The  American Academy of Allergy, Asthma, and Immunology  supports the use of  immunoglobulin  for primary immunodeficiencies, while noting that such usage actually accounts for a minority of usage and acknowledging that immunoglobulin supplementation can be appropriately used for a number of other conditions, [ 32 ]  including neonatal sepsis (citing a sixfold decrease in mortality), considered in cases of HIV (including pediatric HIV), considered as a second line treatment in relapsing-remitting multiple sclerosis, but recommending against its use in such conditions as  chronic fatigue syndrome ,  PANDAS  (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) until further evidence to support its use is found (though noting that it may be useful in PANDAS patients with an autoimmune component), cystic fibrosis, and a number of other conditions. [ 18 ]


Brands include:


Although immunoglobulin is frequently used for long periods of time and is generally considered safe, immunoglobulin therapy can have severe adverse effects, both localized and systemic. Subcutaneous administration of immunoglobulin is associated with a lower risk of both systemic and localized risk when compared to intravenous administration (hyaluronidase-assisted subcutaneous administration is associated with a greater frequency of adverse effects than traditional subcutaneous administration but still a lower frequency of adverse effects when compared to intravenous administration). Patients who are receiving immunoglobulin and experience adverse events are sometimes recommended to take  acetaminophen  and  diphenhydramine  before their infusions to reduce the rate of adverse effects. Additional premedication may be required in some instances (especially when first getting accustomed to a new dosage),  prednisone  or another oral steroid. [ citation needed ]


Local side effects of immunoglobulin infusions most frequently include an  injection site reaction  (reddening of the skin around the injection site), itching, rash, and hives. [ 48 ]  Less serious systemic side effects to immunoglobulin infusions include an increased heart rate, hyper or hypotension, an increased body temperature, diarrhea, nausea, abdominal pain, vomiting, arthralgia or myalgia, dizziness, headache, fatigue, fever, and pain. [ 48 ]


Serious side effects of immunoglobulin infusions in infants, children, [ 49 ]  and adults include chest discomfort or pain,  myocardial infarction ,  tachycardia ,  hyponatremia ,  hemolysis ,  hemolytic anemia ,  thrombosis ,  hepatitis ,  anaphylaxis , backache,  aseptic meningitis ,  acute kidney injury , hypokalemic  nephropathy ,  pulmonary embolism , and  transfusion related acute lung injury . [ 48 ]   hemoThere is also a small chance that even given the precautions taken in preparing immunoglobulin preparations, an immunoglobulin infusion may pass a virus to its recipient. [ 48 ]  Some immunoglobulin solutions also contain isohemagglutinins, which in rare circumstances can cause hemolysis by the isohemagglutinins triggering phagocytosis. [ 50 ]


IVIG has long been known to induce a decrease in peripheral blood neutrophil count, or  neutropenia  in neonates, [ 51 ]  and in patients with  Idiopathic Thrombocytopenic Purpura , resolving spontaneously and without complications within 48 h. [ 52 ]  Possible pathomechanisms include  apoptosis /cell death due to antineutrophil antibodies with or without neutrophil migration into a storage pool outside the blood circulation. [ 53 ]


Immunoglobulin therapy interferes with the ability of the body to produce a normal immune response to an attenuated  live-virus vaccine  (like MMR) for up to a year, [ 48 ]  can result in falsely elevated blood glucose levels, [ 48 ]  and can interfere with many of the IgG-based assays often used to diagnose a patient with a particular infection. [ 54 ]


After immunoglobulin therapy's discovery in 1952, weekly  intramuscular injections  of immunoglobulin (IMIg) were the norm until  intravenous  formulations (IVIg) began to be introduced in the 1980s. [ 55 ]  During the mid and late 1950s, [ vague ]  one-time IMIg injections were a common public health response to outbreaks of  polio  before the widespread availability of vaccines. Intramuscular injections were extremely poorly tolerated due to their extreme pain and poor efficacy – rarely could intramuscular injections alone raise plasma immunoglobulin levels enough to make a clinically meaningful difference. [ 55 ]


Intravenous formulations began to be approved in the 1980s, which represented a significant improvement over intramuscular injections, as they allowed for a sufficient amount of immunoglobulin to be injected to reach clinical efficacy, although they still had a fairly high rate of adverse effects (though the addition of stabilizing agents reduced this further). [ 55 ]


The first description of a  subcutaneous  route of administration for immunoglobulin therapy dates back to 1980, [ 56 ]  but for many years subcutaneous administration was considered to be a secondary choice, only to be considered when peripheral venous access was no longer possible or tolerable. [ 55 ]


During the late 1980s and early 1990s, [ vague ]  it became obvious that for at least a subset of patients the systemic adverse events associated with intravenous therapy were still not easily tolerable, and more doctors began to experiment with subcutaneous immunoglobulin administration, culminating in an  ad hoc  clinical trial in Sweden of 3000 subcutaneous injections administered to 25 adults (most of whom had previously experienced systemic adverse effects with IMIg or IVIg), where no infusion in the  ad hoc  trial resulted in a severe systemic adverse reaction, and most subcutaneous injections were able to be administered in non-hospital settings, allowing for considerably more freedom for the people involved. [ 55 ]


In the later 1990s, [ vague ]  large-scale trials began in Europe to test the feasibility of subcutaneous immunoglobulin administration, although it was not until 2006 that the first subcutaneous-specific preparation of immunoglobulin was approved by a major regulatory agency ( Vivaglobin , which was voluntarily discontinued in 2011). [ 55 ] [ 57 ]  A number of other brand names of subcutaneous immunoglobulin have since been approved, although some small-scale studies have indicated that a particular cohort of patients with  common variable immunodeficiency  (CVID) may develop intolerable side effects with subcutaneous immunoglobulin (SCIg) that they do not with intravenous immunoglobulin (IVIg). [ 55 ]


Although intravenous was the preferred route for immunoglobulin therapy for many years, in 2006, the US  Food and Drug Administration  (FDA) approved the first preparation of immunoglobulin that was designed exclusively for subcutaneous use. [ 55 ]


The precise mechanism by which immunoglobulin therapy suppresses harmful  inflammation  is likely multifactorial. [ 58 ]  For example, it has been reported that immunoglobulin therapy can block  Fas -mediated cell death. [ 59 ]


Perhaps a more popular theory is that the immunosuppressive effects of immunoglobulin therapy are mediated through IgG's  Fc glycosylation . By binding to receptors on  antigen presenting cells , IVIG can increase the expression of the inhibitory  Fc receptor , FcgRIIB, and shorten the half-life of auto-reactive antibodies. [ 60 ] [ 61 ] [ 62 ]  The ability of immunoglobulin therapy to suppress pathogenic immune responses by this mechanism is dependent on the presence of a sialylated glycan at position CH2-84.4 of IgG. [ 60 ]  Specifically, de-sialylated preparations of immunoglobulin lose their therapeutic activity and the anti-inflammatory effects of IVIG can be recapitulated by administration of recombinant sialylated IgG1 Fc. [ 60 ]


Sialylated-Fc-dependent mechanism was not reproduced in other experimental models suggesting that this mechanism is functional under a particular disease or experimental settings. [ 63 ] [ 64 ] [ 65 ] [ 66 ]  On the other hand, several other mechanisms of action and the actual primary targets of immunoglobulin therapy have been reported. In particular, F(ab')2-dependent action of immunoglobulin to inhibit activation of human dendritic cells, [ 67 ]  induction of autophagy, [ 68 ]  induction of COX-2-dependent PGE-2 in human dendritic cells leading to expansion of regulatory T cells, [ 69 ]  inhibition of pathogenic Th17 responses, [ 70 ]  and induction of human basophil activation and IL-4 induction via anti-IgE autoantibodies. [ 71 ] [ 72 ]  Some believe that immunoglobulin therapy may work via a multi-step model where the injected immunoglobulin first forms a type of  immune complex  in the patient. [ 73 ]  Once these immune complexes are formed, they can interact with Fc receptors on  dendritic cells , [ 74 ]  which then mediate anti-inflammatory effects helping to reduce the severity of the autoimmune disease or inflammatory state.


Other proposed mechanisms include the possibility that donor antibodies may bind directly with the abnormal host antibodies, stimulating their removal; the possibility that IgG stimulates the host's  complement system , leading to enhanced removal of all antibodies, including the harmful ones; and the ability of immunoglobulin to block the antibody receptors on immune cells ( macrophages ), leading to decreased damage by these cells, or regulation of macrophage  phagocytosis . Indeed, it is becoming more clear that immunoglobulin can bind to a number of membrane receptors on  T cells ,  B cells , and  monocytes  that are pertinent to autoreactivity and induction of tolerance to self. [ 60 ] [ 75 ]


A report stated that immunoglobulin application to activated T cells leads to their decreased ability to engage  microglia . As a result of immunoglobulin treatment of T cells, the findings showed reduced levels of  tumor necrosis factor-alpha  and  interleukin-10  in T cell-microglia co-culture. The results add to the understanding of how immunoglobulin may affect inflammation of the central nervous system in autoimmune inflammatory diseases. [ 76 ]


Hyperimmune globulins are a class of  immunoglobulins  prepared in a similar way as for  normal human immunoglobulin , except that the donor has high titers of  antibody  against a specific organism or  antigen  in their  plasma . Some agents against which hyperimmune globulins are available include  hepatitis B ,  rabies ,  tetanus  toxin,  varicella-zoster , etc. Administration of hyperimmune globulin provides  "passive" immunity  to the patient against an agent. This is in contrast to  vaccines  that provide  "active" immunity . However, vaccines take much longer to achieve that purpose while hyperimmune globulin provides instant "passive" short-lived immunity. Hyperimmune globulin may have serious  side effects , thus usage is taken very seriously. [ citation needed ]


Hyperimmune  serum  and  plasma  contain high amounts of an antibody, as a consequence of disease convalescence [ 77 ]  or of repeated immunization. [ 78 ]  Hyperimmune plasma is used in veterinary medicine, [ 79 ]  and hyperimmune plasma derivatives are used to treat snakebite. [ 80 ]  It has been hypothesized that hyperimmune serum may be an effective therapy for persons infected with the  Ebola virus . [ 81 ]


In the United Kingdom a dose cost the  NHS  between  £ 11.20 and  £ 1,200.00 depending on the type and amount. [ 14 ]  In the United States, antivenoms may cost thousands of dollars per dose because of markups that occur after manufacturing. [ 82 ]


As  biologicals , various brand names of immunoglobulin products are not necessarily interchangeable, and care must be exercised when changing between them. [ 83 ]  Brand names of intravenous immunoglobulin formulations include Flebogamma, Gamunex, Privigen, Octagam, and Gammagard, while brand names of subcutaneous formulations include Cutaquig, Cuvitru, HyQvia, Hizentra, [ 27 ] [ 84 ] [ 85 ]  Gamunex-C, and Gammaked. [ 86 ]


