In March 2024, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Fabhalta, intended for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). [ 4 ] [ 10 ]  The applicant for this medicinal product is Novartis Europharm Limited. [ 4 ]  Iptacopan was approved for medical use in the European Union in May 2024. [ 4 ]


In August 2024, the US FDA granted accelerated approval to Fabhalta (iptacopan) for reducing proteinuria in adults with primary IgA nephropathy (IgAN). [ 11 ]


In a clinical study with twelve participants, iptacopan as a single drug led to the normalization of hemolytic markers in most patients, and no serious adverse events occurred during the 12-week study. [ 12 ] [ 13 ]


Iptacopan is also investigated as a drug in other complement-mediated diseases, like age-related  macular degeneration  and some types of  glomerulopathies . [ 14 ]


Ischemic preconditioning  (IPC) is an experimental technique [ 1 ]  for producing resistance to the loss of  blood  supply, and thus  oxygen , to  tissues  of many types. In the heart, IPC is an intrinsic process whereby repeated short episodes of  ischaemia  protect the  myocardium  against a subsequent ischaemic insult. It was first identified in 1986 by Murry  et al.  This group exposed anesthetised open-chest dogs to four periods of 5 minute  coronary artery occlusions  followed by a 5-minute period of  reperfusion  before the onset of a 40-minute sustained occlusion of the coronary artery. The control animals had no such period of “ischaemic preconditioning” and had much larger  infarct  sizes compared with the dogs that did. [ 2 ]  The exact molecular pathways behind this phenomenon have yet to be fully understood.


If the blood supply to an  organ  or a tissue is impaired for a short time (usually less than five minutes) then restored so that blood flow is resumed, and the process repeated two or more times, the cells downstream of the tissue or organ are robustly protected from a final  ischemic  insult when the blood supply is cut off entirely and permanently. [ citation needed ]


The protective effect which is imparted by IPC has two windows of protection. The first lasts between 4–6 hours [ 3 ]  and has been named classical or early preconditioning. The second window begins at 24 hours and lasts up to 72 hours after the ischaemia and  reperfusion  stimulus. [ 4 ]


In an experimental setting if the  left anterior descending   coronary artery  of the animal is ligated the downstream cardiac cellular mass is infarcted and will be injured and then die. If on the other hand the tissue is subjected to IPC the downstream cellular mass will sustain only minimal to modest damage. IPC protects the tissue by initiating a cascade of biochemical events that allows for an up-regulation of the energetics of the tissue. The locus of this phenomenon is the intracellular organelle, the  mitochondrion . [ citation needed ]


Investigations of various exogenous circulating ligands such as the delta active  opiates  and  opioids  simulate the phenomenon of IPC thus protecting the downstream tissues without the IPC intermittent ligating procedure.


Methods to either mimic or elicit IPC have been attempted in clinical practice in the area of coronary heart disease in an attempt to limit the injury caused to the heart via ischemia and reperfusion injury. [ 5 ]  Such injury would occur when a patient has an acute myocardial infarct followed by reperfusion by either  percutaneous coronary intervention  or  thrombolysis .


Early preconditioning is thought to be stimulated by local action of  adenosine , opiates, and  bradykinin , which are all  endogenously  released by ischemic cells. The presence of each substance is not required but the protection is more potent if they are. They activate  G-protein  coupled pathways, which carries a protective signal to an end-effector. There have been many suggestions to what this might be, including the  sarcolemmal   ATP-sensitive potassium channel , the mitochondrial ATP-sensitive potassium channel, the  mitochondrial permeability transition pore ,  reactive oxygen species  generation,  chloride channels , the  inward rectifier potassium ion channel , and  connexon  43 related channels. [ citation needed ]


It has also been shown that the protective effect of IPC is suppressed by pathological conditions such as  hypercholesterolemia ,  hyperglycemia ,  hypertension ,  cardiac hypertrophy , and  hyperhomocysteinemia .  [ citation needed ]


The only group of humans who are chronically exposed to an opioid with delta activity are  methadone -maintained patients treated for chronic pain or  opioid addiction . These patients have a coronary risk profile greater than the general population:


Preliminary and as yet unpublished surveys of the methadone-treated population point to a high degree of protection from myocardial ischemic events. The one published study, [ citation needed ]  an autopsy series from the  Office of Chief Medical Examiner of the City of New York  demonstrated significantly less evidence for coronary occlusive disease. Simulation of IPC with methadone could not be evaluated in this  post mortem  investigation.


Rather than blocking a  coronary artery , similar results have been seen by blocking the  brachial artery  using a blood pressure cuff prior to surgery. [ 6 ]  Some research also suggests that ischemic conditioning is also beneficial following a stroke, [ 7 ] [ 8 ]  chronic cerebral hypoperfusion, [ 9 ]  or heart attack. [ 10 ]


Jan Janský  ( Czech pronunciation:   [ˈjan   ˈjanskiː] ; 3 April 1873 – 8 September 1921) was a Czech  serologist ,  neurologist  and  psychiatrist . He is credited with the classification of  blood  into four  types  (I, II, III, IV). [ 1 ]


Janský was born on 3 April 1873 in  Smíchov  (now part of  Prague ). He studied  medicine  at  Charles University  in Prague. From 1899, he worked in the  Psychiatric Clinic in Prague . In 1914, he was named  professor . During  World War I , Janský served two years as a doctor at the front until a heart attack disabled him. After the war he worked as a  neuropsychiatrist  in a military Hospital ( Vojenská nemocnice ). He had angina pectoralis and died of  ischaemic heart disease  in  Dolní Mokropsy  on 8 September 1921, at the age of 48.


Janský was also a proponent of voluntary  blood donations .


Through his psychiatric research, Janský tried to find a correlation between mental diseases and  blood diseases . He found no such correlation existed and published a study,  Hematologická studie u psychotiků  (1907,  Hematological study of psychotics ), in which he classified blood into four groups, I, II, III, and IV. (At the time, Janský was unaware of the work of  Karl Landsteiner , whose discovery of the A, B, and O blood types earned him the  Nobel Prize in Physiology or Medicine  in 1930.) At the time Janský's discovery passed almost unnoticed. In 1921 an American medical commission acknowledged Janský's classification. A similar classification was described by  William Lorenzo Moss , except the I and IV of Moss were the opposite to that of Janský's, leading to confusion in  blood transfusion  until the use of A, B and O became standard.


Jordans' anomaly  (also known as  Jordan anomaly  and  Jordans bodies ) is a familial abnormality of  white blood cell   morphology . Individuals with this condition exhibit persistent  vacuolation  of  granulocytes  and  monocytes  in the  peripheral blood  and  bone marrow . Jordans' anomaly is associated with  neutral lipid storage diseases . [ 1 ] [ 2 ] [ 3 ]


Jordans' anomaly is a characteristic finding in Chanarin-Dorfman syndrome and other neutral lipid storage diseases. [ 2 ] [ 4 ]  The anomaly is associated with mutations in the  PNPLA2  gene, which produces the enzyme  adipose triglyceride lipase  (ATGL), and the  ABHD5  gene, which encodes a cofactor of ATGL. These mutations lead to defective  triglyceride  breakdown and accumulation of lipid droplets in cells throughout the body. [ 3 ] [ 5 ] [ 4 ]


The vacuoles of Jordans' anomaly contain neutral lipids that stain positive with  Sudan staining  techniques. [ 2 ] [ 4 ]


The anomaly was first described in 1953, by Dr. G. H. Jordans, who identified abnormal  vacuolation  in the white blood cells of two brothers with  congenital muscular dystrophy . Using  special staining , Jordans demonstrated that the vacuoles contained  lipids . [ 1 ] [ 6 ]  In 1966, two further cases of persistent lipid vacuoles were reported in sisters presenting with  ichthyosis . [ 7 ]  The  Chanarin-Dorfman syndrome , comprising Jordans' anomaly, ichthyosis and lipid storage abnormalities, was defined in the 1970s, definitively connecting Jordans' anomaly to lipid storage disease. [ 8 ] [ 4 ]  Jordans' anomaly was linked to  genetic mutations  affecting  triglyceride  metabolism in 2006. [ 5 ]


KAHRP  (knob-associated histidine-rich protein) is a  protein  expressed by  Plasmodium falciparum  infecting  erythrocytes . KAHRP is a major component of knobs, feature found on Plasmodium falciparum infected erythrocytes.


It has been suggested that KAHRP may play a role in trafficking or docking  PfEMP1 , major malarial cytoadherence protein to the  erythrocyte membrane ; [ 1 ]  however, these findings were disputed by recent  NMR  and  fluorescence anisotropy  studies showing no interaction between  PfEMP1  and KAHRP. [ 2 ]


Instead, KAHRP was shown to interact with  Ankyrin , more precisely the D3 subunit of the Membrane-binding domain of Ankyrin type 1. [ 3 ]  This interaction was suggested via  SPR ,  ELISA , and  Pulldown  studies, however, it has not been confirmed by NMR,  ITC ,  crystallography , or fluorescence anisotropy. [ citation needed ]


This  protein -related article is a  stub . You can help Wikipedia by  expanding it .


The  Keidel vacuum tube  was a type of  blood  collecting device, first manufactured by Hynson, Wescott and Dunning in around 1922. [ 1 ]  This vacuum was one of the first evacuated systems, predating the more well known  Vacutainer . [ 1 ]  Its primary use was to test for  syphilis  and  typhoid fever . [ 2 ]


Essentially, the Keidel vacuum consists of a sealed  ampule  with or without a  culture medium .  Connected to the ampule was a short rubber tube with a needle at the end, using a small glass tube as a cap.  The insertion of the needle into the  vein  crushes the ampule, thus creating a vacuum and forcing blood into the container.  Typically, a prominent vein in the forearm such as the  median cubital vein  would suffice, although the Keidel vacuum can take blood for any prominent peripheral vein.  This concept did not become popular until during  World War II , when quick and efficient first aid care was necessary in the battle field.  As a result, the vacutainer became the forefront device used for blood collection. [ 1 ]


Leucogenenol  is a blood cell stimulating  secondary metabolite  isolated from the mold  Penicillium gilmanii .  Its chemical structure was reported; [ 1 ]  however, later studies determined that the original structure is incorrect and the true chemical structure of leucogenenol remains unknown. [ 2 ] [ 3 ]


This article about an  organic compound  is a  stub . You can help Wikipedia by  expanding it .


Leukapheresis  ( / ˌ l u ˈ k ʌ f ɜːr iː s ɪ s /   ⓘ ) is a laboratory procedure in which  white blood cells  are separated from a sample of blood. It is a specific type of  apheresis , the more general term for separating out one particular constituent of blood and returning the remainder to the circulation.


