In humans, the majority (85–90%) of the NK cells have a high cytolytic capacity (the ability to  lyse  cells). A smaller subset (10–15%) called NK 'CD56 bright' is chiefly responsible for  cytokine  production and has  enhanced survival . Traveling to  lymph nodes  the 'CD56 bright' NK cells differentiate again into mature NK cells which express  killer cell immunoglobulin-like receptors  (KIR), natural cytotoxicity receptors (NCR), and critical  adhesion molecules . (Medical Immunology, p. 122)


The process by which CLP cells may differentiate to generate  dendritic cells  of lymphoid lineage is not yet well defined. [ 19 ]


DCs are highly specialized and efficient  antigen-presenting cells . Cells identical in appearance come both from a myeloid lineage (referred to as myeloid dendritic cells) and also from a lymphoid lineage (referred to as  plasmacytoid dendritic cells ). [ citation needed ]


The development and regulation of DC is not well-characterized. While the DC precursors have been identified in the human fetal liver, thymus, and bone marrow, during adult life DC are thought to be produced only from the bone marrow and released into the blood to wander and settle down. Overall, a large number of DC of varying types are dispatched throughout the body, especially at epithelia such as skin, to monitor invaders and nibble their antigens. (Medical Immunology, p. 122)


Lymphocytes have a number of alarming properties such as the ability to wander around the body and take up lodging almost anywhere, and while on the way issue commands in the form of  cytokines  and  chemokines  and  lymphokines , commands that affect many cell types in the body and which may also recursively induce further lymphopoiesis. One strong behavior pattern that captivates researchers and the public alike is the ability of lymphocytes to act as police, judge and executioner to kill other cells or demand that they suicide, a command that is usually obeyed. There seems to be no other sentencing option available. [ citation needed ]


Killers are distinguished from cells such as macrophages that eat other cells or munch debris by a method called  phagocytosis . Killers do not use phagocytosis; they just kill and leave the clean-up to other cells.


Killers are known to attack virus-infected cells and cells that have become cancerous. Because of these abilities much research has been done into transforming these qualities into medical therapy, but progress has been slow.


Here is the parade of killers and how they work:


(also called  Tc  or antigen-specific cyto-lytic or -toxic T lymphocytes ( CTL) ). [ 20 ]  Tc kill by apoptosis and either splash their target with  perforin  or  granzymes  or else use  Fas-Fasl Interaction  to command target elimination. This kills cells that are infected and display antigen.


These kill with exactly the same methods as Tc but have no interaction with any antigen. They select their targets based on typical molecules displayed by cells that are under stress by viral infection. NK Cells mainly are in the circulation (5-15% of the circulating lymphocytes) yet are also distributed in tissues everywhere. [ 21 ]


Natural Killer T Cells. Human NK T cells are a unique population (which express NK cell markers such as CD56 and KIR). NKT cells are thought to play an important role in tumor immunity and immunoregulation (Medical Immunology, p. 135), yet little is known. Recent evidence suggests a role working together with  hepatic stellate cells  being a liver-resident antigen-presenting cell that presents lipid antigens to and stimulates proliferation of NKT cells.


A heterogeneous group with ill-defined properties.


However, in summary there is  no known cell or set of cells  that is capable of killing cancerous cells in general.


Because all WBCs are microscopic, colorless and often seemingly identical in appearance they are individually identified by their natural chemical markers, many of which have been analyzed and named. When two cells have the same markers, the reasonable assumption is made that the cells are identical at that time.  A set of markers is colloquially described as the  barcode  for that cell or that cell line.


HSCs are technically described as: lacking  FMS-like tyrosine kinase 3  (Flt3) and lacking the markers specific to discrete lymphoid lineages (Lin) but expressing high levels of Sca1 and c-kit; HSC also express CD44, low levels of Thy1.1 (CD90), but no IL-7Ra or CD27. [ citation needed ]


This is called the (surface) phenotype of an HSC. It can be expressed as a set (Lin2, Sca1high, c-kit high, CD44+, Thy1.1low, CD27 2, and IL-7Ra2). This set is a ‘barcode’ for the HSC, akin to the barcode label attached to your chicken-wing plastic bag for checkout at a supermarket! Scientists use these barcodes to check, categorize and accumulate cells for many purposes often using laboratory methods such as  cell flow cytometry . These barcodes partially define the modern meaning of  phenotype  for  leukocytes .


Progression of HSC differentiation and lineage commitment is indicated by changes in this  phenotype . That is, as the cell changes, the markers will also change, and the barcode will change.


New questions emerge in immunology continuously as though there were a  stem cell  for questions. For example, it was thought that the process of lymphopoiesis was a direct, orderly unidirectional sequence. But it is not clear  if end-stage lymphocytes come from progenitors that are homogeneous populations or overlapping populations. Nor is it clear whether lineages of lymphocytes develop via a continuum of differentiation with a progressive loss of lineage options or whether abrupt events result in the acquisition of certain properties. [ 23 ]


Changes in cytoplasm,  morphology  of the cell nucleus, granules, cell internal biochemistry, signaling molecules and cell surface markers are difficult to correlate with definite stages in lymphopoiesis. The morphological differences do not just correspond to steps in  mitosis  (somatic cell division), but result from continuous "maturation processes" of the cell nucleus, as well as of the cytoplasm and so one must not be too rigid about morphological distinctions between certain cell stages. [ 24 ]


Until recently the model of the CMP generating all myeloid cell and the CLP generating all lymphoid cells was considered necessary and sufficient to explain the known facts observed in the generation of WBCs, and it is still found in most basic textbooks. However, beginning around 2000 and gaining momentum after 2005 [ 25 ]  in both studies in humans and mice, new complexities were noted and published in papers. [ citation needed ]  These studies are important now mainly to immunology researchers but are likely to eventually lead to changes in medical treatments.


The changes were sparked by observations that lymphopoiesis did not always break into two lineages at the level of the CLP. Worse, some macrophages (long considered a myeloid lineage) could be generated by lymphoid lineage progenitors. In essence focus has been shifted away from the CLP to the MLP [ citation needed ]  (lymphoid-specified progenitors), which are clearly lymphoid progenitors yet retain some myeloid potential, particularly the ability in both humans and mice to make macrophages – one of the most versatile of immune cell defenders – and also many dendritic cells, the best 'watchdogs' of antigen invaders.


However, whatever the details may turn out to be, the process of lymphopoiesis always seems to relentlessly give rise to progeny with special attributes and abilities – "superpowers" so to speak – but with progressively more restricted lymphoid developmental potential.


This model of lymphopoiesis had the virtue of relative simplicity, agreement with nomenclature and terminology, and is still essentially valid for the laboratory mouse.


pHSC, MPP and ELP cells are not fully committed to the lymphoid lineage because if one is removed to a different location it may differentiate into non-lymphoid progeny. However CLP  are  committed to the lymphoid lineage. The CLP is the transit cell responsible for these (generally parallel) stages of development, below:


By 2008 it was found that "the majority of early thymic progenitor [ETP] cells do not commit to becoming T cells by the time they get to the thymus gland. ETP cells retained the ability to become either T cells or myeloid cells." [ 28 ]
 [ 29 ]


See also : [ 30 ]
 [ 31 ]
 [ 32 ]
 [ 33 ]
 [ 34 ]
 [ 35 ]


Texts in bold  are the most heavily cited in this article.


Alternate views of lineages


Hematopoietic stem cells  (HSCs) have high regenerative potentials and are capable of differentiating into all blood and immune system cells. Despite this impressive potential, HSCs have limited potential to produce more multipotent stem cells. [ 1 ]  This limited self-renewal potential is protected through maintenance of a quiescent state in HSCs. Stem cells maintained in this quiescent state are known as long term HSCs (LT-HSCs). During quiescence, HSCs maintain a low level of metabolic activity and do not divide. [ 2 ] [ 3 ] [ 4 ]  LT-HSCs can be signaled to proliferate, producing either  myeloid  or  lymphoid  progenitors. Production of these progenitors does not come without a cost: When grown under laboratory conditions that induce proliferation, HSCs lose their ability to divide and produce new progenitors. [ 5 ]  Therefore, understanding the pathways that maintain proliferative or quiescent states in HSCs could reveal novel pathways to improve existing therapeutics involving HSCs. [ 6 ]


All adult stem cells can undergo two types of division: symmetric and asymmetric. When a cell undergoes symmetric division, it can either produce two differentiated cells or two new stem cells. When a cell undergoes asymmetric division, it produces one stem and one differentiated cell. Production of new stem cells is necessary to maintain this population within the body. [ 7 ]  Like all cells, hematopoietic stem cells undergo metabolic shifts to meet their bioenergetic needs throughout development. [ 1 ]  These metabolic shifts play an important role in signaling, generating biomass, and protecting the cell from damage. Metabolic shifts also guide development in HSCs and are one key factor in determining if an HSC will remain quiescent, symmetrically divide, or asymmetrically divide. [ 1 ] [ 8 ] [ 9 ] [ 10 ]  As mentioned above, quiescent cells maintain a low level of oxidative phosphorylation and primarily rely on glycolysis to generate energy. Fatty acid  beta-oxidation  has been shown to influence fate decisions in HSCs. [ 11 ]  In contrast, proliferative HSCs primarily depend on oxidative phosphorylation. This switch is accompanied by an increase in intracellular  reactive oxygen species  (ROS) levels and increased anabolic activity in cells [ 3 ] [ 12 ] [ 13 ] [ 14 ]


It is well understood that quiescent HSCs have very low levels of metabolic activity. LT-HSCs primarily rely on  anaerobic glycolysis  to generate energy. Unlike other types of HSCs, little energy is produced from mitochondrial oxidative respiration. The reason from this is likely two-fold: LT-HSCs reside within the hypoxic niche of the bone marrow, and low levels of mitochondrial respiration protect quiescent cells from damage induced ROS. [ 15 ] [ 16 ]  When excessive levels of ROS are present, LT-HSCs undergo differentiation or  apoptosis , losing their ability to self-renew. [ 17 ]  This suggests that dependence on glycolysis is not only an environmental adaptation, but also a necessity for LT-HSCs to preserve their stemness.


LT-HSC preference for glycolysis is encoded by the transcription factor  MEIS1  and, to a lesser extent, the protein CBP/p300-interacting transactivator 2 ( CITED2 ). [ 18 ] [ 19 ] [ 20 ]  Both enzymes up regulate hypoxia-inducible factor 1α ( HIF1α ). Under hypoxic conditions, HIF1α dimerizes with HIF1ß to increase expression of several glycolytic enzymes to lead to an enhanced rate of glycolysis. [ 19 ]  HIF1α also activates  pyruvate dehydrogenase kinases  (PDK) 2 and 4. [ 15 ]  These enzymes inhibit  pyruvate dehydrogenase  (PDH). PDH converts  pyruvate  into  acetyl-CoA , a crucial first step for metabolite entry into the  TCA cycle  and  oxidative phosphorylation . Because this system inhibits mitochondrial metabolism and activates glycolysis, it is thought that the metabolic reprogramming by HIF1α is a main driver of LT-HSC quiescence.