The United States is one of a handful of countries that allow plasma donors to be paid, meaning that the US supplies much of the plasma-derived medicinal products (including immunoglobulin) used across the world, including more than 50% of the European Union's supply. [ 87 ]  The Council of Europe has officially endorsed the idea of not paying for plasma donations for both ethical reasons and reasons of safety, but studies have found that relying on entirely voluntary plasma donation leads to shortages of immunoglobulin and forces member countries to import immunoglobulin from countries that do compensate donors. [ 87 ]


In Australia, blood donation is voluntary and therefore to cope with increasing demand and to reduce the shortages of locally produced immunoglobulin, several programs have been undertaken including adopting plasma for first time blood donors, better processes for donation, plasma donor centres and encouraging current blood donors to consider plasma only donation. [ 88 ]


Experimental results from a small  clinical trial  in humans suggested protection against the progression of  Alzheimer's disease , but no such benefit was found in a subsequent phase III clinical trial. [ 89 ] [ 90 ] [ 91 ]  In May 2020, the US approved a phase three clinical trial on the efficacy and safety of high-concentration intravenous immune globulin therapy in severe  COVID-19 . [ 92 ]  Efficacy of heterologous immunoglobulin derivatives has been demonstrated in clinical trials of antivenoms for scorpion sting [ 93 ]  and for snakebite. [ 94 ]


The  Indian blood group system  ( In ) is a classification of  blood  based on the presence or absence of  inherited   antigens  that reside within the  CD44  molecule that is expressed on the surface of  blood cells . [ 1 ]  It is named so because 4% of the population in India possess it. [ 2 ]  Most individuals express the In b  antigen that results from an  arginine  residue at position 46 of CD44 .  The In a  blood type results from a substitution  proline  for arginine at this same position.


The  International Society of Blood Transfusion  ( ISBT ) is a  scientific  society founded in 1935 which promotes the study of  blood transfusion  and provides information about the ways in which blood transfusion medicine and science can best serve patients' interests. The society's central office is in  Amsterdam , and there are around 1900 members in 103 countries. [ 1 ]  As of June 2024, the president of the ISBT is Pierre Tiberghien. [ 2 ]


ISBT is governed by a voluntary board of 16 directors, representing all  WHO  regions. [ 1 ] [ 2 ]  ISBT has 16 scientific working parties, which are groups of ISBT members promoting science, research and best practice in their specific areas of expertise. [ 3 ]


ISBT advocates for  standardisation  and  harmonisation  in the field of blood transfusion. [ 4 ]  The other major impact on the transfusion community is the classification of various  human blood group systems  under a common nomenclature. [ 5 ] [ 6 ]  ISBT's coordination also extends to obtaining donors with rare  antigens , a process that often involves international searches in which common terminology is critical.


The ISBT Code of Ethics was developed in response to the  World Health Assembly  resolution WHA 28.72. [ 7 ] [ 8 ]   This resolution called for the establishment of: appropriately governed national blood services; voluntary non-remunerated blood donations (VNRBD); and the promotion of the health of both blood donors and recipients of blood. ISBT works as a  non-state actor  in official relations with WHO. ISBT collaborated with WHO to produce "Educational modules on clinical use of blood". [ 9 ]


In a 2015 review of the history of the ISBT, Hans Erik Heier distinguished four phases in the formation of the society: [ 10 ]


The formation of the International Society of Blood Transfusion, or Societé International de Transfusion Sanguine, as it was called at the time, was initiated in  Rome  at a meeting between representatives from 20 nations, the  International Red Cross  and the Bogdanov institute in  Moscow . Blood transfusion was a rather new therapeutic option, and therefore, it was decided that transfusion-specific congresses should be organised to highlight the potential importance of transfusion. To organize these congresses, a society was needed.


After it was decided that a society dedicated to organizing transfusion-related congresses should be created, it did not take long until ISBT was founded. In 1937, the ISBT central office (CO) was established in  Paris , led by newly appointed Secretary General  Arnault Tzanck . Two years later, in 1939, the activities of the ISBT CO had to be suspended because of the  Second World War  (WWII).


In the period surrounding WWII,  immunohaematology  and transfusion technology developed rapidly.  Blood banks  were created, voluntary  blood donations  came in great numbers in the allied nations, plasma-transfusion became a standard anti-shock treatment, Rh and  Kell  systems were discovered, and industrial  blood plasma fractionation  was developed to produce  albumin , which can be used as a substitute for  plasma . In 1947, the first post-war congress of the ISBT was organised in  Turin, Italy . Here, some specific future goals were laid out to complement the main activity of the Society, the organization of congresses:


After the congress in Turin, the society was able to organise congresses and develop without great difficulties for the next forty years, until 1985.


In 1985, the  HIV/AIDS  epidemic struck transfusion medicine. During that time, the ISBT CO was still located in Paris as a part of the Centre National de Transfusion Sanguine (CNTS) (English: National Centre for Blood Transfusion) as their head, Michel Garretta, was also ISBT Secretary General at the time. In June 1991, he stepped down as head of CNTS, as the HIV/AIDS crisis had become a catastrophe for the transfusion system in France and eventually led to a reorganisation of CNTS in 1991. Subsequently, at the ISBT Congress in Hong Kong it was decided that ISBT could no longer be linked to CNTS, ruling out Garretta's succession of a French colleague. Harold Gunson, who was President of ISBT in 1991, agreed to take on a second role as acting Secretary General. Together with CNTS, and ISBT Secretary Claudine Hossenlopp, he supervised the move of the CO from Paris to Manchester, UK. In 1994, he resigned from his post as blood centre director in Manchester and moved the CO to Lancaster, into his own home. He upheld the CO together with his wife until 1999. The end of Gunson's term meant having to find a new location for the CO, and a new Secretary General.


In 1999, the new location for the ISBT CO was Amsterdam, where it became a part of professional congress organiser (PCO) Eurocongress. Paul Strengers, a doctor at Sanquin Blood Supply, took up the role of Secretary General. A new vision for the 2002–2006 period of ISBT was created by the executive committee, focusing on developing ISBT into an umbrella organization, improving communication with the membership, educational and scientific activities, and professionalizing the CO. In the coming ten years, the society worked to achieve these goals, with Strengers to remain Secretary General for that period. Eurocongress organised ISBT congresses together with the ISBT CO and local organizing committees. The help of Eurocongress took away economic risks attached to congresses, as they were able to provide professional assistance and detailed advice. As the CO had moved to a different country, the ISBT statutes and by-laws were also updated and adapted to Dutch law.


The reformations made in the previous years had led to an increase in workload for the ISBT CO. In order to continue the fulfilment of the strategic plans of the ISBT, a full-time, paid chief executive officer (CEO) was hired in 2010. In 2012, the CO moved to a separate location in Amsterdam as the shared space with Eurocongress did not meet the needs of the expanded office staff. Currently, five paid persons are employed full-time at the CO, managed by CEO Judith Chapman (2010 – today). Congresses are organised by MCI, of which Eurocongress became a part in 2010. In that same year, Martin Olsson was appointed as Scientific Secretary (non-remunerated) to overlook the scientific programming of ISBT congresses and guarantee the high scientific quality. The second Scientific Secretary, Ellen van der Schoot, was in office until 2018. John Semple succeeded Ellen van der Schoot in 2019 through 2021. As of 2024, Jason Ackers is the current ISBT Scientific Secretary until 2025.


Intraoperative blood salvage  ( IOS ), also known as  cell salvage,  is a specific type of autologous blood transfusion. Specifically IOS is a  medical  procedure involving recovering blood lost during  surgery  and re-infusing it into the patient. It is a major form of  autotransfusion .


It has been used for many years and gained greater attention over time as risks associated with allogenic (separate-donor)  blood transfusion  have seen greater  publicity  and become more fully appreciated.  [ citation needed ]  Several  medical devices  have been developed to assist in salvaging the patient's own blood in the perioperative setting. The procedure is frequently used in cardiothoracic and vascular  surgery , during which blood usage has traditionally been high. A greater effort to avoid adverse events due to  transfusion  has also increased the emphasis on blood conservation (see  bloodless surgery ).


Providing safe blood for transfusion remains a challenge despite advances in preventing transmission of  hepatitis B  virus (HBV),  hepatitis C  virus (HCV),  AIDS/HIV , HTLV-I/II,  West Nile virus  (WNV),  syphilis ,  Chagas disease ,  Zika virus , and transfusion-transmitted  bacterial infection . Human errors such as misidentifying  patients  and drawing blood samples from the wrong person (i.e., wrong blood in tube or WBIT) is more of a risk than transmissible diseases in many developed nations. [ citation needed ]


Much more common risks of allogeneic transfusion include  allergic transfusion reactions  as well as  febrile non-hemolytic transfusion reactions . Additional risks include  transfusion related acute lung injury  (TRALI),   transfusion associated circulatory overload  (TACO) and transfusion-associated immunomodulation. TRALI is a potentially life-threatening condition with symptoms such as  dyspnea ,  fever , and  hypotension  occurring within hours of transfusion. TACO is a much more common (even with cases being underreported) potentially life-threatening condition involving respiratory compromise within hours of a transfusion. TACO must be suspected when there is respiratory distress with other signs, including pulmonary edema, unanticipated cardiovascular system changes, and evidence of fluid overload (including improvement after diuresis), during or up to 24 hours after transfusion. [ 1 ]  Transfusion-associated immunomodulation, which may suppress the  immune response  and cause adverse effects such as a small increase in the risk of postoperative infection. [ citation needed ]


Other risks such as classic or variant  Creutzfeldt–Jakob disease  (vCJD), an invariably fatal disease, remain worrisome as there are currently no approved tests for which to screen blood donors for this disease. Blood centers worldwide have instituted criteria to reject donors who may have been exposed to classic CJD and vCJD. Screening for transmissible diseases and deferral policies for classic CJD and vCJD designed to improve safety have unfortunately contributed to shrinking the donor pool. Blood shortages exist in the  United States  and worldwide. In many industrialized countries 5% or less of the eligible population are blood donors. [ citation needed ]


As a result, some in the global medical community have moved from allogeneic blood (blood collected from another person) towards  autologous  transfusion, in which patients receive their own blood. Another impetus for autologous transfusion is the position of  Jehovah's Witnesses on blood transfusions . For religious reasons, Jehovah's Witnesses may choose not to accept any allogeneic transfusions from a volunteer's  blood donation  but may accept the use of autologous blood salvaged during surgery to restore their blood volume and homeostasis during the course of an operation, although not autologous blood donated beforehand. Each Jehovah's Witness patient must be individually counselled as to all the possible blood products that are available as they may choose to accept some and not others (i.e., while not accepting whole blood nor any of the four main components of blood, [plasma; platelets; red cells; white cells] some may accept fractions derived from those components, or medications containing such minor fractions); it is an individual choice for each patient.
There are other religious/ non-religious individuals besides Jehovah's Witnesses that would refuse allogeneic blood products but may choose to accept intraoperative blood salvage. [ citation needed ]


Ways to avoid the adverse events associated with  allogenic  transfusion are often grouped under the umbrella phrase  bloodless surgery . There are several so-called bloodless options. These include:


Regardless of manufacturer, there are many types of cell processors. Cell processors are red cell washing devices that collect anticoagulated shed or recovered blood, wash and separate the  red blood cells  (RBC) by centrifugation or filtration such as the HemoClear filter. After, the washed RBCs can be returned to the same patient by reinfusion. RBC washing devices can help remove byproducts in salvaged blood such as activated  cytokines ,  anaphylatoxins , and other waste substances that may have been collected in the reservoir suctioned from the surgical field. However, they also remove viable  platelets ,  clotting factors , and other  plasma proteins  essential to whole blood and  homeostasis . The various RBC-savers also yield RBC concentrates with different characteristics and quality. [ citation needed ]


Direct transfusion is a blood salvaging method associated with  cardiopulmonary bypass  (CPB) circuits or other extracorporeal circuits (ECC) that are used in surgery such as coronary artery bypass grafts ( CABG ), valve replacement, or surgical repair of the great vessels. Following bypass surgery, the ECC circuit contains a significant volume of diluted whole blood that can be harvested in transfer bags and re-infused into patients. Residual CPB blood is fairly dilute ([Hb] = 6–9 g/dL; 60–90 g/L) compared to normal values (12–18 g/dL; 120–180 g/L) and can also contain potentially harmful contaminants such as activated cytokines, anaphylatoxins, and other waste substances that have been linked to organ  edema  and organ dysfunction and need a  diuretic  to reverse.