Leukapheresis may be performed to decrease a very high white blood cell count, to obtain blood cells from a patient ( autologous ) or donor ( allogeneic ) for later transplant into the patient, or to obtain cells for research purposes. [ citation needed ]


In the case of hematological malignancies such as chronic  leukemias , white blood cell counts may be high enough to cause  leukostasis  and "sludging" in the capillaries (acute leukemias have a more variable white cell count whereas chronic cases typically have higher white cell counts). This can affect retinal vasculature leading to vision changes, pulmonary vasculature leading to shortness of breath from decreased efficiency in oxygen exchange, as well as other organ systems such as the brain which would become clinically apparent with neurological deterioration of a patient from cerebrovascular compromise. [ citation needed ]


Leukapheresis may be performed to obtain the patient's own blood cells for a later transplant. White blood cells may be removed to protect them from damage before high-dose chemotherapy, then transfused back into the patient, in the treatment of advanced breast cancer. [ 1 ]  Another novel use of cells obtained through leukapheresis is to stimulate a patient’s immune system to target prostate cancer cells. [ 2 ]


Alternatively, only  granulocytes ,  macrophages  and  monocytes  may be removed, leaving the  lymphocyte  count largely unchanged. This is used as a treatment for  autoimmune diseases  such as  ulcerative colitis [ 3 ]  and  rheumatoid arthritis , [ 4 ]  where these cells play an active part in the inflammation process.


Leukapheresis, typically for granulocytes, is a rarely performed  blood donation  process.  The product is collected by automated  apheresis  and is used for systemic infections in patients with  neutropenia . [ 5 ]   The donor is typically a blood relative who has received stimulating medications (a directed donation), and the product is irradiated to prevent  GVHD .  The product generally has a 24-hour shelf life from collection and is often transfused before  infectious disease  testing is completed.  It is a therapy of last resort, and its use is controversial and rare.


Leukapheresis is used in evolving  CAR-T   cell therapy  to obtain leukocytes from a cancer patient or donor which can be modified and given to the patient as a therapeutic dose.


The word  leukapheresis  ( / ˌ l uː k ə f ə ˈ r iː s ɪ s / ) uses  combining forms  of  leuk-  +  apheresis , although it quite plausibly could be parsed as  leuko-  +  pheresis , as both of those forms are accepted alternate forms ( leuk-/leuko-; apheresis/pheresis ). The latter parsing explains why people often spell the word with an  -o-  as  *leukopheresis ; nonetheless, no professionally curated dictionaries as of 2016 enter that spelling, and it is traditionally treated as a misspelling by medical  style guides  that mention it. [ citation needed ]


Leukocyte adhesion deficiency  ( LAD ) is a rare  autosomal   recessive  disorder characterized by  immunodeficiency  resulting in recurrent  infections . [ 1 ]  LAD is currently divided into three subtypes:  LAD1 ,  LAD2 , and the recently described  LAD3 , also known as LAD-1/variant. In LAD3, the immune defects are supplemented by a  Glanzmann thrombasthenia -like bleeding tendency. [ 2 ] [ 3 ]


LAD was first recognized as a distinct clinical entity in the 1970s. The classic descriptions of LAD included recurrent  bacterial   infections , defects in  neutrophil  adhesion, and a delay in  umbilical cord  sloughing. The adhesion defects result in poor  leukocyte   chemotaxis , particularly neutrophil, inability to form pus and  neutrophilia . [ 3 ]


Individuals with LAD suffer from bacterial infections beginning in the  neonatal  period. Infections such as  omphalitis ,  pneumonia ,  gingivitis , and  peritonitis  are common and often life-threatening due to the infant's inability to properly destroy the invading  pathogens . These individuals do not form  abscesses  because  granulocytes  cannot migrate to the sites of  infection .


Types of leukocyte adhesion deficiency include LAD1, LAD2, and LAD3. LAD1 is the most common. [ 4 ]


Patients with LAD1 have an  inherited   molecular defect  that causes a deficiency of the β-2  integrin  subunit, [ 5 ]  also called  CD18 , which is encoded by the ITGB2 gene found on  chromosome 21 . This subunit is involved in the formation of the β-2 integrins ( LFA-1 ,  integrin alphaXbeta2 /CR4/p150,95, and  Mac-1/CR3 ) by dimerization with different CD11 subunits. [ 6 ] [ 7 ]


Mutations in the ITGB2 gene lead to absent, reduced, or aberrant  CD18   protein expression , causing a lack of expression in the leukocyte membrane of the β-2 integrins. The main function of these proteins is to allow  neutrophils  to make their way out of the blood stream and into the infected tissues by adhering to different  ligands  expressed by the  endothelium , e.g.  ICAM-1 . In LAD-I patients, neutrophils cannot  extravasate  and fight against bacteria in tissues. The bacteria can then proliferate, leading to  symptomatic  infection, which can spread unimpeded and cause serious injury to important  tissues . [ citation needed ]


Typically,  diagnosis  involves several preliminary tests of  immune  function, including basic evaluation of the  humoral immune system  and the  cell-mediated immune system . A  WBC   differential  will reveal extremely elevated levels of neutrophils (on the order of 6–10x normal) because they are unable to leave the  blood vessels .
In the case of LAD-I, specific diagnosis is done by  flow cytometry . This technique will reveal absent or reduced  CD18  expression in the leukocyte membrane. Recently, prenatal diagnosis systems has been established, allowing an early detection of the disease.
LAD-II diagnosis includes the study of different glycosylated forms of the  transferrin  protein. In LAD-III, as  platelet  function is also affected, this could be used to differentiate it from the other types. [ citation needed ]


Although patients can receive intensive antibiotherapy and even  granulocyte transfusions  from healthy donors, the only current curative therapy is the  hematopoietic stem cell transplant . [ 8 ]  However, progress has been made in  gene therapy , an active area of research. Both  foamyviral  and  lentiviral vectors  expressing the human  ITGB2  gene under the control of different promoters have been developed and have been tested so far in preclinical LAD-I models (such as CD18-deficient mice and canine leukocyte adhesion deficiency-affected dogs). [ citation needed ]


A 2009 study reported results from 36 children who had received a stem cell transplant. At the time of follow-up (median time 62 months), the survival rate was 75%. [ 9 ]


LAD is a rare disease, with an estimated prevalence of one in 100,000 births, with no described racial or ethnic predilection. The most common type is LAD1.


In  immunology ,  leukocyte extravasation  (also commonly known as   leukocyte adhesion cascade  or  diapedesis  – the passage of cells through the intact vessel wall) is the movement of  leukocytes  (white blood cells) out of the  circulatory system  ( extravasation ) and towards the site of tissue damage or  infection . This process forms part of the  innate immune response , involving the recruitment of non-specific leukocytes.  Monocytes  also use this process in the absence of infection or tissue damage during their development into  macrophages .


Leukocyte extravasation occurs mainly in post-capillary  venules , where  haemodynamic   shear forces  are minimised. This process can be understood in several steps: [ citation needed ]


It has been demonstrated that leukocyte recruitment is halted whenever any of these steps is suppressed.


White blood cells (leukocytes) perform most of their functions in tissues. Functions include phagocytosis of foreign particles, production of antibodies, secretion of inflammatory response triggers (histamine and heparin), and neutralization of histamine. In general, leukocytes are involved in the defense of an organism and protect it from disease by promoting or inhibiting inflammatory responses.
Leukocytes use the blood as a transport medium to reach the tissues of the body. Here is a brief summary of each of the four steps currently thought to be involved in leukocyte extravasation:


Upon recognition of and activation by  pathogens , resident macrophages in the affected tissue release  cytokines  such as  IL-1 ,  TNFα  and  chemokines . IL-1, TNFα and C5a [ 1 ]  cause the  endothelial cells  of blood vessels near the site of infection to express  cellular adhesion molecules , including  selectins . Circulating leukocytes are localised towards the site of injury or infection due to the presence of chemokines. [ citation needed ]


Like velcro, carbohydrate ligands on the circulating leukocytes bind to selectin molecules on the inner wall of the vessel, with marginal  affinity . This causes the leukocytes to slow down and begin rolling along the inner surface of the vessel wall. During this rolling motion, transitory bonds are formed and broken between selectins and their  ligands .


For example, the carbohydrate ligand for P-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), is expressed by different types of leukocytes (white blood cells). The binding of PSGL-1 on the leukocyte to P-selectin on the endothelial cell allows for the leukocyte to roll along the endothelial surface. This interaction can be tuned by the glycosylation pattern of PSGL-1, such that certain glycovariants of PSGL-1 will have unique affinities for different selectins, allowing in some cases for cells to migrate to specific sites within the body (e.g. the skin). [ 2 ]


At the same time, chemokines released by macrophages activate the rolling leukocytes and cause surface  integrin  molecules to switch from the default low-affinity state to a high-affinity state. This is assisted through  juxtacrine  activation of integrins by chemokines and soluble factors released by endothelial cells. In the activated state, integrins bind tightly to complementary receptors expressed on endothelial cells, with high affinity. This causes the immobilization of the leukocytes, which varies in vessels that contain different shear forces of the ongoing blood flow. [ citation needed ]


The  cytoskeletons  of the leukocytes are reorganized in such a way that the leukocytes are spread out over the endothelial cells.  In this form, leukocytes extend  pseudopodia  and pass through gaps between endothelial cells. This passage of cells through the intact vessel wall is called  diapedesis . [ 3 ]  These gaps can form through interactions of the leukocytes with the endothelium, but also autonomously through endothelial mechanics. [ 4 ]  Transmigration of the leukocyte occurs as  PECAM  proteins, found on the leukocyte and endothelial cell surfaces, interact and effectively pull the cell through the endothelium. Once through the endothelium, the leukocyte must penetrate the  basement membrane . The mechanism for penetration is disputed, but may involve proteolytic digestion of the membrane, mechanical force, or both. [ 5 ]  The entire process of blood vessel escape is known as  diapedesis . Once in the  interstitial fluid , leukocytes migrate along a  chemotactic  gradient towards the site of injury or infection.


The phases of the leukocyte extravasation depicted in the schema are: approach, capture, rolling, activation, binding, strengthening of the binding and spreading, intravascular creeping, paracellular migration or transcellular migration.


Selectins are expressed shortly after cytokine activation of endothelial cells by tissue macrophages. Activated endothelial cells initially express P-selectin molecules, but within two hours after activation E-selectin expression is favoured. Endothelial selectins bind  carbohydrates  on leukocyte transmembrane  glycoproteins , including  sialyl-Lewis X .


Suppressed expression of some selectins results in a slower immune response. If L-selectin is not produced, the immune response may be ten times slower, as P-selectins (which can also be produced by leukocytes) bind to each other. P-selectins can bind each other with high affinity, but occur less frequently because the receptor-site density is lower than with the smaller E-selectin molecules. This increases the initial leukocyte rolling speed, prolonging the slow rolling phase.


Integrins involved in cellular adhesion are primarily expressed on leukocytes. β2 integrins on rolling leukocytes bind  endothelial   cellular adhesion  molecules, arresting cell movement.


Cellular activation via extracellular chemokines causes pre-formed β2 integrins to be released from cellular stores. Integrin molecules migrate to the cell surface and congregate in high- avidity  patches. Intracellular integrin domains associate with the leukocyte cytoskeleton, via mediation with cytosolic factors such as  talin ,  α-actinin  and  vinculin . This association causes a conformational shift in the integrin's  tertiary structure , allowing ligand access to the binding site.  Divalent cations  (e.g.  Mg 2+ ) are also required for integrin-ligand binding.


