For over a century the casualties of war have provided valuable lessons that can be applied within the civilian sector. Specifically the past decade has seen a paradigm shift in early resuscitation of critically injured patients. Instead of replacing blood volume with high volumes of crystalloid and packed red blood cells with the sporadic use of fresh frozen plasma and platelets, we have now learned that maintaining a transfusion ratio of 1:1:1 of plasma to red blood cells to platelets in patients requiring massive transfusion results in improved outcomes [Borgman 2007] [ 4 ]  While this was initially demonstrated in the military setting, Holcomb and colleagues extrapolated this to the civilian trauma center showing improved results as well  [ 14 ] [ 15 ]  Broad implementation across both the military and civilian sector has demonstrated a decreased mortality in critically injured patients. [ 4 ]  Debate has gone back and forth as to the correct ratio that should be used; however, recently Holcomb and colleagues published the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) Study. [ 15 ] [ 16 ]  They compared administration a higher ratio of plasma and platelets (1:1:1) compared to a lower ratio (1:1:2). The patients that received a higher ratio had an associated three to four-fold decrease in mortality. To help mitigate confounding variables a randomized control trial called the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) has been performed to evaluate the transfusion requirement. There was no difference in 24 hour or 30 day mortality between the 1:1:1 group and the 1:1:2 group -  https://jamanetwork.com/journals/jama/fullarticle/2107789 . [ 14 ]


Initial resuscitation of trauma patients continues to evolve. Massive transfusion (defined as receiving greater than or equal to 10 units of packed red blood cells with a 24-hour period) is required in up to 5% of civilian trauma patients that arrive severely injured. [ 17 ]  Patients who are arriving severely injured to trauma centers can be coagulopathic. Data suggests that around 25% of patients arrive with coagulopathy. [ 18 ]  New ways of measuring coagulopathy such at thromboelastography and rotational thromboelastometry have allowed for a more robust assessment of the coagulation cascade compared to traditional methods of measuring international normalized ratio allowing clinicians to better target areas of deficiency. [ 4 ]  For trauma teams to systematically and efficiently deliver blood products institutions have created protocols that allow for this. The protocols allow for clear communication between the trauma center, blood bank, nurses, and other ancillary staff. They also allow for the quick delivery of certain set of blood products depending upon the institution. One example might be that a “cooler” would contain 10 units of packed red blood cells, 10 units of plasma, and 2 packs of platelets. The idea is that the coolers would continue to be delivered to the location where the patient is being treated until the trauma team leader (typically the trauma surgeon) would discontinue the order. [ 17 ]  Systolic blood pressure <90 mmHg, hemoglobin <11 g/dL, temperature <35.5 o C, international normalized ratio > 1.5, base deficit ≥6 mEq/L, heart rate ≥120 bpm, presence of penetrating trauma, and Focused Abdominal Sonography Trauma exam have been evaluated to determine their predictive ability in patients arriving at trauma centers. All were be predictive of the need of massive transfusion protocol except for temperature. [ 16 ]


Surgeons have used the concept of damage control surgery for years, and controlling hemorrhage with packing is over a century old. Pringle described this technique in patients with substantial hepatic trauma in the early twentieth century. [ 7 ]  The U.S. military did not encourage this technique during World War II and the Vietnam War. Lucas and Ledgerwood described the principle in a series of patients. [ 19 ]  Subsequent studies were repeated by Feliciano and colleagues, [ 20 ]  and they found that hepatic packing increased survival by 90%. This technique was then specifically linked to patients who were hemorrhaging, hypothermic, and coagulopathic. [ 21 ]  This extrapolation allowed for the first article in 1993 by Rotondo and Schwab specifically adapting the term “damage control”. [ 22 ]  This term was taken from the United States Navy who initially used the term as “the capacity of a ship to absorb damage and maintain mission integrity” (DOD 1996). This was the first article that brought together the concept of limiting operative time in these critically ill patients to allow for reversal of physiologic insults to improve survival. In addition, the description illustrated how the three phases of damage control surgery can be implemented. Since this description the development of this concept has grown both within the trauma community and beyond.


The data that have been published regarding definitive laparotomy versus damage control surgery demonstrate a decrease in mortality when performed in the critically ill patient. [ 21 ] [ 6 ]  Subsequent studies by Rotondo and colleagues in a group of 961 patients that had undergone damage control surgery demonstrate an overall mortality of 50% and a 40% morbidity rate. [ 23 ]


There are four main complications. The first is development of an intra-abdominal abscess. This has been reported as high as 83%. [ 20 ] [ 21 ]  Next is the development of an entero-atmospheric fistula, which ranges from 2 to 25%. [ 5 ] [ 24 ]  The third is abdominal compartment syndrome that has been reported anywhere from 10 to 40% of the time. [ 25 ] [ 26 ]  Finally fascial dehiscence has been shown to result in 9–25% of patients that have undergone damage control surgery. [ 27 ] [ 28 ]


This page is currently under construction.


Transfusion-related acute lung injury


Febrile non-hemolytic transfusion reaction


Transfusion-associated graft versus host disease


A  delayed hemolytic transfusion reaction (DHTR)  is a type of  adverse reaction  to a  blood transfusion . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  DHTR is the later-onset manifestation of hemolytic transfusion reaction, which may also present as  acute hemolytic transfusion reaction  (AHTR) in a shorter timeframe from transfusion administration. The prevalence of AHTR has been estimated at 1 in 70,000 blood transfusions, whereas the prevalence of DHTR is thought to be underreported, although various studies estimate the prevalence of DHTR as between 1 in 800, to 1 in 11,000 transfusions. [ 1 ]


Hemolytic transfusion reactions are a possible complication from red blood cell  transfusions . Hemolysis refers to the  lysis  (rupture) of  red blood cells , and the resulting leakage of their contents. Hemolytic reactions may be immune or non-immune mediated. Immune-mediated hemolytic reactions, such as DHTR, represent a type of  alloimmunity . Non-immune hemolysis may result from  thermal ,  osmotic , or  mechanical  damage to red blood cells in transfusion products.


In immune-mediated DHTR, the transfusion recipient has  antibodies  that react with  antigens  on incompatible donor red blood cells, [ 5 ]  prompting lysis of the red blood cells by the recipient's  immune cells , such as  macrophages . The severity of immune-mediated hemolytic reactions may vary based on the type and quantity of both the transfused red blood cell antigens and the recipient's antibodies against them, as well as the ability of the antibodies to activate  complement  or  opsonization . Some recipients do not have significant pre-existing antibodies against transfused red blood cells, but then develop higher levels of such antibodies following immune stimulation by the transfused red blood cells.


While AHTR usually presents within the first 24 hours after transfusion, DHTR has the possibility to present up to 30 days later. Even though DHTR may have a lower chance of severe outcomes than AHTR, it can still be fatal or result in serious complications, and must be treated as an  urgent medical issue .


If a person without a Kidd blood antigen (for example a Jka-Jkb+ patient) receives a  Kidd antigen (Jka-antigen for example)  in a red blood cell transfusion and forms an alloantibody (anti-Jka); upon subsequent transfusion with Jka-antigen positive red blood cells, the patient may have a delayed hemolytic transfusion reaction as their anti-Jka antibody hemolyzes the transfused Jka-antigen positive red blood cells. Other common blood groups with this reaction are  Duffy ,  Rhesus  and  Kell . [ 6 ]


Immune-mediated hemolytic reactions may be classified as either intravascular or extravascular hemolysis. Intravascular hemolysis takes place while the red blood cells are still when the recipient's antibodies bind to the donor's red blood cells and cause complement activation. Extravascular hemolysis is produced when the recipient's antibodies opsonize the donor's red blood cells, leading to their sequestration and  phagocytosis  by phagocyte immune cells such as macrophages. Macrophage activation, in response to antibody-mediated targeting of red blood cells, can also increase production of  cytokines  that induce a systemic response that results in clinical symptoms, such as  fever ,  chills ,  abdominal pain , and  back pain .


Some hemolytic reactions are the product of incompatibility between different blood types of the  ABO blood group system . Hemolytic reactions may also be caused by incompatibilities with  Rh factors ,  Duffy antigens ,  Kell antigens ,  Kidd antigens , [ 6 ]  and  Lewis antigens .


Many people have antibodies to red blood cell antigens not found on the surface of their own red blood cells. Therefore, to use the ABO types as an example, those with type O blood are likely to have antibodies to type A and type B blood. Those with type A blood are likely to have antibodies to type B blood, and vice versa.


Antibodies against Kidd antigens may be difficult to detect because of significant variability in their molecular features, and weak  in vitro  expression. They have been reported to cause severe immediate or delayed hemolytic transfusion reactions, [ 6 ]  with anti-Jk antibodies responsible for 13 of 44 cases of DHTR reported in the UK during 2021. [ 7 ]


Symptoms may include a drop in hemoglobin level, fever, jaundice, or hemoglobinuria. [ 6 ]  It is also "associated with a fall in Hb or failure to increment, rise in bilirubin and LDH and an incompatible crossmatch not detectable pre transfusion." [ 10 ]


DHTR may be diagnosed by the presence of antibodies that react to red blood cells. An  antiglobulin test , also known as a Coombs test, is a type of blood test used in  immunohematology . An antiglobulin test may either be direct (e.g., "direct antiglobulin test" or "direct Coombs test"), or indirect. The direct test is designed to detect antibodies already bound to the surface of red blood cells in a clinical blood sample. By contrast, the indirect test is designed to detect antibodies that are freely floating in the blood, and that display  in vitro  reactivity against red blood cells. Both direct and indirect Coombs tests may be useful for investigating suspected blood transfusion reactions. The indirect test may also be used to determine a patient's reactivity to foreign red blood cell antigens prior to transfusion.


Hyperhemolysis  differs from DHTR in that it involves the lysis of the recipient's own red blood cells in addition to those introduced from the donor. [ 11 ]


Delayed blood transfusion reactions occur at an incidence of about 1/500 to 1/10,000 transfusions in the United States. The subacute presentation, milder symptoms and paucity of reporting data make determination of the true incidence difficult. [ 12 ]


The  Diego antigen (or blood group) system  is composed of 21 blood factors or  antigens  carried on the  Band 3   glycoprotein , also known as Anion Exchanger 1 (AE1). The antigens are inherited through various  alleles  of the gene  SLC4A1  ( Solute carrier family  4), located on  human chromosome 17 . The AE1 glycoprotein is expressed only in  red blood cells  and, in a shortened form, in some cells in the  kidney . The Diego a  antigen is fairly common in  Indigenous peoples of the Americas  (in both North and South America) and  East Asians , but very rare or absent in most other populations, supporting the theory that the two groups share common ancestry.