Acute normovolemic hemodilution (ANH) is a form of autologous transfusion where whole blood is collected from a patient at the start of surgery into a standard blood collection bag with anticoagulant with the simultaneous replacement of intracellular volume using acellular fluids (such as normal saline). The patient's own blood is re-infused at the end of the surgical case (presumably when any bleeding has stopped). [ 2 ]


Hemofiltration or ultrafiltration devices constitute the third major type of blood salvage in operating rooms.  In general, ultrafiltration devices filter the patient's anticoagulated whole blood. The filter process removes unwanted excess non-cellular plasma water, low molecular weight solutes, platelet inhibitors and some particulate matter through hemoconcentration, including activated cytokines, anaphylatoxins, and other waste substances making concentrated whole blood available for reinfusion.
Hemofilter devices return the patient's whole blood with all the blood elements and fractions including platelets, clotting factors, and plasma proteins with a substantial Hb level. Presently, the only whole blood ultrafiltration device in clinical use is the Hemobag. [ 3 ] [ 4 ]  These devices do not totally remove potentially harmful contaminants that can be washed away by most RBC-savers. However, the contaminants that are potentially reduced by using RBC-savers, as shown by data from  in vitro  laboratory tests, are transient and reversible  in vivo  with hemostatic profiles returning to baselines within hours. The key is that  coagulation  and homeostasis are immediately improved with the return of concentrated autologous whole blood.


Over the years numerous studies have been done to compare these methods of blood salvage in terms of safety, patient outcomes, and cost effectiveness, often with equivocal or contradictory results. [ 5 ] [ 6 ] [ 7 ] [ 8 ]


An  Intrauterine transfusion (IUT)  is a procedure that provides blood to a fetus, most commonly through the umbilical cord. [ 1 ] [ 2 ]  It is used in cases of severe fetal anemia, such as when fetal red blood cells are being destroyed by maternal antibodies, or  parvovirus B19  infection, homozygous  alpha-thalassemia , or  twin-to-twin transfusion syndrome . [ 3 ]  IUTs are performed by  perinatologists  at hospitals or specialized centers. [ 4 ]


Intrauterine transfusion (IUT) was introduced in 1963 by A.W. Liley. Early IUTs involved transfusion into the fetal peritoneum (abdomen). Almost 20 years later, the procedure was improved to a transfusion into the umbilical vein, which allowed for better absorption of red blood cells. [ 5 ]


Hemolytic disease of the fetus and newborn  (HDFN) is a rare condition that affects 3 out of 100,000 to 80 out of 100,000 patients per year. It occurs when maternal  antibodies  cross the  placenta  during pregnancy and destroy fetal  red blood cells  (RBCs). This process can lead to fetal  anemia , and in severe cases can progress to  hydrops  (edema), ascites, heart failure, and death. [ 6 ]


For HDFN to occur, the fetus must be  antigen  positive (paternally inherited) and the mother must have antibodies to the given antigen. Such antibodies typically form when the mother undergoes  alloimmunization  to the antigen during a previous pregnancy or transfusion. Historically,  RhD  alloimmunization accounted for the majority of cases. However, the rates of these cases have been significantly reduced by RhIg ( RhoGam ) administration. Measures are not available for preventing alloimmunization to non-RhD antigens ( Kell ,  Duffy ,  Rhc ,  RhE , etc.), which can also cause HDFN. [ 6 ]


Fetal anemia is monitored throughout pregnancy using  Doppler  measurement of the middle cerebral artery (MCA) peak systolic velocity (PSV). This non-invasive technique is used as a surrogate measurement for assessing fetal anemia. Doppler multiples of median (MoM) measurements exceeding 1.5 are correlated with moderate to severe anemia. At this point, invasive testing via  percutaneous umbilical cord blood sampling  (PUBS, also called cordocentesis), potentially followed by fetal transfusion is indicated. [ 6 ]


Prior to the procedure, compatible blood is obtained. This is usually type O, RhD-negative, and antigen-negative for maternal RBC antibodies. The selected blood then undergoes irradiation and leukocyte reduction. [ 6 ]  Antenatal corticosteroids are typically given to mothers before IUT to anticipate the need for an emergency cesarean section [ 5 ]


The procedure is usually performed in a hospital under sterile conditions, within or near an operating room in case an emergency cesarean section is necessary due to complications caused by the procedure. The mother's abdomen is cleaned with an antiseptic solution, and she may or may not be given a local anesthetic injection to numb the abdominal area where the transfusion needle will be inserted. During the procedure, medicine may be given to the fetus to temporarily stop fetal movement. [ 4 ]


An ultrasound is performed to view the position of the fetus and to help guide the needle. The first step is to locate a relatively stable segment of the umbilical cord. The procedure may be achieved with more ease if the placenta is in the anterior position. However, if the placenta is in the posterior position, the fetus might block direct access to the umbilical cord. Once a suitable location is established, the needle is inserted through the mother's abdomen into an umbilical vessel using ultrasound guidance. If insertion into an umbilical vessel is not possible, blood may be transfused into the fetal abdomen. [ citation needed ]


Prior to the transfusion, percutaneous umbilical cord blood sampling (PUBS) is conducted. The fetal blood sample is drawn and immediately analyzed for  hematocrit  using an automated analyzer in the operating room or hospital hematology laboratory. The result confirms the level of fetal anemia and indicates the correct amount of blood to be transfused.


With the needle still in place, the blood is delivered into the fetus's umbilical cord blood vessel. Following the transfusion, an additional blood sample is drawn and analyzed to determine the ending hematocrit level. The target hematocrit is usually at least 40. In a study of 135 IUTs performed on 56 fetuses, the mean hematocrit was 25.2 before IUT and 40.3 after IUT. This study also noted that repeated IUTs were generally needed in anemic fetuses. In this study, there was a median of two IUTs per fetus, with a range of one to seven. [ 5 ]


An IUT is typically only performed when the fetus is known or suspected to have life-threatening anemia. Risks of intrauterine transfusions may include uterine infection, fetal infection, preterm labor, excessive bleeding and mixing of fetal and maternal blood,  amniotic fluid  leakage from the uterus, or (rarely) fetal death. Fetal survival rates after intrauterine transfusion through the umbilical cord are more than 90% for fetuses that do not have hydrops and about 75% for fetuses that have hydrops. [ 4 ]


In a study of 135 IUTs performed on 56 fetuses over 14 years, 121 (90%) of the procedures were uneventful. In 14 cases, (10%), mild adverse events occurred. The most common mild events were prolonged hemorrhage from the puncture site and uterine contractions. In two cases, these led to a severe adverse event: one emergency  cesarean section  within 24 hours after IUT and one  preterm birth  within 7 days after IUT. There were no fetal or neonatal deaths in the study population. [ 5 ]


Risks associated with an IUT may be avoided by delivering the fetus (via  induction  or cesarean section) if an acceptable gestational age has been reached. Following delivery, the majority of neonates will require treatment such as phototherapy and top-up transfusion and/or exchange transfusion. [ 5 ]


The  Irish Blood Transfusion Service  ( IBTS ), or  Seirbhís Fuilaistriúcháin na hÉireann  in  Irish , was established in  Ireland  as the  Blood Transfusion Service Board  ( BTSB ) by the  Blood Transfusion Service Board (Establishment) Order, 1965 . [ 1 ]  It took its current name in April 2000 by  Statutory Instrument  issued by the  Minister for Health and Children  to whom it is responsible. The Service provides blood and blood products for humans.


The service is the successor to the  National Blood Transfusion Association  which was established in 1948 and was, itself, born from the work carried out by the  St. John Ambulance Brigade of Ireland  in setting up an 'on call' blood donor panel [ 2 ]  to serve hospitals in the  Dublin  area. In 1975 the  Cork  Blood Transfusion Service  was amalgamated with the board, and in 1991 the  Limerick  Blood Transfusion Service  was amalgamated with the board.


The symbol of the service is a stylised  pelican , recalling the legend of the  Pelican in her piety . For most of its existence, the headquarters of the service was located at Pelican House (first in  Lower Leeson Street  and then Mespil Road) in Dublin. In 2000 the service moved to the National Blood Centre on the grounds of  St. James's Hospital  near  Dublin Heuston railway station , on which it remains. The service maintains regional facilities at  Ardee ,  Carlow ,  Cork ,  Limerick  and  Tuam .


In 1994, the BTSB informed the Minister for Health that a batch of "Anti-D" blood product they had distributed in 1977 for the treatment of pregnant mothers had been contaminated with the Hepatitis C virus. Following a report by an expert group, it was discovered that the BTSB had produced and distributed a second infected batch in 1991. The Government established a  Tribunal of Enquiry [ 3 ]  to establish the facts of the case and also agreed to establish a tribunal for the compensation of victims.
The  Hepatitis C and HIV Compensation Tribunal  was established by the  Hepatitis C Compensation Tribunal Act, 1997 , and amended by the  Hepatitis C Compensation Tribunal (Amendment) Act, 2002 , to compensate people who contracted Hepatitis C or  HIV  as a result of receiving blood or blood products from the Service.


The  BTSB anti-D scandal  triggered a general examination of the BTSB's procedures for screening blood products for the treatment of Hemophilia and exposed the unwitting infection of many Hemophiliacs with HIV, Hepatitis B and Hepatitis C.  This resulted in the closure of the BTSB's main laboratory, curtailment in the production of some blood products, widespread changes to the management and structure of the organization and its eventual renaming in 2000.


