation procedures, including pasteurisation at 60 °C.


This is a more efficient alternative than the Cohn process for four main reasons:
1) smooth automation and a relatively inexpensive plant was needed,
2) easier to sterilize equipment and maintain a good manufacturing environment,
3) chromatographic processes are less damaging to the albumin protein, and
4) a more successful albumin end result can be achieved.


Compared with the Cohn process, the albumin purity went up from about 95% to 98% using chromatography, and the yield increased from about 65% to 85%.  Small percentage increases make a difference in regard to  sensitive measurements like purity. There is one big drawback in using chromatography, which has to do with the economics of the process. Although the method was efficient from the processing aspect, acquiring the necessary equipment is a big task.  Large machinery is necessary, and for a long time the lack of equipment availability was not conducive to its widespread use.  The components are more readily available now but it is still a work in progress and will possibly be ready in the future to help the world.


Integrating traditional and modern methods is a useful way to process albumin.


There are three main steps that combine Cohn fractionation with chromatography: 1) factors I, II, and III are removed via cold ethanol fractionation, 2)  Sepharose  fast flow ion exchange and sepharose fast flow chromatography procedures are run, and 3) gel filtration is run. The result is albumin with 9% lower aluminum levels with a processing time that is almost twice as fast.


Although it was hard to make chromatographic processing methods widely adopted, global expansion is a work in progress.  Various blood components must be readily available at various medical treatment centers around the world.  The Institute of Transfusion Medicine in  Skopje ,  North Macedonia  is a plasma fractionation center in the Balkans. Their modernized albumin purification process consists of five steps:


The end result is a highly pure and safe batch of albumin that is 100% non- pyrogenic , sterile, and free of active  HIV virus . The product purity is greater than 98% and the protein content is about 50 g/L.


Other plasma processing methods exist, but generally do not provide the resolution or purity of chromatographic methods.
 Two-phase liquid extraction  may be performed using  polyethylene glycol  (PEG)-phosphate  Aqueous two-phase systems , with a PEG-rich top layer and a phosphate-rich bottom layer. Although this method is somewhat useful for protein recovery, it does not work as well for the recovery of other blood components.
Membrane fractionation has the advantage of minimal protein loss yet high removal of pathological plasma components.  This method incorporates processes such as thermofiltration and applying pulsate flow. The latest two-stage membrane system utilizes a high flow recirculation circuit that is effective for removal of  LDL  cholesterol.  It may prove useful for patients that have clogged arteries and other cardiovascular problems involving cholesterol.
Batch adsorption, e.g. onto ion exchange media, is only useful when dealing with smaller samples of plasma, typically 200 mL or less. Batch adsorption recovers the product in a larger volume of elution buffer than does column chromatography or frontal chromatography, and the resulting more dilute product requires concentration, typically on a membrane system, which can lead to loss of product by irreversible adsorption to the membrane.


Clonal hematopoiesis of indeterminate potential , or  CHIP , is a common aging-related phenomenon in which  hematopoietic stem cells (HSCs)  or other early blood  cell progenitors  contribute to the formation of a genetically distinct subpopulation of  blood cells . [ 1 ] [ 2 ] [ 3 ]  As the name suggests, this subpopulation in the blood is characterized by a shared unique  mutation  in the cells'  DNA ; it is thought that this subpopulation is "clonally" derived from a single founding cell and is therefore made of genetic "clones" of the founder. [ 4 ] [ 5 ] [ 6 ] [ 7 ]  The establishment of a clonal population may occur when a stem or progenitor cell acquires one or more somatic mutations that give it a competitive advantage in  hematopoiesis  over the stem/progenitor cells without these mutations. [ 1 ] [ 3 ]  Alternatively, clonal hematopoiesis may arise without a driving mutation, through mechanisms such as  neutral drift  in the stem cell population. [ 8 ]  Clonal hematopoiesis may occur in people who are completely healthy but has also been found in people with hematologic diseases. [ 1 ] [ 9 ] [ 10 ]  The clonal population may vary in size depending on the person, where it can be less than 2% of the blood or, at the other end, can sometimes grow close to 100%. [ 4 ] [ 9 ]  The incidence of clonal hematopoiesis has been found to rise dramatically with age. Recent studies have demonstrated that less than 1% of the population under age 40 but approximately 10-20% of the population over age 70 has observable clonal hematopoiesis. [ 4 ] [ 5 ] [ 6 ]  Having clonal hematopoiesis has been linked to a more than 10-fold increased risk of developing a blood cancer, though the overall likelihood is still low. [ 4 ] [ 5 ]  Clonal hematopoiesis does not typically give rise to noticeable symptoms, but does lead to increased risk of  cardiovascular disease . [ 1 ] [ 5 ] [ 11 ]  Patients with solid tumors or lymphoma and clonal hematopoiesis have been shown to have an inferior outcome. [ 12 ]