The Diego system is named after a pair of types, Diego a  (Di a ) and Diego b  (Di b ), which differ by one  amino acid  in the AE1 glycoprotein, corresponding to one difference in the  nucleotide  sequence of the SLC4A1 gene. Di b  is common or ubiquitous in all populations which have been screened for it, while Di a  has been found only in Indigenous peoples of the Americas (in both North and South America) and East Asians, and in people with some ancestors from those groups. People  heterozygous  for the two alleles produce both antigens. No individual has been tested who does not produce one, or both, of the two antigens. [ 1 ]  Anti-Di a  (the  antibody  to Di a ) can cause severe  hemolytic disease of the newborn  and severe  transfusion reaction . Anti-Di b  usually causes milder reactions. [ 2 ]


The Wright blood system is another pair of types, Wright a  (Wr a ) and Wright b  (Wr b ), also differing by one amino acid on the AE1 glycoprotein and one nucleotide on the SLC4A1 gene. Wr a  always expresses antigens, but the antibody reaction of Wr b  depends on a variation in the structure of  glycophorin A , which binds with Wr b . [ 3 ]  Anti-Wr a  can also cause severe  hemolytic disease of the newborn  and severe  transfusion reaction . Anti-Wr b  is very rare, and little data is available on its severity. [ 2 ]


Seventeen other rare blood types (as of 2002) are included in the Diego antigen system, as they are produced by mutations on the SLC4A1 gene. These include the Waldner (Wd a ), Redelberger (Rb a ), Warrior (WARR), ELO, Wulfsberg (Wu), Bishop (Bp a ), Moen (Mo a ), Hughes (Hu a ), van Vugt (Vg a ), Swann (Sw a ), Bowyer (BOW), NFLD, Nunhart (Jn a ), KREP, Traversu (Tr a ), Froese (Fra) and SW1 types. [ 4 ]


The first Diego antigen, Di a , was discovered in 1953, when a child in  Venezuela  died of hemolytic disease three days after birth.  Rh  and  ABO  blood type mismatches were soon ruled out, and investigators began searching for a rare blood factor. Red blood cells from the father reacted strongly to  blood serum  from the mother. Rare blood types known at the time were eliminated, and the new type was classified as a "private" or "family" blood type. The investigators, with the agreement of the father, named the new type after his surname, "Diego". In 1955 investigators found that the Diego family included ancestry from Indigenous peoples of the Americas, and that the Diego factor (Di a ) was not restricted to the Diego family, but occurred in several populations in Venezuela and elsewhere in South America. Investigators suspected that the Diego factor might be a  Mongoloid  trait, and tested groups of  Native Americans in the United States  and people of  Chinese  and  Japanese  ancestry, and found Di a  in those groups. Anti-Di b  was found in 1967, establishing the Diego group as a two-antigen system. In 1993 the Diego pair of antigens was found to result from a single point mutation (nucleotide 2561) on what is now called the SLC4A1 gene on chromosome 17. [ 1 ]


The Wright a  antigen (Wr a ), a very low frequency blood type, was also discovered in 1953. The Wright b  antigen (Wr b ), a very high frequency blood type, was discovered about a decade later, but the two types were not recognized as a pair for another 20 years. The Wright group was eventually identified as a single point mutation on the SLC4A1 gene. The Wright group was subsumed into the Diego group in 1995, since its location on the SLC4A1 gene had been determined after the Diego group had been located there. [ 2 ]


Starting in 1995, various rare antigen types, some of which had been known for 30 years, were found to also be caused by mutations on the SLC4A1 gene, and were therefore added to the Diego system. [ 2 ]


The Di b  antigen has been found in all populations tested. The Di a  antigen, however, has been found only in populations of  indigenous peoples of the Americas  and East Asians, and people with some ancestry in those populations. Some groups in South America have a relatively high frequency of Di a +. A sample of the  Kaingang people  of Brazil was 49% Di a +. Samples of other groups in  Brazil  and Venezuela were 14% to 36% Di a +. [ 2 ]


While the Di a  antigen is found at moderate to high frequencies in most populations of indigenous peoples in South America, it is absent in the  Waica people , and occurs at very low frequencies in the  Warao  and  Yaruro  people of interior northern South America. Layrisse and Wilbert, who characterize these people as "Marginal Indians", proposed that they are remnants of a first migration into South America of people who had not acquired the allele for the Di a  antigen, with other indigenous peoples of South America resulting from a later migration. [ 6 ]


Samples of groups in  Guatemala  and  Mexico  have 20% to 22% Di a +. Samples from Native American groups in the United States and  First Nations  groups in  Canada  have 4% to 11% Di a +. [ 1 ] [ 7 ]  Although the incidence of Diego a + is relatively high in  Siberian Eskimos  and  Aleut people  (the incidence of Diego a + in Aleuts is comparable to South American levels), it occurs at a much lower frequency (less than 0.5%) among  Alaskan   Eskimos  and has not been found in the  Inuit  of Canada. [ 8 ] [ 9 ] [ 10 ] [ 11 ]


The Di a  antigen is widespread in East Asian populations. Samples of East Asian populations show 4% Di a + for the  Ainu  of  Hokkaido , [ 11 ]  2% to 10% Di a + for Japanese, 6% to 15% Di a + for  Koreans , 7% to 13% Di a + for  Mongolians , 10% Di a + for northern Chinese and 3% to 5% Di a + for southern Chinese. [ 1 ] [ 12 ]


The Di a  antigen is also found in northern  India  and in  Malaysia , where there are populations of East Asian ancestry. North Indians (of unspecified ethnicity) are reported to be 4% Di a +. On the other hand, a sample of Indian students attending the University of Michigan, the majority of which were  Gujarati , found none to be Di a +. [ 7 ]  A survey of residents of the  Klang Valley  in Malaysia found the incidence of Di a + in ethnic Chinese to be 4%, in  ethnic Malays  to be a little over 1%, and in ethnic Indians (descended from southern Indians) to be a little under 1%. (A smaller sample of Malays in  Penang , Malaysia, were 4% Di a +.) [ 12 ]


The Di a  antigen is very rare in  African  and European populations. [ 12 ]  One  West African  subject had an ambiguous possible reaction to Di a . [ 7 ]  About 0.5% of Europeans of  Polish  ancestry have been found to be Di a +. This incidence has been attributed to gene mixture from  Tatars  who invaded Poland five to seven centuries ago. [ 2 ]  Diego Antigen has been found in 0.89% of Germans from Berlin. [ 13 ]  The Di a  antigen is very rare or absent in  Aboriginal Australians ,  Papuans , natives of  New Britain , and  Polynesians . [ 11 ]


The distribution of the Di a  antigen has been cited as proof that the Americas were populated by migrations from Siberia. Differences in the frequency of the antigen in populations of indigenous people in the Americas correlate with major language families, modified by environmental conditions. [ 14 ]  Another study suggests that the distribution of the Di a  antigen in central and eastern Asia has been shaped by the expansion of Mongolian and related populations that resulted in the creation of the  Mongol Empire  in the 13th- and 14th-centuries. [ 15 ]


4NUU ,  4NUV


NM_002036 NM_001122951


NP_001116423 NP_002027


Duffy antigen/chemokine receptor  ( DARC ), also known as  Fy glycoprotein  ( FY ) or   CD234  ( Cluster of Differentiation 234 ), is a  protein  that in humans is encoded by the  ACKR1   gene . [ 5 ] [ 6 ] [ 7 ]


The Duffy antigen is located on the surface of  red blood cells , and is named after the patient in whom it was discovered. The protein encoded by this gene is a  glycosylated   membrane protein  and a non-specific  receptor  for several  chemokines . The protein is also the receptor for the human malarial parasites  Plasmodium vivax ,  Plasmodium knowlesi  and simian malarial parasite  Plasmodium cynomolgi . [ 8 ]   Polymorphisms  in this gene are the basis of the Duffy blood group system. [ 9 ]


It was noted in the 1920s that black Africans had some intrinsic resistance to malaria, but the basis for this remained unknown. The Duffy antigen gene was the fourth gene associated with the resistance after the genes responsible for  sickle cell anaemia ,  thalassemia  and  glucose-6-phosphate dehydrogenase . [ citation needed ]


In 1950, the Duffy  antigen  was discovered in a multiply-transfused  hemophiliac  named Richard Duffy, whose serum contained the first example of anti-Fya  antibody . [ 10 ]
In 1951, the antibody to a second antigen, Fyb, was discovered in  serum . Using these two antibodies, three common  phenotypes  were defined: Fy(a+b+), Fy(a+b-), and Fy(a-b+). [ citation needed ]


Several other types were later discovered bringing the current total up to 6: Fya, Fyb, Fy3, Fy4, Fy5 and Fy6. Only Fya, Fyb and Fy3 are considered clinically important. Reactions to Fy5 have also rarely been reported.  The Fy4 antigen, originally described on Fy (a–b–) RBCs, is now thought to be a distinct, unrelated antigen and is no longer included in the FY system. [ citation needed ]


The Duffy antigen/chemokine  receptor  gene (gp-Fy; CD234) is located on the long arm of  chromosome 1  (1.q22-1.q23) and was cloned in 1993. [ 6 ]  The gene was first localised to chromosome 1 in 1968, and was the first blood system antigen to be localised. It is a single copy gene spanning over 1500 bases and is in two  exons . The gene encodes a 336 amino acid acidic  glycoprotein . It carries the antigenic determinants of the Duffy blood group system which consist of four codominant  alleles —FY*A and FY*B—coding for the Fy-a and Fy-b antigens respectively, FY*X and FY*Fy, five  phenotypes  (Fy-a, Fy-b, Fy-o, Fy-x and Fy-y) and five antigens. Fy-x is a form of Fy-b where the Fy-b gene is poorly expressed. Fy-x is also known as Fy-b weak  or Fy-b Wk .


This gene has been redesignated  ACKR1 .