Metabolic reprogramming by HIF1α does not always happen through action on PDKs. HIF1α can also promote expression of the cytosolic protein  CRIPTO . CRIPTO then interacts with its cell surface receptor  GRP78  to activate glycolytic enzymes. [ 21 ] [ 22 ]  Extracellular cytokines and chemokines may also contribute to HIF1α activity, but further work is required to elucidate the exact contribution of these signaling molecules.


In addition to HIF1α, MEIS1 induces transcription of  HIF2α . Though this enzyme is structurally similar to HIF1α, HIF2α has distinct functions. HIF2α is thought to protect HSCs from mitochondrial ROS production. An accumulation of ROS in HSCs causes stress at the endoplasmic reticulum, eventually inducing the  unfolded protein response  and apoptosis. [ 23 ]  HIF2α protects the cell from ROS accumulation by up regulating several genes involved in ROS quenching, including  catalase ,  glutathione peroxidase type I , and  superoxide dismutases . [ 8 ]  Activation of HIF2α is therefore necessary to maintain cellular health during quiescence.


Despite low levels of mitochondrial respiration, emerging evidence shows that LT-HSCs with the highest regenerative potential also have a high number of mitochondria. [ 25 ]  Despite this, quiescent HSC mitochondria have a low membrane potential and low rates of oxidative phosphorylation. This again highlights the dependence of LT-HSCs on glycolysis to generate energy. Despite their inactivity, possessing many mitochondria may indicate that the quiescent HSCs are prepared for proliferation once an appropriate signal is received [ 24 ]


Recently, it has been discovered that fatty acid oxidation (FAO) is a major determinant in whether a stem cell will symmetrically or asymmetrically divide. [ 26 ]  Transport of fatty acids into the mitochondria and their subsequent metabolism must be efficient in order for cells to maintain the ability to self-renew. In HSCs, transcriptional activation of nuclear genes involved in fatty acid transport and β-oxidation through a promyelocytic leukemia protein (PML)/peroxisome proliferation-activated receptor-gamma coactivator 1α ( PGC-1α )/peroxisome proliferator-activating receptor type δ ( PPARδ ) mediates efficiency of these processes. This pathway is also essential for HSC self-renewal because it promotes maintenance of the stem cell population. [ 26 ]  FAO promotes asymmetric HSC division to produce one progenitor and one stem cell. Inhibition of FAO has been shown to expand the population of progenitor cells, thus decreasing the stem cell population. [ 27 ]  Despite correlations between FAO and asymmetrical HSC divisions, the exact mechanism by which FAO governs stem cell fate decisions is still unclear.


Though maintenance of quiescence is important to HSCs to preserve their self-renewal capacity, proliferation is necessary to regenerate blood cells and immune cells for the body. During divisions, HSCs leave the hypoxic niche and begin circulating. Under these normoxic conditions, HIF1α is hydroxylated by prolyl hydroxylases PHD1, 2 and 3. [ 29 ] [ 30 ] [ 31 ]  This hydroxylation triggers the cell to degrade HIF1α through the von Hippel-Lindau ( VHL ) ubiquitin ligases. Degradation of HIF1α prevents dimerization with HIF1ß, impeding the transcription of glycolytic genes. Degrading HIF1α also prevents activation of PDK2 and 4, thus resuming function of PDH in the mitochondria. Because the cell is now able to catalyze the production of acetyl-CoA, mitochondrial metabolism is able to resume. Restoration of this mitochondrial metabolism is coordinated by reentry into the cell cycle. Concurrent with reinitiation of mitochondrial metabolism is an upregulation in transcription of cell cycle genes and genes involved in anabolic activities. [ 32 ] [ 33 ]  As expected, HSCs with a high mitochondrial membrane potential have higher rates of expression for genes related to the cell cycle and metabolism. [ 33 ]  The accompanying increase in ROS levels in these proliferating HSCs may in part drive differentiation of HSCs, but more work is needed to fully elucidate the role of ROS in this process [ 27 ]


Accompanying the processes driven by HIF1α is an activation of mitochondrial oxidative phosphorylation through inactivation of the protein tyrosine phosphatase mitochondrial 1 ( PTPMT1 ) enzyme. [ 27 ]  PTPMT-1 is essential for differentiation of HSCs into progenitors, and loss of this enzyme results in failure to produce blood cells in mice. [ 34 ]  Targets of PTPMT-1 include phosphatidylinositol phosphates (PIPs). When PIPs are acted upon by PTPMT-1, the mitochondrial membrane potential decreases. This decrease inhibits glucose entry into the TCA cycle and subsequent ATP generation through the electron transport chain. [ 34 ]  Thus, PTPMT-1 activity is crucial for HSCs to differentiate.


Another important suppressor of mitochondrial metabolism during quiescence is mitochondrial carrier homolog 2 ( MTCH2 ). [ 16 ]  Loss of MTCH2 increases oxidative phosphorylation and triggers HSC differentiation. As expected, this increase in oxidative phosphorylation increases ROS levels, ATP levels, and mitochondrial size. These phenotypes highlight the importance of MTCH2 in directing HSC fate.


Upregulation of glycolysis in proliferative HSCs may drive the  pentose phosphate pathway  (PPP) to maintain redox balance upon mitochondrial activation. [ 35 ] [ 36 ]  The PPP generates nicotinamide adenine dinucleotide phosphate ( NADPH ), which is a powerful cellular reducing agent. Production of NADPH may protect cells against accumulation of ROS because it is a key component in the glutathione-reductase system. [ 36 ]  Additionally, NADPH is required for synthesis of nucleic acids and lipids. Thus, high intracellular NADPH may be essential to generate biomass for HSCs as they reenter the cell cycle. [ 35 ]  Work in ex- vivo  HSC expansion systems supports this idea, but further work is needed to characterize the role of the PPP  in vivo [ 35 ]


Several signaling pathways also have roles in mediating the metabolic shift from quiescent to proliferative HSCs. For example, purine metabolism is upregulated and thus promotes entry into the cell cycle through signaling in the  p38 MAPK  pathway.  ERK  and  mTOR , other major signaling pathways, are also activated during cell cycle entry. Among other functions, these pathways promote protein, nucleotide, and lipid synthesis. Active ERK and mTOR pathways also lead to increased nutrient uptake in HSCs. In addition to this biosynthetic role, mTOR can also increase the rate of ATP production in cells. [ 28 ]


Thrombopoiesis  is the formation of  thrombocytes  (blood platelets) in the  bone marrow .  Thrombopoietin  is the main regulator of thrombopoiesis. Thrombopoietin affects most aspects of the production of platelets. This includes  self-renewal  and expansion of  hematopoietic stem cells , stimulating the increase of megakaryocyte progenitor cells, and supporting these cells so they mature to become platelet-producing cells. [ 2 ]
The process of thrombopoiesis is caused by the breakdown of proplatelets (mature megakaryocyte membrane  pseudopodial  projections). During the process almost all of the membranes, organelles, granules, and soluble macromolecules in the cytoplasm are being consumed. Apoptosis also plays a role in the final stages of thrombopoiesis by letting proplatelet processes to occur from the cytoskeleton of actin. [ 3 ]


Platelets are formed by megakaryocytes and are present in the bloodstream for 5–7 days. Platelets are regulators of hemostasis and thrombosis. Platelets become active in the blood following vascular injury. Vascular injury causes platelets to stick to the cellular matrix that is exposed under the endothelium, form a platelet plug, and then form a  thrombus . Platelets are essential in the formation of an occlusive thrombus and are the main target of preventing the formation of an arterial thrombus. Platelets are also important in innate immunity and regulating tumor growth and vessel leakage. [ 4 ]


The  megakaryoblast  is a platelet precursor that undergoes  endomitosis  to form megakaryocytes that have 8 to 64 nuclei. Megakaryocytes shed platelets into the bloodstream. β1-tubulin microtubules, which are found in megakaryocytes, facilitate this process of shedding platelets into the bloodstream. [ 5 ]  Megakaryocytes are precursor cells that are highly specialized. Megakaryocytes give rise to 1,000 to 3,000 platelets. Megakaryocytes function in the process of Thrombopoiesis by producing platelets and releasing platelets into the bloodstream. [ 6 ]  Megakaryocyte development is regulated mainly by thrombopoietin. IL-3, IL-6, and IL-11 also play a role in the development of megakaryocytes by working closely with thrombopoietin. [ 7 ]


Thrombopoietin is the main regulator in the process of thrombopoiesis. In the liver and renal tubular epithelial cells, thrombopoietin is constantly being produced. Platelets and platelet precursors clear and destroy the thrombopoietin that is produced so the concentration of plasma thrombopoietin levels and platelet and platelet precursor mass are inversely proportional. If there is less platelet mass present, less thrombopoietin is cleared, which causes an increase in free plasma thrombopoietin that stimulates thrombopoiesis. [ 5 ]


Transfusion medicine  (or  transfusiology ) is the branch of medicine that encompasses all aspects of the  transfusion  of blood and  blood components  including aspects related to hemovigilance. It includes issues of  blood donation ,  immunohematology  and other laboratory testing for transfusion-transmitted diseases, management and monitoring of clinical transfusion practices,  patient blood management , therapeutic  apheresis ,  stem cell  collections,  cellular therapy , and  coagulation . Laboratory management and understanding of state and federal regulations related to blood products are also a large part of the field.


In most countries,  immunohematology  and transfusion medicine specialists provide expert opinion on  massive transfusions , difficult/incompatible transfusions and rational use of specialised blood product therapy like irradiated blood/ leukodepleted /washed blood products.


The blood donor center is the facility that collects blood components from screened blood donors, either whole blood or separate components such as plasma or platelets only via apheresis. These blood components are then transported to a central location for processing such as fractionation, testing and redistribution. The testing includes determining blood type and testing for infectious diseases. Whole blood is fractionated into red blood cells, platelets and plasma whilst plasma can be further refined into separate components such as albumin, clotting factor concentrates and immunoglobulin.


The  blood bank  is the section of the clinical laboratory where  laboratory scientists  store and distribute  blood components . Both areas are typically overseen by a specialist in transfusion medicine. Transfusion medicine was earlier a branch of  clinical pathology , however the field has now expanded into a clinical, hospital-based specialty. The practice of transfusion medicine involves both laboratory and clinical aspects of transfusion as communication between blood bank and patients, treating specialists and other medical staff is vital in situations such as massive transfusions or  transfusion reactions .


To ensure the safety of blood components, regimented procedures and quality assurance systems must be in place covering all aspects of the transfusion chain, from donation to transfusion outcomes. Within hospitals, transfusion committees are established to ensure safe hospital transfusion practice such as compliance with standards and guidelines, reviewing transfusion reactions and management of blood supply. These multidisciplinary committees are composed of transfusion medicine specialists,  transfusion nurses , laboratory scientists, clinicians and staff from hospital management and the quality team.