Integrin ligands ICAM-1 and VCAM-1 are activated by inflammatory cytokines, while ICAM-2 is constitutively expressed by some endothelial cells but downregulated by inflammatory cytokines. ICAM-1 and ICAM-2 share two  homologous   N-terminal   domains ; both can bind LFA-1.


During chemotaxis, cell movement is facilitated by the binding of β1 integrins to components of the  extracellular matrix : VLA-3, VLA-4 and VLA-5 to  fibronectin  and VLA-2 and VLA-3 to  collagen  and other extracellular matrix components.


Extravasation is regulated by the background cytokine environment produced by the  inflammatory response , and is independent of specific cellular  antigens . Cytokines released in the initial immune response induce  vasodilation  and lower the electrical charge along the vessel's surface. Blood flow is slowed, facilitating intermolecular binding.


In 1976, SEM images showed that there were homing receptors on microvilli-like tips on leukocytes that would allow white blood cells to get out of the blood vessel and get into tissue. [ 7 ]  Since the 1990s the identity of ligands involved in leukocyte extravasation have been studied heavily. This topic was finally able to be studied thoroughly under physiological shear stress conditions using a typical flow chamber. [ 8 ]    Since the first experiments, a strange phenomenon was observed. Binding interactions between the white blood cells and the vessel walls were observed to become stronger under higher force. Selectins (E-selectin, L-selectin, and P-selectin) were found to be involved in this phenomenon.
The shear threshold requirement seems counterintuitive because increasing shear elevates the force applied to adhesive bonds and it would seem that this should increase the dislodging ability. Nevertheless, cells roll more slowly and more regularly until an optimal shear is reached where rolling velocity is minimal. This paradoxical phenomenon has not been satisfactorily explained despite the widespread interest.


One initially dismissed hypothesis that has been gaining interest is the catch bond hypothesis, where the increased force on the cell slows off-rates and lengthen the bond lifetimes and stabilizing the rolling step of leukocyte extravasation. [ 9 ]
Flow-enhanced cell adhesion is still an unexplained phenomenon that could result from a transport-dependent increase in on-rates or a force-dependent decrease in off-rates of adhesive bonds. L-selectin requires a particular minimum of shear to sustain leukocyte rolling on P-selectin glycoprotein ligand-1 (PSGL-1) and other vascular ligands. It has been hypothesized that low forces decrease L-selectin–PSGL-1 off-rates (catch bonds), whereas higher forces increase off-rates (slip bonds).
Experiments have found that a force-dependent decrease in off-rates dictated flow-enhanced rolling of L-selectin–bearing microspheres or neutrophils on PSGL-1.  [5]  Catch bonds enable increasing force to convert short bond lifetimes into long bond lifetimes, which decrease rolling velocities and increase the regularity of rolling steps as shear rose from the threshold to an optimal value. As shear increases, transitions to slip bonds shorten their bond lifetimes and increase rolling velocities and decrease rolling regularity.
It is hypothesized that force-dependent alterations of bond lifetimes govern L-selectin–dependent cell adhesion below and above the shear optimum. These findings establish a biological function for catch bonds as a mechanism for flow-enhanced cell adhesion. [ 10 ]   While leukocytes seem to undergo a catch bond behavior with increasing flow leading to the tethering and rolling steps in leukocyte extravasation, firm adhesion is achieved through another mechanism, integrin activation.


Other biological examples of a catch bond mechanism is seen in bacteria that tightly cling to urinary tract walls in response to high fluid velocities and large shear forces exerted on the cells and bacteria with adhesive tips of fimbria. [ 9 ] [ 11 ]   Schematic mechanisms of how increased shear force is proposed to cause stronger binding interactions between bacteria and target cells show that the catch bond acts very similar to a Chinese finger trap. For a catch-bond, the force on the cell pulls the adhesive tip of a fimbria to close tighter on its target cell. As the strength of the forces increases, the stronger the bond between the fimbria and the cell-receptor on the surface of the target cell. [ 11 ]  For a cryptic-bond, the force causes the fimbria to swivel toward the target cell and have more binding sites able to attach to the target cell ligands, mainly sugar molecules. This creates a stronger bonding interaction between the bacteria and the target cell.


Parallel plate flow chambers are among the most popular flow chambers used to study the leukocyte-endothelial interaction in vitro. They have been used for investigation since the later 1980s. [ 12 ]  Although flow chambers have been an important tool to study leukocyte rolling, there are several limitations when it comes to  studying the physiological in vivo conditions, as they lack correspondence with in vivo geometry, including scale/aspect ratio (microvasculature vs large vessel models), flow conditions (e.g. converging vs diverging flows at bifurcations), and require large reagent volumes (~ ml) due to their large size (height > 250 μm and width > 1mm). [ 13 ]
With the advent of microfluidic-based devices, these limitations have been overcome. A new in vitro model, called SynVivo Synthetic microvascular network (SMN) was produced by the CFD Research Corporation (CFDRC) and developed using the polydimethylsiloxane (PDMS) based soft-lithography process. The SMN can recreate the complex in vivo vasculature, including geometrical features, flow conditions, and reagent volumes, thereby providing a biologically realistic environment for studying the extravasation cellular behavior, but also for drug delivery and drug discovery.  [ 14 ] [ 15 ]


Leukocyte adhesion deficiency (LAD) is a genetic disease associated with a defect in the leukocyte extravasation process, caused by a defective integrin β2 chain (found in LFA-1 and Mac-1). This impairs the ability of the leukocytes to stop and undergo diapedesis. People with LAD suffer from recurrent bacterial infections and impaired wound healing.  Neutrophilia  is a hallmark of LAD.


In widespread diseases such as sepsis, leukocyte extravasation enters an uncontrolled stage, where white blood neutrophils begin destroying host tissues at unprecedented rates, claiming the lives of about 200,000 people in the United States alone. [ 16 ]  Neutrophil dysfunction is usually preceded by an infection of some sort, which triggers pathogen-associated molecular patterns (PAMP). As leukocyte extravasation intensifies, more tissues are damaged by neutrophils, which release oxygen radicals and proteases. [ 16 ]


Recent studies with SynVivo Synthetic microvascular network (SMN) made it possible to study anti-inflammatory therapeutics to treat pathologies caused by neutrophil dysfunction. The SMN enables the thorough analysis of each stage of leukocyte extravasation, thereby providing a methodology to quantify the effect of the drug in impeding leukocyte extravasation. Some of the recent findings demonstrate the effect of hydrodynamics on neutrophil-endothelial interactions. In other words, adhesion of neutrophils is heavily impacted by shear forces as well as molecular interactions. Moreover, as shear rate decreases (e.g., in post-capillary venules), immobilization of the leukocytes becomes easier and thus, more prevalent. The opposite is also true; vessels in which shear forces are high render the immobilization of the leukocytes more difficult. This has high implications in various diseases, where disruptions in blood flow gravely impact immune system response by impeding or expediting the immobilization of the leukocytes. Having this knowledge allows for better studies of the effect of drugs on  leukocyte extravasation. [ 13 ] [ 16 ] [ 14 ]


Leukocyte-promoting factor , more commonly known as  leukopoietin , is a category of substances produced by  neutrophils  when they encounter a foreign  antigen . Leukopoietin stimulates the bone marrow to increase the rate of  leukopoiesis  in order to replace the neutrophils that will inevitably be lost when they begin to  phagocytose  the foreign antigens. [ citation needed ]


Leukocyte-promoting factors include  colony stimulating factors  (CSFs) (produced by  monocytes  and  T lymphocytes ),  interleukins   (produced by monocytes,  macrophages , and  endothelial cells ),  prostaglandins , and  lactoferrin . [ 1 ]


Lymphoma  is a group of  blood and lymph tumors  that develop from  lymphocytes  (a type of  white blood cell ). [ 7 ]  The name typically refers to just the  cancerous  versions rather than all such tumours. [ 7 ]  Signs and symptoms may include  enlarged lymph nodes ,  fever , drenching  sweats , unintended weight loss,  itching , and constantly  feeling tired . [ 1 ] [ 2 ]  The enlarged lymph nodes are usually painless. [ 1 ]  The sweats are most common at night. [ 1 ] [ 2 ]


Many subtypes of lymphomas are known. [ 8 ]  The two main categories of lymphomas are the  non-Hodgkin lymphoma  (NHL) (90% of cases) [ 9 ] [ 10 ]  and  Hodgkin lymphoma  (HL) (10%). [ 9 ]   Lymphomas,  leukemias  and myelomas are a part of the broader group of  tumors of the hematopoietic and lymphoid tissues . [ 11 ]


Risk factors for Hodgkin lymphoma include infection with  Epstein–Barr virus  and a history of the disease in the family. [ 1 ]  Risk factors for common types of non-Hodgkin lymphomas include  autoimmune diseases ,  HIV/AIDS , infection with  human T-lymphotropic virus ,  immunosuppressant medications , and some  pesticides . [ 2 ] [ 12 ]  Eating large amounts of red meat and  tobacco smoking  may also increase the risk. [ 3 ] [ 13 ] [ 14 ]  Diagnosis, if enlarged lymph nodes are present, is usually by  lymph node biopsy . [ 1 ] [ 2 ]  Blood, urine, and  bone marrow testing  may also be useful in the diagnosis. [ 2 ]   Medical imaging  may then be done to determine if and where the cancer has spread. [ 1 ] [ 2 ]  Lymphoma most often spreads to the lungs, liver, and brain. [ 1 ] [ 2 ]


Treatment may involve one or more of the following:  chemotherapy ,  radiation therapy ,  proton therapy ,  targeted therapy , and surgery. [ 1 ] [ 2 ]  In some non-Hodgkin lymphomas, an increased amount of protein produced by the lymphoma cells causes the blood to become so thick that  plasmapheresis  is performed to remove the protein. [ 2 ]   Watchful waiting  may be appropriate for certain types. [ 2 ]  The outcome depends on the subtype, with some being curable and treatment prolonging survival in most. [ 9 ]  The  five-year survival rate  in the United States for all Hodgkin lymphoma subtypes is 85%, [ 4 ]  while that for non-Hodgkin lymphomas is 69%. [ 15 ]  Worldwide, lymphomas developed in 566,000 people in 2012 and caused 305,000 deaths. [ 16 ]  They make up 3–4% of all cancers, making them as a group the seventh-most-common form. [ 16 ] [ 17 ]  In children, they are the third-most-common cancer. [ 18 ]  They occur more often in the  developed world  than in the  developing world . [ 16 ]


Lymphoma may present with certain nonspecific symptoms; if the symptoms are persistent, an evaluation to determine their cause, including possible lymphoma, should be undertaken.