Fy-a and Fy-b differ by in a single  amino acid  at position 42:  glycine  in Fy-a and  aspartic acid  in Fy-b ( guanine  in Fy-a and  adenosine  in Fy-b at position 125). A second mutation causing a Duffy negative phenotype is known: the responsible mutation is G -> A at position 298. The genetic basis for the Fy(a-b-) phenotype is a  point mutation  in the erythroid specific  promoter  (a T -> C mutation at position -33 in the  GATA box ). [ 11 ]  This mutation occurs in the Fy-b allele and has been designated Fy-b Es  (erythroid silent). Two isotypes have been identified. The Fy-x allele is characterized by a weak anti-Fy-b reaction and appears to be the result of two separate  transitions :  Cytosine 265 Threonine  ( Arginine 89 Cysteine ) and  Guanine 298 Adenosine  ( Alanine 100 Threonine ). A third mutation (a  transversion ) in this gene has also been described - G145T ( Alanine 49 Serine ) - that has been associated with the Fy-x phenotype.


Most Duffy negative  black people  carry a silent Fy-b  allele  with a single T to C substitution at  nucleotide  -33, impairing the  promoter  activity in erythroid cells by disrupting a binding site for the  GATA1  erythroid  transcription factor . The gene is still transcribed in non erythroid cells in the presence of this  mutation .


The Duffy negative phenotype occurs at low frequency among whites (~3.5%) and is due to a third mutation that results in an unstable protein (Arg89Cys:  cytosine  ->  thymidine  at position 265). [ 12 ]


The silent allele has evolved at least twice in the black population of Africa and evidence for selection for this allele has been found. [ 13 ]  The selection pressure involved here appears to be more complex than many text books might suggest. [ 14 ]  An independent evolution of this phenotype occurred in  Papua New Guinea  has also been documented. [ 15 ]


A comparative study of this gene in seven mammalian species revealed significant differences between species. [ 16 ]  The species examined included  Pan troglodytes  (chimpanzee),  Macaca mulatta  (rhesus monkey),  Pongo pygmaeus  (orangutan),  Rattus norvegicus  (brown rat),  Mus musculus  (mouse),  Monodelphis domestica  (opossum),  Bos taurus  (cow) and  Canis familiaris  (dog).


Three exons are present in humans and chimpanzees, whereas only two exons occur in the other species. This additional exon is located at the 5' end and is entirely non coding. Both intron and exon size vary considerably between the species examined. Between the chimpanzee and the human, 24 differences in the nucleotide sequence were noted. Of these 18 occurred in non coding regions. Of the remaining 6, 3 were synonymous and 3 non synonymous mutations. The significance of these mutations if any is not known.


The mouse ortholog has been cloned and exhibits 63% homology to the human gene at the amino acid level. The mouse gene is located on chromosome 1 between the genetic markers Xmv41 and D1Mit166. The mouse gene has two exons (100 and 1064 nucleotides in length), separated by a 461 base pair intron. In the mouse DARC is expressed during embryonic development between days 9.5 and 12. [ citation needed ]


In yellow baboons ( Papio cynocephalus ) mutations in this gene have been associated with protection from infection with species of the genus  Hepatocystis . [ 17 ]


The ancestral form of extant DARC alleles in humans appears to be the FY*B allele. [ 18 ]


The gene appears to be under strong purifying selection. [ 19 ]  The cause of this selective pressure has not yet been identified.


Biochemical analysis of the Duffy antigen has shown that it has a high content of α-helical secondary structure - typical of chemokine receptors. [ 20 ]  Its N-glycans are mostly of the triantennary complex type terminated with α2-3- and α2-6-linked sialic acid residues with bisecting GlcNAc and α1-6-linked fucose at the core.


The Duffy antigen is expressed in greater quantities on  reticulocytes  than on mature erythrocytes. [ 21 ]   While the Duffy antigen is expressed on bone marrow  erythroblasts  and circulating  erythrocytes  it is also found on  Purkinje cells  of the  cerebellum , [ 22 ]  endothelial cells of  thyroid   capillaries , the post-capillary  venules  of some organs including the spleen, liver and kidney [ 23 ]  and the large pulmonary venules. Duffy antigen has then a very unique cell expression profile in cerebellar neurons, venular endothelial cells and erythroid cells. [ 24 ]
In some people who lack the Duffy antigen on their erythrocytes it is still expressed in the other cell types. [ 25 ]


It has two potential N-linked glycosylation sites at  asparagine  (Asn) 16 and Asn27.


The Duffy antigen has been found to act as a multispecific receptor for chemokines of both the C-C and C-X-C families, including:


and the angiogenic CXC chemokines:


Consequently, the Fy protein is also known as DARC (Duffy Antigen Receptor for Chemokines). The chemokine binding site on the receptor appears to be localised to the  amino terminus . [ 30 ]  The antigen is predicted to have 7 transmembrane domains, an exocellular N-terminal domain and an endocellular C-terminal domain. Alignment with other seven transmembrane  G-protein-coupled receptors  shows that DARC lacks the highly conserved DRY motif in the second intracellular loop of the  protein  that is known to be associated with G-protein signaling. Consistent with this finding ligand binding by DARC does not induce G-protein coupled signal transduction nor a Ca2+ flux unlike other chemokine receptors. Based on these alignments the Duffy antigen is considered to be most similar to the  interleukin-8B receptors .


Scatchard analysis  of competition binding studies has shown high affinity binding to the Duffy antigen with dissociation constants (KD) binding values of 24 ± 4.9, 20 ± 4.7, 41.9 ± 12.8, and 33.9 ± 7 nanoMoles for MGSA, interleukin-8, RANTES and monocyte chemotactic peptide-1 respectively. [ 31 ]


In DARC-transfected cells, DARC is internalized following ligand binding and this led to the hypothesis that expression of DARC on the surface of erythrocytes,  endothelial , neuronal cells and  epithelial  cells may act as a sponge and provide a mechanism by which inflammatory chemokines may be removed from circulation as well as their concentration modified in the local environment. [ 32 ]   This hypothesis has also been questioned after  knock out  mice were created. These animals appeared healthy and had normal responses to infection. While the function of the Duffy antigen remains presently (2006) unknown, evidence is accumulating that suggests a role in  neutrophil  migration from the blood into the tissues [ 33 ]  and in modulating the inflammatory response. [ 34 ] [ 35 ] [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ] [ 42 ] [ 43 ]


The protein is also known to interact with the protein KAI1 ( CD82 ) a surface glycoprotein of  leukocytes  and may have a role in the control of cancer.


The Duffy antigen has been shown to exist as a constitutive homo-oligomer and that it hetero-oligomerizes with the CC chemokine receptor CCR5 ( CD195 ). The formation of this heterodimer impairs  chemotaxis  and calcium flux through CCR5, whereas internalization of CCR5 in response to ligand binding remains unchanged. [ 44 ]


DARC has been shown to internalise chemokines but does not scavenge them. [ 45 ]  It mediates chemokine transcytosis, which leads to apical retention of intact chemokines and more leukocyte migration.


Binding melanoma growth-stimulating activity inhibits the binding of  P. knowlesi  to DARC.


Differences in the racial distribution of the Duffy antigens were discovered in 1954, when it was found that the overwhelming majority of people of African descent had the  erythrocyte  phenotype Fy(a-b-): 68% in  African Americans  and 88-100% in African people (including more than 90% of  West African  people). [ 46 ]  This phenotype is exceedingly rare in Whites. Because the Duffy antigen is uncommon in those of  Black African  descent, the presence of this antigen has been used to detect  genetic admixture . In a sample of unrelated African Americans (n = 235), Afro-Caribbeans (n = 90) and Colombians (n = 93), the frequency of the -46T (Duffy positive) allele was 21.7%, 12.2% and 74.7% respectively. [ 47 ]


Overall the frequencies of Fya and Fyb antigens in Whites are 66% and 83% respectively, in Asians 99% and 18.5% respectively and in blacks 10% and 23% respectively. The frequency of Fy3 is 100% Whites, 99.9% Asians and 32% Blacks. Phenotype frequencies are:


While a possible role in the protection of humans from malaria had been previously suggested, this was only confirmed clinically in 1976. [ 48 ]  Since then many surveys have been carried out to elucidate the prevalence of Duffy antigen alleles in different populations including:


There appears to have been a selective sweep in Africa which reduced the incidence of this antigen there. This sweep appears to have occurred between 6,500 and 97,200 years ago (95% confidence interval) [ 13 ]


The distribution within India has been studied in some detail. [ 64 ]


Historically the role of this antigen other than its importance as a receptor for  Plasmodium  protozoa has not been appreciated. Recent work has identified a number of additional roles for this protein.


On erythrocytes, the Duffy antigen acts as a  receptor  for invasion by the human  malarial  parasites  P. vivax  and  P. knowlesi . This was first shown in 1980. Duffy negative individuals whose erythrocytes do not express the receptor are believed to be resistant to merozoite invasion [ 65 ]  although  P. vivax  infection has been reported in Duffy negative children in Kenya, suggesting a role in resistance to disease, not infection. [ 65 ]  This antigen may also play a role in  erythrocyte  invasion in the rodent malarial parasite  P. yoelii . The  epitope  Fy6 is required for  P. vivax  invasion. [ 21 ]


The protection to  P. vivax  malaria conferred by the absence of the Duffy antigen appears to be very limited at best in  Madagascar . Although 72% of the population are Duffy antigen negative, 8.8% of the Duffy antigen negative individuals were  asymptomatic carriers  of  P. vivax . [ 66 ]  Malaria has also been found in  Angola  and  Equatorial Guinea  in Duffy negative individuals. [ 67 ]   P. vivax  malaria in a Duffy antigen negative individual in  Mauritania  has also been reported. [ 68 ]  Similar infections have been reported in Brazil [ 69 ] [ 70 ]  and  Kenya . [ 65 ]  Additional cases of infection in Duffy antigen negative individuals have been reported from the Congo [ 71 ]  and Uganda. [ 72 ]  A study in  Brazil  of the protection against  P. vivax  offered by the lack of the Duffy antigen found no differential resistance to malaria vivax between Duffy antigen positive and negative individuals. [ 73 ]


Nancy Ma's night monkey ( A. nancymaae ) is used as an animal model of  P. vivax  infection. This species' erythrocytes possess the Duffy antigen and this antigen is used as the receptor for  P. vivax  on the erythrocytes in this species. [ 74 ]


Examination of this gene in 497 patients in the  Amazonas State , Brazil, made by the doctor Sérgio Albuquerque, suggests that the genotypes FY*A/FY*B-33 and FY*B/FY*B-33 (where -33 refers to the null mutation at position -33 in the GATA box) may have an advantage over the genotypes FY*A/FY*B and FY*A/FY*A, FY*A/FY*B, FY*A/FY*X and FY*B/FY*X. [ 75 ]  FY*A/FY*B and FY*A/FY*A genotypes showed to be associated with increased rates of  P. vivax  infection and FY*B/FY*X and FY*A/FY*X were shown to be associated with the low levels of parasitism.