In 1628,  English  physician  William Harvey  discovered that blood circulates around the body. Soon thereafter, the first blood transfusion was attempted. In 1665 another English doctor  Richard Lower  successfully used blood transfusion between dogs to keep them alive. [ 1 ]


Karl Landsteiner  is recognized as the father of transfusion medicine. Landsteiner is credited with the first classification of human blood into the four types (A, B, AB, O) of the  ABO blood group system .


Australia


In Australia, transfusion medicine is a sub-specialty of haematology. Training in transfusion medicine is covered by the Royal College of Pathologists of Australasia (RCPA).


Australia has national blood services operated by the  Australian Red Cross Blood Service . There are a series of guidelines and standards relevant to the laboratory released by the National Association of Testing Authorities, Australia (NATA), [ 2 ]  Australian and New Zealand Society of Blood Transfusion (ANZSBT) [ 3 ]  and RCPA. [ 4 ]  Similarly, there are a series of clinical practice,  patient blood management guidelines  by the National Blood Authority.


In Australia, the Serious Transfusion Incident Reporting (STIR) system is in place to capture serious transfusion incidents and near-miss incidents. [ 5 ]


In Denmark, the subject is covered by the specialty, "Clinical Immunology".


In Germany, transfusion medicine is an independent specialty. Physicians complete a three-year residency in transfusion medicine and two years in another relevant clinical settings like internal medicine or surgery.


In India, Immunohematology and Transfusion Medicine is a medical post graduate specialty (MD) recognized by Medical Council of India since 2009.


Physicians completing their internship may pursue a four-year Master of Medicine (Transfusion Medicine) programme to specialize in transfusion medicine in Malaysia. [ 6 ]  They are eligible for registration with National Specialist Registry as transfusion medicine specialists after completion of gazettement upon graduation. [ 7 ]  Transfusion medicine specialists in Malaysia may further their sub-specialty training in the field of immunohaematology, cord blood, patient blood management, cellular therapy, and regenerative medicine.


In Norway, the subject is covered by the specialty, "Immunology and Transfusion medicine"


In the United Kingdom, transfusion medicine is a sub-speciality of  hematology .


Serious Hazards of Transfusion  (SHOT) collects and analyses reports of adverse events related to transfusion, aiming to improve patient safety. [ 8 ]  Its reports have led to wider training for medical staff in the UK and a central reporting scheme to allow errors to be reported. [ 9 ]


There is the Better Blood Continuing Education Programme, which is organised by the  EUB  which is part of the  SNBTS . The EUB consists of many specialist  healthcare professionals . The programme's aim is to improve transfusion medicine practise. The programme is reviewed each annually in January. [ 10 ]


In the UK, there are restrictions in place to decrease the risk of the transmission of  Creutzfeldt–Jakob disease .


Physicians from a wide range of backgrounds, including  pathology ,  internal medicine ,  anesthesiology  and  pediatrics , are eligible for board certification in Transfusion Medicine following a 1–2 year fellowship.  It is a board-certified sub-specialty recognized by the  American Board of Pathology . [ 11 ]   These specialists are often considered consultants for physicians who require expert advice on the subjects listed above. Transfusiology is not a recognized term in the US.


The  ABO blood group system  is used to denote the presence of one, both, or neither of the A and B  antigens  on  erythrocytes  (red blood cells). [ 1 ]  For human  blood transfusions , it is the most important of the 44 different  blood type  (or group) classification systems currently recognized by the  International Society of Blood Transfusions  (ISBT) as of
December 2022. [ 2 ] [ 3 ]  A mismatch in this  serotype  (or in various others) can cause a potentially fatal  adverse reaction  after a transfusion, or an  unwanted immune response  to an organ transplant. [ 4 ]  Such mismatches are rare in modern medicine. The associated anti-A and anti-B  antibodies  are usually  IgM  antibodies, produced in the first years of life by sensitization to environmental substances such as food, bacteria, and viruses.


The ABO blood types were discovered by  Karl Landsteiner  in 1901; he received the  Nobel Prize in Physiology or Medicine  in 1930 for this discovery. [ 5 ]  ABO blood types are also present in other  primates  such as  apes , monkeys and  Old World monkeys . [ 6 ]


The ABO 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 red blood cells would clump together ( agglutinate ) when mixed in test tubes with sera from different persons, and that some human blood also agglutinated with animal blood. [ 7 ]  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. [ 8 ]


This was the first evidence that blood variations exist in humans — it was believed that all humans have similar blood. 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 blood 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. [ 9 ]


This was the discovery of blood groups for which Landsteiner was awarded the  Nobel Prize in Physiology or Medicine  in 1930. In his paper, he referred to the specific blood group interactions as isoagglutination, and also introduced the concept of agglutinins (antibodies), which is the actual basis of  antigen-antibody reaction  in the ABO system. [ 10 ]  He asserted:


[It] may be said that there exist at least two different types of agglutinins, one in A, another one in B, and both together in C. The red blood cells are inert to the agglutinins which are present in the same serum. [ 9 ]


Thus, he discovered two antigens ( agglutinogens  A and B) and two antibodies (agglutinins — anti-A and anti-B). His third group (C) indicated absence of both A and B antigens, but contains anti-A and anti-B. [ 10 ]  The following year, his students Adriano Sturli and Alfred von Decastello discovered the fourth type (but not naming it, and simply referred to it as "no particular type"). [ 11 ] [ 12 ]


In 1910,  Ludwik Hirszfeld  and  Emil Freiherr von Dungern  introduced the term 0 (null) for the group Landsteiner designated as C, and AB for the type discovered by Adriano sturli and Alfred von decastello ( https://www.rockefeller.edu/our-scientists/karl-landsteiner/2554-nobel-prize/ ). They were also the first to explain the genetic inheritance of the blood groups. [ 13 ] [ 14 ]


Czech serologist  Jan Janský  independently introduced blood type classification in 1907 in a local journal. [ 15 ]  He used the Roman numerical I, II, III, and IV (corresponding to modern O, A, B, and AB). Unknown to Janský, an American physician  William L. Moss  devised a slightly different classification using the same numerical; [ 16 ]  his I, II, III, and IV corresponding to modern AB, A, B, and O. [ 12 ]


These two systems created confusion and potential danger in medical practice. Moss's system was adopted in Britain, France, and US, while Janský's was preferred in most European countries and some parts of US. To resolve the chaos, 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. [ 17 ]  But it was not followed particularly where Moss's system had been used. [ 18 ]


In 1927, Landsteiner had moved to the  Rockefeller Institute for Medical Research  in New York. As a member of a committee of the  National Research Council  concerned with blood grouping, he suggested to substitute Janský's and Moss's systems with the letters O, A, B, and AB. (There was another confusion on the use of figure 0 for German  null  as introduced by Hirszfeld and von Dungern, because others used the letter O for  ohne , meaning without or zero; Landsteiner chose the latter. [ 18 ] ) This classification was adopted by the National Research Council and became variously known as the National Research Council classification, the International classification, and most popularly the "new" Landsteiner classification. The new system was gradually accepted and by the early 1950s, it was universally followed. [ 19 ]


The first practical use of blood typing in transfusion was by an American physician  Reuben Ottenberg  in 1907. Large-scale application began during the First World War (1914–1915) when  citric acid  began to be used for  blood clot prevention . [ 10 ]   Felix Bernstein  demonstrated the correct blood group inheritance pattern of multiple  alleles  at one locus in 1924. [ 20 ]  Watkins and Morgan, in England, discovered that the ABO  epitopes  were conferred by sugars, to be specific,  N -acetylgalactosamine  for the A-type and  galactose  for the B-type. [ 21 ] [ 22 ] [ 23 ]  After much published literature claiming that the ABH substances were all attached to glycosphingolipids, Finne  et al . (1978) found that the human erythrocyte glycoproteins contain polylactosamine chains [ 24 ]  that contains ABH substances attached and represent the majority of the antigens. [ 25 ] [ 26 ] [ 27 ]  The main glycoproteins carrying the ABH antigens were identified to be the Band 3 and Band 4.5 proteins and glycophorin. [ 28 ]  Later, Yamamoto's group showed the precise glycosyl transferase set that confers the A, B and O epitopes. [ 29 ]


Blood groups are inherited from both parents. The ABO blood type is controlled by a single  gene  (the  ABO gene ) with three types of  alleles  inferred from  classical genetics :  i ,  I A , and  I B . The  I  designation stands for  isoagglutinogen , another term for  antigen . [ 31 ]  The gene encodes a  glycosyltransferase —that is, an  enzyme  that modifies the  carbohydrate  content of the  red blood cell  antigens. The gene is located on the long arm of the  ninth chromosome  (9q34). [ 32 ]


The  I A  allele gives type A,  I B  gives type B, and  i  gives type O. As both  I A  and  I B  are dominant over  i , only  ii  people have type O blood. Individuals with  I A I A  or  I A i  have type A blood, and individuals with  I B I B  or  I B i  have type B.  I A I B  people have both  phenotypes , because A and B express a special dominance relationship:  codominance , which means that type A and B parents can have an AB child. A couple with type A and type B can also have a type O child if they are both heterozygous ( I B i  and  I A i ). The  cis-AB  phenotype has a single enzyme that creates both A and B antigens. The resulting red blood cells do not usually express A or B antigen at the same level that would be expected on common group A 1  or B red blood cells, which can help solve the problem of an apparently genetically impossible blood group. [ 33 ]


Individuals with the rare  Bombay phenotype  (hh) produce antibodies against the A, B, and O groups and can only receive transfusions from other hh individuals. The table above summarizes the various blood groups that children may inherit from their parents. [ 34 ] [ 35 ]  Genotypes are shown in the second column and in small print for the offspring: AO and AA both test as type A; BO and BB test as type B. The four possibilities represent the combinations obtained when one allele is taken from each parent; each has a 25% chance, but some occur more than once. The text above them summarizes the outcomes.