The frequency of  blood groups  in Ireland is as follows: [ 4 ]


It is important that the IBTS collects enough O Rh D positive blood as almost half the population are that blood type. Donors with O Rh D negative are known as universal donors. Their blood can be transfused to patients of any other blood group in an emergency or if the patient's own blood group is unavailable. Because any patient can receive O Rh D negative blood, the IBTS need to have extra O Rh D negative blood available at all times.


The service depends entirely on voluntary donations from the public. New donors must be aged between 18 and 64, weigh over 50 kilograms (7 stone 12 lbs), and be in good health. At every donation  haemoglobin  levels are checked and donors complete a detailed health and lifestyle questionnaire. Donors can donate blood every 90 days.


The IBTS imposes a number of restrictions on those who can give blood. A four-month restriction is placed on donors who have had piercings or tattoos or had acupuncture, and a similar restriction on anyone who has visited a tropical country (three months). There is a year-long deferral for those who have visited a  malarial  area.
Additionally, there are groups of people who are permanently barred from donating blood based on their membership of high-risk groups. People who have ever been injected with any kind of non-prescription drug, and anyone who have ever been paid for sex with money or drugs are also permanently barred from donating blood.


Up to 28 November 2022,  men who have sex with men  (MSM) could not donate blood if they had engaged in oral or anal sex with another man at least 4 months prior to a donation. This policy came into effect from 28 March 2022 and came under heavy criticism from politicians, such as the Labour Party's Senator  Annie Hoey  and Sinn Féin Senator  Lynn Boylan , [ 5 ]  as well as the public [ 6 ]  due to a perceived lack of scientific basis for the policy and the lack of information on the reason for the rule. [ 7 ]  The IBTS has also been criticised for rolling back on the recommendation formally adopted by its Board in September 2021 to remove oral sex between men as a grounds for deferral from March 2022. [ 8 ]


From January 2017 to March 2022, MSM were required to abstain from all oral and anal sex for a 12-month period prior to donation. This position had replaced the previous lifetime deferral for any man who had ever engaged in oral or anal sex with another man.


From the end of November 2022, all prospective blood donors, regardless of sexual orientation or gender, may donate blood if they have not engaged in anal sex with a new partner, or multiple partners, in the 4 months prior to the donation. [ 9 ]


Donors are recognised for their commitment by being awarded as follows: A silver award is given for 10 donations; a gold award for 20 donations; a gold drop-shaped lapel pin (representing blood) for 50 donations; and presentation at an awards dinner ceremony, and a porcelain pelican, for 100 donations.


The Irish Blood Transfusion Service is also responsible for the collection of blood  platelets  and for managing the Unrelated Bone Marrow registry in Ireland. Donors can give platelets at the National Blood Centre in St James Hospital in Dublin or at  St Finbarr's Hospital  in Cork. Donors can join the unrelated bone marrow registry through their local blood clinic by offering an extra blood sample and satisfying suitability criteria.


ISBT 128  is a global standard for the identification, labeling, and information transfer of medical products of human origin (MPHO) across international borders and disparate health care systems. MPHO includes  blood ,  cells ,  tissues ,  human milk , and  organ  products among others. The Standard is managed by the  International Council for Commonality in Blood Banking Automation (ICCBBA) .


The  International Society of Blood Transfusion  (ISBT) working group on automation and data processing began in the early 1990s and was later joined by the  AABB , the  American Red Cross  (ARC), the US  Department of Defense , [ 1 ]  and the Health Industry Manufacturers Association in the development of the symbology which would come to be known as the ISBT 128 international standard.


The acronym ISBT was originally derived from the important role played by the  International Society of Blood Transfusion  (ISBT) in the development of the standard. [ citation needed ]   Today it expands as International Standard for Blood and Transplant. The number 128 reflects the 128 characters of the  ASCII  7 bit character set that the standard uses. [ citation needed ]


ICCBBA  was established in 1995 and given the responsibility for implementation and management of the new standard. [ 2 ]


Version 1.0 of the ISBT 128 Standard Technical Specification was first published in 1997, and was intended to replace the ABC  Codabar  and other similar CODABAR-based standards in use in  transfusion medicine  at that time with a more secure bar code symbology which contains more information. The current version of the ISBT 128 Standard Technical Specification can be found at the ISBT 128 website  [1] .


Information transfer involves text on labels, but it also involves information transfer among computer systems. Increasingly, facilities


involved in MPHO operate sophisticated computer systems to enhance safety and efficiency. Transfer of information between such facilities by electronic means ensures accuracy, but can only be effectively achieved in a global context by use of internationally agreed standards to define the information environment.


The ISBT 128 standard provides the specification for many of the elements of the information environment required in transfusion and transplantation. It contains definitions, reference tables, and data structures. Minimum requirements are also defined for delivery mechanisms and labeling. By complying with ISBT 128, collection and processing facilities can provide electronically readable information that can be read by any other compliant system. [ 3 ]


ISBT 128 specifies:


The delivery mechanism is the means of delivering the electronic information. Probably the most well-known delivery mechanism is the linear bar code that has been used in blood transfusion practice for many years. There are in fact several types of linear bar codes, including Code 128, a bar code standard widely used in coding standards such as  GS1  and ISBT 128.


Higher capacity delivery systems are available using  2-dimensional  or reduced space symbology bar codes. These codes can carry much more information in each symbol.  Data Matrix  has been chosen as the 2-D symbology used with ISBT 128 in labeling applications.


More recently the use of  Radio frequency identification  (RFID) chips that can carry encoded information is being developed for medical products of human origin.


It is important to recognize that a range of delivery systems can sit at this level of the hierarchy. The standardized terminology, reference tables, and data structures of the information standard can be delivered as easily in a linear bar code as they can in an RFID tag. The standards themselves need to be adaptable in order to make best use of new delivery mechanisms as they are developed.


The final element in the information environment is the associated  labeling . Although there will be other labeling requirements that fall outside the information environment described in this document, an effective system needs to consider the physical association between the information and the product. Whether incorporated into a  bar code  or an electronic tag, there needs to be a mechanism that will ensure correct physical assignment of information to the product, and confidence in the association between electronically stored information and eye-readable printed information. This latter requirement must not be overlooked in the enthusiasm to embrace remotely re-writable tags.


Following meetings between  FACT ,  JACIE , and  ICCBBA , an agreement was reached to support the use of ISBT 128 for coding and labeling cellular therapy products, and this decision has been  endorsed  by the Boards of major cellular therapy professional organizations.


Jehovah's Witnesses  believe that the  Bible  prohibits Christians from accepting  blood transfusions . Their literature states that, "'abstaining from ... blood' means not accepting blood transfusions and not donating or storing their own blood for transfusion." [ 1 ] [ 2 ]  The belief is based on an interpretation of scripture that differs from other Christian denominations. [ 3 ]  It is one of the doctrines for which Jehovah's Witnesses are best known. [ 4 ]


Jehovah's Witnesses' literature teaches that their refusal of transfusions of whole blood or its four primary components—red cells, white cells, platelets, and plasma—is a non-negotiable religious stand and that those who respect life as a gift from  God  do not try to sustain life by taking in blood, [ 5 ] [ 6 ]  even in an emergency. [ 7 ]  Witnesses are taught that the use of fractions such as  albumin ,  immunoglobulins , and  hemophiliac  preparations are not absolutely prohibited and are instead a matter of personal choice. [ 6 ] [ 8 ]


The doctrine was introduced in 1945 and has undergone some changes since then. Members of the group who voluntarily accept a transfusion and are not deemed repentant are regarded as having disassociated themselves from the group by abandoning its doctrines [ 9 ] [ 10 ] [ 11 ]  and are subsequently  shunned  by members of the organization. [ 12 ]  Although the majority of Jehovah's Witnesses accept the doctrine, a minority do not. [ 13 ] [ 14 ]


The Watch Tower Society has established Hospital Information Services to provide education and facilitate  bloodless surgery . This service also maintains Hospital Liaison Committees. [ 15 ]


On the basis of various biblical texts, including  Genesis 9:4 ,  Leviticus 17:10 , and  Acts 15:28–15:29 , Jehovah's Witnesses believe:


Certain medical procedures involving blood are specifically prohibited by Jehovah's Witnesses' blood doctrine. This includes the use of  red blood cells ,  white blood cells ,  platelets , and  blood plasma . Other fractions derived from blood are not prohibited.  Watch Tower  publications state that some products derived from one of the four primary components may be so similar to the function of the whole component and carry on such a life-sustaining role in the body that "most Christians would find them objectionable". [ 6 ]  For procedures where there is no specific doctrinal prohibition, individuals are to obtain details from medical personnel and then make a personal decision. [ 21 ]


The following medical procedures are prohibited:


The following procedures and products are not prohibited and are left to the decision of individual members: [ 23 ]


Many physicians have expressed a willingness to respect patients' preferences and provide bloodless treatment [ 27 ] [ need quotation to verify ]  and about 200 hospitals offer bloodless medicine and surgery programs for patients who wish to avoid or limit blood transfusions. [ 27 ]  Bloodless surgery has been successfully performed in significant procedures including  open-heart surgery  and total  hip replacements . [ 28 ]  A 2012 study in  JAMA Internal Medicine  concluded that "Witnesses do not appear to be at increased risk for surgical complications or long-term mortality when comparisons are properly made by transfusion status. Thus, current extreme blood management strategies do not appear to place patients at heightened risk for reduced long-term survival." The study also stated that "Survival estimates of Witnesses were 86%, 69%, 51%, and 34% at 5, 10, 15, and 20 years after surgery, respectively, vs 74%, 53%, 35%, and 23% among non-Witnesses who received transfusions." [ 29 ]


Bloodless medical and surgical techniques have limitations, and surgeons say the use of various allogeneic blood products and pre-operative autologous blood transfusion are appropriate standards of care for certain patient presentations. [ 30 ] [ 31 ]  The Watch Tower Society states that in  medical emergencies  where blood transfusions seem to be the only available way to save a life, Jehovah's Witnesses request that doctors provide the best alternative care possible under the circumstances with respect for their personal conviction. [ 32 ]  The Watch Tower Society has acknowledged that some members have died after refusing blood. [ 33 ]


In some countries, including Canada and the United Kingdom, a parent or guardian's decision can be legally overruled by medical staff. In this case, medical staff may act without consent, by obtaining a  court order  in a non-emergency situation, or without such in an emergency. [ 34 ] [ 35 ]  In Japan, children under 15 can be administered blood transfusions against their and their parents' wishes, and children between the ages of 15 and 18 can be similarly treated provided they, or at least one of their legal guardians, consent to the procedure. [ 36 ]  In the  United States , the  American Academy of Pediatrics  recommends that in cases of "an imminent threat to a child's life", physicians in some cases may "intervene over parental objections". [ 37 ]