The first major evidence for the existence of prevalent clonal hematopoiesis in healthy people was put forth in the 1990s. Using the  HUMARA assay , scientists found that there was nonrandom  X-inactivation  of the  X chromosome  in the blood of some healthy women. [ 13 ] [ 14 ]  This means that a greater than expected proportion of the blood had the silencing of one specific X chromosome in the chromosome pair. Just as the observation of the same DNA mutation in a subset of cells suggests a single founding source, this X-inactivation skew suggests that a greater than expected number of cells are being generated from the same precursor. Importantly, these findings described an increase in this nonrandom skewing with increasing age, hinting that unobserved mutations acquired with age could be driving a  clonal expansion . In a similar vein, other studies using the HUMARA technology had found that hematologic malignancies are clonal diseases even when there is no apparent chromosomal abnormality, [ 15 ] [ 16 ]  and that there are pre-leukemic clonal populations which precede  acute myeloid leukemia (AML) . [ 17 ]  As the HUMARA assay is based on the  epigenetic  state of cells, the underlying genetic determinants of the clonal expansion remained to be uncovered.


This set of evidence led to the suggestion in 2005 that driving mutations in leukemia are acquired in a step-wise manner. [ 18 ]  This model has received support from studies showing subpopulations of blood cells harboring initiating but not late somatic mutations in patients with  chronic lymphocytic leukemia (CLL) , [ 19 ] [ 20 ]   hairy cell leukemia (HCL) , [ 21 ]  and AML. [ 22 ] [ 23 ] [ 24 ]


The combination of these two ideas, that clonal hematopoiesis might be common in the elderly population and that AML evolves from pre-leukemic populations, led to the hypothesis that malignancy-associated mutations could also contribute to asymptomatic clonal hematopoiesis in healthy individuals. [ 1 ]  This view gained mechanistic support in 2012 when it was found a number of the women who showed evidence for clonal hematopoiesis through X-inactivation skew also had mutations in the hematologic-malignancy-associated gene  TET2 . [ 25 ]


In 2014, several independent studies confirmed the presence of malignancy-associated mutations in the blood of individuals who have no clinical signs of hematologic malignancy. [ 4 ] [ 5 ] [ 6 ]  In combination, these studies have demonstrated the widespread incidence of clonal hematopoiesis in the healthy adult population and have stimulated further efforts to broaden our understanding of clonal hematopoiesis in health and disease.  The term "clonal hematopoiesis of indeterminate potential" (CHIP) was proposed later that year to describe persons who do not have a malignancy meeting World Health Organization diagnostic criteria, yet have somatic mutations in hematopoietic stem and progenitor cells involving genes that have been associated with hematological malignancy, and these mutations are present in blood cells with a variant allele frequency of at least 2%. [ 3 ]   The 2% threshold was chosen in part because of technical limitations (i.e., analytic sensitivity of clinically available sequencing assays) but also because very small clones are of unclear clinical significance.


The advent of next-generation DNA sequencing has allowed for the targeted identification of somatic mutations involved in clonal hematopoiesis at the population level. The studies undertaken as of 2017 are largely consistent in their main findings. One common finding has been that observable clonal hematopoiesis is virtually absent from the under-40 population, with a sharp uptick in frequency past 60 years of age. [ 4 ] [ 5 ] [ 6 ]  Indeed, the evidence from these studies suggests that between 10% and 20% of the population over age 70 have clonal hematopoiesis. In the U.S. alone, this means that, at the low end, some 2,975,000 seniors over 70 years of age are living with this condition. [ 26 ]


The other main common finding is that there are many different mutations involved in clonal hematopoiesis. Many of these fall into the categories of epigenetic regulators ( DNMT3a ,  TET2 , and  ASXL1 ), signaling proteins ( JAK2 ),  spliceosome  components ( SF3B1  and  SRSF2 ), or members of the DNA damage response ( TP53  and  PPM1D ). [ 4 ] [ 5 ] [ 6 ]  Many people identified as having clonal hematopoiesis have a mutation in a single gene, though a significant number have mutations in two or more genes. [ 4 ] [ 5 ] [ 6 ]  The number and variety of observed mutations suggests that these mutations may contribute to clonal hematopoiesis by several distinct mechanisms, discussed in more detail below.  While  DNMT3A  is the most prevalent driver mutation,  TET2  and splicing gene mutations are more prevalent in those over 75 years old. [ 27 ]