A difference between the susceptibility to  Plasmodium vivax  malaria has been reported. [ 76 ]  Erythrocytes expressing Fya had 41-50% lower binding of  P. vivax  compared with Fyb cells. Individuals with the Fy(a+b-) phenotype have a 30-80% reduced risk of clinical vivax but not falciparum malaria.


The binding of platelet factor 4 ( CXCL4 ) appears to be critical for the platelet induced killing of  P. falciparum . [ 77 ]


The Duffy antigen binding protein in  P. vivax   is composed of three subdomains and is thought to function as a dimer. [ 78 ]  The critical DARC binding residues are concentrated at the dimer interface and along a relatively flat surface spanning portions of two subdomains.


A study in Brazil confirmed the protective effect of FY*A/FY*O against malaria. [ 79 ]  In contrast the genotype FY*B/FY*O was associated with a greater risk.


Asthma  is more common and tends to be more severe in those of African descent. There appears to be a correlation with both total  IgE  levels and asthma and mutations in the Duffy antigen. [ 80 ]


Duffy antigen plays a fundamental role on  hematopoiesis . [ 81 ]  Indeed,  nucleated red blood cells  present in the bone marrow have high expression of DARC, which facilitates their direct contact with  hematopoietic stem cells . The absence of erythroid DARC alters hematopoiesis including stem and progenitor cells, which ultimately gives rise to phenotypically distinct neutrophils. As a result, mature neutrophils of Duffy-negative individuals carry more molecular "weapons" against infectious pathogens. [ 82 ]  Therefore, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of DARC in the erythroid lineage. [ 81 ]


Individuals with the Duffy-null genotype have a persistently lower  neutrophil  count than the typical laboratory normal range, [ 83 ]  but the lower amount of circulating neutrophils associated with this genotype does not seem to confer an increased risk of infection. [ 84 ] [ 85 ]   Clinical use of the term "benign ethnic neutropenic" to describe this phenomenon remains widespread, but the term is problematic as the Duffy-null genotype is common in individuals with African and certain Middle Eastern ancestries, and the term implies that individuals with European ancestry have the normal reference neutrophil count. [ 81 ] [ 82 ]   The term "Duffy-null associated neutrophil count" (DANC) has been proposed as a replacement. [ 86 ]


The distinctive neutrophils that are formed in the absence of DARC on erythroid lineage (see above - role of DARC on hematopoiesis) readily leave the blood stream, which explains the apparent lower numbers of neutrophils in the blood of Duffy-null individuals. [ 81 ] [ 82 ]  Failure to recognize that individuals with African ancestry often have healthy Duffy-null antigen-associated neutrophil counts instead of neutropenia has historically contributed to inequity in access to medications that require blood monitoring due to risk of neutropenia, including chemotherapy and the antipsychotic medication clozapine. [ 87 ]  The lower number of circulating neutrophils can cause individuals with the Duffy-null genotype to fall below what typically would be considered safe to continue these treatments, despite new data showing that neutrophil functioning is preserved in these individuals. [ 88 ]


Interactions between the metastasis suppressor  KAI1  on tumor cells and the cytokine receptor DARC on adjacent vascular cells suppresses tumor  metastasis . [ 89 ]  In human breast cancer samples low expression of the DARC protein is significantly associated with estrogen receptor status, both lymph node and distant metastasis and poor survival. [ 90 ]


The procoagulant response to lipopolysaccharide (bacterial endotoxin) is reduced in Duffy antigen negative Africans compared with Duffy positive Whites. [ 91 ]  This difference is likely to involve additional genes.


A connection has been found between  HIV  susceptibility and the expression of the Duffy antigen. The absence of the DARC receptor appears to increase the susceptibility to infection by HIV. However once established, the absence of the DARC receptor appears to slow down the progression of the disease. [ 92 ]


HIV-1 appears to be able to attach to erythrocytes via DARC. [ 92 ]


The association between the Duffy antigen and HIV infection appears to be complex.  Leukopenia  (a low total white cell count) is associated with relatively poor survival in HIV infection and this association is more marked in  whites  than in  people of Black African descent , despite the (on average) lower white cell counts found in black Africans. This difference appears to correlate with a particular genotype (-46C/C) associated with the absence of the Duffy antigen. [ 93 ]  This genotype has only been found in black Africans and their descendants. The strength of this association increases inversely with the total white cell count. The basis for this association is probably related to the role of the Duffy antigen in  cytokine  binding but this has yet to be verified.


A study of 142 black South African high-risk female sex workers over 2 years revealed a seroconversion rate of 19.0%. [ 94 ]  Risk of seroconversion appeared to be correlated with Duffy-null-associated low neutrophil counts.


An association with the levels  monocyte chemoattractant protein-1  has been reported. [ 95 ]


In the  Sardinian population , an association of several variants in the DARC gene (coding and non-coding) correlates with increased serum levels of monocyte chemoattractant protein (MCP -1). A new variant in this population, consisting of the amino acid substitution of arginine for a cysteine at position 89 of the protein diminishes the ability to bind chemokines. [ 96 ]


DARC has also been linked to rheumatoid arthritis (RA), possibly displaying chemokines such as CXCL5 on the surface of endothelial cells within the synovium, increasing the recruitment of neutrophils in the disease state. [ 97 ]


The Duffy antigen has been implicated in lung transplantation rejection. [ 98 ]


An increased incidence of Duffy antigen has been reported in patients with multiple myeloma compared with healthy controls. [ 99 ]


The Duffy antigen is present in the normal pulmonary vascular bed. Its expression is increased in the vascular beds and alveolar septa of the lung parenchyma during suppurative pneumonia. [ 100 ]


Duffy antigen has been implicated in haemolytic disease of the newborn.


Experimental work has suggested that DARC expression inhibits prostate tumor growth. Men of black African descent are at greater risk of prostate cancer than are men of either European or Asian descendant (60% greater incidence and double the mortality compared to Whites). However, the contribution of DARC to this increased risk has been tested in  Jamaican  males of black African descent. [ 101 ]  It was found that none of the increased risk could be attributed to the DARC gene. The reason for this increased risk is as yet unknown.


Antibodies and a cellular response to the Duffy antigen have been associated with renal transplant rejection. [ 102 ]


Duffy antigen-negative individuals with  sickle cell anaemia  tend to sustain more severe organ damage than do those with the Duffy antigen. [ 103 ]  Duffy-positive patients exhibit higher counts of white blood cells, polynuclear neutrophils, higher plasma levels of IL-8 and RANTES than Duffy-negative patients. [ 104 ]


There is a ~10% increase in Fy expression in  Southeast Asian ovalocytosis  erythrocytes. [ 105 ]


A Duffy negative blood recipient may have a transfusion reaction if the donor is Duffy positive. [ 47 ]  Since most Duffy-negative people are of African descent, blood donations from people of black African origin are important to transfusion banks.


International Society for Blood Transfusion (ISBT) symbol: FY


ISBT number: 008


Gene symbol: FY


Gene name: Duffy blood group


Number of Duffy antigens: 6


Almost entirely IgG. IgG1 usually predominates.  IgM does occur but is rare.


Anti-Fy a  is a common antibody while anti-Fy b  is approximately 20 times less common., [ 106 ] [ 107 ]  They are reactive at body temperature and are therefore clinically significant, although they do not typically bind complement.  Antibodies are acquired through exposure (pregnancy or history of blood transfusion) and subsequent alloimmunization. They display dosage (react more strongly to homozygous cells versus heterozygous cells). [ 106 ]


Typically mild but may be serious, even fatal. Although these usually occur immediately they may occur after a delay (up to 24 hours). These reactions are usually caused by anti-Fy a  or anti-Fy b . anti-Fy3 may cause acute or delayed  hemolytic transfusion reactions , but only rarely. Anti-Fy5 may also cause delayed hemolytic transfusion reactions. [ 106 ]


Hemolytic disease of the fetus and newborn  is typically mild but rarely may be serious. Almost always due to anti-Fy a  and rarely anti-Fyb or Fy3.


Emergency bleeding control  describes actions that control  bleeding  from a  patient  who has suffered a  traumatic injury  or who has a medical condition that has caused bleeding. Many bleeding control techniques are taught as part of  first aid  throughout the world. [ 1 ]  Other advanced techniques, such as  tourniquets , are taught in advanced first aid courses and are used by  health professionals  to prevent blood loss by arterial bleeding. [ 2 ]  To manage bleeding effectively, it is important to be able to readily identify types of wounds and types of bleeding.


Wounds are normally described in a variety of ways.  Descriptions may include wound size (length) and thickness; plainly visible wound characteristics such as shape and open or closed; and origin, acute or chronic. [ 3 ]   The most common descriptors of wounds are these:


External bleeding is generally described in terms of the origin of the blood flow by vessel type.  The basic categories of external  bleeding  are:


The treatment of wounds depends on whether they are external or internal.


The  type of wound  ( incision ,  laceration ,  puncture , etc.) has a major effect on the way a wound is managed, as does the area of the body affected and presence of any foreign objects in the wound. A serious wound or any complication may require a call to  emergency medical services . Any wound requires being disinfected after it stops bleeding. The eyes and other delicate tissue require special products for disinfection.


Main methods of wound management are: [ 13 ]


Direct pressure is the common method. The pressure on the wound constricts the blood vessels manually, helping to stem blood flow.  When applying pressure, the type and direction of the wound may have an effect, for instance, a cut lengthways on the hand would be opened up by closing the hand into a fist, whilst a cut across the hand would be sealed by making a fist. A patient can apply pressure directly to their own wound, if their level of  consciousness  allows.


Ideally, a barrier, such as sterile, low-adherent gauze should be used between the pressure supplier and the wound, to help reduce chances of  infection  and help the wound to seal. Third parties assisting a patient are always advised to use protective  latex  or  nitrile   medical gloves  to reduce risk of infection or contamination passing either way.


Direct pressure can be used with some foreign objects protruding from a wound. Then, padding is applied from each side of the object to push in and seal the wound. The foreign objects are not removed until arriving to a medical center.