In 1988, the Watch Tower Society formed  Hospital Information Services , a department to help locate doctors or surgical teams who are willing to perform medical procedures on Witnesses without blood transfusions. [ 38 ]  The department was given oversight of each branch office's  Hospital Information Desk , [ 39 ] [ 40 ] [ 41 ]  and of one hundred  Hospital Liaison Committees  established throughout the United States. [ 32 ] [ 42 ]  As of 2003, about 200 hospitals worldwide provide bloodless medical programs. [ 27 ]  As of 2006, there are 1,535 Hospital Liaison Committees worldwide coordinating communication between 110,000 physicians. [ 42 ] [ 43 ]


Hospital Information Services researches medical journals to locate information on the availability and effectiveness of bloodless surgery methods. [ 32 ]  It disseminates information about treatment options to local Hospital Liaison Committees, and to doctors and hospitals. [ 43 ]


Annually since 2004, Jehovah's Witnesses in the United States have been informed that "with your consent, the law allows for the  elders  to learn of your admission [to hospital] and provide spiritual encouragement", [ 44 ]  but that "elders serving on a Patient Visitation Group [could] have access to your name" only if patients made their wishes known according to the  Health Insurance Portability and Accountability Act  (HIPAA). [ 45 ]


Jehovah's Witnesses' branch offices communicate directly with congregations regarding "ways to benefit from the activities of the Hospital Liaison Committee (HLC) and the Patient Visitation Group (PVG)." [ 46 ]  A Jehovah's Witnesses publication in 2000 reported that Argentina had fewer than a hundred HLC committeemen "giving vital information to the medical community", adding that "their work is complemented by hundreds of other self-sacrificing elders who make up Patient Visitation Groups that call on Witness patients to help and encourage them". [ 47 ]  Each branch office appoints PVG committeemen, who serve as volunteers. [ 48 ] [ 49 ]


Since the elaboration of the blood doctrine to the point of prohibiting transfusion, the majority of Jehovah's Witnesses have adopted the organization's position. [ 50 ] [ 51 ]  Those Jehovah's Witnesses who accept the blood doctrine typically hold strongly to their convictions. [ 52 ]  In the August 1998 issue of  Academic Emergency Medicine , Donald Ridley, a Jehovah's Witness and organization staff attorney, argued that carrying an up-to-date Medical Directive card issued by the organization indicates that an individual personally agrees with the established religious position of Jehovah's Witness. [ 53 ]


In 1958,  The Watchtower  reported on a particular member of Jehovah's Witnesses who voluntarily accepted blood transfusion, contrary to Watch Tower Society doctrine. [ 54 ]  The organization confirms that members have accepted blood transfusions, despite the imposition in 1961 of a communal shunning policy for willful acceptance. [ 55 ] [ 56 ]


In 1982, a peer-reviewed case study of a congregation of 59 Jehovah's Witnesses was undertaken by Drs. Larry J. Findley and Paul M. Redstone to evaluate individual belief in respect to blood among Jehovah's Witnesses. The researchers stated, "The members of this congregation are adamant in their refusal to accept all blood products... Not one of the members stated they would receive a blood transfusion even if their refusal meant death, Almost one-third of the respondents had personally refused blood transfusions". However, the study also showed that seven respondents were willing to accept plasma transplants and one member an autotransfusion, both therapies forbidden by Jehovah's Witnesses' doctrine. The researchers commented, "There is either some lack of understanding or refusal to follow doctrine among some members". The researchers noted that the contact details of the respondents were provided by congregation elders, which may have influenced the responses given. [ 57 ]  Another peer-reviewed study examining medical records indicated a similar percentage of Jehovah's Witnesses willing to accept blood transfusions for their children. Young adults also showed a willingness to accept blood transfusions. [ 50 ]  In another study, Jehovah's Witness patients presented for labor and delivery showed a willingness to accept some form of blood or blood products. Of these patients, 10 percent accepted whole blood transfusion. [ 51 ]


Watch Tower publications have noted that within religions, the personal beliefs of members often differ from official doctrine. [ 58 ]  Regarding Jehovah's Witnesses' acceptance of the organization's official position on blood, Drs Cynthia Gyamfi and Richard Berkowitz state, "It is naïve to assume that all people in any religious group share the exact same beliefs, regardless of doctrine. It is well known that Muslims, Jews, and Christians have significant individual variations in their beliefs. Why should that not also be true of Jehovah's Witnesses?" [ 59 ]


Ambivalence and rejection of the blood doctrine dates back to at least the 1940s. After the Watch Tower Society established the doctrine, teaching that blood should not be eaten ( c.  1927 –1931), Margaret Buber, who was never a member of the denomination, offered a firsthand eyewitness account of Jehovah's Witnesses in the  Nazi   Ravensbrück concentration camp . She relates that an overwhelming majority were willing to eat  blood sausage  despite having alternate food to choose from, specifically after considering biblical statements regarding blood. [ 60 ]


From 1931, [ 61 ]  when the name "Jehovah's witnesses" was adopted, Watch Tower Society publications maintained the view of Society founder  Charles Taze Russell  that the reference to abstaining from the eating of blood in the  Apostolic Decree  of Acts 15:19–29 was a "suggestion" to be given to  Gentile  converts. [ 62 ] [ 63 ]  Watch Tower publications during the presidency of  Joseph Franklin Rutherford  commended the commercial and emergency uses of blood. [ 64 ] [ 65 ]  A 1925 issue of  The Golden Age  commended a man for donating blood 45 times without payment. [ 66 ]  In 1927,  The Watchtower  noted, without elaboration, that in Genesis 9, God decreed that  Noah  and his offspring "must not eat the blood, because the life is in the blood". [ 67 ]  In 1940,  Consolation  magazine reported on a woman who accidentally shot herself with a revolver in her heart and survived a major surgical procedure during which an attending physician donated a quart of his own blood for transfusion. [ 68 ]


In 1944, with the Watch Tower Society under the administration of president  Nathan Homer Knorr ,  The Watchtower  asserted that the decrees contained in Genesis 9:4 and Leviticus 17:10–14 forbade the eating or drinking of blood in biblical times "whether by transfusion or by the mouth" and that this applied "in a spiritual way to the consecrated persons of good-will today, otherwise known as ' Jonadabs ' of the Lord's 'other sheep'." [ 69 ]


In September 1945, representatives of the Watch Tower Society in the  Netherlands  commented on blood transfusion in the  Dutch  edition of  Consolation . A translation of their comments into English reads:


When we lose our life because we refuse inoculations, that does not bear witness as a justification of Jehovah's name. God never issued regulations which prohibit the use of drugs, inoculations or blood transfusions. It is an invention of people, who, like the Pharisees, leave Jehovah's mercy and love aside. [ 70 ]


According to sociologist Richard Singelenbreg, the statement appearing in the Dutch edition of  Consolation  may have been published without knowledge of the doctrinal position published in the English July 1945 issue of  Consolation  by the Watch Tower Society's headquarters in the United States. [ 71 ]


In 1945, the application of the doctrine on blood was expanded to prohibit blood transfusions of whole blood, whether allogeneic or autologous. [ 72 ]  The prohibition did not specify any punitive measures for accepting a transfusion, but by January 1961—in what was later described as an application of "increased strictness" [ 73 ] —it was ruled that it was a disfellowshipping offense to conscientiously accept a blood transfusion. [ 55 ]  The Watch Tower Society warned that accepting a blood transfusion "may result in the immediate and very temporary prolongation of life, but that at the cost of eternal life for a dedicated Christian." [ 74 ]


In September 1956,  Awake!  stated, "certain blood fractions ... also come under the Scriptural ban". [ 75 ]  A position against "the various blood fractions" was reiterated in September 1961. [ 76 ]  In November of the same year, the doctrine was modified to allow individual members to decide whether they could conscientiously accept fractions used from blood for purposes such as vaccination. [ 77 ]  This position has been expanded on since; the pre-formatted Durable Power of Attorney form provided by the Watch Tower Society includes an option for Jehovah's Witnesses to "accept all fractions derived from any primary component of blood." [ 78 ]


In 1964, Jehovah's Witnesses were prohibited from obtaining transfusions for  pets , from using fertilizer containing blood, and were even advised (if their conscience troubled them) to write to dog food manufacturers to verify that their products were blood-free. [ 79 ]  Later that year, it was stated that doctors or nurses who are Jehovah's Witnesses would not administer blood transfusions to fellow dedicated members. As to administering transfusions to non-members,  The Watchtower  stated that such a decision is "left to the Christian doctor's own conscience." [ 80 ]


In 1982, an article in  The Watchtower  stated that it would be wrong for Witnesses to allow leeches to feed on their own blood as part of a medical procedure, due to the sacredness of blood. [ 81 ]


In 1989,  The Watchtower  stated, "Each individual must decide" whether to accept hemodilution and autologous blood salvage (cell saver) procedures. [ 21 ]  In 1990, a brochure entitled  How Can Blood Save Your Life?  was released, outlining Jehovah's Witnesses' general doctrine on blood.


In 2000, the Watch Tower Society's stand on blood fractions was clearly stated. [ 22 ]  Members were instructed to personally decide if accepting a fraction would violate the doctrine on blood. In a later article, members were reminded that Jehovah's Witnesses do not donate blood or store their own blood prior to surgery. [ 20 ]


In May 2001, the Watch Tower Society revised its medical directives and identity cards addressing its doctrinal position on blood; the revised materials were distributed from May 3, 2001. [ 82 ]  These revised documents specified that "allogeneic blood transfusions" were unacceptable whereas the former document (dated 1999) stated that "blood transfusions" were unacceptable. The revised 2001 documents were active until December 20, 2001. The Watch Tower Society then rescinded the revised document, stating, "After further review, it has been determined that the cards dated "md-E 6/01" and "ic-E 6/01" should not be used. Please destroy these items and make sure that they are not distributed to the publishers." Elders were instructed to revert to the older 1999 edition of the medical directives and identity cards. [ 83 ]


Watch Tower Society publications frequently claim negative consequences of blood transfusions:


Opposition to the Watch Tower doctrines on blood transfusions has come from both members and non-members. A group of dissident Witnesses known as  Associated Jehovah's Witnesses for Reform on Blood  (AJWRB) states that there is no biblical basis for the prohibition of blood transfusions and seeks to have some policies changed. [ 13 ]  In a series of articles in the  Journal of Medical Ethics , US neurologist Osamu Muramoto, who is a medical adviser to the AJWRB, has raised issues including what he claims is coercion to refuse transfusions, doctrinal inconsistency, selective use of information by the Watch Tower Society to exaggerate the dangers of transfusions and the use of outdated medical beliefs. [ 89 ] [ 90 ] [ 9 ]


Dissident Witnesses say the Society's use of Leviticus 17:12 to support its opposition to blood transfusions [ 91 ] [ 92 ]  conflicts with its own teachings that Christians are not under the Mosaic law. [ 93 ] [ 89 ]  Theologian  Anthony Hoekema  claims the blood prohibited in Levitical laws was not human, but animal. He cites other authors who support his view that the direction in Acts 15 to abstain from blood was intended not as an everlasting covenant but a means of maintaining a peaceful relationship between Jewish and Gentile Christians. [ 94 ] [ 95 ]  He has described as "absurd literalism" the Witnesses' use of a scriptural prohibition on eating blood to prohibit the medical transfusion of human blood. [ 96 ]