Historically, ABO blood tests were used in  paternity testing , but in 1957 only 50% of American men falsely accused were able to use them as evidence against paternity. [ 36 ]  Occasionally, the blood types of children are not consistent with expectations—for example, a type O child can be born to an AB parent—due to rare situations, such as  Bombay phenotype  and  cis AB . [ 37 ]


The A blood type contains about 20 subgroups, of which A1 and A2 are the most common (over 99%). A1 makes up about 80% of all A-type blood, with A2 making up almost all of the rest. [ 38 ]  These two subgroups are not always interchangeable as far as transfusion is concerned, as some A2 individuals produce antibodies against the A1 antigen. Complications can sometimes arise in rare cases when typing the blood. [ 38 ]


With the development of  DNA sequencing , it has been possible to identify a much larger number of alleles at the ABO locus, each of which can be categorized as A, B, or O in terms of the reaction to transfusion, but which can be distinguished by variations in the  DNA  sequence. There are six common  alleles  in white individuals of the  ABO gene  that produce one's blood type: [ 39 ] [ 40 ]


The same study also identified 18 rare alleles, which generally have a weaker glycosylation activity. People with weak alleles of A can sometimes express anti-A antibodies, though these are usually not clinically significant as they do not stably interact with the antigen at body temperature. [ 41 ]


Cis AB  is another rare variant, in which A and B genes are transmitted together from a single parent. [ 42 ]


The distribution of the blood groups A, B, O and AB varies across the world according to the population. There are also variations in blood type distribution within human subpopulations. [ citation needed ]


In the UK, the distribution of blood type frequencies through the population still shows some correlation to the distribution of  placenames  and to the successive invasions and migrations including  Celts ,  Norsemen ,  Danes ,  Anglo-Saxons , and  Normans  who contributed the  morphemes  to the placenames and the  genes  to the population. The native Celts tended to have more type O blood, while the other populations tended to have more type A. [ 43 ]


The two common O alleles, O01 and O02, share their first 261  nucleotides  with the group A allele A01. [ 44 ]  However, unlike the group A allele, a  guanosine  base is subsequently deleted. A premature  stop codon  results from this  frame-shift mutation . This variant is found worldwide, and likely predates human migration from  Africa . The O01 allele is considered to predate the O02 allele. [ citation needed ]


Some evolutionary biologists theorize that there are four main lineages of the ABO gene and that mutations creating type O have occurred at least three times in humans. [ 45 ]  From oldest to youngest, these lineages comprise the following alleles:  A101/A201/O09 ,  B101 ,  O02  and  O01 . The continued presence of the O alleles is hypothesized to be the result of  balancing selection . [ 45 ]  Both theories contradict the previously held theory that type O blood evolved first. [ citation needed ]


It is possible that food and environmental antigens (bacterial, viral, or plant antigens) have  epitopes  similar enough to A and B glycoprotein antigens. The antibodies created against these environmental antigens in the first years of life can cross-react with ABO-incompatible red blood cells that it comes in contact with during blood transfusion later in life. Anti-A antibodies are hypothesized to originate from immune response towards  influenza virus , whose epitopes are similar enough to the α-D-N-galactosamine on the A glycoprotein to be able to elicit a cross-reaction. Anti-B antibodies are hypothesized to originate from antibodies produced against  Gram-negative bacteria , such as  E. coli , cross-reacting with the α-D-galactose on the B glycoprotein. [ 46 ]


However, it is more likely that the force driving evolution of allele diversity is simply negative frequency-dependent selection; cells with rare variants of membrane antigens are more easily distinguished by the immune system from pathogens carrying antigens from other hosts. Thus, individuals possessing rare types are better equipped to detect pathogens. The high within-population diversity observed in human populations would, then, be a consequence of natural selection on individuals. [ 47 ]


The carbohydrate molecules on the surfaces of red blood cells have roles in  cell membrane  integrity,  cell adhesion , membrane transportation of molecules, and acting as receptors for extracellular ligands, and enzymes. ABO antigens are found having similar roles on  epithelial cells  as well as red blood cells. [ 48 ] [ 49 ]


The ABO antigen is also expressed on the  von Willebrand factor  (vWF)  glycoprotein , [ 50 ]  which participates in  hemostasis  (control of bleeding). In fact, having type O blood predisposes to bleeding, [ 51 ]  as 30% of the total genetic variation observed in plasma vWF is explained by the effect of the ABO blood group, [ 52 ]  and individuals with group O blood normally have significantly lower plasma levels of vWF (and  Factor VIII ) than do non-O individuals. [ 53 ] [ 54 ]  In addition, vWF is degraded more rapidly due to the higher prevalence of blood group O with the Cys1584 variant of vWF (an amino acid  polymorphism  in VWF): [ 55 ]  the gene for  ADAMTS13  (vWF-cleaving  protease ) maps to human  chromosome 9  band q34.2, the same  locus  as ABO blood type. Higher levels of vWF are more common amongst people who have had  ischemic stroke  (from blood clotting) for the first time. The results of this study found that the occurrence was not affected by ADAMTS13 polymorphism, and the only significant genetic factor was the person's blood group. [ 56 ]


ABO(H) blood group antigens are also carried by other hemostatically relevant glycoproteins, such as platelet glycoprotein Ibα, which is a ligand for vWF on platelets. [ 57 ]  The significance of ABO(H) antigen expression on these other hemostatic glycoproteins is not fully defined, but may also be relevant for bleeding and thrombosis.


ABO blood group incompatibilities between the mother and child do not usually cause  hemolytic disease of the newborn  (HDN) because antibodies to the ABO blood groups are usually of the  IgM  type, which do not cross the placenta. However, in an O-type mother,  IgG  ABO antibodies are produced and the baby can potentially develop  ABO hemolytic disease of the newborn . [ 58 ]


In human cells, the ABO alleles and their encoded glycosyltransferases have been described in several oncologic conditions. [ 59 ]  Using anti-GTA/GTB monoclonal antibodies, it was demonstrated that a loss of these enzymes was correlated to malignant bladder and oral epithelia. [ 60 ] [ 61 ]  Furthermore, the expression of ABO blood group antigens in normal human tissues is dependent the type of differentiation of the epithelium. In most human carcinomas, including oral carcinoma, a significant event as part of the underlying mechanism is decreased expression of the A and B antigens. [ 62 ]  Several studies have observed that a relative down-regulation of GTA and GTB occurs in oral carcinomas in association with tumor development. [ 62 ] [ 63 ]  More recently, a genome wide association study (GWAS) has identified variants in the ABO locus associated with susceptibility to pancreatic cancer. [ 64 ]
In addition, another large GWAS study has associated ABO-histo blood groups as well as FUT2 secretor status with the presence in the intestinal microbiome of specific bacterial species. In this case the association was with  Bacteroides  and  Faecalibacterium spp .   Bacteroides  of the same OTU (operational taxonomic unit) have been shown to be associated with inflammatory bowel disease, [ 65 ] [ 66 ]  thus the study suggests an important role for the ABO histo-blood group antigens as candidates for direct modulation of the human microbiome in health and disease. [ 67 ]


A multi-locus genetic risk score study based on a combination of 27 loci, including the ABO gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). [ 68 ]


In April 2007, an international team of researchers announced in the journal  Nature Biotechnology  an inexpensive and efficient way to convert types A, B, and AB blood into type O. [ 69 ]  This is done by using  glycosidase  enzymes from specific bacteria to strip the blood group antigens from  red blood cells . The removal of A and B antigens still does not address the problem of the  Rh blood group  antigen on the blood cells of Rh positive individuals, and so blood from Rh negative donors must be used. The modified blood is named "enzyme converted to O" (ECO blood) but despite the early success of converting B- to O-type RBCs and clinical trials without adverse effects transfusing into A- and O-type patients, [ 70 ]  the technology has not yet become clinical practice. [ 71 ]


Another approach to the blood antigen problem is the manufacture of  artificial blood , which could act as a substitute in emergencies. [ 72 ]


In Japan and other parts of East Asia, there is a popular belief in  Blood type personality theory , which claims that blood types predict or influence personality. This claim is not scientifically based, and there is  scientific consensus  that no such link exists; the scientific community considers it a  pseudoscience  and a  superstition . [ 73 ]


The belief originated in the 1930s, when it was introduced as part of Japan's  eugenics  program. [ 74 ]  Its popularity faded following Japan's defeat in World War 2 and Japanese support for eugenics faltered, but it resurfaced in the 1970s by a journalist named  Masahiko Nomi . Despite its status as a pseudoscience, it remains widely popular throughout East Asia. [ 75 ]


Other popular ideas are  blood type-specific dietary needs , that group A causes severe  hangovers , that group O is associated with better teeth, and that those with group A2 have the highest  IQ scores . As with blood type personality theory, these and other popular ideas lack scientific evidence, and many are discredited or pseudoscientific. [ 76 ]


An  acute hemolytic transfusion reaction  ( AHTR ), also called  immediate hemolytic transfusion reaction , is a life-threatening reaction to receiving a  blood transfusion . AHTRs occur within 24 hours of the transfusion and can be triggered by a few milliliters of blood. The reaction is triggered by host antibodies destroying donor red blood cells. AHTR typically occurs when there is an  ABO blood group  incompatibility, and is most severe when type A donor blood is given to a type O recipient. [ 1 ] [ 2 ] [ 3 ]


Early acute hemolytic transfusion reactions are typically characterized by fever, which may be accompanied by  rigors  (chills). Mild cases are also typically characterized by abdominal, back, flank, or chest pain. More severe cases may be characterized by  shortness of breath ,  low blood pressure ,  hemoglobinuria , and may progress to  shock  and  disseminated intravascular coagulation . In anesthetized or unconscious patients,  hematuria  (blood in the urine) may be the first sign of AHTR. Other symptoms include nausea, vomiting, and  wheezing . [ 4 ]


The most common cause of acute hemolytic transfusion reaction is  ABO incompatibility , which is typically due to human error that results in a recipient receiving the incorrect blood product. Rarely, other blood type incompatibilities can cause AHTR, the most common of which is  Kidd antigen  incompatibility. [ 4 ]   Rh ,  Kell , and  Duffy  antigen incompatibility have also been implicated in AHTR. [ 5 ]


Acute hemolytic transfusion reactions result when  antibodies  against A and/or B antigens (isohemagglutinins) present in the recipient's blood destroy the respective donor  red blood cells . [ 4 ] [ 5 ]  This is mediated through the antibodies  IgM  (and to a lesser extent  IgG ) which cause activation of the  complement cascade , with complement C5-C9 forming the  membrane attack complex  which leads to pore formation and red blood cell lysis. [ 6 ]  The lysed red blood cells release free hemoglobin into the bloodstream, overwhelming hemoglobin binding proteins such as  albumin ,  haptoglobin , and  hemopexin , with the excess free hemoglobin leading to renal vasoconstriction (via nitric oxide scavenging), which then leads to  acute tubular necrosis  and  acute kidney injury . [ 6 ]


The antibodies also activate the  coagulation cascade  (blood clotting system) via  factor XII , which can lead to disseminated intravascular coagulation and kidney damage. Isohemagglutinins also activate the complement cascade via  C3a  and  C5a , which then promote inflammatory  cytokine  release from  white blood cells . C3a and C5a also activate  mast cells  which release  serotonin  and  histamine , which along with fragments of red blood cells that were destroyed, further stimulate the release of inflammatory cytokines. [ 6 ]  These inflammatory cytokines include  IL-1 ,  IL-6 ,  IL-8 , and  TNF-alpha , which cause increased capillary permeability and vasodilation leading to symptoms of low blood pressure, fever, chest pain, nausea, vomiting, and wheezing. [ 4 ] [ 6 ]