Elevation was commonly recommended for the control of haemorrhage. Some protocols continue to include it, but recent studies have failed to find any evidence of its effectiveness and it was removed from the  PHTLS  guidance in 2006. [ 14 ]


The cold can add some utility, at least to compress the blood vessels.


In situations where direct pressure and elevation are either not possible or proving ineffective, and there is a risk of  exsanguination , some training protocols advocate the use of pressure points to constrict the major artery that feeds the point of the bleed.  This is usually performed at a place where a  pulse  can be found, such as in the  femoral artery . [ 15 ]   There are significant risks involved in performing pressure point constriction, including  necrosis  of the area below the constriction, and most protocols give a maximum time for constriction (often around 10 minutes).  There is particularly high danger if constricting the  carotid artery  in the neck, as the brain is sensitive to  hypoxia  and brain damage can result within minutes of application of pressure. Pressure on the carotid artery can also cause vagal tone induced bradycardia, which can eventually stop the heart. Other dangers in use of a constricting method include  rhabdomyolysis , which is a buildup of toxins below the pressure point, which if released back into the main bloodstream may cause  kidney failure . [ citation needed ]


Another method of achieving constriction of the supplying artery is a  tourniquet  - a band tied tightly around a limb to restrict blood flow.  Tourniquets are routinely used to bring  veins  to the surface for  cannulation , though their use in emergency medicine is more limited.  Many armies carry a tourniquet as part of their personal first aid kit.


Improvised tourniquets, in addition to creating potential problems for the ongoing medical management of the patient, usually fail to achieve force enough to adequately compress the arteries of the limb.  As a result, they not only fail to stop arterial bleeding, but may actually increase bleeding by impairing venous bloodflow. [ 16 ]


Some protocols call for the use of clotting accelerating agents, which can be either externally applied as a powder or gel, or pre-dosed in a dressing or as an  intravenous  injection. These may be particularly useful in situations where the wound is not clotting, which can be due to external factors, such as size of wound, or medical factors such as  haemophilia . [ 17 ]


For stopping or preventing bleeding in people who do not have haemophilia, there is weak to little evidence to support the use of clotting factors to prevent death. [ 18 ]  Prophylactic fibrinogen may reduce the risk of bleeding after heart or orthoscopic surgery and prophylactic factor XII may be effective after heart surgery, however, both medications require high-quality randomized clinical trials to understand more about the potential benefits and risks. [ 18 ]   Recombinant factor VIIa ( rFVIIa ) is not, as of 2012, supported by the evidence for most cases of major bleeding. [ 19 ]  Its use brings a significant risk of arterial thrombosis, and therefore it should only be used in clinical trials or with patients with  factor VII deficiency . [ 19 ] [ 20 ]


A new product of this type (Cresilon Hemostatic Gel or  CHG ,  Vetigel  in its veterenary version) [ 21 ] [ 22 ]  allows to close great wounds in a few moments.


Internal wounds (usually to the  torso ) are harder to deal with than external wounds, although they often have an external cause. The key dangers of internal bleeding include  hypovolaemic shock  (leading to  exsanguination ), a  tamponade  on the heart or a  haemothorax  on the lung. The  aortic aneurysm  is a special case where the  aorta , the body's main blood vessel, becomes ruptured through an inherent weakness, although exertion, raised blood pressure or sudden movements could cause a sudden catastrophic failure. [ 23 ]  This is one of the most serious  medical emergencies  a patient can face, as the only treatment is rapid surgery.


An internal bleeding require to  call to emergency medical services .


In the event of bleeding caused by an external source (trauma, penetrating wound), the patient is usually inclined to the injured side, so that the 'good' side can continue to function properly, without interference from the blood inside the body cavity. [ citation needed ]


Use of cold around the damaged area (for example: with ice) can help to compress the blood vessels.


Treatment of internal bleeding is beyond the scope of simple first aid, and a person giving first aid should consider it potentially life-threatening.  The definitive treatment for internal bleeding is always surgical treatment, and medical advice must be sought urgently for any victim of internal bleeding. [ 24 ]


The  Er blood group system  consists of five human  red blood cell  surface  antigens , Er a , Er b , Er3, Er4 and Er5. [ 1 ]  The incidences of Er a  and Er3 are each greater than 99% of the human population, while the incidence of Er b  is less than 0.01%. [ 2 ] [ 3 ]  Er4 and Er5 are found at a high frequency in the general population. [ 1 ]


Individuals with  antibodies  against Er3 may develop  acute hemolytic transfusion reaction  upon transfusion with an incompatible unit, while Er a  and Er b  are unlikely to be clinically significant. [ 4 ]  The clinical significance of antibodies against Er4 and Er5 is poorly understood due to a lack of data, but two cases of severe  hemolytic disease of the fetus and newborn  have been reported in women with these antibodies. [ 1 ]  Expression of the Er blood group antigens is controlled by the gene  PIEZO1 . [ 1 ]


Er a  was first identified in 1982 and Er b  was identified in 1988. [ 2 ]  Er was recognized as a blood group collection by the  International Society of Blood Transfusion  in 1990 [ 2 ]  and promoted to a blood group in 2022. [ 1 ]


An  exchange transfusion  is a  blood transfusion  in which the  patient 's  blood  or components of it are exchanged with (replaced by) other blood or  blood products . [ 1 ]  The patient's blood is removed and replaced by donated blood or blood components. This exchange transfusion can be performed manually or using a machine ( apheresis ). [ 2 ]


Most blood transfusions involve adding blood or blood products without removing any blood, these are also known as  simple transfusions  or  top-up transfusions . [ 3 ] [ 4 ]


Exchange transfusion is used in the treatment of a number of  diseases , including  sickle-cell disease  and  hemolytic disease of the newborn . Partial exchange might be required for  polycythemia .


Nearly all exchange transfusions are  allogeneic  (that is, the new blood or blood products come from another person or persons, via donated blood);  autologous  exchange transfusion is possible (using autologous blood banking), but there are not many situations in which a need for it arises, as most autologous transfusions involve no exchange.


An exchange transfusion requires that the patient's blood can be removed and replaced. In most cases, this involves placing one or more thin tubes, called catheters, into a blood vessel. The exchange transfusion is done in cycles: each one usually lasts a few minutes. [ 1 ]


The patient’s blood is slowly withdrawn (usually about 5 to 20 mL at a time, depending on the patient’s size and the severity of illness), and a slightly larger amount of fresh, prewarmed blood or plasma flows into the patient's body. This cycle is repeated until the correct volume of blood has been replaced. [ 1 ]


After the exchange transfusion, catheters may be left in place in case the procedure needs to be repeated.


In diseases such as  sickle cell anemia , blood is removed and replaced with donor blood. [ 5 ]


In conditions such as neonatal polycythemia, a specific amount of the child’s blood is removed and replaced with normal saline, plasma (the clear liquid portion of blood), or an albumin solution. This decreases the total number of red blood cells in the body and makes it easier for blood to flow through the body. [ 5 ]


Transfusion therapy  is used as an emergency procedure to treat life-threatening complications of  sickle-cell disease  as well as an elective procedure to stop these complications occurring. [ 3 ] [ 4 ]


The commonest emergency reason is to treat an acute chest syndrome. [ 6 ]


The most common routine reason is to prevent a stroke occurring or re-occurring. [ 6 ]


Exchange transfusion to treat  hemolytic disease of the newborn  is now uncommon since the introduction of  Anti-D prophylaxis  in pregnancy. However, it can occur due to the development of other antibodies such as  anti-c ,  anti-E , and  ABO . [ 5 ]


Polycythemia , a condition in which the number of red cells in the blood is too high, is usually diagnosed when the  hematocrit  is above 65%. [ 8 ] [ 9 ]  Polycythemia can occur in neonates for multiple different reasons including: babies born after 42 weeks gestation (post-term), babies born to diabetic mothers,  twin to twin transfusion ,  intrauterine growth restriction , and babies with genetic abnormalities. [ 8 ]  Polycythemia can make the blood thicker than normal and therefore lead to complications. Partial exchange transfusion has been used as a treatment to prevent complications, and has been shown to improve cerebral blood flow, [ 10 ]  but there is no evidence that it prevents long-term complications. [ 8 ]


Exchange transfusion has been used for the treatment of severe  malaria  in the past. [ 11 ] [ 12 ]  However, in 2013 the CDC examined the limited evidence available and found no evidence that exchange transfusion has any beneficial effects (decreased mortality) in people with very high parasite loads (> 10%). [ 12 ]  Also, although uncommon, exchange transfusion can cause complications (low blood pressure ( hypotension ), abnormal heart rhythms ( ventricular fibrillation ) and breathing problems ( acute respiratory distress syndrome )). [ 12 ]  Based on this evidence, the CDC no longer recommend the use of exchange transfusion in the treatment of malaria. [ 12 ]


General risks are the same as with any transfusion. Other possible complications include: [ 1 ]


The person may need to be monitored for several days in the hospital after the transfusion, but the length of stay generally depends on the condition for which the exchange transfusion was performed. Sickle Cell Disease patients may be exchanged in an outpatient setting and can be sent home the very same day. [ 13 ]


The technique was originally developed by  Alexander S. Wiener , soon after he co-discovered the  Rh factor [ broken anchor ] . [ 14 ]


Febrile non-hemolytic transfusion reaction (FNHTR)  is the most common type of  transfusion reaction . It is a benign occurrence with symptoms that include  fever  but not directly related with  hemolysis . [ 1 ]  It is caused by  cytokine  release from leukocytes within the donor product as a consequence of white blood cell breakdown. [ 2 ] [ 3 ] [ 4 ]  These inflammatory mediators accumulate during the storage of the donated blood, [ 5 ]  and so the frequency of this reaction increases with the storage length of donated blood. [ 6 ]  This is in contrast to  transfusion-associated acute lung injury , in which the donor plasma has antibodies directed against the recipient HLA antigens, mediating the characteristic lung damage. [ citation needed ]


Symptoms must manifest within 4 hours of cessation of the transfusion, and should not be due to another cause such as an underlying infection, bacterial contamination of the blood component, or another type of transfusion reaction, e.g.  acute hemolytic transfusion reaction . [ 7 ]


Fever must be at least 38 °C/100.4 °F oral and a change of at least 1 °C/1.8 °F from pre-transfusion value OR chills and/or rigors must be present. [ 7 ] [ 8 ]


The UK hemovigilance system ( SHOT ) categorizes the severity of the reaction. [ 9 ]