Lymphoma is definitively diagnosed by a  lymph-node biopsy , meaning a partial or total excision of a  lymph node  examined under the microscope. [ 22 ]  This examination reveals  histopathological  features that may indicate lymphoma. After lymphoma is diagnosed, a variety of tests may be carried out to look for specific features characteristic of different types of lymphoma. These include:


According to the World Health Organization (WHO), lymphoma classification should reflect in which lymphocyte population the neoplasm arises. [ 23 ]  Thus, neoplasms that arise from precursor lymphoid cells are distinguished from those that arise from mature lymphoid cells. [ 23 ]  Most mature lymphoid neoplasms comprise the non-Hodgkin lymphomas. [ 23 ]  Historically, mature histiocytic and dendritic cell (HDC) neoplasms have been considered mature lymphoid neoplasms, since these often involve lymphoid tissue. [ 23 ]


Lymphoma can also spread to the  central nervous system , often around the brain in the  meninges , known as lymphomatous meningitis (LM). [ 24 ]


Hodgkin lymphoma accounts for about 15% of lymphomas. [ 25 ]  It differs from other forms of lymphomas in its  prognosis  and several  pathological  characteristics. A division into Hodgkin and non-Hodgkin lymphomas is used in several of the older classification systems. A Hodgkin lymphoma is marked by the presence of a type of cell called the  Reed–Sternberg cell . [ 26 ] [ 27 ]


Non-Hodgkin lymphomas , which are defined as being all lymphomas except Hodgkin lymphoma, are more common than Hodgkin lymphoma. A wide variety of lymphomas are in this class, and the causes, the types of cells involved, and the prognoses vary by type. The number of cases per year of non-Hodgkin lymphoma increases with age. It is further divided into several subtypes. [ 28 ]


Epstein–Barr virus-associated lymphoproliferative diseases  are a group of benign,  premalignant , and malignant diseases of  lymphoid cells  (i.e.,  B cells ,  T cells ,  NK cells , and  histiocytic-dendritic cells ) in which one or more of these cell types is infected with the  Epstein–Barr virus  (EBV). The virus may be responsible for the development and/or progression of these diseases. In addition to  EBV-positive Hodgkin lymphomas , the World Health Organization (2016) includes the following lymphomas, when associated with EBV infection, in this group of diseases:  Burkitt lymphoma ;  large B cell lymphoma, not otherwise specified ;  diffuse large B cell lymphoma associated with chronic inflammation ;  fibrin-associated diffuse large B cell lymphoma ;  primary effusion lymphoma ;  plasmablastic lymphoma ;  extranodal NK/T cell lymphoma, nasal type ;  peripheral T cell lymphoma, not otherwise specified ;  angioimmunoblastic T-cell lymphoma ;  follicular T cell lymphoma ; and  systemic T cell lymphoma of childhood . [ 29 ]


The WHO classification, published in 2001 and updated in 2008, 2017, and 2022, [ 30 ]  is based upon the foundations laid within the "revised European–American lymphoma classification" (REAL). This system groups lymphomas by cell type (i.e., the normal cell type that most resembles the tumor) and defining  phenotypic ,  molecular , or  cytogenetic  characteristics. The five groups are shown in the table. Hodgkin lymphoma is considered separately within the WHO and preceding classifications, although it is recognized as being a tumor, albeit markedly abnormal, of lymphocytes of mature B cell lineage. [ 31 ]


Of the many forms of lymphoma, some are categorized as indolent (e.g.  small lymphocytic lymphoma ), compatible with a long life even without treatment, whereas other forms are aggressive (e.g.  Burkitt's lymphoma ), causing rapid deterioration and death. However, most of the aggressive lymphomas respond well to treatment and are curable. The  prognosis , therefore, depends on the correct diagnosis and classification of the disease, which is established after examination of a biopsy by a  pathologist  (usually a  hematopathologist ). [ 32 ]


Several previous classifications have been used, including Rappaport 1956, Lennert/Kiel 1974, BNLI, Working formulation (1982), and REAL (1994).


The  Working Formulation  of 1982 was a classification of  non-Hodgkin lymphoma . It excluded the Hodgkin lymphomas and divided the remaining lymphomas into four grades (low, intermediate, high, and miscellaneous) related to prognosis, with some further subdivisions based on the size and shape of affected cells. This purely histological classification included no information about  cell surface markers  or genetics and made no distinction between  T-cell lymphomas  and  B-cell lymphomas . It was widely accepted at the time of its publication but by 2004 was obsolete. [ 40 ]


In 1994, the Revised European-American Lymphoma (REAL) classification applied immunophenotypic and genetic features in identifying distinct clinicopathologic entities among all the lymphomas except Hodgkin lymphoma. [ 41 ]  For coding purposes, the  ICD-O  (codes 9590–9999) [ 42 ]  and  ICD-10  (codes C81-C96) [ 43 ]  are available.


After a diagnosis and before treatment, cancer is  staged . This refers to determining if the cancer has spread, and if so, whether locally or to distant sites. Staging is reported as a grade between I (confined) and IV (spread). The stage of a lymphoma helps predict a patient's prognosis and is used to help select the appropriate therapy. [ 44 ]


The  Ann Arbor staging system  is routinely used for staging of both HL and NHL. In this staging system, stage I represents localized disease contained within a lymph node group, II represents the presence of lymphoma in two or more lymph nodes groups, III represents spread of the lymphoma to lymph nodes groups on both sides of the  diaphragm , and IV indicates spread to tissue outside the lymphatic system. Different suffixes imply the involvement of different organs, for example, S for the spleen and H for the liver. Extra-lymphatic involvement is expressed with the letter E. In addition, the presence of B symptoms (one or more of the following: unintentional loss of 10% body weight in the last 6 months, night sweats, or persistent fever of 38 °C or more) or their absence is expressed with B or A, respectively. [ 45 ]


CT scan  or  PET scan  imaging modalities are used to stage cancer. PET scanning is advised for  fluorodeoxyglucose -avid lymphomas, such as Hodgkin lymphoma, as a staging tool that can even replace bone marrow biopsy. For other lymphomas, CT scanning is recommended for staging. [ 44 ]


Age and poor  performance status  are other established poor prognostic factors. [ 46 ]   This means that people who are elderly or too sick to take care of themselves are more likely to be killed by lymphoma than others.


Certain lymphomas ( extranodal NK/T-cell lymphoma, nasal type  and  type II enteropathy-associated T-cell lymphoma ) can be mimicked by two benign diseases that involve the excessive proliferation of nonmalignant NK cells in the GI tract,  natural killer cell enteropathy , a disease wherein NK cell infiltrative lesions occur in the intestine, colon, stomach, or esophagus, and  lymphomatoid gastropathy , a disease wherein these cells' infiltrative lesions are limited to the stomach. These diseases do not progress to cancer, may regress spontaneously and do not respond to, and do not require, chemotherapy or other lymphoma treatments. [ 47 ]


Prognoses and treatments are different for HL and between all the different forms of NHL, [ 48 ]  and also depend on the  grade  of tumour, referring to how quickly a cancer replicates. Paradoxically, high-grade lymphomas are more readily treated and have better prognoses: [ 49 ]   Burkitt lymphoma , for example, is a high-grade tumour known to double within days, and is highly responsive to treatment.


Many low-grade lymphomas remain  indolent  (growing slowly or not at all) for many years – sometimes, for the rest of the person's life. With an indolent lymphoma, such as follicular lymphoma,  watchful waiting  is often the initial course of action, because monitoring is less risky and less harmful than early treatment. [ 50 ]


If a low-grade lymphoma becomes symptomatic, radiotherapy or chemotherapy are the treatments of choice.  Although these treatments do not permanently cure the lymphoma, they can alleviate the symptoms, particularly painful  lymphadenopathy . People with these types of lymphoma can live near-normal lifespans, even though the disease is technically  incurable .


Some centers advocate the use of single agent  rituximab  in the treatment of follicular lymphoma rather than the wait-and-watch approach.  Watchful waiting  is not a desirable strategy for everyone, as it leads to significant distress and  anxiety  in some people. It has been called "watch and worry". [ 51 ]


Treatment of some other, more aggressive, forms of lymphoma  [ which? ]  can result in a cure in the majority of cases, but the prognosis for people with a poor response to therapy is worse. [ 52 ]  Treatment for these types of lymphoma typically consists of aggressive chemotherapy, including the  CHOP or R-CHOP  regimen. A number of people are cured with first-line chemotherapy. Most relapses occur within the first two years, and the relapse risk drops significantly thereafter. [ 53 ]  For people who relapse, high-dose chemotherapy followed by autologous stem cell transplantation is a proven approach. [ 54 ]


The treatment of side effects is also important as they can occur due to the chemotherapy or the  stem cell transplantation . It was evaluated whether mesenchymal stromal cells can be used for the treatment and prophylaxis of  graft-versus-host diseases . The evidence is very uncertain about the therapeutic effect of mesenchymal stromal cells to treat graft-versus-host diseases on the all-cause mortality and complete disappear of chronic acute graft-versus-host diseases. Mesenchymal stromal cells may result in little to no difference in the all-cause mortality, relapse of malignant disease and incidence of acute and chronic graft-versus-host diseases if they are used for prophylactic reason. [ 55 ]  Moreover, it was seen that  platelet transfusions  for people undergoing a chemotherapy or a stem cell transplantation for the prevention of bleeding events had different effects on the number of participants with a bleeding event, the number of days on which a bleeding occurred, the mortality secondary to bleeding and the number of platelet transfusions depending on the way they were used (therapeutic, depending on a threshold, different dose schedules or prophylactic). [ 56 ] [ 57 ]


Four  chimeric antigen receptor T cell  therapies are FDA-approved for non-Hodgkin lymphoma, including  lisocabtagene maraleucel  (for relapsed or refractory large B-cell lymphoma with two failed systemic treatments),  axicabtagene ciloleucel ,  tisagenlecleucel  (for large B-cell lymphoma), and  brexucabtagene autoleucel  (for  mantle cell lymphoma ). These therapies come with certification and other restrictions. [ 58 ]


Hodgkin lymphoma typically is treated with radiotherapy alone, as long as it is localized. [ 59 ]


Advanced Hodgkin disease requires systemic chemotherapy, sometimes combined with radiotherapy. [ 60 ]  Chemotherapy used includes the  ABVD  regimen, which is commonly used in the United States. Other regimens used in the management of Hodgkin lymphoma include  BEACOPP  and  Stanford V . Considerable controversy exists regarding the use of ABVD or BEACOPP. Briefly, both regimens are effective, but BEACOPP is associated with more toxicity. Encouragingly, a significant number of people who relapse after ABVD can still be salvaged by stem cell transplant. [ 61 ]


Scientists evaluated whether  positron emission tomography  scans between the chemotherapy cycles can be used to make assumptions about the survival. The evidence is very uncertain about the effect of negative (= good prognosis) or positive (= bad prognosis) interim PET scan results on the progression-free survival. Negative interim PET scan results may result in an increase in progression-free survival compared if the adjusted result was measured. Negative interim PET scan results probably result in a large increase in the overall survival compared to those with a positive interim PET scan result. [ 62 ]


Current research evaluated whether  Nivolumab  can be used for the treatment of a Hodgkin's lymphoma. The evidence is very uncertain about the effect of Nivolumab for patients with a Hodgkin's lymphoma on the overall survival, the quality of life, the survival without a progression, the response rate (=complete disappear) and grade 3 or 4 serious adverse events. [ 63 ]


Palliative care , a specialized medical care focused on the symptoms, pain, and stress of a serious illness, is recommended by multiple national cancer treatment guidelines as an accompaniment to curative treatments for people with lymphoma. [ 64 ] [ 65 ]  It is used to address both the direct symptoms of lymphoma and many unwanted side effects that arise from treatments. [ 66 ] [ 67 ]  Palliative care can be especially helpful for children who develop lymphoma, helping both children and their families deal with the physical and emotional symptoms of the disease. [ 66 ] [ 68 ] [ 69 ] [ 70 ]  For these reasons, palliative care is especially important for people requiring bone marrow transplants. [ 71 ] [ 72 ]


Adding physical exercises to the standard treatment for adult patients with haematological malignancies like lymphomas may result in little to no difference in the mortality, the quality of life and the physical functioning. These exercises may result in a slight reduction in depression. Furthermore, aerobic physical exercises probably reduce fatigue. The evidence is very uncertain about the effect on anxiety and serious adverse events. [ 73 ]


Lymphoma is the most common form of  hematological malignancy , or "blood cancer", in the developed world.