There is also limited evidence suggesting clonal hematopoiesis may be ubiquitous in healthy adults, albeit at extremely low levels (less than 0.1% of peripheral blood cells). A study employing the ultra-sensitive  digital droplet PCR  method found that 95% of studied individuals (19 out of 20) between the ages of 50 and 70 had at least low-level clonal hematopoiesis. [ 28 ]  This finding does not necessarily conflict with earlier reports that clonal hematopoiesis is not ubiquitous in this age bracket, as these previous studies' experimental designs compels the use of a higher threshold to identify legitimate clonal hematopoiesis. [ 4 ] [ 5 ] [ 6 ]


Ongoing studies are examining what genetic and epidemiological factors may influence the acquisition of mutations in clonal hematopoiesis.  Once mutated, the HSCs with a relative fitness advantage give rise to clones capable of expansion, in a type of Darwinian selection. [ 27 ]


Clonal hematopoiesis is thought to originate with the hematopoietic stem cells that make blood. An adult human has approximately 10,000 to 20,000 HSCs. [ 29 ]  The fact that these cells are maintained for life and each HSC may acquire about one mutation in a protein-coding  exon  each decade [ 30 ]  means that an elderly individual will have a certain amount of genetic mosaicism, or a variety of cells with different unique mutations, within their HSC population. However, this does not lead to clonal hematopoiesis in all cases. It is only when the genetic mutation confers a selective advantage on its host or there is another favorable stem cell dynamic that there is a clonal expansion.


There are several general mechanisms by which a mutation could provide such an advantage and it is likely that the mutations found in clonal hematopoiesis act through different pathways. First, a mutation could provide a growth advantage, causing HSCs to divide more rapidly and contribute a larger proportion of the mature blood cells. This may be the case for mutations in genes related to signaling, such as that which causes the activating V617F substitution in the JAK2 signaling protein. Mutations in the DNA damage response genes would appear more likely to act via a second mechanism: allowing for HSC survival and proliferation under normally lethal cytotoxic stress. [ 1 ]


Other mechanisms are more likely to be associated with the disruption of epigenetic regulators, which comprises 80% of observed mutations in clonal hematopoiesis. A third potential mechanism of action is that the mutation makes the HSC-derived progenitor cells less able to differentiate into mature blood cells. This would allow these cells to continue to divide even after they would have normally stopped, since progenitor cells may divide whereas normal mature blood cells cannot. A fourth possibility is that the mutation makes the progenitor cells and cells derived from them more like stem cells in their ability to keep dividing. The previous two possibilities are very similar in terms of physiologic outcome and mainly differ on what is happening at the DNA level: whether differentiation genes are suppressed or a stem cell program is upregulated. A final possibility is that a gradient of epigenetic states is created in the HSC and progenitor cells and the cells with the most favorable epigenetics are able to grow out faster than unmutated cells. [ 1 ]


An expansion of blood cells from a single source does not necessarily require a mutation to act as the driving force. A large proportion of the population who exhibit clonal hematopoiesis have no identifiable mutations in known candidate driver genes. [ 4 ] [ 8 ]  One possible explanation is that among a naturally-occurring spectrum of inheritable epigenetic states, there are those which augment the self-renewal or proliferation of a stem cell and its progeny. [ 8 ]  Another explanation is that a process of "neutral drift" [ 31 ]  causes the predominance of a clonal stem cell population over time. In this scenario, all stem cells have an equal proliferative potential but some of them die out in a stochastic manner leading some of the remaining cells to proliferate to replace them. [ 8 ] [ 32 ]  This can be equated to a game of chance where all players start with the same odds of winning. As the game is played, winners and losers will arise despite the equal starting positions. [ 32 ]


Clonal hematopoiesis by itself is not considered to be a hematologic cancer; nevertheless, evidence is mounting that this condition may adversely affect human health. It has been proposed to label the group of individuals who have clonal hematopoiesis defined by a mutation in a malignancy-associated gene but without evidence of disease (such as  cytopenia ,  dysplasia  or immature "blast" cells in the bone marrow) as having  Clonal Hematopoiesis of Indeterminate Potential (CHIP) . [ 1 ] [ 3 ] [ 33 ]  A clonal involvement (sometimes referred to simply as the size of a "clone") of 2% of the blood has been tentatively proposed as a cutoff, though there is discussion that a lower floor that is more inclusive could also be appropriate. [ 1 ] [ 3 ] [ 28 ] [ 34 ]  This cutoff may ultimately depend on whether clones must reach a certain size before influencing health. The level at which a clone begins to have a potential clinical impact is an open question, though there is already data to suggest larger clones have a larger effect on health. [ 5 ]