Fever of at least 38 °C/100.4 °F oral and a change of between 1 and 2 °C from pre-transfusion values but no other symptoms or signs. [ 9 ]


Fever of at least 39 °C, OR a rise in temperature of at least 2 °C from pre-transfusion values AND/OR other symptoms or signs, including chills ( rigors ), painful muscles ( myalgia ), or  nausea  that are severe enough that the transfusion is stopped. [ 9 ]


Fever of at least 39 °C, OR a rise in temperature of at least 2 °C from pre-transfusion values AND/OR other symptoms or signs, including chills ( rigors ), painful muscles ( myalgia ), or  nausea  that are severe enough that the transfusion is stopped AND requires immediate medical treatment, admission to hospital, or lengthens the duration of hospital admission. [ 9 ]


Paracetamol  has been used in treatment, and  leukoreduction  of future transfusions is sometimes performed. [ 10 ]


Fresh frozen plasma  ( FFP ) is a  blood product  made from the liquid portion of  whole blood . [ 3 ]  It is used to treat conditions in which there are low  blood clotting factors  (INR > 1.5) or low levels of other  blood proteins . [ 3 ] [ 1 ]  It may also be used as the replacement fluid in  plasma exchange . [ 2 ] [ 4 ]  Using  ABO compatible  plasma, while not required, may be recommended. [ 5 ] [ 6 ]  Use as a  volume expander  is not recommended. [ 3 ]  It is administered by  slow injection into a vein . [ 2 ]


Side effects include nausea and itchiness. [ 3 ]  Rarely there may be  allergic reactions ,  blood clots , or  infections . [ 1 ] [ 3 ]  It is unclear if use during  pregnancy  or  breastfeeding  is safe for the baby. [ 2 ]  Greater care should be taken in people with  protein S deficiency ,  IgA deficiency , or  heart failure . [ 2 ]  Fresh frozen plasma is made up of a complex mixture of water,  proteins ,  carbohydrates , fats, and  vitamins . [ 1 ]  When frozen it lasts about a year. [ 1 ]


Plasma first came into medical use during the  Second World War . [ 1 ]  It is on the  World Health Organization's List of Essential Medicines . [ 7 ]  In the United Kingdom it costs about £30 per unit. [ 8 ]  A number of other versions also exist including  plasma frozen within 24 hours after phlebotomy ,  cryoprecipitate reduced plasma , thawed plasma, and  solvent detergent plasma . [ 1 ]


In the United States it refers to the fluid portion of one unit of  whole blood  that has been centrifuged, separated, and frozen solid at −18 °C (0 °F) or colder within eight hours of collection from whole blood donation or was otherwise collected via apheresis device. [ 9 ]  The phrase "FFP" is often used to mean any transfused plasma product. The other commonly transfused plasma, plasma frozen within 24 hours after phlebotomy ( PF24 ), has similar indications as those for FFP. PF24 has slightly lower levels of Factors V and VIII than FFP. PF24 is more commonly used than FFP in the United States.


There are few specific indications for FFP. These generally are limited to the treatment of deficiencies of coagulation proteins for which specific factor concentrates are unavailable or undesirable. A usual dose of plasma is 10–20 mL/kg recipient weight. [ 10 ]


Indications for the use of FFP include the following:


FFP is not recommended unless there is ongoing bleeding or there is a significant blood clotting problem. That is, FFP is not used in people to reverse warfarin if there is no bleeding, even for an INR > 9 unless they need urgent surgery. It is also not used in elective surgery, or non-emergency surgery. [ 13 ]


Thawed plasma is made from FFP or PF24 and kept refrigerated (at 1–6 °C) after thawing can be stored for 5 days post thaw. [ 10 ]


Prophylactic plasma  transfusions  might have an effect for people with a blood clotting disorder and receive an invasive procedure.


For people with a blood clotting disorder and receive a planned invasive non-cardiac procedure it is not certain if prophylactic plasma transfusions improve all-cause mortality up to 30 days, major bleeding within 24 hours, number of transfusions per participants within one week, number of individuals requiring a transfusion within one week and serious adverse events measured by plasma-related complications within 24 hours. [ 14 ]   Different triggers for fresh frozen plasma may have little to no effect on major bleeding within 24 hours and serious adverse events measured by plasma transfusion-related complications within 24 hours. Furthermore, different triggers for fresh frozen plasma may reduce the number of individuals requiring a transfusion within 7 days. [ 14 ]


The risks of FFP include disease transmission, anaphylactoid reactions, and excessive intravascular volume (transfusion associated circulatory overload (TACO)), as well as  transfusion related acute lung injury  (TRALI). Risks of transfusion transmitted infections are similar to that of whole blood and red blood cells.


FFP is made by  centrifugation  of whole blood or apheresis device followed by freezing and preservation.


The use of plasma and its products has evolved over a period of four decades. The use of FFP has increased tenfold in the United States between the years 2000 and 2010 and has reached almost 2 million units annually. [ citation needed ]  This trend may be attributable to multiple factors, possibly including decreased availability of whole blood due to widespread acceptance of the concept of component therapy.


Evidence indicates that other plasma components (e.g., single-donor plasma) that do not meet the criteria of FFP may have adequate levels of coagulation factors and are suitable for patients in whom FFP is indicated. Single-donor plasma is efficacious in the treatment of mild deficiencies of stable clotting factors. It also is of value in treatment of multiple deficiencies as in reversal of warfarin effects or in liver disease. [ citation needed ]


Safe and effective alternative treatment often exists so that FFP is no longer the therapy of choice in many conditions.  Cryoprecipitate  or fibrinogen concentrates should be used when fibrinogen is needed. For treatment of  hemophilia A , recombinant factor VIII concentrates are available. For treatment of severe  hemophilia B , recombinant factor IX concentrates are available.


Crystalloid or colloid solutions such as  human serum albumin  or plasma protein fraction, are preferable to FFP for volume replacement.


For nutritional support,  amino acid  solutions and  dextrose  are available. [ citation needed ]  The most important alternative to the use of FFP is a comprehensive program of blood conservation. This includes measures such as  intraoperative cell salvage [ 10 ]  and the realization that in many patients  normovolemic anemia  is not an indication for transfusion. [ citation needed ]


Gastrointestinal bleeding  ( GI bleed ), also called  gastrointestinal hemorrhage  ( GIB ), is all forms of  bleeding  in the  gastrointestinal tract , from the  mouth  to the  rectum . [ 9 ]  When there is significant  blood  loss over a short time, symptoms may include  vomiting red blood ,  vomiting black blood ,  bloody stool , or  black stool . [ 1 ]  Small amounts of bleeding over a long time may cause  iron-deficiency anemia  resulting in  feeling tired  or  heart-related chest pain . [ 1 ]  Other symptoms may include  abdominal pain ,  shortness of breath ,  pale skin , or  passing out . [ 1 ] [ 9 ]  Sometimes in those with small amounts of bleeding no symptoms may be present. [ 1 ]


Bleeding is typically divided into two main types:  upper gastrointestinal bleeding  and  lower gastrointestinal bleeding . [ 2 ]  Causes of upper GI bleeds include:  peptic ulcer  disease,  esophageal varices  due to liver  cirrhosis  and  cancer , among others. [ 3 ]   Causes of lower GI bleeds include:  hemorrhoids , cancer, and  inflammatory bowel disease  among others. [ 2 ] [ 1 ]  Small amounts of bleeding may be detected by  fecal occult blood  test. [ 1 ]   Endoscopy  of the lower and upper gastrointestinal tract may locate the area of bleeding. [ 1 ]   Medical imaging  may be useful in cases that are not clear. [ 1 ]  Bleeding may also be diagnosed and treated during  minimally invasive   angiography  procedures such as  hemorrhoidal artery embolization . [ 10 ] [ 11 ]


Initial treatment focuses on  resuscitation  which may include  intravenous fluids  and  blood transfusions . [ 4 ]  Often blood transfusions are not recommended unless the  hemoglobin  is less than 70 or 80 g/L. [ 7 ] [ 12 ]  Treatment with  proton pump inhibitors ,  octreotide , and  antibiotics  may be considered in certain cases. [ 5 ] [ 6 ] [ 13 ]  If other measures are not effective, an  esophageal balloon  may be attempted in those with presumed esophageal varices. [ 2 ]   Endoscopy of the esophagus, stomach, and duodenum  or  endoscopy of the large bowel  are generally recommended within 24 hours and may allow treatment as well as diagnosis. [ 4 ]


An upper GI bleed is more common than lower GI bleed. [ 2 ]  An upper GI bleed occurs in 50 to 150 per 100,000 adults per year. [ 8 ]  A lower GI bleed is estimated to occur in 20 to 30 per 100,000 per year. [ 2 ]  It results in about 300,000 hospital admissions a year in the  United States . [ 1 ]  Risk of death from a GI bleed is between 5% and 30%. [ 1 ] [ 7 ]  Risk of bleeding is more common in males and increases with age. [ 2 ]


Gastrointestinal bleeding can be roughly divided into two clinical syndromes:  upper gastrointestinal bleeding  and  lower gastrointestinal bleeding . [ 2 ]  About 2/3 of all GI bleeds are from upper sources and 1/3 from lower sources. [ 14 ]  Common causes of gastrointestinal bleeding include  infections ,  cancers , vascular disorders, adverse effects of medications, and  blood clotting disorders . [ 2 ]  Obscure gastrointestinal bleeding (OGIB) is when a source is unclear following investigation. [ 15 ]


Upper gastrointestinal bleeding is from a source between the  pharynx  and the  ligament of Treitz . An upper source is characterised by  hematemesis  (vomiting up blood) and  melena  (tarry stool containing altered blood). About half of cases are due to  peptic ulcer disease  ( gastric  or  duodenal ulcers ). [ 3 ]   Esophageal inflammation  and erosive disease are the next most common causes. [ 3 ]  In those with  liver cirrhosis , 50–60% of bleeding is due to  esophageal varices . [ 3 ]  Approximately half of those with peptic ulcers have an  H. pylori  infection. [ 3 ]  Other causes include  Mallory-Weiss tears , cancer, and  angiodysplasia . [ 2 ]


A number of medications are found to cause upper GI bleeds. [ 16 ]   NSAIDs  or  COX-2 inhibitors  increase the risk about fourfold. [ 16 ]   SSRIs ,  corticosteroids , and  anticoagulants  may also increase the risk. [ 16 ]  The risk with  dabigatran  is 30% greater than that with  warfarin . [ 17 ]