The diagnosis of AHTR is made with microscopic examination of the recipient's blood and a  direct antiglobulin test  (direct Coombs test) which detects IgG antibodies or complement bound to red blood cells and is usually diagnostic of acute hemolytic transfusion reactions. [ 6 ]  The donor and recipient blood can be re-tested with a type, crossmatch, and antibody screen to determine the cause of the reaction. [ 4 ]  The donor blood should be examined for any labelling error or other possible errors from the blood bank, which may help prevent other mislabeled blood products from being distributed. [ 6 ]  Testing the donor blood using a  gram stain  and  blood culture  can also help to rule out an infectious cause of the symptoms (such as the donor receiving infected blood). [ 6 ]  Testing for urine or plasma free hemoglobin may also assist in the diagnosis. [ 6 ]


Initial treatment for any type of transfusion reaction, including AHTR, is discontinuation of the transfusion.  Fluid replacement  and close monitoring of vital signs are important. People with AHTR are managed with  supportive care , which may include  diuretics , blood pressure support, and treatment of disseminated intravascular coagulation (with  fresh frozen plasma ,  cryoprecipitate , and  platelet transfusion ). [ 6 ]  The use of steroids, intravenous immune-globulins ( IVIG ) or plasma exchange is not supported by evidence. [ 6 ]   Furosemide  is the diuretic of choice in treatment of AHTR with decreased urine output, because it increases the amount of blood that reaches the  renal cortex . [ 4 ]   Mannitol  may also be used. [ 5 ]   Dopamine  is used for blood pressure support because it causes  vasodilation  (dilation of blood vessels) in the kidneys as well as increasing the  cardiac output  (amount of blood pumped by the heart each minute). [ 4 ]


The severity and prognosis of acute hemolytic transfusion depends on the rate of blood administration and the total volume of the transfusion. The levels of anti-A and anti-B antibodies in the recipients blood may also predict the prognosis, with higher levels of antibodies thought to portend a more severe course. [ 6 ]  Approximately 2% of cases are fatal. Reactions that begin sooner are typically more severe. [ 4 ]


Acute hemolytic transfusion reaction is estimated to occur in 1 in 38,000 to 1 in 70,000 transfusions. An estimated 41% of ABO-incompatible transfusions result in AHTR. [ 4 ]


An  allergic transfusion reaction  is when a  blood transfusion  results in  allergic reaction . It is among the most common  transfusion reactions  to occur.  Reported rates depend on the degree of active surveillance versus passing reporting to the blood bank. [ 1 ] [ 2 ]  Overall, they are estimated to complicate up to 3% of all transfusions. [ 3 ]   The incidence of allergic transfusion reactions is associated with the amount of plasma in the product. [ 3 ]  More than 90% of these reactions occur during transfusion.


Allergic reactions from blood transfusion may occur from the presence of allergy-causing antigens within the donor's blood, [ 4 ]  or transfusion of antibodies from a donor who has allergies, followed by antigen exposure. [ 5 ] [ 6 ]


An allergic transfusion reaction is a type of transfusion reaction that is defined according to the Center for Disease Control (CDC)  [ 7 ]  as:


An allergic transfusion reaction is diagnosed if two or more of the following occur within 4 hours of cessation of transfusion: [ 8 ]


A probable diagnosis results if any one of the following occurring within 4 hours of cessation of transfusion: [ citation needed ]


The UK hemovigilance reporting system ( SHOT ), has classified allergic reactions in to mild, moderate and severe. [ 9 ]  Reactions can occur that have features of both allergic and  febrile reactions . [ 9 ]


A rash,  urticaria , or flushing [ 9 ]


Wheeze ( bronchospasm ) or  angioedema  but blood pressure normal and no respiratory compromise. There may or may not be an associated rash or  urticaria . [ 9 ]


This can be due to: [ citation needed ]


To prevent allergic transfusion reaction it is possible to use patients own blood for transfusion, this is referred to as  autologous blood transfusion . Patients' own blood is collected and washed to produce concentrated red blood cells (this blood product is also called  packed red blood cells ). There are multiple ways to  wash red blood cells . The two main methods that are used to wash the cells are centrifugation, or filtration methods like the Hemoclear microfilter. The last option is reinfusion without washing. This is the least preferred method because of the chance of complications. [ 10 ]


There is no evidence that antihistamine premedication prevents allergic transfusion reactions, although these drugs can mitigate symptoms once they occur. [ 11 ] [ 12 ] [ 3 ]


Treatment of an allergic transfusion reaction is to immediately stop the transfusion. If the only symptoms are mild (i.e., hives and itching), the patient may be treated with an antihistamine and if the symptoms completely disappear and the patient feels well, the transfusion may be restarted. A mild transfusion reaction during infusion usually does not progress to a more severe anaphylactic reaction after infusion of additional product from the same unit. [ 3 ]  If the symptoms are more than mild, the transfusion should not be restarted. [ citation needed ]


The  American Society for Apheresis  ( ASFA ) is an organization of  physicians , scientists,  nurses , and  allied health professionals  whose mission is to advance  apheresis  medicine for patients, donors and practitioners through education, evidence-based practice, research and advocacy.  ASFA represents a broad range of health care professionals involved in  apheresis  medicine including those practicing  pathology ,  transplantation ,  hematology ,  oncology ,  neurology ,  rheumatology ,  nephrology ,  hepatology ,  gastroenterology ,  cardiology , and  ophthalmology .  These health care providers are involved in the performance of therapeutic apheresis procedures including  plasma exchange ,  red cell exchange ,  leukocytapheresis ,  plateletapheresis ,  photopheresis ,  LDL apheresis , and hematopoietic progenitor cell collection. ASFA also represents those physicians and allied health professionals involved in the  collection of blood products from blood donors  using apheresis instruments. [ 1 ]


The major activities of ASFA are member driven and educational, including publication of the  Journal of Clinical Apheresis  Special Issue: Clinical Applications of Therapeutic Apheresis: An Evidence Based Approach, [ 2 ]  publication of Principles of Apheresis Technology Textbook, [ 3 ]  publication of Therapeutic Apheresis: A Physician's Handbook, [ 4 ]  monthly apheresis educational  webinar  program  [ 5 ]  and developing programming for the ASFA Annual Meeting. [ 6 ]


ASFA was formed in 1982. It grew from the merger of two organizations, the  Society of Hemapheresis Specialists  (SHS) and the original ASFA. The SHS was formed by nursing and allied health personnel, who were responsible for performing the donor and therapeutic procedures and operating the various  blood cell  separators.  It was formed provide educational and networking opportunities in the field of apheresis medicine that were not available and which were needed by the original members in order to advance the field. SHS became a national forum for the exchange of views and best practices and was the forerunner of the efforts directed toward apheresis practitioner  certification . [ citation needed ]


The original ASFA developed from a physician-scientist symposia.  It was originally developed for the purpose to present scientific research on donor and therapeutic apheresis topics. The first apheresis symposium was held in  Chicago  in 1979, and was the first of annual symposia.  The subsequent symposia were named the ASFA Symposia. Most of the initial Officers and Board of Directors of ASFA presented at these symposia, from which the structure of the organization grew. In 1982,  John Verrier-Jones , became the first president of ASFA. He noted that the term “apheresis” had been in use since 1914, and that the appropriate terms was “apheresis”, not “pheresis” as was quite widely used at the time. [ 7 ]


In addition to providing education in apheresis medicine for healthcare professionals, ASFA also now seeks to provide education to patients undergoing apheresis treatment. [ citation needed ]


Anemia  or  anaemia  ( British English ) is a  blood disorder  in which the  blood  has a reduced ability to carry  oxygen . This can be due to a lower than normal number of  red blood cells , a reduction in the amount of  hemoglobin  available for oxygen transport, or abnormalities in hemoglobin that impair its function. [ 3 ] [ 4 ]  The name is derived from  Ancient Greek     ἀν - (an-)  'not' and    αἷμα  (haima)  'blood'. [ 5 ]


When anemia comes on slowly, the symptoms are often vague, such as  tiredness ,  weakness ,  shortness of breath ,  headaches , and a  reduced ability to exercise . [ 1 ]  When anemia is acute, symptoms may include  confusion ,  feeling like one is going to pass out ,  loss of consciousness , and  increased thirst . [ 1 ]  Anemia must be significant before a person becomes noticeably  pale . [ 1 ]  Additional symptoms may occur depending on the underlying cause. [ 1 ]  Anemia can be temporary or long term and can range from mild to severe. [ 6 ]


Anemia can be caused by  blood loss , decreased red blood cell production, and increased  red blood cell breakdown . [ 1 ]  Causes of blood loss include  bleeding due to inflammation of the stomach or intestines , bleeding from  surgery , serious  injury , or  blood donation . [ 1 ]  Causes of decreased production include  iron deficiency ,  folate deficiency ,  vitamin B 12  deficiency ,  thalassemia  and a number of  bone marrow tumors . [ 1 ]  Causes of increased breakdown include  genetic disorders  such as  sickle cell anemia , infections such as  malaria , and certain  autoimmune diseases  like  autoimmune hemolytic anemia . [ 1 ]


Anemia can also be classified based on the  size of the red blood cells  and  amount of hemoglobin in each cell . [ 1 ]  If the cells are small, it is called  microcytic anemia ; if they are large, it is called  macrocytic anemia ; and if they are normal sized, it is called  normocytic anemia . [ 1 ]  The diagnosis of anemia in men is based on a hemoglobin of less than 130 to 140 g/L (13 to 14 g/dL); in women, it is less than 120 to 130 g/L (12 to 13 g/dL). [ 1 ] [ 7 ]  Further testing is then required to determine the cause. [ 1 ] [ 8 ]


Treatment depends on the specific cause. Certain groups of individuals, such as pregnant women, can benefit from the use of  iron pills  for prevention. [ 1 ] [ 9 ]   Dietary supplementation , without determining the specific cause, is not recommended. [ 1 ]  The use of  blood transfusions  is typically based on a person's signs and symptoms. [ 1 ]  In those without symptoms, they are not recommended unless hemoglobin levels are less than 60 to 80 g/L (6 to 8 g/dL). [ 1 ] [ 10 ]  These recommendations may also apply to some people with acute bleeding. [ 1 ]   Erythropoiesis-stimulating agents  are only recommended in those with severe anemia. [ 10 ]


Anemia is the most common blood disorder, affecting about a fifth to a third of the global population. [ 1 ] [ 11 ] [ 12 ] [ 13 ]   Iron-deficiency anemia  is the most common cause of anemia worldwide, and affects nearly one billion people. [ 14 ]  In 2013, anemia due to iron deficiency resulted in about 183,000 deaths – down from 213,000 deaths in 1990. [ 15 ]  This condition is most prevalent in children [ 16 ] [ 17 ]  with also an above average prevalence in elderly [ 1 ]  and women of reproductive age (especially during pregnancy). [ 14 ]  Anemia is one of the six  WHO  global nutrition targets for 2025 and for diet-related global targets endorsed by  World Health Assembly  in 2012 and 2013. Efforts to reach global targets contribute to reaching  Sustainable Development Goals  (SDGs), [ 18 ]  with anemia as one of the targets in  SDG 2  for achieving zero world hunger. [ 19 ]