Osamu Muramoto has argued that the refusal by Jehovah's Witnesses of "life-saving" blood treatment [ 9 ]  creates serious bio-medical ethical issues. He has criticized the "controlling intervention" of the Watch Tower Society by means of what he claims is information control and its policy of penalising members who accept blood transfusions or advocate freedom to choose blood-based treatment. [ 89 ] [ 9 ]  He says the threat of being classified as a disassociated Witness and subsequently shunned by friends and relatives who are members coerces Jehovah's Witnesses to accept and obey the prohibition on blood transfusions. [ 10 ] [ 89 ] [ 90 ]  In one particular case involving a Russian district court decision, however, the  European Court of Human Rights  (ECHR) found nothing in the judgments to suggest that any form of improper pressure or undue influence was applied. It noted: "On the contrary, it appears that many Jehovah's Witnesses have made a deliberate choice to refuse blood transfusions in advance, free from time constraints of an emergency situation." The court said: "The freedom to accept or refuse specific medical treatment, or to select an alternative form of treatment, is vital to the principles of self-determination and personal autonomy. A competent adult patient is free to decide ... not to have a blood transfusion. However, for this freedom to be meaningful, patients must have the right to make choices that accord with their own views and values, regardless of how irrational, unwise or imprudent such choices may appear to others." [ 97 ]


Muramoto has claimed the intervention of Hospital Liaison Committees can add to "organisational pressure" applied by family members, friends, and congregation members on Witness patients to refuse blood-based treatment. He notes that while HLC members, who are church elders, "may give the patient 'moral support', the influence of their presence on the patient is known to be tremendous. Case reports reveal JW patients have changed their earlier decision to accept blood treatment after a visit from the elders." He claims such organizational pressure compromises the autonomy of Witness patients and interferes with their privacy and confidentiality. He has advocated a policy in which the Watch Tower organization and congregation elders would not question patients on the details of their medical care and patients would not disclose such information. He says the Society adopted such a policy in 1983 regarding details of sexual activity between married couples. [ 9 ] [ 98 ] [ 99 ]


Watch Tower spokesman Donald T. Ridley says neither elders nor HLC members are instructed or encouraged to probe into the health care decisions of Witness patients and do not involve themselves in patient hospitalisations unless patients request their assistance. Yet Watch Tower Society HLC representative David Malyon says he would respond to the "sin" of Witnesses he is privy to by effectively saying "Are you going to tell them or shall I!" [ 100 ]  Nevertheless Ridley says Muramoto's suggestion that Witnesses should be free to disregard Watch Tower scriptural teachings and standards is preposterous. He says loving God means obeying commandments, not disobeying them, and hiding one's disobedience from others. [ 99 ] [ 101 ]


Muramoto recommends doctors have a private meeting with patients to discuss their wishes, and that church elders and family members not be present, enabling patients to feel free of church pressure. He suggests doctors question patients on (a) whether they have considered that the Watch Tower Society might soon approve some medical practices they currently find objectionable, in the same manner that it has previously abandoned its opposition to vaccination and organ transplants; (b) whether Witness patients know which blood components are allowed and which are prohibited, and whether they acknowledge that those rulings are organizational policy rather than biblical teachings; and (c) whether they realize that although some Bible scriptures proscribe the eating of blood, eating and transfusing blood have entirely different effects on the body. [ 90 ]  HLC representative David Malyon has responded that Muramoto's suggested questions are an affront to coerce Jehovah's Witnesses with a "complicated philosophical inquisition" and, if used by doctors, would be "an abusive transformation of the medical role of succour and care into that of devil's advocate and trickster". [ 100 ]


Muramoto has claimed many Watch Tower Society publications employ exaggeration and emotionalism to emphasize the dangers of transfusions and the advantages of alternative treatments but present a distorted picture by failing to report any benefits of blood-based treatment. Nor do its publications acknowledge that in some situations, including rapid and massive  haemorrhage , there are no alternatives to blood transfusions. [ 89 ] [ 90 ]  He states that Watch Tower Society publications often discuss the risk of death as a result of refusing blood transfusions, but give little consideration to the prolonged suffering and disability, producing an added burden on family and society, that can result from refusal. [ 90 ]  Attorney and former Witness Kerry Louderback-Wood [ 102 ]  also claims that Witness publications exaggerate the medical risks of taking blood and the efficiency of non-blood medical therapies in critical situations. [ 103 ]


Douglas E. Cowan , an academic in the sociology of religion, has claimed that members of the  Christian countercult movement  who criticize the Watch Tower Society make selective use of information themselves. For example,  Christian apologist  Richard Abanes wrote that their ban on blood transfusions "has led to countless Witness deaths over the years, including many children." [ 104 ]  Cowan wrote: "When the careful reader checks [Abanes' footnote], however, looking perhaps for some statistical substantiation, he or she finds only a statistical conjecture based on 1980 Red Cross blood use figures." Cowan also says Abanes omits "critical issues" in an attempt to "present the most negative face possible." Cowan wrote that "the reader is left with the impression that the Watchtower Society knowingly presides over a substantial number of preventable deaths each year." [ 105 ]


Osamu Muramoto says the Watch Tower Society relies on discarded, centuries-old medical beliefs to support its assertion that blood transfusions are the same as eating blood. [ 106 ]  The Watch Tower Society's 1990 brochure  How Can Blood Save Your Life?  quoted 17th-century anatomist  Thomas Bartholin  to support its view. [ 107 ]  Muramoto says the view that blood is nourishment—still espoused in Watch Tower publications [ 108 ] —was abandoned by modern medicine many decades ago. [ 89 ]  He has criticized an analogy commonly used by the Society [ 109 ]  in which it states: "Consider a man who is told by the doctor that he must abstain from alcohol. Would he be obedient if he quit drinking alcohol but had it put directly into his veins?" [ 106 ]  Muramoto says the analogy is false, explaining: "Orally ingested alcohol is absorbed as alcohol and circulated as such in the blood, whereas orally eaten blood is digested and does not enter the circulation as blood. Blood introduced directly into the veins circulates and functions as blood, not as nutrition. Hence, blood transfusion is a form of cellular organ transplantation. And ... organ transplants are now permitted by the WTS." [ 89 ]  He says the objection to blood transfusions on the basis of biblical proscriptions against eating blood is similar to the refusal of a heart transplant on the basis that a doctor warned a patient to abstain from eating meat because of his high cholesterol level. [ 90 ]


David Malyon, chairman of the English Hospital Liaison Committee in  Luton ,  England , has claimed that Muramoto's discussion of the differences between consuming blood and alcohol is pedantic and says blood laws in the Bible are based upon the reverence for life and its association with blood, and that laws should be kept in the spirit as much as in the letter. [ 100 ]


Muramoto has described as peculiar and inconsistent the Watch Tower policy of acceptance of all the individual components of blood plasma as long as they are not taken at the same time. [ 89 ]  He says the Society offers no biblical explanation for differentiating between prohibited treatments and those considered a "matter of conscience", explaining the distinction is based entirely on arbitrary decisions of the  Governing Body , to which Witnesses must adhere strictly on the premise of them being Bible-based truth. [ 89 ]  He has questioned why white blood cells (1 per cent of blood volume) and platelets (0.17 per cent) are forbidden, yet albumin (2.2 per cent of blood volume) is permitted. [ 89 ]  He has questioned why donating blood and storing blood for autologous transfusion is deemed wrong, but the Watch Tower Society permits the use of blood components that must be donated and stored before Witnesses use them. [ 90 ]  He has questioned why Witnesses, although viewing blood as sacred and symbolizing life, are prepared to let a person die by placing more importance on the symbol than the reality it symbolizes. [ 90 ]


Kerry Louderback-Wood says that by labeling the currently acceptable blood fractions as "minute" in relation to whole blood, the Watch Tower Society causes followers to misunderstand the scope and extent of allowed fractions. [ 103 ]


The Watch Tower Society's response is that the real issue is not of the fluid  per se , but of respect and obedience to God. [ 77 ] [ 110 ]  They say their principle of abstaining from blood as a display of respect is demonstrated by the fact that members are allowed to eat  meat  that still contains some blood. As soon as blood is drained from an animal, the  respect  has been shown to God, and then a person can eat the meat even though it may contain a small amount of blood. [ 77 ]  Jehovah's Witnesses' view of meat and blood is different from that of kosher Jewish adherents, who go to great lengths to remove minor traces of blood. [ 111 ] [ 112 ]


The  Junior blood group system  (or  JR ) is a human  blood group  defined by the presence or absence of the  Jr(a) antigen , a high-frequency antigen that is found on the red blood cells of most individuals. [ 1 ]  People with the rare Jr(a) negative blood type can develop  anti-Jr(a)  antibodies, which may cause  transfusion reactions  and  hemolytic disease of the newborn  on subsequent exposures. Jr(a) negative blood is most common in people of Japanese heritage. [ 2 ]


The gene  ABCG2 , located on chromosome 4q22.1, encodes an  ATP-binding cassette transporter  protein that carries the Jr(a) antigen. The Jr(a) negative blood type is inherited in an  autosomal recessive  manner: individuals who are  homozygous  for a  null mutation  of  ABCG2  express this phenotype. [ 1 ]  Homozygosity for certain  missense mutations , or heterozygosity for a missense mutation and a null mutation, can result in a weak phenotype with decreased expression of Jr(a) antigen. [ 2 ] [ 3 ]  As of 2018, over 25 null and weak alleles of  ABCG2  have been described. [ 4 ]


The highest rates of the Jr(a) negative blood type have been reported in Japan, [ 5 ]  where its prevalence ranges from 1 in 60 in the  Niigata  region to 1 in 3800 in the  Tokyo  region. [ 1 ]  Additionally, a number of cases have been documented in European  Romani  populations. [ 6 ]  The Jr(a) negative blood type is very rare in America: a study of 9,545 Americans failed to identify any Jr(a) negative individuals. [ 5 ]


Anti-Jr(a) antibodies are generally composed of  Immunoglobulin G  and develop when individuals are exposed to Jr(a) positive blood through pregnancy or  blood transfusion . Some cases of anti-Jr(a) have been reported in patients who have not been previously transfused or pregnant. [ 2 ] [ 5 ]


Jr(a) is more strongly expressed on  cord blood  cells than on adult red blood cells, [ 4 ]  and anti-Jr(a) has been reported to cause  hemolytic disease of the newborn  (HDN), [ 2 ]  including fatal cases of HDN. [ 5 ] [ 7 ]   The antibody has also been implicated in  delayed hemolytic transfusion reactions . [ 2 ]  However, the clinical significance of the antibody is variable: in some cases, individuals with anti-Jr(a) have been transfused with Jr(a) positive blood or given birth to Jr(a) positive babies without incident. It is recommended to transfuse individuals with anti-Jr(a) with Jr(a) negative blood if the  antibody titer  is high. In other cases, "least incompatible" blood (the blood unit that gives the weakest reactions during  crossmatching ) may be suitable. [ 5 ] [ 4 ]  It is difficult to secure Jr(a) negative donor blood due to the rarity of this blood type. [ 6 ]