Taken together, lymphomas represent 5.3% of all cancers (excluding simple basal cell and squamous cell skin cancers) in the United States and 55.6% of all blood cancers. [ 75 ]


According to the  U.S. National Institutes of Health , lymphomas account for about 5%, and Hodgkin lymphoma in particular accounts for less than 1% of all cases of cancer in the United States. [ 76 ]


Because the whole lymphatic system is part of the body's immune system, people with a weakened immune system such as from HIV infection or from certain drugs or medication also have a higher number of cases of lymphoma. [ 77 ]


Thomas Hodgkin  published the first description of lymphoma in 1832, specifically of the form named after him. [ 78 ]  Since then, many other forms of lymphoma have been described.


The term "lymphoma" is from Latin  lympha  ("water") and from Greek  -oma  ("morbid growth, tumor"). [ 79 ]


The two types of lymphoma research are clinical or  translational research  and  basic research . Clinical/translational research focuses on studying the disease in a defined and generally immediately applicable way, such as testing a new drug in people. Studies may focus on effective means of treatment, better ways of treating the disease, improving the quality of life for people, or appropriate care in remission or after cures. Hundreds of  clinical trials  are being planned or conducted at any given time. [ 80 ]


Basic science research studies the disease process at a distance, such as seeing whether a suspected carcinogen can cause healthy cells to turn into lymphoma cells in the laboratory or how the DNA changes inside lymphoma cells as the disease progresses. The results from basic research studies are generally less immediately useful to people with the disease, [ 81 ]  but can improve scientists' understanding of lymphoma and form the foundation for future, more effective treatments.


hidden


Dominique Meyer [ 1 ]  (born 5 October 1939, in Gérardmer (Vosges)) is a French M.D. biologist and member of the  French Academy of Sciences . [ 2 ]


Medical Doctor and researcher, she was both director of an  Inserm  research unit at Bicêtre Hospital and head of the biological hematology department at Antoine Béclère Hospital. [ 3 ]  She has done extensive work at the  Scripps Research Institute  in  La Jolla ,  California  and was President of the International Society on Thrombosis and Hemostasis from 1992 to 1994. [ 4 ]  She was President of the Scientific Council of the Fondation pour la Recherche Médicale, [ 5 ]  President of the Board of Directors of Inserm, [ 6 ]  Vice-president of the Board of Directors of the  Institut Curie , Member of the  Institut universitaire de France , [ 7 ]  Member of the  Ethics Committee  of the  CNRS , [ 8 ]  Member of the Conseil Économique, Social et Environnemental (CESE) [ 9 ]  and Head of Scientific Information and Communication of the  Académie des Sciences . [ 2 ]


Dominique Meyer is currently professor emeritus of Hematology at the University of Paris XI, member of the Scientific Council of the Parliamentary Office for the Assessment of Scientific and Technological Choices (OPECST) [ 10 ]  and member of the Institut de France, whose Central Administrative Commission she chaired in 2019. [ 11 ]  Her world-renowned work has been devoted to the study of hemostasis and more specifically to the analysis of one of the proteins involved, von Willebrand factor, [ 12 ] [ 13 ]  which is the central focus of her research on the molecular mechanisms that ensure a balance between bleeding and thrombosis.


- On her research: more than 350 original articles and about fifty general reviews, book chapters or didactic articles. [ 14 ]  More than 300 communications presented at scientific conferences.


Her main scientific publications are:


Member of the Conseil de l'Ordre de la Légion d'Honneur from 2010 to 2016.


Microtransplantation  ( MST ) is an advanced technology to treat malignant hematological diseases and tumors by infusing patients with  granulocyte colony-stimulating factor  (G-CSF) mobilized  human leukocyte antigen  (HLA)-mismatched allogeneic  peripheral blood stem cells  following a reduced-intensity chemotherapy or targeted therapy. The term "microtransplantation" comes from its mechanism of reaching donor cell microchimerism.


Chemotherapy is used by lower doses only to destroy cancer and partially suppress patient’s immune system, which will be reinitiated by donor’s stem cells soon after transplantation, and will play a role as recipient-versus-tumor (RVT) effect combining donor cells’ graft-versus-tumor (GVT) effect. Donor’s stem cells, which have been processed, will also accelerate functional recovery of recipient’s hematopoietic stem cells, greatly reducing infections and transplant-related mortality. Practices of microtransplantation has shown none  graft-versus-host disease  (GVHD) till present, thus  immunosuppressive drugs  for relieving GVHD wouldn't be necessary. Possible mechanisms of the successful avoidance of GVHD include donor cell microchimerism, less-toxic cells processed prior to transplantation, and the preservation of host immune system that is capable of resisting the GVH alloresponse. Moreover, as HLA-mismatched stem cells are employed, donor availability is extremely extended. [ citation needed ]


Indications for microtransplantation are as follows:


Hematologic Malignancies Tumors


The cells employed are allogeneic peripheral blood stem cells. Matched HLA between donor and recipient is not necessary. The stem cells are collected from donor’s blood through a process known as apheresis after a certain period of daily subcutaneous injections of Granulocyte-colony stimulating factor, serving to mobilize stem cells from the donor's bone marrow into the peripheral circulation. Fresh cells are infused to recipient for the first time, and then stored in a controlled-rate freezer. [ citation needed ]


Donor’s Requirements:


In a randomized controlled trial from 2004 to 2009, 58 AML patients aged 60–88 years were randomly assigned to receive chemotherapy (control group; n=28) or it plus HLA-mismatched G-CSF–mobilized donor peripheral blood stem cell (G-PBSC) (G-PBSC group/ Microtransplantation; n = 30). The complete remission rate was significantly higher in the G-PBSC group than in the control group (80.0% vs 42.8%); The median recovery times of neutrophils and platelets were 11 days and 14.5 days, respectively, in the G-PBSC group and 16 days and 20 days, respectively, in the control group after chemotherapy; The 2-year probability of disease-free survival (DFS) was significantly higher in the G-PBSC group than in the control group (38.9% vs 10.0%). [ 1 ]  No graft-versus-host disease was observed in any patient. [ 2 ]  Persistent donor microchimerism was successfully detected in all of the 4 female patients. [ 3 ]


In another long-term research from 2004–2011, 101 patients with AML-CR1 (9 to 65 years old) received Microtransplantation regimen. The 6-year leukemia-free survival (LFS) and overall survival (OS) rates were 84.4% and 89.5%, respectively, in the low-risk group, which were similar to the rates in the intermediate-risk group (59.2% and 65.2%, respectively); The 6-year LFS and OS were 76.4% and 82.1%, respectively, in patients who received a high dose of donor CD3+ T cells, which were significantly higher than the LFS and OS in patients who received a lower dose of donor CD3+ T cells (49.5% and 55.3%, respectively). [ 4 ]  No GVHD was observed in any of the patients. [ 5 ]


The positive results have also been verified by healthcare centers in Italy, [ 6 ]  America, [ 7 ]  Spain, [ 8 ]  etc.


Led by Dr. Huisheng Ai and his medical team at MST International Clinic for Leukemia in the 307th Hospital of Chinese People’s Liberation Army located in Beijing, multicenter collaborative study on Microtransplantation has started since 2013 in nine authoritative blood institutes from China, Duke University and Keck School of Medicine-University of Southern California in United States, University of Sydney in Australia and University of Montreal in Canada. [ citation needed ]


To overcome the intolerable severe reactions of high-dose chemotherapy and GVHD, as well as the challenge to find HLA-matched donors for conventional hematopoietic stem cell transplantation, Dr  Huisheng Ai ,  Guo Mei , etc. developed a new regimen of reduced-intensity chemotherapy plus G-CSF mobilized HLA-mismatched allogeneic peripheral blood stem cell infusion, which was firstly employed for a 75-year-old patient in 2002 and later named as microtransplantation. [ citation needed ]


Mixed autoimmune hemolytic anemia  ( MAIHA ) is a type of  autoimmune hemolytic anemia  which combines the features of  cold sensitive antibody -induced diseases and  warm autoimmune hemolytic anemia . The work-up for diagnosis is complex and the condition can be over-diagnosed. [ 1 ] [ 2 ] [ better source needed ]


People diagnosed with warm autoimmune hemolytic anemia (WAIHA) caused by  immunoglobulin G  (IgG) [ 3 ]  may also have a high number of  immunoglobulin M  ( IgM ) antibodies. These antibodies are active at room temperature, but are believed to be harmless since they are not the main antibodies responsible for WAIHA. [ citation needed ]


However, studies revealed the existence of a few cases of WAIHA that may also carry  cold agglutinin antibodies  that are active at the environment where the temperatures is generally equal to or warmer than 30 °C (86 °F). Such coexistence suggests a diagnosis of the mixed (warm- and cold-antibody) autoimmune hemolytic anemia abbreviated as  MAIHA . [ 4 ] [ better source needed ]


Mixed warm and cold AIHA runs a chronic course with severe intermittent exacerbations, such as serious anemia, and is treated by  blood transfusion . Successful therapeutic options for the treatment of hemolysis associated with mixed AIHA are limited but increasing. [ 5 ] [ non-primary source needed ] [ 6 ] [ better source needed ]


In the past, there were two obvious sources of error regarding the diagnosis of AIHA. First, patients with w-AIHA can produce low- titer , low-thermal amplitude CA of no clinical significance. Second, up to 20% of patients with CAD have IgG on the RBC surface in addition to C3d. [ 7 ] [ 1 ] [ 6 ] [ non-primary source needed ]


A  myeloma protein  is an abnormal  antibody  (immunoglobulin) or (more often) a fragment thereof, such as an  immunoglobulin light chain , that is produced in excess by an abnormal  monoclonal  proliferation of  plasma cells , typically in  multiple myeloma  or  Monoclonal gammopathy of undetermined significance . Other terms for such a protein are  monoclonal protein ,  M protein ,  M component ,  M spike ,  spike protein , or  paraprotein . This proliferation of the myeloma protein has several deleterious effects on the body, including impaired immune function, abnormally high  blood viscosity   ("thickness" of the blood), and  kidney damage .