A person with anemia may not have any symptoms, depending on the underlying cause, and no symptoms may be noticed, as the anemia is initially mild, and then the symptoms become worse as the anemia worsens. A patient with anemia may report  feeling tired , weak, decreased ability to concentrate, and sometimes  shortness of breath  on  exertion . [ 21 ]  These symptoms are unspecific and none of the symptoms alone or in combination show a good predictive value for the presence of anemia in non-clinical patients. [ 22 ]


Symptoms of anemia can come on quickly or slowly. [ 23 ]  Early on there may be few or no symptoms. [ 23 ]  If the anemia continues slowly (chronic), the body may adapt and compensate for this change. In this case, no symptoms may appear until the anemia becomes more severe. [ 20 ] [ 24 ]  Symptoms can include feeling tired, weak,  dizziness , headaches,  intolerance to physical exertion , shortness of breath, difficulty concentrating,  irregular  or  rapid  heartbeat, cold hands and feet,  cold intolerance ,  pale  or  yellow  skin,  poor appetite , easy bruising and bleeding, and  muscle weakness . [ 23 ]


Anemia that develops quickly, often, has more severe symptoms, including,  feeling faint ,  chest pain , sweating, increased thirst, and confusion. [ 23 ] [ 25 ] [ 26 ] [ 27 ]  There may be also additional symptoms depending on the underlying cause. [ 1 ]


In more severe anemia, the body may compensate for the lack of oxygen-carrying capability of the blood by increasing  cardiac output . The person may have symptoms related to this, such as  palpitations ,  angina  (if pre-existing  heart disease  is present), intermittent  claudication  of the legs, and symptoms of  heart failure . [ 28 ]


On examination, the signs exhibited may include  pallor  (pale skin,  mucosa ,  conjunctiva  and  nail beds ), but this is not a reliable sign.


Iron-deficiency anemia may give symptoms that can include  spoon-shaped  nails, restless legs syndrome, and pica (the medical condition indicates the desire for things that are not food, such as ice, dirt, etc.). [ 29 ]  A blue coloration of the  sclera  may be noticed in some cases of iron-deficiency anemia. [ 30 ]  Vitamin B 12  deficiency anemia may result in decreased ability to think, memory loss, confusion, personality or mood changes, depression, difficulty walking, blurred vision, and irreversible nerve damage. [ 31 ] [ 32 ]  Other specific causes of anemia may have signs and/or complications such as,  jaundice  with the rapid break down of  red blood cells  as with  hemolytic anemia , bone abnormalities with  thalassemia major , or leg  ulcers  as seen in  sickle cell disease .


In severe anemia, there may be signs of a  hyperdynamic circulation :  tachycardia  (a fast heart rate),  bounding pulse ,  flow murmurs , and  cardiac   ventricular hypertrophy  (enlargement). There may be signs of  heart failure .
 Pica , the consumption of non-food items such as ice, paper, wax, grass, hair or dirt, may be a symptom of iron deficiency; [ 29 ]  although it occurs often in those who have normal levels of  hemoglobin . Chronic anemia may result in behavioral disturbances in children as a direct result of impaired neurological development in infants, and reduced academic performance in children of school age.  Restless legs syndrome  is more common in people with  iron-deficiency anemia  than in the general population. [ 33 ]


The causes of anemia may be classified as impaired red blood cell (RBC) production, increased RBC destruction (hemolytic anemia), blood loss and fluid overload ( hypervolemia ). Several of these may interplay to cause anemia. The most common cause of anemia is blood loss, but this usually does not cause any lasting symptoms unless a relatively impaired RBC production develops, in turn, most commonly by  iron deficiency . [ 4 ]


Anemias of increased  red blood cell destruction  are generally classified as  hemolytic anemias . These types generally feature  jaundice , and elevated levels of  lactate dehydrogenase . [ 38 ] [ 39 ]


The roots of the words  anemia  and  ischemia  both refer to the basic idea of "lack of blood", but anemia and  ischemia  are not the same thing in modern medical terminology. The word  anemia  used alone implies  widespread   effects  from blood that either is too scarce (e.g., blood loss) or is dysfunctional in its oxygen-supplying ability (due to whatever type of hemoglobin or erythrocyte problem). In contrast, the word  ischemia  refers solely to the lack of blood (poor  perfusion ). Thus ischemia in a body part can cause localized anemic effects within those tissues. [ 50 ]


Fluid overload (hypervolemia) causes decreased hemoglobin concentration and apparent anemia: [ 51 ]


Certain gastrointestinal disorders can cause anemia. The mechanisms involved are multifactorial and not limited to malabsorption but mainly related to chronic intestinal inflammation, which causes dysregulation of  hepcidin  that leads to decreased access of iron to the circulation. [ 54 ] [ 55 ] [ 56 ]


There are a number of definitions of anemia;  reviews  provide comparison and contrast of them. [ 62 ]  A strict but broad definition is an absolute decrease in red blood cell mass, [ 63 ]  however, a broader definition is a lowered ability of the blood to carry  oxygen . [ 64 ]  An  operational definition  is a decrease in whole-blood  hemoglobin  concentration of more than 2  standard deviations  below the  mean  of an age- and sex-matched  reference range . [ 65 ]


It is difficult to directly measure RBC mass, [ 66 ]  so the  hematocrit  (amount of RBCs) or the hemoglobin (Hb) in the  blood  are often used instead to indirectly estimate the value. [ 67 ]  Hematocrit; however, is concentration dependent and is therefore not completely accurate. For example, during pregnancy a woman's RBC mass is normal but because of an increase in blood volume the hemoglobin and hematocrit are diluted and thus decreased. Another example would be bleeding where the RBC mass would decrease but the concentrations of hemoglobin and hematocrit initially remains normal until fluids shift from other areas of the body to the intravascular space. [ citation needed ]


The anemia is also classified by severity into mild (110 g/L to normal), moderate (80 g/L to 110 g/L), and severe anemia (less than 80 g/L) in adults. [ 68 ]  Different values are used in pregnancy and children. [ 68 ]


Anemia is typically diagnosed on a  complete blood count . Apart from reporting the number of  red blood cells  and the hemoglobin level, the  automatic counters  also measure the size of the red blood cells by  flow cytometry , which is an important tool in distinguishing between the causes of anemia. Examination of a stained  blood smear  using a  microscope  can also be helpful, and it is sometimes a necessity in regions of the world where automated analysis is less accessible. [ citation needed ]


A blood test will provide counts of white blood cells, red blood cells and platelets. If anemia appears, further tests may determine what type it is, and whether it has a serious cause. although of that, it is possible to refer to the genetic history and physical diagnosis. [ 70 ]  These tests may also include  serum ferritin ,  iron studies ,  vitamin B 12 , genetic testing, and a  bone marrow sample , if needed. [ 71 ] [ 72 ]


Reticulocyte counts, and the "kinetic" approach to anemia, have become more common than in the past in the large medical centers of the United States and some other wealthy nations, in part because some automatic counters now have the capacity to include reticulocyte counts. A  reticulocyte  count is a quantitative measure of the  bone marrow 's production of new red blood cells. The  reticulocyte production index  is a calculation of the ratio between the level of anemia and the extent to which the reticulocyte count has risen in response. If the degree of anemia is significant, even a "normal" reticulocyte count actually may reflect an inadequate response.


If an automated count is not available, a reticulocyte count can be done manually following special staining of the blood film. In manual examination, activity of the bone marrow can also be gauged qualitatively by subtle changes in the numbers and the morphology of young RBCs by examination under a microscope. Newly formed RBCs are usually slightly larger than older RBCs and show polychromasia. Even where the source of blood loss is obvious, evaluation of  erythropoiesis  can help assess whether the bone marrow will be able to compensate for the loss and at what rate.


When the cause is not obvious, clinicians use other tests, such as:  ESR , serum iron,  transferrin ,  RBC folate level ,  hemoglobin electrophoresis ,  renal function  tests (e.g.  serum creatinine ) although the tests will depend on the clinical hypothesis that is being investigated.


When the diagnosis remains difficult, a  bone marrow examination  allows direct examination of the precursors to red cells, although is rarely used as is painful, invasive and is hence reserved for cases where severe pathology needs to be determined or excluded. [ medical citation needed ]


In the morphological approach, anemia is classified by the size of red blood cells; this is either done automatically or on microscopic examination of a peripheral blood smear. The size is reflected in the  mean corpuscular volume  (MCV). If the cells are smaller than normal (under 80  fl ), the anemia is said to be  microcytic ; if they are normal size (80–100 fl), normocytic; and if they are larger than normal (over 100 fl), the anemia is classified as  macrocytic . This scheme quickly exposes some of the most common causes of anemia; for instance, a microcytic anemia is often the result of  iron deficiency .


In clinical workup, the MCV will be one of the first pieces of information available, so even among clinicians who consider the "kinetic" approach more useful philosophically, morphology will remain an important element of classification and diagnosis.
Limitations of MCV include cases where the underlying cause is due to a combination of factors – such as iron deficiency (a cause of microcytosis) and vitamin  B12 deficiency  (a cause of macrocytosis) where the net result can be normocytic cells. [ medical citation needed ]


The "kinetic" approach to anemia yields arguably the most clinically relevant classification of anemia. This classification depends on evaluation of several hematological parameters, particularly the blood reticulocyte (precursor of mature RBCs) count. This then yields the classification of defects by decreased RBC production versus increased RBC destruction or loss. Clinical signs of loss or destruction include abnormal  peripheral blood smear  with signs of hemolysis; elevated  LDH  suggesting cell destruction; or clinical signs of bleeding, such as guaiac-positive stool, radiographic findings, or frank bleeding. [ medical citation needed ]
The following is a simplified schematic of this approach: [ medical citation needed ]


*   For instance, sickle cell anemia with superimposed iron deficiency; chronic gastric bleeding with B 12  and folate deficiency; and other instances of anemia with more than one cause.
 **   Confirm by repeating reticulocyte count: ongoing combination of low reticulocyte production index, normal MCV and hemolysis or loss may be seen in bone marrow failure or anemia of chronic disease, with superimposed or related hemolysis or blood loss.
Here is a schematic representation of how to consider anemia with MCV as the starting point:


Other characteristics visible on the peripheral smear may provide valuable clues about a more specific diagnosis; for example, abnormal  white blood cells  may point to a cause in the  bone marrow .


Microcytic anemia is primarily a result of hemoglobin synthesis failure/insufficiency, which could be caused by several etiologies:


Iron-deficiency anemia is the most common type of anemia overall and it has many causes. RBCs often appear hypochromic (paler than usual) and microcytic (smaller than usual) when viewed with a microscope.