ABCG2 is a  uric acid  transporter, and the Jr(a) negative phenotype is associated with  gout  in Japanese populations. [ 8 ]


An individual's Junior blood type can be determined by  serologic testing , which uses a  monoclonal antibody  reagent directed against the Jr(a) antigen. [ 6 ]   DNA testing  may be impractical due to the high number of mutations affecting Jr(a) expression. [ 9 ]


Anti-Jr(a) antibodies are most easily detected by the  indirect antiglobulin test , and their reactivity is enhanced by enzyme treatment with  ficin  or  papain . [ 2 ]


The Junior blood group system was discovered in 1970 by researchers Stroup and MacIllroy, who reported on five patients whose blood was incompatible with all samples tested except each other's. They named the causative antigen "JR" after Rose Jacobs, one of the five patients — the common name "Junior" is in fact a misnomer. [ 2 ]


In 2012, two research groups [ 6 ] [ 10 ]  independently identified ABCG2 as the basis of the Junior blood group system. The Junior system was officially designated a blood group by the  International Society of Blood Transfusion  that year. [ 11 ]


The  Kell antigen system  (also known as the  Kell–Cellano system ) is a  human blood group system , that is, a group of  antigens  on the human red blood cell surface which are important determinants of  blood type  and are targets for  autoimmune  or  alloimmune  diseases which destroy red blood cells. The Kell antigens are  K ,  k ,  Kp a ,  Kp b ,  Js a  and  Js b . [ 1 ]  The Kell antigens are  peptides  found within the  Kell protein , a 93- kilodalton   transmembrane   zinc -dependent  endopeptidase  which is responsible for cleaving  endothelin-3 . [ 2 ] [ 3 ]


The  KEL  gene encodes a type II transmembrane  glycoprotein [ 4 ]  that is the highly  polymorphic  Kell blood group antigen. The Kell glycoprotein links via a single  disulfide bond  to the  XK membrane protein [ 5 ]  that carries the  Kx antigen . The encoded protein contains sequence and structural similarity to members of the  neprilysin  (M13) family of  zinc   endopeptidases . [ 6 ]


There are several  alleles  of the  gene  which creates Kell protein. Two such alleles,  K 1  (Kell) and  K 2  (Cellano), are the most common. The kell protein is tightly bound to a second protein,  XK , by a  disulfide bond . Absence of the XK protein (such as through  genetic deletion  or through a single point mutation within the coding region of the XK gene [ 7 ] ), leads to marked reduction of the Kell antigens on the red blood cell surface. Absence of the Kell protein (K 0 ), however, does not affect the XK protein. [ 8 ]


The Kell protein has also recently been designated  CD238  ( cluster of differentiation  238).


Kell antigens are important in  transfusion medicine ,  autoimmune hemolytic anemia  and  hemolytic disease of the newborn (anti-Kell) . Anti-K is the next most common immune red cell antibody after those in the ABO and Rh system. Anti-K typically presents as IgG class alloantibody. Individuals lacking a specific Kell antigen may develop  antibodies  against Kell antigens when transfused with blood containing that antigen. This is particularly true for the "K" antigen which shows a relatively high antigenicity and moderately low frequency (~9%) in Caucasian populations. Anti-K can also occur following transplacental hemorrhage associated with childbirth making Kell an important concern for  hemolytic disease of the newborn . Following the formation of anti-K, subsequent blood transfusions may be marked by destruction of the new cells by these antibodies, a process known as  hemolysis . Anti-K does not bind complement, therefore hemolysis is extravascular. Individuals without K antigens(K 0 ) who have formed an antibody to a K antigen, must be transfused with blood from donors who are also K 0  to prevent hemolysis. [ citation needed ] [ 9 ]


Autoimmune hemolytic anemia  (AIHA) occurs when the body produces an antibody against a blood group antigen on its own red blood cells. The antibodies lead to destruction of the red blood cells with resulting  anemia . Similarly, a pregnant woman may develop antibodies against fetal red blood cells, resulting in destruction, anemia, and  hydrops fetalis  in a process known as  hemolytic disease of the newborn  (HDN). Both AIHA and HDN may be severe when caused by anti-Kell antibodies, [ 10 ]  as they are the most immunogenic antigens after those of the  ABO  and  Rhesus blood group systems . [ citation needed ]


McLeod phenotype (or McLeod syndrome) is an  X-linked  anomaly of the Kell blood group system in which Kell antigens are poorly detected by laboratory tests. The McLeod gene encodes the XK protein, a protein with structural characteristics of a membrane transport protein but of unknown function. The XK appears to be required for proper synthesis or presentation of the Kell antigens on the red blood cell surface. [ citation needed ]


The Kell group was named after the first patient described with antibodies to K 1 , a pregnant woman named Mrs. Kellacher in 1945. [ 11 ]  Mrs. Cellano was likewise a pregnant woman with the first described antibodies to K 2 . The K 0   phenotype  was first described in 1957 and the McLeod phenotype was found in Hugh McLeod, a  Harvard  dental student, in 1961. [ 12 ] [ 13 ]
King  Henry VIII of England  may have had Kell-positive blood type, explaining the deaths of seven of his ten children at, or soon after, birth, and suggesting that his mental deterioration around age 40 could be explained by McLeod Syndrome; [ 14 ]  this was supported by the revelation that Henry may have inherited Kell from his maternal great-grandmother,  Jacquetta of Luxembourg . [ 15 ]


Evidence supports a genetic link between the Kell blood group (on  chromosome 7  q33) and the ability to taste  phenylthiocarbamide , or PTC, a bitter-tasting  thiourea  compound. [ 16 ] [ 17 ]  Bitter taste receptor proteins in the taste buds of the tongue that recognise PTC are encoded on nearby chromosome  locus  7 q35-6. [ citation needed ]


The  Kidd antigen system  (also known as  Jk antigen ) are proteins found in the Kidd's blood group, which act as antigens, i.e., they have the ability to produce antibodies under certain circumstances. The Jk  antigen  is found on a  protein  responsible for  urea  transport in the red blood cells and the kidney. [ 1 ]  They are important in  transfusion medicine . People with two Jk(a) antigens, for instance, may form  antibodies  against donated blood containing two Jk(b) antigens (and thus no Jk(a) antigens). This can lead to  hemolytic anemia , in which the body destroys the transfused blood, leading to low red blood cell counts. Another disease associated with the Jk antigen is  hemolytic disease of the newborn , in which a pregnant woman's body creates antibodies against the blood of her fetus, leading to destruction of the fetal blood cells. Hemolytic disease of the newborn associated with Jk antibodies is typically mild, though fatal cases have been reported. [ 2 ]


The  gene  encoding this protein is found on  chromosome 18 . [ 3 ]  Three Jk  alleles  are Jk (a), Jk (b)and Jk3. Jk (a) was discovered by Allen et al. in 1951 and is named after a patient (Mrs Kidd delivered a baby with a haemolytic disease of the newborn associated with an antibody directed against a new antigen Jk (a). Whereas Jk (b) was discovered by Plant et al. in 1953, individuals who lack the Jk antigen (Jk null) are unable to maximally concentrate their urine. [ 4 ]


Kidd comprises three antigens on a  glycoprotein  with 10  transmembrane  spanning  domains ,  cytoplasmic   N-  and  C-termini  and one extracellular  N-glycosylation  site. [ 5 ]
The Kidd gene has 11  exons  with exons 4-11 encoding the mature protein. The Kidd gene ( SLC14A1 ) is on chromosome 18q12.3. [ citation needed ]


Jka and Jkb are the products of alleles with Asp280 and Asn280 in the fourth external loop of the Kidd glycoprotein. Jka and Jkb have similar prevalences in White and Asian populations but Jka is more common in Black populations than Jkb. [ 5 ]


Kidd antigens are enhanced by enzymes [ citation needed ]


Jk(a-b-) represents the null phenotype and usually results from homozygosity for a silent gene at the JK locus. [ 5 ]  The null phenotype is rare in most populations but does have increased prevalence in Polynesians (one in 400) and Niueans (1.4%). [ 5 ]


In Polynesians the null allele contains a splice site mutation in intron 5 causing a loss of exon 6 from the mRNA product. [ citation needed ]


In Finns (null phenotype less rare than in other European populations), the null phenotype results from a mutation encoding a Ser291Pro substitution. [ citation needed ]


A rare null phenotype in Japanese individuals results from heterozygosity for an inhibitor gene. In(Jk) in analogy with the In(Lu) dominant inhibitor of Lutheran and other antigens. [ 5 ]


Immunized individuals with the Jk(a-b-) phenotype may produce anti-Jk3. [ citation needed ]


Very weak expression of Jka and/or Jkb can be detected on In(Jk) red blood cells in adsorption/elution tests. [ 5 ]


Anti-Jka and -Jkb are not common. They are usually warm-reacting IgG1 and IgG3 but may also include IgG2, IgG4 or IgM. Approximately 50% of anti-Jka and -Jkb antibodies are capable of binding complement. [ 6 ]


Kidd antibodies display dosage: red cells from  homozygous  individuals (JkaJka or Jk(a+b-)) express more antigen than  heterozygous  individuals (JkaJkb or Jk(a+b+)). [ 7 ]  Anti-Kidd antibodies appear to react more strongly against cells that are homozygous. [ citation needed ]


Kidd antibodies can be difficult to detect by direct agglutination testing and generally require addition of antihuman globulin after a warm incubation period. [ citation needed ]


Kidd antibodies are dangerous as they are capable of causing severe acute  hemolytic transfusion reactions . They are unique in that they are capable of dropping to low or even undetectable levels after several months following an exposure. [ 5 ]  Thus, on pre-transfusion testing, an anti-Jka or -Jkb may go undetected. Following transfusion, a subsequent robust antibody response in the patient can occur ( anamnestic response ), resulting in hemolysis of the transfused red blood cells. Kidd antibodies are often capable of binding complement and causing intravascular hemolysis.  More often, however, Kidd antibodies cause acute extravascular hemolysis. [ 7 ]  They are a notorious cause of delayed hemolytic transfusion reactions, and may occur up to a week after transfusion in some instances. Kidd antibodies only rarely cause  hemolytic disease of the fetus and newborn . [ 5 ]


Kidd antigens are located on a red blood cell urea transporter (human urea transporter 11- HUT11 or UT-B1). [ 8 ]  As red blood cells approach the renal medulla (where there is a high concentration of urea), the urea transporter allows for rapid uptake of urea and prevents cell shrinkage in the hypertonic environment of the medulla. [ 5 ]  As the red cell leaves the medulla, the urea is transported back out of the cell, preventing cellular swelling and preventing the urea from being carried away from the kidney. [ 5 ]   HUT11 was detected on endothelial cells of the vasa recta (vascular supply of the renal medulla) but it is not present in renal tubules. [ 5 ]