In 1940, senior  pathologist   Kurt Apitz  of the   Charité – Berlin University Medicine  hospital, introduced the concept and word  paraprotein . [ 1 ]


Myeloma is a  malignancy  of plasma cells.  Plasma cells produce immunoglobulins, which are commonly called antibodies.  There are thousands of different antibodies, each consisting of pairs of heavy and light chains.  Antibodies are typically grouped into five classes:  IgA, IgD, IgE, IgG, and IgM.  When someone has myeloma, a malignant clone, a rogue plasma cell, reproduces in an uncontrolled fashion, resulting in overproduction of the specific antibody the original cell was generated to produce.  Each type of antibody has a different number of light chain and heavy chain pairs.  As a result, there is a characteristic normal distribution of these antibodies in the blood by molecular weight.


When there is a malignant clone, there is usually overproduction of a single antibody, resulting in a "spike" on the normal distribution (sharp peak on the graph), which is called an M spike (or monoclonal spike).  People will sometimes develop a condition called MGUS ( Monoclonal gammopathy of undetermined significance ), where there is overproduction of one antibody but the condition is benign (non-cancerous).  An explanation of the difference between multiple myeloma and MGUS can be found in the International Myeloma Foundation's Patient Handbook. [ 2 ]  and Concise Review [ 3 ]


Detection of paraproteins in the  urine  or  blood  is most often associated with MGUS, where they remain "silent", [ 4 ]  and  multiple myeloma . An excess in the blood is known as  paraproteinemia . Paraproteins form a narrow band, or 'spike' in  protein electrophoresis  as they are all exactly the same protein. Unlike normal immunoglobulin antibodies, paraproteins cannot fight infection.


Serum free light-chain measurement  can detect free light chains in the blood. Monoclonal free light chains in the serum or urine are called  Bence Jones proteins .


Blood serum  paraprotein levels of more than 30 g/L is diagnostic of  smouldering myeloma , an intermediate in a spectrum of step-wise progressive diseases termed  plasma cell dyscrasias . Elevated paraprotein level (above 30 g/L) in conjunction with end organ damage (elevated calcium,  kidney failure , anemia, or bone lesions) or other biomarkers of malignancy, is diagnostic of  multiple myeloma , according to the diagnostic criteria of the  International Myeloma Working Group , [ 5 ]  which were updated in 2014. [ 6 ]  Detection of paraprotein in serum of less than 30 g/L is classified as  monoclonal gammopathy of undetermined significance  in cases where clonal plasma cells constitute less than 10% on bone marrow biopsy and there is no myeloma-related organ or tissue impairment. [ 5 ] [ 6 ]


Neonates are defined as babies up to 28 days after birth. [ 1 ]  Most extremely preterm babies (less than 28 weeks) require at least one red cell transfusion; [ 2 ]  this is partly due to the amount of blood removed with blood samples compared to the baby's total blood volume (iatrogenic anemia) [ 3 ]  and partly due to  anemia of prematurity . Most transfusions are given as small volume top-up transfusions to increase the baby's  hemoglobin  above a certain pre-defined level, or because the baby is unwell due to the  anemia . [ 2 ]  Possible side-effects of anemia in babies can be poor growth,  lethargy  and episodes of  apnea . Exchange blood transfusion is used to treat a rapidly rising  bilirubin  that does not respond to treatment with  phototherapy  or  intravenous immunoglobulin . [ 4 ]  This is usually due to  hemolytic disease of the newborn , but may also be due to other causes, e.g.,  G6PD deficiency .


Below are suggested transfusion thresholds for very preterm neonates (less than 32 weeks gestation) by the British Society of Haematology. [ 2 ]  These are based on systematic reviews of transfusion in very preterm babies. [ 5 ] [ 6 ]


Hb g/L


There is no evidence for red cell transfusion thresholds in preterm neonates between 32 and 37 weeks gestation, and the British Society of Haematology suggests using the same thresholds as very preterm neonates that require no respiratory support. [ 2 ]


A small volume transfusion is usually 10 to 20 ml/kg administered at a rate of 5 ml/kg/hour. [ 1 ] [ 2 ]


A large volume transfusion is the estimated entire blood volume of the baby (80 ml/kg) and is usually given during cardiac surgery. [ 1 ]


A red cell exchange transfusion is usually given to treat severe  hyperbilirubinemia  or anemia in babies with  hemolytic disease of the newborn . It removes neonatal red cells coated with maternal antibody and reduces the level of bilirubin. A ‘double volume exchange’ (160–200 ml/kg) removes around 90% of neonatal red cells and 50% of bilirubin. [ 1 ]


The specification of the blood product differs depending on whether it is to be used for a small volume, large volume or exchange transfusion. [ 1 ] [ 7 ]


There does not appear to be any benefit to giving fresher red blood cells (less than a week from donation) compared to standard red cells (usually two weeks after donation) for small volume transfusions. [ 8 ]


The  Serious Hazards of Transfusion  (SHOT) hemovigilance reporting scheme has shown that there are a disproportionate number of transfusion errors in babies. There are multiple reasons why this occurs. [ 9 ]  It can be due to confusion between samples from the mother and the baby, birth of more than one baby, babies who don’t yet have a first name, or that no ID information has been attached to the baby (e.g. wristband). [ 8 ] [ 9 ] [ 10 ]


Paedipacks are multiple aliquots made from one adult blood donation. By using paedipacks, the baby is exposed to blood from fewer blood donors. [ 1 ]


ABO  blood grouping and screening for antibodies in neonates differs from blood grouping in adults and older children. [ 8 ]  Any antibodies detected are the mother's antibodies rather than the baby's. [ 8 ]  Therefore, any donor blood given to the baby must be ABO and D compatible with both mother and baby; and antigen-negative for any clinically significant maternal antibodies. [ 2 ] [ 8 ]


Necrotising enterocolitis  may occur after a red cell transfusion in neonates, although there is an association between the two there is no evidence that the transfusion causes the disorder. [ 2 ]


The  oxygen–hemoglobin dissociation curve , also called the  oxyhemoglobin dissociation curve  or  oxygen dissociation curve  ( ODC ), is a  curve  that plots the proportion of  hemoglobin  in its saturated (oxygen-laden) form on the vertical axis against the prevailing  oxygen tension  on the horizontal axis. This curve is an important tool for understanding how our blood carries and releases oxygen. Specifically, the oxyhemoglobin dissociation curve relates  oxygen saturation  (S O 2 ) and  partial pressure  of oxygen in the blood (P O 2 ), and is determined by what is called "hemoglobin affinity for oxygen"; that is, how readily hemoglobin acquires and releases oxygen molecules into the fluid that surrounds it.


Hemoglobin  (Hb) is the primary vehicle for transporting  oxygen  in the  blood . Each hemoglobin molecule has the capacity to carry four oxygen molecules. These molecules of oxygen bind to the globin chain of the  heme   prosthetic group . [ 1 ]


When hemoglobin has no bound oxygen, nor bound  carbon dioxide , it has the unbound conformation (shape). The binding of the first oxygen molecule induces change in the shape of the hemoglobin that increases its ability to bind to the other three oxygen molecules.


In the presence of dissolved carbon dioxide, the  pH  of the blood changes; this causes another change in the shape of hemoglobin, which increases its ability to bind carbon dioxide and decreases its ability to bind oxygen. With the loss of the first oxygen molecule, and the binding of the first carbon dioxide molecule, yet another change in shape occurs, which further decreases the ability to bind oxygen, and increases the ability to bind carbon dioxide. The oxygen bound to the hemoglobin is released into the blood's plasma and absorbed into the  tissues , and the carbon dioxide in the tissues is bound to the hemoglobin.


In the  lungs  the reverse of this process takes place. With the loss of the first carbon dioxide molecule the shape again changes and makes it easier to release the other three carbon dioxides.


Oxygen is also carried dissolved in the blood's  plasma , but to a much lesser degree. Hemoglobin is contained in  red blood cells . Hemoglobin releases the bound oxygen when  carbonic acid  is present, as it is in the tissues. In the  capillaries , where  carbon dioxide  is produced, oxygen bound to the hemoglobin is released into the blood's plasma and absorbed into the tissues.


How much of that capacity is filled by oxygen at any time is called the  oxygen saturation . Expressed as a percentage, the oxygen saturation is the ratio of the amount of oxygen bound to the hemoglobin, to the oxygen-carrying capacity of the hemoglobin. The oxygen-carrying capacity of hemoglobin is determined by the type of hemoglobin present in the blood. The amount of oxygen bound to the hemoglobin at any time is related, in large part, to the  partial pressure  of oxygen to which the hemoglobin is exposed. In the lungs, at the  alveolar–capillary interface , the partial pressure of oxygen is typically high, and therefore the oxygen binds readily to hemoglobin that is present. As the blood circulates to other body tissue in which the partial pressure of oxygen is less, the hemoglobin releases the oxygen into the tissue because the hemoglobin cannot maintain its full bound capacity of oxygen in the presence of lower oxygen partial pressures.


The curve is usually best described by a  sigmoid  plot, using a formula of the kind:


A hemoglobin molecule can bind up to four oxygen molecules in a reversible method.


The shape of the curve results from the interaction of bound oxygen molecules with incoming molecules. The binding of the first molecule is difficult. However, this facilitates the binding of the second, third and fourth, this is due to the induced conformational change in the structure of the hemoglobin molecule induced by the binding of an oxygen molecule.


In its simplest form, the oxyhemoglobin dissociation curve describes the relation between the partial pressure of oxygen (x axis) and the oxygen saturation (y axis). Hemoglobin's affinity for oxygen increases as successive molecules of oxygen bind. More molecules bind as the oxygen partial pressure increases until the maximum amount that can be bound is reached. As this limit is approached, very little additional binding occurs and the curve levels out as the hemoglobin becomes saturated with oxygen. Hence the curve has a sigmoidal or S-shape. At pressures above about 60 mmHg, the standard dissociation curve is relatively flat, which means that the oxygen content of the blood does not change significantly even with large increases in the oxygen partial pressure. To get more oxygen to the tissue would require blood transfusions to increase the hemoglobin count (and hence the oxygen-carrying capacity), or supplemental oxygen that would increase the oxygen dissolved in plasma.
Although binding of oxygen to hemoglobin continues to some extent for pressures about 50 mmHg, as oxygen partial pressures decrease in this steep area of the curve, the oxygen is unloaded to peripheral tissue readily as the hemoglobin's affinity diminishes.
The partial pressure of oxygen in the blood at which the hemoglobin is 50% saturated, typically about 26.6 mmHg (3.5 kPa) for a healthy person, is known as the  P 50 . The P 50  is a conventional measure of hemoglobin affinity for oxygen. In the presence of disease or other conditions that change the hemoglobin oxygen affinity and, consequently, shift the curve to the right or left, the P 50  changes accordingly. An increased P 50  indicates a rightward shift of the standard curve, which means that a larger partial pressure is necessary to maintain a 50% oxygen saturation. This indicates a decreased affinity. Conversely, a lower P 50  indicates a leftward shift and a higher affinity.