The presence of clonal hematopoiesis/CHIP has been shown to increase blood cancer risk and is correlated with an increased risk of mortality overall. [ 4 ] [ 5 ] [ 8 ]  This is true both of clonal hematopoiesis with known candidate drivers as well as in cases without such drivers. [ 8 ]


One area of health that CHIP has been definitively shown to influence is the risk of progression to blood cancer. In a given year, a tiny fraction of the general population will develop a hematologic cancer such as  myelodysplastic syndrome (MDS)  or AML; it is estimated that just 3 to 4 people per 100,000 will get MDS in a given year, [ 35 ]  and 4 people per 100,000 will develop AML. [ 36 ]  With CHIP, the risk of acquiring a hematologic malignancy like MDS or AML is increased more than 10-fold. [ 4 ] [ 5 ]  Despite this increased risk, people with CHIP are still at low overall risk for developing a blood cancer, with only about 0.5-1.0% transformation per year. [ 1 ]


The risk of transformation to myeloid malignancy depends on the specific mutation and the size of the clone. Single  DNMT3A  mutations have the lowest risk of progression, while splicing factor genes,  JAK2 ,  TP53 ,  IDH1 ,  IDH2 ,  FLT3 , and  RUNX1  have the highest risk. The clonal hematopoiesis risk score (CHRS) can be used to estimate the risk of progression to myeloid malignancy. CHRS predicts high, intermediate, or low risk based on the presence or absence of mutations in high-risk genes, the clone size, number of different mutations, findings of  macrocytosis  (MCV ≥100 fL),  anisocytosis  (RDW ≥ 15%), cytopenias ( anemia ,  neutropenia , or  thrombocytopenia ) and age ≥ 65 years. [ 37 ]


A second area of health that may be affected by CHIP is the risk for  heart attack  and  stroke . A strong association between CHIP and heart attack/ischemic stroke has been identified in one human genetic dataset, where CHIP was a stronger predictor of heart attack/stroke than if a patient was a smoker, had hypertension, had high cholesterol, or was overweight. In this study, which shows correlation but not causation, people with CHIP were 2.3 times more likely to have a heart attack, or 4.4 times as likely if the variant allele frequency (VAF, a measure of clone size) [ 38 ]  in their blood was greater than 0.10, than matched controls without CHIP. [ 5 ]  It has also been found that there is an increased risk of cardiovascular mortality in patients who exhibit CHIP and receive self-derived stem cell transplantation. [ 10 ]  In addition to heart attack and stroke, human studies further suggest an association of CHIP with  heart failure  and cardiac  arrhythmias . [ 39 ] [ 40 ]


The idea of CHIP having a causal role in human heart attacks/strokes has been given support by a 2017 study that showed impairment of the  Tet2  CHIP gene in mice causally led to accelerated atherosclerosis, [ 41 ]  and this finding in mice has been independently validated. [ 11 ]  The possibility of somatic mutations in the blood contributing not only to cancer risk but also to heart attack and stroke has generated much discussion in top-level scientific publications [ 42 ] [ 43 ]  and a large multi-cohort study published in 2017 appears to confirm the causal link between CHIP and cardiovascular disease in humans. [ 11 ]


In addition to its effects on those who would otherwise be considered healthy, CHIP may have implications in certain disease contexts. It has been shown that patients with CHIP who receive  autologous stem cell transplantation (ASCT)  as part of their treatment for  lymphoma  have worse outcomes than patients without CHIP. The poorer prognosis for these patients is due to both an increase in subsequent therapy-related myeloid neoplasms and increased risk for cardiovascular mortality. [ 10 ]   Clonal expansion may be related to  inflammaging , the low-level systemic inflammation implicated in age-related chronic illnesses. [ 44 ]  Aging and persistent inflammation both exhaust normal  hematopoietic stem cells  by requiring increased proliferation to replenish immune cells. [ 45 ]  CHIP has been documented in people with HIV infection [ 46 ]  and autoimmune disease. [ 47 ]   Interferons ,  Interleukin-6 ,  TNF-alpha  and the  TGF-beta  pathway are all thought to play a role in  inflammaging  as it relates to hematologic malignancies. [ 48 ]