Due to absence of the urea transporter, Jk(a-b-) cells are not hemolyzed by 2M urea. This can be used as a screening test for Jk(a-b-) donors. [ citation needed ]


The Jk(a-b-) phenotype has no clinical defect, although two individuals with this phenotype have been reported to have mild urine-concentrating defects. [ 4 ]


Kidd antibodies are capable of behaving as histocompatibility antigens in renal transplants and may be responsible for allograft rejection in some cases. [ 9 ]


The  Lan blood group system  (short for  Langereis ) is a human  blood group  defined by the presence or absence of the  Lan antigen  on a person's red blood cells. More than 99.9% of people are positive for the Lan antigen. Individuals with the rare Lan-negative blood type, which is a  recessive trait , can produce an  anti-Lan   antibody  when exposed to Lan-positive blood. Anti-Lan antibodies may cause  transfusion reactions  on subsequent exposures to Lan-positive blood, and have also been implicated in mild cases of  hemolytic disease of the newborn . However, the clinical significance of the antibody is variable. The antigen was first described in 1961, and Lan was officially designated a blood group in 2012. [ 1 ] [ 2 ]


The Lan antigen is carried on the protein  ABCB6 , an  ATP-binding cassette transporter  encoded by the  ABCB6  gene on chromosome 2q36. The Lan-negative blood type is inherited in an  autosomal recessive  manner, being expressed by individuals who are  homozygous  for nonfunctional  alleles  of  ABCB6 . [ 1 ] [ 2 ]  Some variant alleles cause a weak positive phenotype, which may be mistaken for a Lan-negative phenotype in serologic testing. [ 2 ]  As of 2018, more than 40 null or weak alleles of  ABCB6  have been described. [ 3 ]


ABCB6 is involved in  heme  synthesis and  porphyrin  transport and is widely expressed throughout the body, particularly in the heart,  skeletal muscle , eye, fetal liver,  mitochondrial membrane , and  Golgi bodies . [ 4 ] : 220   The Lan antigen is more strongly expressed on  cord blood  cells than on adult red blood cells. [ 5 ] : 490   Despite the protein's wide distribution, Lan-negative individuals do not appear to experience any adverse effects from the absence of ABCB6. [ 1 ] [ 2 ]  It is thought that other porphyrin transporters, such as  ABCG2  (which carries the  Junior blood group antigen ), may compensate. [ 4 ] : 220  [ 6 ]  A 2018 study found that Lan-negative blood cells exhibited resistance to  Plasmodium falciparum   in vitro . [ 7 ]


The prevalence of the Lan antigen exceeds 99.9% in most populations. The frequency of the Lan-negative blood type is estimated at 1 in 50,000 in Japanese populations, 1 in 20,000 in Caucasians, and 1 in 1,500 in black people from South Africa. [ 2 ]


When Lan-negative individuals are exposed to Lan-positive blood through  transfusion  or pregnancy, they may develop an anti-Lan antibody. Anti-Lan is considered a clinically significant antibody, [ 4 ] : 220   but its effects are variable. It has been associated with severe  transfusion reactions  and mild cases of  hemolytic disease of the newborn , but in some cases individuals with the antibody have not experienced any adverse effects from exposure to Lan-positive blood. It is recommended that individuals with anti-Lan are transfused with Lan-negative blood, especially if the  antibody titer  is high. [ 2 ]  One case of  autoimmune hemolytic anemia  involving auto-anti-Lan has been described. [ 2 ]


Serologic reagents and molecular assays for Lan  antigen typing  were not commercially available as of 2013. [ 2 ]


Anti-Lan antibodies are typically composed of  immunoglobulin G  and may bind  complement . As an IgG antibody, anti-Lan can be detected using the  indirect antiglobulin test . The antibody is resistant to treatment with  ficin ,  papain ,  trypsin ,  DTT , and EDTA/glycine-acid. [ 2 ] [ 4 ] : 220


The Lan antigen was first described in 1961 by Van der Hart et al., [ 8 ]  when a Dutch patient suffered a severe hemolytic transfusion reaction. [ 4 ] : 220  [ 5 ] : 489   The patient was found to produce an antibody that reacted with all but 1 out of 4,000 blood donors tested. The causative antigen was identified and designated "Langereis" after the patient's last name. [ 2 ]  Lan was officially designated a blood group by the  International Society of Blood Transfusion  in 2012, following the discovery of the molecular basis of the Lan-negative phenotype. [ 4 ] : 220  [ 9 ] [ 10 ]


Samuel Armstrong Lane  FRCS (1802 – 2 August 1892) was an English  surgeon , consulting surgeon to  St Mary's Hospital .


In 1840 while practicing in London England, Samuel Armstrong Lane, aided by consultant Dr. Blundell, performed the first successful whole Blood transfusion in an attempt to treat  hemophilia .


In 1843 he was elected one of the original 300  Fellow of the Royal College of Surgeons


Media related to  Samuel Armstrong Lane  at Wikimedia Commons


Leukoreduction  is the removal of  white blood cells  (or  leukocytes ) from the  blood  or blood components supplied for  blood transfusion .  After the removal of the leukocytes, the blood product is said to be  leukoreduced .


It is theorized that  transfusions  that contain white blood cells may cause adverse effects through multiple mechanisms.  White blood cells may themselves harbor infectious disease and some  pathogens  will be more concentrated in white blood cells than the rest of the blood product. [ 1 ]   It is also theorized that the donor white blood cells may  suppress  the recipient's  immune system  by interacting with it. [ citation needed ]


An April 2007  meta-analysis  by Dr. Neil Blumberg and others and covering 3093 patients who received leukoreduced blood was published in the scientific journal  Transfusion .  According to the meta-analysis, use of leukoreduced blood reduced the frequency of post-transfusion infection by 50%. [ 2 ]    In a previous study, Blumberg and others reported that a change to universal use of leukoreduced blood at  Strong Memorial Hospital  at  University of Rochester  reduced post-transfusion infection by 33-45%. [ 3 ]


However, other scientific studies question the effectiveness of leukoreduction.  A March 2007 study by researchers at  University of South Alabama  Medical Center found no reduction of mortality or length of hospital stay in 439 trauma patients who received leukoreduced transfusions compared to 240 patients who did not. [ 4 ]   University of Washington  researchers reported in October 2006 that a study of 286 transfused injury patients showed no reduction in mortality or length of stay, although a 16% reduction in rate of infection was shown with marginal statistical significance. [ 5 ]


Leukoreduction has the inadvertent effect of removing approximately 10% of  red blood cells  from a processed unit of Red Blood Cells. [ 6 ]   Because blood from persons who possess the  sickle cell  mutation is difficult to filter, leukoreduction is often not performed on donors who may have the sickle cell gene, which is most common in people of  African  descent. [ 6 ]


Dr. Blumberg, the lead author of the meta-analysis covering 3093 patients, stated in the press that the cost savings due to universal leukoreduction exceeds the cost of performing the leukoreduction. [ 7 ] [ medical citation needed ]   The cost of leukoreduction is an increase of approximately US$30 per unit of blood product. [ 4 ] [ medical citation needed ]


Universal leukoreduction is currently not practiced in all countries. [ citation needed ]


As of 2008, most developed nations have adopted universal leukoreduction of transfusions (defined as the routine application of this blood-processing step to all units of whole blood, red blood cells, and platelets prior to storage) with the notable exception of the  United States . [ 8 ]   Canada ,  Britain  and  France  adopted universal leukoreduction in the late 1990s.  Germany  adopted it in 2001. [ 9 ]  Leukoreduced products are commonly available in the United States and some hospitals use only leukoreduced blood while others only use leukoreduced products in certain patient populations.  For example,  Strong Memorial Hospital  began universal use of leukoreduced blood in July 2000; [ 7 ]  University of South Alabama Medical Center began use in January 2002. [ 4 ]
Woodlands Medical Centre is beginning a randomised controlled trial to look into the benefits of transfusing leukoreduced whole blood for the ICCU patients.


The  Lewis antigen system  is a  human blood group system . It is based upon two genes on  chromosome 19 :  FUT3 , or Lewis gene; and  FUT2 , or Secretor gene. Both genes are expressed in glandular epithelia. FUT2 has a dominant allele which codes for an enzyme (designated Se) and a recessive allele which does not produce a functional enzyme (designated se). Similarly, FUT3 has a functional dominant allele (Le) and a non-functional recessive allele (le).


The proteins produced by the FUT2 and FUT3 genes modify type I oligosaccharide chains to create Lewis antigens. These oligosaccharide chains are similar to the type II chains of the  ABO blood system , with a single bond in a different position. The link between the Lewis blood group and secretion of the ABO blood group  antigens  was possibly the first example of multiple effects of a human  gene : [ 1 ]  the same enzyme (fucosyltransferase2) which converts the Le-a antigen to Le-b is also responsible for the presence of soluble A, B and H antigens in bodily fluids.


There are two main types of Lewis antigens, Lewis a (Le-a) and Lewis b (Le-b). There are three common phenotypes: Le(a+b-), Le(a-b+), and Le(a-b-). [ 2 ]


The enzyme fucosyltransferase 3 (FUT3), encoded by Le gene, adds a fucose to the precursor  oligosaccharide  substrate, converting it to the Le-a antigen. People who have the Le allele and who are non-secretors (homozygous for the nonfunctional se allele) will express the Le-a antigen in their bodily fluids and on their erythrocytes.


If a person has both the Le and Se alleles, their exocrine cells will also have the enzyme fucosyltransferase 2 (FUT2). This adds fucose to the oligosaccharide precursor in a different position from the FUT3 enzyme. This produces the Le-b antigen. In most people having both Le and Se, it is difficult to detect the antigen Le-a. This is because the activity of the FUT2 enzyme is more efficient than the FUT3 enzyme, so the type I oligosaccharide chain is mostly converted into Le-b instead of Le-a. Therefore, people with readily detectable Lewis-a antigen are non-secretors; they do not have FUT2 activity. Lewis-b antigen is found only in secretors: people who possess the Se allele and thus have FUT2 activity. Lewis negative people (Le a-, Le b-) are homozygous for the recessive le allele and can be either secretors or non-secretors.


Lewis antigens are expressed on the surface of  red blood cells ,  endothelium , kidney, genitourinary and  gastrointestinal epithelium . [ 3 ] [ 4 ] [ 5 ]  Lewis antigens are  red blood cell  antigens which are not produced by the cell itself. Instead, Lewis antigens are components of  exocrine   epithelial  secretions, and are subsequently adsorbed onto the surface of the red cell. [ 6 ]


The three above-stated common Lewis phenotypes represent the presence or absence of Lewis and Secretor enzymes. [ citation needed ]