The 'plateau' portion of the oxyhemoglobin dissociation curve is the range that exists at the pulmonary capillaries (minimal reduction of oxygen transported until the p(O 2 ) falls 50 mmHg).


The 'steep' portion of the oxyhemoglobin dissociation curve is the range that exists at the systemic capillaries (a small drop in systemic capillary p(O 2 ) can result in the release of large amounts of oxygen for the metabolically active cells).


To see the relative affinities of each successive oxygen as you remove/add oxygen from/to the hemoglobin from the curve compare the relative increase/decrease in p(O 2 ) needed for the corresponding increase/decrease in s(O 2 ).


The strength with which oxygen binds to hemoglobin is affected by several factors. These factors shift or reshape the oxyhemoglobin dissociation curve. A  shift to right indicates that the hemoglobin under study has a decreased affinity for oxygen. This makes it more difficult for hemoglobin to bind to oxygen (requiring a higher partial pressure of oxygen to achieve the same oxygen saturation), but it makes it easier for the hemoglobin to release oxygen bound to it.
The effect of this shift of the curve increases the partial pressure of oxygen in the tissues when it is most needed, such as during exercise, or hemorrhagic shock.


In contrast, the curve is shifted to the left by the opposite of these conditions.


This shift indicates that the hemoglobin under study has an increased affinity for oxygen so that hemoglobin binds oxygen more easily, but unloads it more reluctantly.
Left shift of the curve is a sign of hemoglobin's increased affinity for oxygen (e.g. at the lungs).


Similarly, right shift shows decreased affinity, as would appear with an increase in either body temperature, hydrogen ions,  2,3-bisphosphoglycerate  (2,3-BPG) concentration or carbon dioxide concentration.


Note:


The causes of shift to right can be remembered using the  mnemonic , " CADET , face Right!" for  C O 2 ,  A cid, 2,3- D PG, [ Note 1 ]   E xercise and  T emperature. [ 2 ]  Factors that move the oxygen dissociation curve to the right are those physiological states where tissues need more oxygen. For example, during exercise, muscles have a higher metabolic rate, and consequently need more oxygen, produce more carbon dioxide and lactic acid, and their temperature rises.


A decrease in pH (increase in    H +  ion concentration) shifts the standard curve to the right, while an increase shifts it to the left. This occurs because at greater    H +  ion concentration, various amino acid residues, such as Histidine 146 exist predominantly in their protonated form allowing them to form ion pairs that stabilize deoxyhemoglobin in the T state. [ 3 ]  The T state has a lower affinity for oxygen than the R state, so with increased acidity, the hemoglobin binds less O 2  for a given P O2  (and more H + ). This is known as the  Bohr effect . [ 4 ]  A reduction in the total binding capacity of hemoglobin to oxygen (i.e. shifting the curve down, not just to the right) due to reduced pH is called the  root effect . This is seen in bony fish. The binding affinity of hemoglobin to O 2  is greatest under a relatively high pH.


Carbon dioxide  affects the curve in two ways. First, CO 2  accumulation causes  carbamino  compounds to be generated through chemical interactions, which bind to hemoglobin forming  carbaminohemoglobin . CO 2  is considered an  Allosteric regulation  as the inhibition happens not at the binding site of hemoglobin. [ 5 ]  Second, it influences  intracellular pH  due to formation of bicarbonate ion. Formation of carbaminohemoglobin stabilizes T state hemoglobin by formation of ion pairs. [ 3 ]  Only about 5–10% of the total CO 2  content of blood is transported as carbamino compounds, whereas (80–90%) is transported as bicarbonate ions and a small amount is dissolved in the plasma. The formation of a bicarbonate ion will release a proton into the plasma, decreasing pH (increased acidity), which also shifts the curve to the right as discussed above; low CO 2  levels in the blood stream results in a high pH, and thus provides more optimal binding conditions for hemoglobin and O 2 . This is a physiologically favored mechanism, since hemoglobin will drop off more oxygen as the concentration of carbon dioxide increases dramatically where tissue respiration is happening rapidly and oxygen is in need. [ 6 ] [ 7 ]


2,3-Bisphosphoglycerate or 2,3-BPG (formerly named 2,3-diphosphoglycerate or 2,3-DPG) is an organophosphate formed in  red blood cells  during  glycolysis  and is the  conjugate base  of  2,3-bisphosphoglyceric acid . The production of 2,3-BPG is likely an important adaptive mechanism, because the production increases for several conditions in the presence of diminished peripheral tissue O 2  availability, such as  hypoxemia , chronic lung disease,  anemia , and  congestive heart failure , among others, which necessitate easier oxygen unloading in the peripheral tissue. High levels of 2,3-BPG shift the curve to the right (as in childhood), while low levels of 2,3-BPG cause a leftward shift, seen in states such as  septic shock , and  hypophosphataemia . [ 4 ]  In the absence of 2,3-BPG, hemoglobin's affinity for oxygen increases. 2,3-BPG acts as a  heteroallosteric effector  of hemoglobin, lowering hemoglobin's affinity for oxygen by binding preferentially to deoxyhemoglobin. An increased concentration of BPG in red blood cells favours formation of the T (taut or tense), low-affinity state of hemoglobin and so the oxygen-binding curve will shift to the right.


Increase in temperature shifts the oxygen dissociation curve to the right. When temperature is increased keeping the oxygen concentration constant, oxygen saturation decreases as the bond between oxygen and iron gets denatured. Additionally, with increased temperature, the partial pressure of oxygen increases as well. So, one will have a lesser amount of hemoglobin saturated for the same oxygen concentration but at a higher partial pressure of oxygen. Thus, any point in the curve will shift rightwards (due to increased partial pressure of oxygen) and downwards (due to weakened

 Hb

 −

 O

 2

 {\displaystyle {\ce {Hb-O2}}}

 bond), hence, the rightward shift of the curve. [ 8 ]


Hemoglobin binds with  carbon monoxide  210 times more readily than with oxygen. [ 4 ]  Because of this higher affinity of hemoglobin for carbon monoxide than for oxygen, carbon monoxide is a highly successful competitor that will displace oxygen even at minuscule partial pressures. The reaction HbO 2  + CO → HbCO + O 2  almost irreversibly displaces the oxygen molecules forming  carboxyhemoglobin ; the binding of the carbon monoxide to the iron centre of hemoglobin is much stronger than that of oxygen, and the binding site remains blocked for the remainder of the life cycle of that affected red blood cell. [ 9 ]   With an increased level of carbon monoxide, a person can suffer from severe tissue  hypoxia  while maintaining a normal pO 2  because carboxyhemoglobin does not carry oxygen to the tissues.


Methemoglobinaemia  is a form of abnormal hemoglobin where the iron centre has been oxidised from the  ferrous +2   oxidation state  (the normal form, which on binding with oxygen changes to the ferric state) to the  ferric +3  state. This causes a leftward shift in the oxygen hemoglobin dissociation curve, as any residual heme with oxygenated ferrous iron (+2 state) is unable to unload its bound oxygen into tissues (because 3+ iron impairs hemoglobin's cooperativity), thereby increasing its affinity with oxygen. However, methemoglobin has increased affinity for  cyanide , and is therefore useful in the treatment of  cyanide poisoning . In cases of accidental ingestion, administration of a  nitrite  (such as  amyl nitrite ) can be used to deliberately oxidise hemoglobin and raise methemoglobin levels, restoring the functioning of  cytochrome oxidase . The nitrite also acts as a  vasodilator , promoting the cellular supply of oxygen, and the addition of an iron salt provides for competitive binding of the free cyanide as the biochemically inert  hexacyanoferrate(III)  ion, [Fe(CN) 6 ] 3− . An alternative approach involves administering  thiosulfate , thereby converting cyanide to  thiocyanate , SCN − , which is excreted  via  the kidneys.  Methemoglobin is also formed in small quantities when the dissociation of oxyhemoglobin results in the formation of methemoglobin and  superoxide , O 2 − , instead of the usual products. Superoxide is a  free radical  and causes biochemical damage, but is neutralised by the action of the enzyme  superoxide dismutase .


Myo-inositol trispyrophosphate  (ITPP), also known as OXY111A, is an  inositol phosphate  that causes a rightward shift in the oxygen hemoglobin dissociation curve through  allosteric modulation  of hemoglobin within red blood cells.  It is an experimental drug intended to reduce tissue  hypoxia .  The effects appear to last roughly as long as the affected red blood cells remain in circulation.


Fetal hemoglobin  (HbF) is structurally different from normal  adult hemoglobin  (HbA), giving HbF a higher affinity for oxygen than HbA.  HbF is composed of two alpha and two gamma chains whereas HbA is composed of two alpha and two beta chains.  The fetal dissociation curve is shifted to the left relative to the curve for the normal adult because of these structural differences:


In adult hemoglobin, the binding of 2,3-bisphosphoglycerate (2,3-BPG) primarily occurs with the beta chains, preventing the binding of oxygen with haemoglobin. This binding is crucial for stabilizing the  deoxygenated state of hemoglobin, promoting the efficient release of oxygen to body tissues.


In fetal hemoglobin, which possesses a gamma chain instead of a beta chain, the interaction with 2,3-BPG differes because 2,3 - -BPG not binds with gamma chain as it has lower to no affinity with gamma chain.This distinction contributes to fetal hemoglobin having a higher affinity for oxygen.


Typically, fetal arterial oxygen pressures are lower than adult arterial oxygen pressures.  Hence higher affinity to bind oxygen is required at lower levels of partial pressure in the fetus to allow diffusion of oxygen across the  placenta .  At the placenta, there is a higher concentration of  2,3-BPG  formed, and 2,3-BPG binds readily to beta chains rather than to alpha chains. As a result, 2,3-BPG binds more strongly to adult hemoglobin, causing HbA to release more oxygen for uptake by the fetus, whose HbF is unaffected by the 2,3-BPG. [ 10 ]  HbF then delivers that bound oxygen to tissues that have even lower partial pressures where it can be released.