Lower gastrointestinal bleeding is typically from the colon, rectum or anus. [ 2 ]  Common causes of lower gastrointestinal bleeding include  hemorrhoids , cancer, angiodysplasia,  ulcerative colitis ,  Crohn's disease , and  aortoenteric fistula . [ 2 ]  It may be indicated by the passage of  fresh red blood rectally , especially in the absence of  bloody vomiting . Lower gastrointestinal bleeding could also lead to melena if the bleeding occurs in the small intestine or proximal colon. [ 1 ]


Gastrointestinal bleeding can range from small non-visible amounts, which are only detected by laboratory testing, to massive bleeding where bright red blood is passed and  shock  develops. Rapid bleeding may cause  syncope . [ 18 ]  The presence of bright red blood in stool, known as  hematochezia , typically indicates lower gastrointestinal bleeding. Digested blood from the upper gastrointestinal tract may appear black rather than red, resulting in "coffee ground" vomit or melena. [ 2 ]  Other signs and symptoms include  feeling tired ,  dizziness , and pale skin color. [ 18 ]


A number of foods and medications can turn the stool either red or black in the absence of bleeding. [ 2 ]   Bismuth  found in many antacids may turn stools black as may  activated charcoal . [ 2 ]  Blood from the vagina or urinary tract may also be confused with blood in the stool. [ 2 ]


Diagnosis is often based on direct observation of blood in the stool or vomit.  Although  fecal occult blood  testing has been used in an emergency setting, this use is not recommended as the test has only been validated for colon cancer screening. [ 19 ]  Differentiating between upper and lower bleeding in some cases can be difficult. The severity of an upper GI bleed can be judged based on the  Blatchford score [ 4 ]  or  Rockall score . [ 16 ]  The Rockall score is the more accurate of the two. [ 16 ]  As of 2008 there is no scoring system useful for lower GI bleeds. [ 16 ]


Gastric aspiration and or lavage , where a tube is inserted into the stomach via the nose in an attempt to determine if there is blood in the stomach, if negative does not rule out an upper GI bleed [ 20 ]  but if positive is useful for ruling one in. [ 14 ]  Clots in the stool indicate a lower GI source while melana stools an upper one. [ 14 ]


Recommended laboratory blood testing includes: cross-matching blood, hemoglobin, hematocrit, platelets, coagulation time, and electrolytes. [ 4 ]  If the ratio of  blood urea nitrogen  to  creatinine  is greater than 30 the source is more likely from the upper GI tract. [ 14 ]


A  CT angiography  is useful for determining the exact location of the bleeding within the gastrointestinal tract. [ 21 ]  Nuclear scintigraphy is a sensitive test for detecting occult gastrointestinal bleeding when direct imaging with upper and lower endoscopies are negative. Direct angiography allows for embolization of a bleeding source, but requires a bleeding rate faster than 1mL/minute. [ 22 ]


In patients with significant varices or cirrhosis  nonselective β-blockers  reduce the risk of future bleeding. [ 13 ]  With a target heart rate of 55 beats per minute B-blockers reduce the absolute risk of bleeding by 10%. [ 13 ]   Endoscopic band ligation  (EBL) is also effective at improving outcomes. [ 13 ]  Either B-blockers or EBL is recommended as initial preventative measures. [ 13 ]  In patients who have had a previous variceal bleed both treatments are recommended. [ 13 ]  Some evidence supports the addition of  isosorbide mononitrate . [ 23 ]  Testing for and treating those who are positive for  H. pylori  is recommended. [ 16 ]   Transjugular intrahepatic portosystemic shunting  (TIPS) may be used to prevent bleeding in people who re-bleed despite other measures. [ 16 ]


Among patients admitted to the ICU with high risk of bleeding, a PPI or H2RA appears useful. [ 24 ] [ 25 ]


The initial focus is on  resuscitation  beginning with airway management and fluid resuscitation using either intravenous fluids and or blood. [ 4 ]  A number of medications may improve outcomes depending on the source of the bleeding. [ 4 ]


Based on evidence from people with other health problems  crystalloid  and  colloids  are believed to be equivalent for peptic ulcer bleeding. [ 4 ]   Proton pump inhibitor  (PPI) treatment before endoscopy may decrease the need for endoscopic hemostatic treatment, however it is not clear if this treatment reduces mortality, the risk of re-bleeding, or the  [ clarification needed ]  and the need for surgery. [ 26 ]  Oral and intravenous formulations may be equivalent; however, the evidence to support this is suboptimal. [ 27 ]  In those with less severe disease and where endoscopy is rapidly available, they are of less immediate clinical importance. [ 26 ]  There is tentative evidence of benefit for  tranexamic acid  which inhibits clot breakdown. [ 28 ]   Somatostatin  and  octreotide , while recommended for varicial bleeding, have not been found to be of general use for non variceal bleeds. [ 4 ]  After treatment of a high risk bleeding ulcer endoscopically giving a PPI once or a day rather than as an infusion appears to work just as well and is less expensive (the method may be either by mouth or intravenously). [ 29 ]


For initial fluid replacement, colloids or  albumin  is preferred in people with cirrhosis. [ 4 ]  Medications typically include  octreotide  or, if not available,  vasopressin  and  nitroglycerin  to reduce portal venous pressures. [ 13 ]   Terlipressin  appears to be more effective than octreotide, but it is not available in many areas of the world. [ 16 ] [ 30 ]  It is the only medication that has been shown to reduce mortality in acute variceal bleeding. [ 30 ]  This is in addition to  endoscopic banding  or  sclerotherapy  for the varices. [ 13 ]  If this is sufficient then  beta blockers  and  nitrates  may be used for the prevention of re-bleeding. [ 13 ]  If bleeding continues, balloon tamponade with a  Sengstaken-Blakemore tube  or  Minnesota tube  may be used in an attempt to mechanically compress the varices. [ 13 ]  This may then be followed by a  transjugular intrahepatic portosystemic shunt . [ 13 ]  In those with cirrhosis,  antibiotics  decrease the chance of bleeding again, shorten the length of time spent in hospital, and decrease mortality. [ 5 ]  Octreotide reduces the need for blood transfusions [ 31 ]  and may decrease mortality. [ 32 ]  No trials of  vitamin K  have been conducted. [ 33 ]


The evidence for benefit of blood transfusions in GI bleed is poor with some evidence finding harm. [ 8 ]  In those in  shock   O-negative packed red blood cells  are recommended. [ 2 ]  If large amounts of pack red blood cells are used additional  platelets  and  fresh frozen plasma  (FFP) should be administered to prevent  coagulopathies . [ 4 ]  In  alcoholics  FFP is suggested before confirmation of a coagulopathy due to presumed blood clotting problems. [ 2 ]  Evidence supports holding off on blood transfusions in those who have a  hemoglobin  greater than 7 to 8 g/dL and moderate bleeding, including in those with preexisting  coronary artery disease . [ 7 ] [ 12 ]


If the INR is greater than 1.5 to 1.8 correction with fresh frozen plasma or  prothrombin complex  may decrease mortality. [ 4 ]  Evidence of a harm or benefit of  recombinant activated factor VII  in those with liver diseases and gastrointestinal bleeding is not determined. [ 34 ]  A  massive transfusion protocol  may be used, but there is a lack of evidence for this indication. [ 16 ]


The benefits versus risks of placing a  nasogastric tube  in those with upper GI bleeding are not determined. [ 4 ]  Endoscopic evaluation within 24 hours is recommended, [ 4 ]  in addition to medical management. [ 35 ]  A number of endoscopic treatments may be used, including:  epinephrine  injection, band ligation, sclerotherapy, and fibrin glue depending on what is found. [ 2 ]  Prokinetic agents such as  erythromycin  before endoscopy can decrease the amount of blood in the stomach and thus improve the operators view. [ 4 ]  They also decrease the amount of blood transfusions required. [ 36 ]  Early endoscopy decreases hospital and the amount of blood transfusions needed. [ 4 ]  A second endoscopy within a day is routinely recommended by some [ 16 ]  but by others only in specific situations. [ 22 ]  Proton pump inhibitors, if they have not been started earlier, are recommended in those in whom high risk signs for bleeding are found. [ 4 ]  High and low dose PPIs appear equivalent at this point. [ 37 ]  It is also recommended that people with high risk signs are kept in hospital for at least 72 hours. [ 4 ]  Those at low risk of re-bleeding may begin eating typically 24 hours following endoscopy. [ 4 ]  If other measures fail or are not available,  esophageal balloon tamponade  may be attempted. [ 2 ]  While there is a success rate up to 90%, there are some potentially significant complications including  aspiration  and  esophageal perforation . [ 2 ]


Colonoscopy  is useful for the diagnosis and treatment of lower GI bleeding. [ 2 ]  A number of techniques may be employed including clipping, cauterizing, and sclerotherapy. [ 2 ]  Preparation for colonoscopy takes a minimum of six hours which in those bleeding briskly may limit its applicability. [ 38 ]  Surgery, while rarely used to treat upper GI bleeds, is still commonly used to manage lower GI bleeds by cutting out the part of the intestines that is causing the problem. [ 2 ]   Angiographic embolization  may be used for both upper and lower GI bleeds. [ 2 ]   Transjugular intrahepatic portosystemic shunting  (TIPS) may also be considered. [ 16 ]


Death in those with a GI bleed is more commonly due to other illnesses (some of which may have contributed to the bleed, such as cancer or cirrhosis) than the bleeding itself. [ 2 ]  Of those admitted to a hospital because of a GI bleed, death occurs in about 7%. [ 16 ]  Despite treatment, re-bleeding occurs in about 7–16% of those with upper GI bleeding. [ 3 ]  In those with esophageal varices, bleeding occurs in about 5–15% a year and if they have bled once, there is a higher risk of further bleeding within six weeks. [ 13 ]  Testing and treating  H. pylori  if found can prevent re-bleeding in those with peptic ulcers. [ 4 ]  The benefits versus risks of restarting blood thinners such as  aspirin  or  warfarin  and  anti-inflammatories  such as  NSAIDs  need to be carefully considered. [ 4 ]  If aspirin is needed for cardiovascular disease prevention, it is reasonable to restart it within seven days in combination with a PPI for those with nonvariceal upper GI bleeding. [ 22 ]


Gastrointestinal bleeding from the upper tract occurs in 50 to 150 per 100,000 adults per year. [ 8 ]  It is more common than lower gastrointestinal bleeding which is estimated to occur at the rate of 20 to 30 per 100,000 per year. [ 2 ]  Risk of bleeding is more common in males and increases with age. [ 2 ]


Globosides  (also known as  globo-series glycosphingolipids ) are a sub-class of the lipid class  glycosphingolipid [ 1 ]  with three to nine  sugar  molecules as the side chain (or  R group ) of  ceramide . The sugars are usually a combination of  N -acetylgalactosamine ,  D -glucose  or  D -galactose . One characteristic of globosides is that the "core" sugars consists of Glucose-Galactose-Galactose (Ceramide-βGlc4-1βGal4-1αGal), like in the case of the most basic globoside,  globotriaosylceramide  (Gb3), [ 2 ]  also known as pk-antigen. Another important characteristic of globosides is that they are neutral at pH 7, because they usually do not contain  neuraminic acid , a sugar with an acidic carboxy-group. However, some globosides with the core structure Cer-Glc-Gal-Gal do contain neuraminic acid, e.g. the globo-series glycosphingolipid "SSEA-4-antigen".