The  Mentzer index  (mean cell volume divided by the RBC count) predicts whether microcytic anemia may be due to iron deficiency or thalassemia, although it requires confirmation. [ 80 ] [ citation needed ]


Macrocytic anemia can be further divided into "megaloblastic anemia" or "nonmegaloblastic macrocytic anemia". The cause of megaloblastic anemia is primarily a failure of DNA synthesis with preserved RNA synthesis, which results in restricted cell division of the progenitor cells. The megaloblastic anemias often present with neutrophil hypersegmentation (six to 10 lobes). The nonmegaloblastic macrocytic anemias have different etiologies (i.e. unimpaired DNA globin synthesis,) which occur, for example, in alcoholism.
In addition to the nonspecific symptoms of anemia, specific features of vitamin B 12  deficiency include  peripheral neuropathy  and  subacute combined degeneration of the cord  with resulting balance difficulties from posterior column spinal cord pathology. [ 82 ]  Other features may include a smooth, red tongue and  glossitis .
The treatment for vitamin B 12 -deficient anemia was first devised by  William Murphy , who bled dogs to make them anemic, and then fed them various substances to see what (if anything) would make them healthy again. He discovered that ingesting large amounts of liver seemed to cure the disease.  George Minot  and  George Whipple  then set about to isolate the curative substance chemically and ultimately were able to isolate the  vitamin B 12  from the liver. All three shared the 1934  Nobel Prize in Medicine . [ 83 ]


Normocytic anemia occurs when the overall hemoglobin levels are decreased, but the red blood cell size ( mean corpuscular volume ) remains normal. Causes include:


A dimorphic appearance on a peripheral blood smear occurs when there are two simultaneous populations of red blood cells, typically of different size and hemoglobin content (this last feature affecting the color of the red blood cell on a stained peripheral blood smear). For example, a person recently transfused for iron deficiency would have small, pale, iron deficient red blood cells (RBCs) and the donor RBCs of normal size and color. Similarly, a person transfused for severe folate or vitamin B12 deficiency would have two cell populations, but, in this case, the patient's RBCs would be larger and paler than the donor's RBCs.


A person with sideroblastic anemia (a defect in heme synthesis, commonly caused by alcoholism, but also drugs/toxins, nutritional deficiencies, a few acquired and rare congenital diseases) can have a dimorphic smear from the sideroblastic anemia alone. Evidence for multiple causes appears with an elevated RBC distribution width (RDW), indicating a wider-than-normal range of red cell sizes, also seen in common nutritional anemia. [ citation needed ]


Heinz bodies  form in the cytoplasm of RBCs and appear as small dark dots under the microscope. In animals, Heinz body anemia has many causes. It may be drug-induced, for example in cats and dogs by  acetaminophen  (paracetamol), [ 84 ]  or may be caused by eating various plants or other substances:


Hyperanemia is a severe form of anemia, in which the  hematocrit  is below 10%. [ 87 ]


Refractory anemia, an anemia which does not respond to  treatment , [ 88 ]  is often seen secondary to myelodysplastic syndromes. [ 89 ]  Iron-deficiency anemia may also be refractory as a manifestation of gastrointestinal problems which disrupt  iron absorption  or cause  occult bleeding .
 [ 90 ]


Transfusion dependent anemia is a form of anemia where ongoing blood transfusion are required. [ 91 ]  Most people with myelodysplastic syndrome develop this state at some point in time. [ 92 ]   Beta thalassemia  may also result in transfusion dependence. [ 93 ] [ 94 ]  Concerns from repeated blood transfusions include  iron overload . [ 92 ]  This iron overload may require  chelation therapy . [ 95 ]


The global market for anemia treatments is estimated at more than USD 23 billion per year and is fast growing because of the rising prevalence and awareness of anemia. The types of anemia treated with drugs are iron-deficiency anemia,  thalassemia , aplastic anemia,  hemolytic anemia ,  sickle cell anemia , and pernicious anemia, the most important of them being deficiency and sickle cell anemia with together 60% of market share because of highest prevalence as well as higher treatment costs compared with other types. [ 13 ]  Treatment for anemia depends on cause and severity. Vitamin supplements given orally ( folic acid  or vitamin B 12 ) or intramuscularly ( vitamin B 12 ) will replace specific deficiencies. [ 1 ]


Apart from that, iron supplements, antibiotics, immunosuppressant, bone marrow stimulants, corticosteroids, gene therapy and iron chelating agents are forms of anemia treatment drugs, with immunosuppressants and corticosteroids accounting for 58% of the market share. A paradigm shift towards gene therapy and monoclonal antibody therapies is observed. [ 13 ]


Nutritional iron deficiency is common in developing nations. An estimated two-thirds of children and of women of childbearing age in most developing nations are estimated to have iron deficiency without anemia with one-third of them having an iron deficiency with anemia. [ 96 ]  Iron deficiency due to inadequate dietary iron intake is rare in men and postmenopausal women. The diagnosis of iron deficiency mandates a search for potential sources of blood loss, such as gastrointestinal bleeding from ulcers or colon cancer. [ citation needed ]


Mild to moderate iron-deficiency anemia is treated by oral iron supplementation with  ferrous sulfate ,  ferrous fumarate , or  ferrous gluconate . Daily iron supplements have been shown to be effective in reducing anemia in women of childbearing age. [ 97 ]  When taking iron supplements, stomach upset or darkening of the feces are commonly experienced. The stomach upset can be alleviated by taking the iron with food; however, this decreases the amount of iron absorbed.  Vitamin C  aids in the body's ability to absorb iron, so taking oral iron supplements with orange juice is of benefit. [ 98 ]


In the anemia of chronic kidney disease,  recombinant   erythropoietin  or  epoetin alfa  is recommended to stimulate RBC production, and if iron deficiency and inflammation are also present, concurrent  parenteral iron  is also recommended. [ 99 ]


In cases where oral iron has either proven ineffective, would be too slow (for example, pre-operatively), or where absorption is impeded (for example in cases of inflammation),  parenteral iron  preparations can be used. Parenteral iron can improve iron stores rapidly and is also effective for treating people with postpartum haemorrhage, inflammatory bowel disease, and chronic heart failure. [ 100 ]  The body can absorb up to 6 mg iron daily from the gastrointestinal tract. In many cases, the patient has a deficit of over 1,000 mg of iron which would require several months to replace. This can be given concurrently with  erythropoietin  to ensure sufficient iron for increased rates of  erythropoiesis . [ 101 ]


Blood transfusions in those without symptoms is not recommended until the hemoglobin is below 60 to 80 g/L (6 to 8 g/dL). [ 1 ]  In those with  coronary artery disease  who are not actively bleeding transfusions are only recommended when the hemoglobin is below 70 to 80g/L (7 to 8 g/dL). [ 10 ]  Transfusing earlier does not improve survival. [ 102 ]  Transfusions otherwise should only be undertaken in cases of cardiovascular instability. [ 103 ]


A 2012 review concluded that when considering blood transfusions for anaemia in people with advanced cancer who have fatigue and breathlessness (not related to cancer treatment or haemorrhage), consideration should be given to whether there are alternative strategies can be tried before a blood transfusion. [ 104 ]


In many cases, vitamin B 12  is used by  intramuscular injection  in severe cases or cases of malabsorption of dietary-B 12 . Pernicious anemia caused by loss of intrinsic factor cannot be prevented. [ 105 ]  If there are other, reversible causes of low vitamin B 12  levels, the cause must be treated. [ 106 ]


Vitamin B 12  deficiency anemia is usually easily treated by providing the necessary level of vitamin B 12  supplementation. [ 107 ]  The injections are quick-acting, and symptoms usually go away within one to two weeks. [ 107 ]  As the condition improves, doses are reduced to weeks and then can be given monthly. Intramuscular therapy leads to more rapid improvement and should be considered in patients with severe deficiency or severe  neurologic  symptoms. [ 107 ]  Treatment should begin rapidly for severe neurological symptoms, as some changes can become permanent. [ 32 ]  In some individuals lifelong treatment may be needed. [ 32 ]


The objective for the administration of an  erythropoiesis-stimulating agent  (ESA) is to maintain hemoglobin at the lowest level that both minimizes transfusions and meets the individual person's needs. [ 108 ]  They should not be used for mild or moderate anemia. [ 102 ]  They are not recommended in people with  chronic kidney disease  unless hemoglobin levels are less than 10 g/dL or they have symptoms of anemia. Their use should be along with parenteral iron. [ 108 ] [ 109 ]  The 2020 Cochrane Anaesthesia Review Group review of erythropoietin (EPO) plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non-cardiac surgery  [ 110 ]  demonstrated that patients were much less likely to require red cell transfusion and in those transfused, the volumes were unchanged (mean difference -0.09, 95% CI -0.23 to 0.05). Pre-operative hemoglobin concentration was increased in those receiving 'high dose' EPO, but not 'low dose'. [ citation needed ]


Treatment of exceptional blood loss (anemia) is recognized as an indication for  hyperbaric oxygen  (HBO) by the  Undersea and Hyperbaric Medical Society . [ 111 ] [ 112 ]  The use of HBO is indicated when  oxygen  delivery to tissue is not sufficient in patients who cannot be given  blood transfusions  for  medical  or  religious  reasons. HBO may be used for medical reasons when threat of  blood product  incompatibility or concern for  transmissible disease  are factors. [ 111 ]  The beliefs of some religions (ex:  Jehovah's Witnesses ) may require they use the HBO method. [ 111 ]  A 2005 review of the use of HBO in severe anemia found all publications reported positive results. [ 113 ]


An estimated 30% of adults who require non-cardiac surgery have anemia. [ 114 ]  In order to determine an appropriate preoperative treatment, it is suggested that the cause of anemia be first determined. [ 115 ]  There is moderate level medical evidence that supports a combination of iron supplementation and erythropoietin treatment to help reduce the requirement for red blood cell transfusions after surgery in those who have preoperative anemia. [ 114 ]


Anemia affects 27% of the world's population with iron-deficiency anemia accounting for more than 60% of it. [ 116 ]  A moderate degree of iron-deficiency anemia affected approximately 610 million people worldwide or 8.8% of the population. [ 14 ]  It is somewhat more common in females (9.9%) than males (7.8%). [ 14 ]  Mild iron-deficiency anemia affects another 375 million. [ 14 ]  Severe anaemia is prevalent globally, and especially in sub-Saharan Africa [ 117 ]  where it is associated with infections including malaria and invasive bacterial infections. [ 118 ]


Signs of severe anemia in human bones from 4000 years ago have been uncovered in Thailand. [ 119 ]


Anemia  is a condition in which  blood  has a lower-than-normal amount of  red blood cells  or  hemoglobin . [ 1 ]   Anemia in pregnancy  is a decrease in the total red blood cells (RBCs) or hemoglobin in the blood during  pregnancy . Anemia is an extremely common condition in pregnancy world-wide, conferring a number of health risks to mother and child. [ 2 ]  While anemia in pregnancy may be pathologic, in normal pregnancies, the increase in RBC mass is smaller than the increase in plasma volume, leading to a mild decrease in hemoglobin concentration referred to as physiologic (or dilutional) anemia. [ 3 ]  Maternal signs and symptoms are usually non-specific, but can include:  fatigue ,  pallor ,  dyspnea ,  palpitations , and  dizziness . [ 4 ]  There are numerous well-known maternal consequences of anemia including: maternal cardiovascular strain, reduced physical and mental performance, reduced peripartum blood reserves, increased risk for peripartum blood product transfusion, and increased risk for maternal mortality. [ 5 ]