Red blood cell concentrates , also known as red cell concentrates or packed red blood cells, are  red blood cells  that have been separated for  blood transfusion . [ 1 ]  A red blood cell concentrate typically has a haematocrit of 0.50 – 0.70 L/L and a volume between 250 and 320 mL. Transfusion of red blood cell concentrates is indicated to compensate for a deficit caused by critical bleeding or to correct anaemic conditions, in order to increase the oxygen-carrying capacity and avoid detrimental effects caused by oxygen debt. [ 2 ]


In adults, one unit brings up hemoglobin levels by about 10 g/L (1 g/dL). [ 3 ] [ 4 ]  Repeated transfusions may be required in people receiving  cancer chemotherapy  or who have  haemoglobin disorders .  Cross-matching  may be required before the blood is given. [ 1 ]  A red blood cell concentrate is given by  injection into a vein . [ 5 ]  The widespread use of red blood cell concentrates as part of blood component therapy began in the middle of the 20th century, when polyvinyl chloride (PVC) blood bags were introduced as storage containers. [ 6 ]  Transfusion is on the  World Health Organization's List of Essential Medicines . [ 7 ]


The widespread use of packed red blood cells began in the 1960s. [ 8 ]  It is on the  World Health Organization's List of Essential Medicines . [ 9 ] [ 10 ]  A number of other versions also exist including whole blood,  leukocyte reduced red blood cells , and  washed red blood cells . [ 11 ]


Red blood cells are used to restore oxygen-carrying capacity in people with  anaemia  due to trauma or other medical problems


Whenever a red blood cell transfusion is being considered for a patient, it is good practice to consider not only the haemoglobin level, but also the overall clinical context, patient preferences, and whether there are alternative treatments. If a patient is stable and has a haematinic deficiency, they should be treated for the deficiency ( iron deficiency ,  B 12  deficiency , or  folate deficiency ) rather than being given a red blood cell transfusion. [ 3 ] [ 4 ]


In adults, blood transfusion is typically recommended when hemoglobin levels are below 70 g/L (7 g/dL) in those who have stable vital signs, unless they have anemia due to a  haematinic  deficiency. Transfusing at a restrictive haemoglobin threshold of between 70 g/L to 80 g/L (7 to 8g/dL) decreased the proportion of people given a red blood cell transfusion by 41% across a broad range of clinical specialties, including those people who are critically ill. There is no evidence that a restrictive transfusion strategy are stronger associated with death or major adverse events (e.g. cardiac events,  myocardial infarction ,  stroke ,  pneumonia ,  thromboembolism , infection) compared with a liberal transfusion strategy. There is not enough information in some patient groups to say whether a restrictive or liberal transfusion threshold is better. [ 12 ] [ 13 ] [ 14 ]


This refers to transfusing a  single unit  or bag of red blood cells to a person who is not bleeding and haemodynamically stable followed by an assessment to see if further transfusion is required. [ 15 ] [ 16 ]  The benefits of single unit transfusion include reduced exposure to blood products. Each unit transfused increases the associated risks of transfusion such as infection,  transfusion associated circulatory overload  and other side effects. [ 17 ] [ 18 ]  Transfusion of a single unit also encourages less wastage of red blood cells. [ 19 ]


In adults with  upper gastrointestinal bleeding  transfusing at a higher threshold caused harm (increased risk of death and bleeding). [ 20 ]


A review established that in patients undergoing heart surgery a restrictive transfusion strategy of 70 to 80 g/L (7 to 8 g/dL) is safe and decreased red cell use by 24%. [ 21 ]


There is less evidence available for the optimal transfusion threshold for people with heart disease, including those who are having a heart attack. [ 22 ] [ 21 ] [ 23 ]  Guidelines recommend a higher threshold for people with  heart disease  of 80 g/L (8 g/dL) if they are not undergoing cardiac surgery. [ 24 ] [ 25 ]


There is insufficient evidence to suggest how to manage anemia in people with blood cancers in terms of transfusion thresholds. [ 26 ]


People with  thalassaemia  who are transfusion dependent require a higher hemoglobin threshold to suppress their own red cell production. To do this their hemoglobin levels should not be allowed to drop below 90 to 105 g/L (9 to 10.5 g/dL). [ 27 ]


There is insufficient evidence to recommend a particular hemoglobin threshold in people with  myelodysplasia  or  aplastic anemia , [ 28 ]  and guidelines recommend an individualized approach to transfusion. [ 25 ]


There is less evidence for specific transfusion thresholds in children compared to adults. [ 22 ] [ 24 ]  There has only been one randomized trial assessing different thresholds in children, and this showed no difference between a restrictive or liberal transfusion strategy. [ 29 ]  This trial used similar thresholds to the adult studies, and transfusing when the hemoglobin is less than 70 g/L is also recommended in children. [ 30 ]


Neonatal red cell transfusion , and when it is appropriate depends on: the gestational age of the baby; how long since the baby had been born; and also on whether the baby is well or ill. [ 30 ]


To avoid transfusion reactions, the donor and recipient blood are tested, typically ordered as a "type and screen" for the recipient. The "type" in this case is the  ABO  and  Rh  type, specifically the  phenotype , and the "screen" refers to testing for atypical antibodies that might cause transfusion problems. The typing and screening are also performed on donor blood. The blood groups represent  antigens  on the surface of the red blood cells which might react with  antibodies  in the recipient. [ citation needed ]


The ABO blood group system has four basic phenotypes: O, A, B, and AB. In the former  Soviet Union  these were called I, II, III, and IV, respectively. There are two important antigens in the system: A and B. Red cells without A or B are called type O, and red cells with both are called AB. Except in unusual cases like infants or seriously  immunocompromised  individuals, all people will have antibodies to any ABO blood type that isn't present on their own red blood cells, and will have an immediate hemolytic reaction to a unit that is not compatible with their ABO type. In addition to the A and B antigens, there are rare variations which can further complicate transfusions, such as the  Bombay phenotype . [ citation needed ]


The Rh blood group system consists of nearly around 50 different antigens, but the one of the greatest clinical interest is the "D" antigen, though it has  other names  and is commonly just called "negative" or "positive". Unlike the ABO antigens, a recipient will not usually react to the first incompatible transfusion because the  adaptive immune system  does not immediately recognize it. After an incompatible transfusion the recipient may develop an antibody to the antigen and will  react  to any further incompatible transfusions. This antibody is important because it is the most frequent cause of  hemolytic disease of the newborn . Incompatible red blood cells are sometimes given to recipients who will never become pregnant, such as males or postmenopausal women, as long as they do not have an antibody, since the greatest risk of Rh incompatible blood is to current or future pregnancies. [ 31 ]


For RBCs, type O negative blood is considered a "universal donor" as recipients with types A, B, or AB can almost always receive O negative blood safely. Type AB positive is considered a "universal recipient" because they can receive the other ABO/Rh types safely. These are not truly universal, as other red cell antigens can further complicate transfusions. [ citation needed ]


There are many other  human blood group systems  and most of them are only rarely associated with transfusion problems. A screening test is used to identify if the recipient has any antibodies to any of these other blood group systems. If the screening test is positive, a complex set of tests must follow to identify which antibody the recipient has by process of elimination. Finding suitable blood for transfusion when a recipient has multiple antibodies or antibodies to extremely common antigens can be very difficult and time-consuming. [ citation needed ]


Because this testing can take time, doctors will sometimes order a unit of blood transfused before it can be completed if the recipient is in critical condition. Typically two to four units of O negative blood are used in these situations, since they are unlikely to cause a reaction. [ 32 ]  A potentially fatal reaction is possible if the recipient has pre-existing antibodies, and uncross matched blood is only used in dire circumstances. Since O negative blood is not common, other blood types may be used if the situation is desperate. [ citation needed ]


Red blood cell concentrates are produced either from  whole blood  or by  apheresis . Production from whole blood is far more common than apheresis due to collection and production efficacy as well as economical purposes. When red blood cell concentrates are produced from whole blood, the whole blood is first separated through centrifugation (usually between 3000 to 5000 x  g ). The red blood cells are denser than plasma and the other present blood cells (platelets, white blood cells) and settle at the bottom of the blood bag. After centrifugation, the red blood cells are separated from the other components (the majority of the plasma, platelets and white blood cells) through the use of an extractor (also referred to as blood press).


After extraction, an additive solution is usually added in a ratio of 1:1.5 to 1:2. The purpose of the additive solution is to maintain adequate viscosity, provide nutrients and ATP/GTP building blocks and reduce haemolysis generation throughout blood bank storage. Choice of additive solution has an impact on the red blood cell viability and, thereby, shelf life (expiry date) of the red blood cell concentrate. Usually, shelf life is limited to 4 to 6 weeks, provided that the red blood cell concentrates are stored in adequate conditions (2-6 °C).  Commercial additive solutions are typically based on saline. They usually contain glucose, adenine, mannitol and, sometimes, phosphate and guanosine. [ 33 ]  The additive solution has no, or very little, buffering capacity, but buffering is provided by the red blood cells themselves. Traditional additive solutions are hypotonic, although experiments with next-generation additive solutions suggest that an alkali pH in combination with low chloride concentrations may be able to prolong the red blood cell viability. [ 34 ]


Leucocyte depletion of blood components, including red blood cell concentrates, is increasingly becoming standard practise; in many of the high-income countries of the world, 100% of the red blood cell supply is already being leucocyte depleted. [ 35 ]  Leucocyte depletion, usually by a leucocyte filter included in the blood bag system, is an efficient yet relatively cheap way of reducing the risk of transfusion reactions. Leucocyte depletion is most commonly performed as an integrated processing step, as bedside filtration is considered a less efficient method. [ 36 ] [ 37 ]


Red blood cell concentrates are sometimes modified to address specific needs of patients who, for different reasons, are unable to tolerate standard red blood cell concentrates.


Even after leucocyte filtration, a residual number of leucocytes remain in the red blood cell concentrate (<1 x 10 6  per unit). [ 38 ]  These may be harmful for patients who have an impaired, reduced or not yet fully developed immune system, or if the blood donor and recipient are closely related. Therefore, such patients may be issued irradiated blood components, including irradiated red blood cells. [ 39 ] [ 40 ]  X-ray or gamma sources are usually used for irradiation. [ 40 ]  When blood components are irradiated, the DNA is destroyed in any remaining white blood cells (leucocytes), which stops the leucocytes from being able to proliferate further. Although efficient in reducing the risk of transfusion reactions including fatal transfusion-associated graft-versus-host disease (TA-GvHD), irradiation is damaging to the red blood cell membrane, which can be seen as increased levels of haemolysis during storage. As a consequence, irradiated red blood cell concentrates are usually given a reduced shelf life. Therefore, irradiation of red blood cell concentrates is commonly only performed on demand or for specific parts of the supply. [ 41 ] [ 42 ] [ 43 ]


Red blood cell concentrates still contain a small amount of plasma after standard processing (usually 10-15 mL). In order to reduce the risk of allergic reactions to plasma proteins, or to modify the red blood cell concentrates for patients who are sensitive to IgA or potassium ions (K + ), the red blood cell concentrates can be washed. [ 44 ] [ 45 ]  Washing typically consists of diluting the red blood cells in saline-based washing solution or red blood cell additive solutions and then washing away any remaining plasma and debris during one or several centrifugation cycles. The process can be performed manually, or with an automated cell washer or processor. [ 46 ]


To increase the availability of RBCs of rare blood types, red blood cells can be stored cryopreserved (frozen) instead of refrigerated. With a controlled, standardised freezing and thawing process, the red blood cells can be stored in frozen condition for up to 30 years. [ 38 ] [ 47 ]  Also for cryopreservation, cell processors are frequently used for both the pre-freezing glycerolisation procedure and for washing away the glycerol after thawing of the red blood cells. Using an automated device allows for standardised processing to ensure optimal protection from ice crystal formation, which otherwise could damage the red blood cells. [ 48 ]