Inherited  bone marrow failure  syndromes carry a risk of myeloid malignancy, particularly when there are germ line mutations in  CEBPA ,  DDX41 ,  GATA2 ,  RUNX1 , or SAMD9/9L.  Examples include ribosomopathies such as  Schwachman-Diamond syndrome , in which mutations in  EIF6  may lead to aberrant  p53  activation;  Severe Congenital Neutropenia , in which  CSF3R  mutation may lead to myeloid hyperproliferation; telomeropathies such as  dyskeratosis congenita  with acquired mutations in the  TERT  promoter, and  Fanconi anemia . [ 49 ]  Inherited  DNMT3A  mutations cause Tatton-Brown-Rahman syndrome, characterized by larger body habitus and intellectual disability. [ 50 ]


Inherited  bone marrow failure  syndromes represent a kind of premature aging of the bone marrow.  In patients with these syndromes and in elderly patients, mutations associated with Clonal Hematopoiesis may arise as an adaptive response to a progressively deteriorating hematopoietic niche, i.e., a depleting pool of  Hematopoietic stem cells .  The mutated stem cells then acquire a self-renewal advantage. [ 48 ]


There are currently no therapies for slowing or targeting CHIP mutations. Together with the fact that progression from CHIP to outright hematologic malignancy remains infrequent, medical experts have argued against preemptive screening for CHIP but suggest routine follow-up for incidental CHIP findings. [ 1 ] [ 3 ]


Clonal hematopoiesis is sometimes compared to the unrelated blood disorders of  monoclonal gammopathy of undetermined significance (MGUS)  and  monoclonal B-cell lymphocytosis (MBL)  to which it bears similarities in its apparent priming for more advanced hematologic disease combined with a lack of symptoms and overall low risk of progression. [ 1 ] [ 3 ]


The acquisition of additional mutations can cause CHIP to transform into the related blood disorders  MDS  and  AML . [ 3 ] [ 33 ]  Clonal Cytopenias of Undetermined Significance (CCUS) is defined [ 51 ]  as:


CCUS has a much higher risk of progression to MDS/AML than CHIP.  The most frequent CCUS mutations are in epigenetic regulators ( DNMT3A ,  TET2 , and  ASXL1 ), RNA splicing factors ( SF3B1 , SRSF2),  TP53 , and  PPM1D . [ 48 ]  It is likely that a mutational progression occurs, such that splicing factors are mutated early in the development of MDS, while mutations in signaling pathways ( FLT3 ,  PTPN11 , and  RAS ) and transcription factors ( CEBPA  and  RUNX1 ) occur as a late event. [ 48 ]


Cold sensitive antibodies  ( CSA ) are  antibodies  sensitive to cold temperature. Some cold sensitive antibodies are pathological and can lead to  blood disorder . These pathological cold sensitive antibodies include  cold agglutinins ,  Donath–Landsteiner antibodies , and  cryoglobulins  which are the culprits of  cold agglutinin disease ,  paroxysmal cold hemoglobinuria  in the process of  Donath–Landsteiner hemolytic anemia , and  vasculitis , respectively.


Cold agglutinins are  antibodies , typically  immunoglobulin M  ( IgM ), that are acquainted with and then binding the antigens on red blood cells, typically  antigens "I" or "i"  on the RBC surface, [ 1 ]  in the environment in which the temperatures are lower than normal core body temperature and, thus, ends up leading to  agglutinations of the red blood cells and hemolysis reaction occurring outside the vessels  (extra-vessels), resulting in anemia without  hemoglobinuria  in ordinary cases. [ 2 ]


Cold agglutinins can cause two pathological conditions, that are, primary cold agglutinin disease (CAD) [ 3 ]  and secondary cold agglutinin syndrome (CAS), [ 2 ]  both of which are sole two  subtypes of  cold agglutinin disease .


Primary cold agglutinin disease is idiopathic, meaning the phenomenons of agglutinations of the red blood cells and hemolysis reaction occurring outside the vessels are absent from any underlying cause. [ 3 ]  Nevertheless, what is known is, those with idiopathic cold agglutinin disease are susceptible to having or developing mild  clonal bone marrow disorder . [ 3 ]


Secondary cold agglutinin syndrome refers to cold agglutinin disease that is identified to be caused by  viral infection ,  autoimmune disorder ,  lymphoid malignancy , or any other underlying disease. [ 4 ]


Cold agglutinins (CA) are autoantibodies that agglutinate RBCs with a temperature optimum of 3-4 °C but may also act in a warmer environment, depending on the  thermal amplitude  of the CA. If the thermal amplitude exceeds 28–30 °C, the CA will be pathogenic. Low- affinity  CA also occurs in many healthy individuals; these nonpathogenic CA are  polyclonal , have low thermal amplitude, and are present in low  titers , not higher than 256 and usually lower than 64. More than 90% of pathogenic CA are of the IgM class and these IgM macromolecules can be  pentameric  or  hexameric . [ 5 ]