Common symptoms are  headache , fatigue,  lethargy ,  tachycardia ,  tachypnea ,  paresthesia ,  pallor ,  glossitis  and  cheilitis . [ 6 ] [ 7 ]  Severe symptoms include  congestive heart failure ,  placenta previa ,  abruptio placenta , and operative delivery. [ 6 ] [ 8 ]


Dilutional anemia : There is an increase in overall blood volume during pregnancy, and even though there is an increase in overall red blood cell mass, the increase in the other parts of the blood like plasma decrease the overall percentage of red blood cells in circulation. [ 9 ]


Iron deficiency anemia : this can occur from the increased production of red blood cells, which requires a lot of iron and also from inadequate intake of iron, which increase in pregnancy. [ 7 ]


Hemoglobinopathies : Thalassemia and sickle cell disease. [ 7 ]


Dietary deficiencies :  Folate deficiency  and  vitamin B12 deficiency  are common causes of anemia in pregnancy. Folate deficiency occurs due to diets low in leafy green vegetables, and animal sources of protein. [ 10 ]  B12 deficiency tends to be more common in individuals with  Crohn's disease  or gastrectomies. [ 11 ]


Cell membrane disorders:   Hereditary spherocytosis [ 7 ]


Autoimmune causes:  lead to the hemolysis of red blood cells (Ex:  autoimmune hemolytic anemia ). [ 12 ]


Hypothyroidism  and chronic kidney disease [ 13 ] [ 14 ]


Parasitic infestations:  some examples are  hookworm  or  Plasmodium species [ 7 ]


Bacterial or viral infections


Iron deficiency is the most common cause of anemia in the pregnant woman. During pregnancy, the average total iron requirement is about 1200 mg per day for a 55 kg woman. This iron is used for the increase in red cell mass, placental needs and fetal growth. About 40% of women start their pregnancy with low to absent iron stores and up to 90% have iron stores insufficient to meet the increased iron requirements during pregnancy and the postpartum period. [ 15 ]


The majority of women presenting with postpartum anemia have pre-delivery iron deficiency anemia or iron deficiency anemia combined with acute blood loss during delivery. [ 16 ]


Studies have suggested that severe maternal morbidity (SMM) is increased approximately twofold in antepartum maternal anemia. SMM is defined by maternal death,  eclampsia , transfusion, hysterectomy, or intensive care unit admission at delivery. Additional complications may include  postpartum haemorrhage ,  preeclampsia ,  cesarean delivery , and infections. [ 17 ]


Iron deficiency during pregnancy is linked to a number of harmful effects on the fetus such as intrauterine growth restriction, death in utero, infection, preterm delivery and neurodevelopmental damage, which may be irreversible. [ 18 ] [ 19 ] [ 20 ]


The most useful test with which to render a diagnosis of anemia is a low RBC count, however hemoglobin and hematocrit values are most commonly used in making the initial diagnosis of anemia. Testing involved in diagnosing anemia in pregnant women must be tailored to each individual patient. Suggested tests include: hemoglobin and hematocrit (ratio of red blood cells to the total blood volume),  mean corpuscular volume  (MCV),  mean corpuscular hemoglobin  (MCH), erythrocyte count (number of red blood cells in the blood),  red cell distribution width  (RDW),  reticulocyte  count, and a  peripheral smear  to assess red blood cell morphology. If iron deficiency is suspected, additional tests such as: serum iron, total iron-binding capacity (TIBC),  transferrin  saturation, and plasma or serum  ferritin  may be warranted. It is important to note that references ranges for these values are often not the same for pregnant women. Additionally, laboratory values for pregnancy often change throughout the duration of a woman's gestation. For example, the reference values for what level of hemoglobin is considered anemic varies in each trimester of pregnancy. [ 21 ] [ 9 ]


-  First trimester hemoglobin < 11 g/dL


-  Second trimester hemoglobin < 10.5 g/dL


-  Third trimester hemoglobin < 11 g/dL


-  Postpartum hemoglobin < 10 g/dL


Listed below are normal ranges for important lab values in the diagnosis of anemia. Keep in mind that these ranges might change based on each patient's stage in pregnancy: [ 7 ]


- Hemoglobin: Men (13.6-16.9), women (11.9-14.8)


- Hematocrit: Men (40-50%), women (35-43%)


- MCV: 82.5 - 98


- Reticulocyte count: Men (16-130X10^3/microL or X10^9), Women (16-98/microL or     X10^9)


Differential using MCV


MCV can be a great measure for differentiating between different forms of anemia. MCV measures the average size of your red blood cells. There are three cut off measurements for MCV. If the MCV is < 80fL it is considered microcytic. If the MCV is from 80 to 100 fL then it is considered a normocytic anemia. If the MCV is > 100 fL it is considered a macrocytic anemia. Some causes of anemia can be characterized by different ranges of MCV depending upon the severity disease.  Here are common causes of anemia organized by MCV. [ 22 ]


MCV < 80 fL


- Iron deficiency


- Thalassemia


- Anemia of chronic disease or anemia of inflammation


MCV 80 - 100 fL


-  Iron deficiency


- Infection


- Hypothyroidism


- Liver disease or alcohol use


- Drug-induced


- Hemolysis


- Vitamin B12 or folate deficiency


MCV > 100 fL


- Drug induced


- Myelodysplastic Syndromes


Pregnant women need almost twice as much iron as women who are not pregnant do. Not getting enough iron during pregnancy raises risk of  premature birth  or a  low-birth-weight  baby. [ 23 ]  Hormonal changes in the pregnant woman result in an increase in circulating blood volume to 100 mL/kg with a total blood volume of approximately 6000–7000 mL. While red cell mass increases by 15–20% during pregnancy, plasma volume increases by 40%. [ 24 ]  Hemoglobin levels less than 11 g/dL during the first trimester, less than 10.5 g/dL during the second and third trimesters and less than 10 mg/dL in the postpartum period are considered anemic. [ 25 ]


Anemia is a very common complication of pregnancy. A mild form of anemia can be a result of dilution of blood. There is a relatively larger increase in blood plasma compared to total red cell mass in all pregnancies, which results in dilution of the blood and causes physiologic anemia . These changes take place to ensure adequate amount of blood is supplied to the fetus and prepares body for expected blood loss at the time of delivery. [ 26 ]


Iron deficiency is the most common cause of non-physiologic anemia. Iron deficiency anemia can be prevented with supplemental oral iron 27–30 mg daily. [ 27 ]  This dose typically corresponds to the amount of iron found in iron-containing prenatal vitamins. Consult with your medical provider to determine whether additional supplements are needed. Complete routine labs during pregnancy for early detection of iron deficiency anemia. [ 27 ]


Iron deficiency anemia can also be prevented by eating iron-rich foods. This includes dark green leafy vegetables, eggs, meat, fish, dried beans, and fortified grains. [ 28 ]


This may be only applicable to select individuals.


Vitamin B12 : Women who consume strictly vegan diets are advised to take Vitamin B12 supplements; this helps prevent anemia due to low Vitamin B12 levels. [ 29 ]


Folic Acid:  Folic acid supplement recommended for women with history of documented folate deficiency. Folic acid supplementation also recommended for prevention of neural tube defects in the fetus. [ 29 ]


For treatment of iron deficiency anemia in pregnant women, iron supplementation at doses higher than prenatal supplements is recommended. The standard doses of oral iron ranges from 40 mg to 200 mg elemental iron daily. [ 30 ]  Consult with your medical provider to determine the exact dose needed for your condition, higher than needed doses of iron supplements may sometimes lead to more adverse effects. [ 21 ]


Iron supplements are easy to take, however adverse effects in some cases may include gastrointestinal side effects, nausea, diarrhea, and/or constipation. In cases when oral iron supplement is not tolerable, other options include longer intervals between each oral dose, liquid iron supplements, or intravenous iron. [ 21 ]  Intravenous iron may also be used in cases of severe iron deficiency anemia during second and third trimesters of pregnancy. [ 31 ]


Anemias due to other deficiencies such as folic acid or vitamin B12 can also be treated with supplementation as well; dose may vary based on level of deficiency. [ 32 ]


Other forms of anemias, such as inherited or acquired anemias prior to pregnancy, will require continuous management during pregnancy as well. [ 29 ]


Treatment should target the underlying disease or condition affecting the patient.


According to the WHO estimation, the global prevalence of anemia during pregnancy is over 40%, and the prevalence of anemia during pregnancy in North America is 6%. [ 36 ]  Prevalence of anemia in pregnancy is higher in developing countries compared to developed countries. 56% of pregnant women from low and middle income countries were reported to have anemia. [ 37 ]


An  antibody elution  is a  clinical laboratory  diagnostic procedure which removes sensitized  antibodies  from  red blood cells , in order to determine the  blood group system antigen  the antibody targets. [ 1 ]  An antibody elution is deemed necessary when antibodies of the  immunoglobulin class G  (IgG) are found sensitized (bound) to peripheral red cells collected from a blood product transfusion recipient. [ 2 ]  IgG antibodies are detected using an assay known as the  direct antiglobulin test . [ 3 ]


Antibody elutions are specialized tests used in clinical  blood banks . Examples of routine tests include  ABO/Rh , antibody screen, antibody identification, and  antiglobulin testing . Examples of other specialized tests used in blood banking include: treatment with thiol reagent,  monocyte monolayer assay , enzyme treatment, and adsorptions. [ 2 ]


This procedure aids in the investigation of antibodies that are difficult to identify, distinguishing  transfusion reactions ,  hemolytic disease of the fetus and newborn , and warm autoantibody workups. [ 4 ]


Red blood cell membranes consist of a  phospholipid  bilayer, littered with  proteins ,  lipids ,  carbohydrates , and combinations of these substances. [ 5 ]  These substances are called  antigens  because they stimulate an  immune response  when an individual is exposed to the substance, but the exposed individual does not carry nor express the genes which encode said antigens. [ 6 ]  Each individual has a unique genetic and phenotypic makeup of antigens, much like the dermatoglyphics of human  fingerprints .


As of 2023, there are 44 blood group systems, each containing several red blood cell antigens totaling 354, determined by approximately 49 separate genes. [ 7 ]  Of these antigens, only a handful are considered clinically significant, meaning that they can stimulate the production of antibodies capable of causing red cell  hemolysis . This is particularly important for the transfusion of packed red blood cells and other cellular blood products. Examples of blood group systems that contain antigens capable of inducing clinically significant alloantibodies (antibodies against non-self antigens) include, but are not limited to the  ABO ,  Rh ,  Kell ,  Duffy ,  Kidd , and  MNS  blood group systems. [ 8 ]