The side chain can be cleaved by  galactosidases  and  glucosidases . The deficiency of  α-galactosidase A  causes  Fabry's disease , an inherited metabolic disease characterized by the accumulation of the globoside  globotriaosylceramide . [ 3 ]


Globoside 4 (Gb4) has been known as the receptor for  parvovirus B19 , due to observations that B19V binds to the thin-layered  chromatogram  of the  structure .  However, the binding on its surface does not match well with the  virus , which raised debates on whether or not GB4 is the cause for productive infection. [ 4 ]  Additional research using the technique Knockout Cell Line has shown that although GB4 does not have the direct entry  receptor  for B19V, it plays a post-entry role in productive infection. [ 5 ]


Globoside 4 (Gb4) are a type of  SSEA , stage-specific embryonic antigen, that is present in cellular development and tumorous tissues without the mechanism of Gb4 being completely known. However a study has shown Gb4 directly activates the epidermal growth factor receptor through a ERK signaling. When the globo-series glycosphingolipid (GSL) was reduced in the experiment the ERK signaling from the receptor tyrosine kinase was also inhibited. The ERK was reactivated with the addition of the Gb4 and henceforth heightened proliferation of tumorous cells and opened up the possibility of testing Gb4 for further studies on potential drugs that can target cancerous cells. [ 6 ]


Globoside-5 is also known as  stage-specific embryonic antigen 3 .


Glycophorin C  ( GYPC ;  CD236 / CD236R ;  glycoprotein beta ;  glycoconnectin ;  PAS-2 ' ) plays a functionally important role in maintaining erythrocyte shape and regulating membrane material properties, possibly through its interaction with protein 4.1. Moreover, it has previously been shown that membranes deficient in protein 4.1 exhibit decreased content of glycophorin C. It is also an  integral membrane protein  of the  erythrocyte  and acts as the  receptor  for the  Plasmodium falciparum  protein PfEBP-2 (erythrocyte binding protein 2; baebl; EBA-140).


The antigen was discovered in 1960 when three women who lacked the antigen made anti-Gea in response to pregnancy. The antigen is named after one of the patients – a Mrs Gerbich. [ 1 ]  The following year a new but related antigen was discovered in a Mrs Yus for whom an antigen in this system is also named. In 1972 a numerical system for the antigens in this blood group was introduced.


Despite the similar names glycophorin C and D are unrelated to the other three glycophorins which encoded on  chromosome 4  at location 4q28-q31. These latter proteins are closely related.  Glycophorin A  and  glycophorin B  carry the  blood group   MN  and  Ss   antigens  respectively. There are ~225,000 molecules of GPC and GPD per erythrocyte. [ 2 ]


Originally it was thought that glycophorin C and D were the result of a gene duplication event but it was only later realised that they were encoded by the same gene. Glycophorin D (GPD) is generated from the glycophorin C  messenger RNA  by  leaky translation  at an in frame AUG at  codon  30: glycophorin D =  glycophorin  C residues 30 to 128. This leaky translation appears to be a uniquely human trait. [ 3 ]


Glycophorin C (GPC) is a single  polypeptide  chain of 128  amino acids  and is encoded by a  gene  on the long arm of  chromosome 2  (2q14-q21). The gene was first cloned in 1989 by High  et al. [ 4 ]  The GPC gene is organized in four  exons  distributed over 13.5 kilobase pairs of  DNA . Exon 1 encodes residues 1-16, exon 2 residues 17-35, exon 3 residues 36-63 and exon 4 residues 64-128. Exons 2 and 3 are highly homologous, with less than 5% nucleotide divergence. These exons also differ by a 9 amino acid insert at the 3' end of exon 3. The direct repeated segments containing these exons is 3.4 kilobase pairs long and may be derived from a recent duplication of a single ancestral domain. Exons 1, 2 and most of exon 3 encode the N-terminal extracellular domain while the remainder of exon 3 and exon 4 encode transmembrane and cytoplasmic domains.


Two  isoforms  are known and the gene is expressed in a wide variety of  tissues  including  kidney ,  thymus ,  stomach ,  breast , adult  liver  and erythrocyte. In the non erythroid cell lines, expression is lower than in the erythrocyte and the protein is differentially  glycosylated . In the erythrocyte glycophorin C makes up ~4% of the membrane  sialoglycoproteins . The average number of O linked chains is 12 per molecule.


The  gene  is expressed early in the development of the erythrocyte, specifically in the erythroid  burst-forming unit  and erythroid  colony-forming unit . The mRNA from human erythroblasts is ~1.4 kilobases long and the transcription start site in erythroid cells has been mapped to 1050 base pairs 5' of the start codon. It is expressed early in development and before the  Kell antigens ,  Rhesus-associated glycoprotein , glycophorin A,  band 3 , the  Rhesus antigen  and glycophorin B. [ 5 ]


In melanocytic cells Glycophorin C gene expression may be regulated by  MITF . [ 6 ]


GPC appears to be synthesized in excess in the erythrocyte and that the membrane content is regulated by band 4.1 (protein 4.1). Additional data on the regulation of glycophorin C is  here .


In a study of this gene among the  Hominoidea  two finding unique to humans emerged: (1) an excess of non-synonymous divergence among species that appears to be caused solely by accelerated evolution and (2) the ability of the single GYPC gene to encode both the GPC and GPD proteins. [ 3 ]  The cause for this is not known but it was suggested that these findings might be the result of infection by  Plasmodium falciparum .


After separation of red cell membranes by  SDS-polyacrylamide gel electrophoresis  and staining with  periodic acid-Schiff staining  (PAS) four glycophorins have been identified. These have been named glycophorin A, B, C and D in order of the quantity present in the membrane – glycophorin A being the most and glycophorin D the least common. A fifth ( glycophorin E ) has been identified within the human genome but cannot easily be detected on routine gel staining. In total the glycophorins constitute ~2% of the total erythrocyte membrane protein mass. Confusingly these proteins are also known under different nomenclatures but they are probably best known as the glycophorins.


Glycophorin C was first isolated in 1978. [ 7 ]  Glycophorin C and D are minor sialoglycoproteins contributing to 4% and 1% to the PAS-positive material and are present at about 2.0 and 0.5 x 10 5  copies/cell respectively. In polyacrylimide gels glycophorin C's apparent weight is 32 kilodaltons (32 kDa). Its structure is similar to that of other glycophorins: a highly glycoslated extracellular domain (residues 1-58), a transmembrane domain (residues 59-81) and an intracellular domain (residues 82-128). About 90% of the glycophorin C present in the erythrocyte is bound to the cytoskeleton and the remaining 10% moves freely within the membrane.


Glycophorin D's apparent molecular weight is 23kDa. On average this protein has 6 O linked oligosaccharides per molecule.


Within the erythrocyte it interacts with  band 4.1  (an 80-kDa protein) and p55 (a  palmitoylated  peripheral membrane phosphoprotein and a member of the membrane-associated guanylate kinase family) to form a  ternary complex  that is critical for the shape and stability of erythrocytes. The major attachment sites between the erythrocyte  spectrin - actin   cytoskeleton  and the lipid bilayer are glycophorin C and  band 3 . The interaction with band 4.1 and p55 is mediated by the N terminal 30 kD domain of band 4.1 binding to a 16 amino acid segment (residues 82-98: residues 61-77 of glycophorin D) within the cytoplasmic domain of glycophorin C and to a positively charged 39 amino acid motif in p55. [ 8 ]  The majority of  protein 4.1  is bound to glycophorin C. The magnitude of the strength of the interaction between glycophorin C and band 4.1 has been estimated to be 6.9 microNewtons per meter, a figure typical of protein–protein interactions.


Glycophorin C normally shows oscillatory movement in the erythrocyte membrane. This is reduced in  Southeast Asian ovalocytosis  a disease of erythrocytes due to a mutation in band 3. [ 9 ]


These glycophorins are associated with eleven antigens of interest to transfusion medicine: the Gerbich (Ge2, Ge3, Ge4), the Yussef (Yus), the Webb (Wb or Ge5), the Duch (Dh(a) or Ge8), the Leach, the Lewis II (Ls(a) or Ge6), the Ahonen (An(a) or Ge7) and GEPL (Ge10*), GEAT (Ge11*) and GETI (Ge12*). Six are of high prevalence (Ge2, Ge3, Ge4, Ge10*, Ge11*, Ge12*) and five of low prevalence (Wb, Ls(a), An(a), Dh(a) and Ge9). [ 10 ]


Glycophorin C and D encode the Gerbich (Ge)  antigens . There are four  alleles , Ge-1 to Ge-4. Three types of Ge antigen negativity are known: Ge-1,-2,-3 (Leach phenotype), Ge-2,-3 and Ge-2,+3. A 3.4 kilobase pair deletion within the gene, which probably arose because of unequal crossing over between the two repeated domains, is responsible for the formation of the Ge-2,-3  genotype . The breakpoints of the deletion are located within  introns  2 and 3 and results in the deletion of  exon  3. This mutant gene is transcribed as a  messenger RNA  with a continuous  open reading frame  extending over 300  nucleotides  and is translated into the  sialoglycoprotein  found on Ge-2,-3 red cells. A second 3.4 kilobase pair deletion within the glycophorin C gene eliminates only exon 2 by a similar mechanism and generates the mutant  gene  encoding for the abnormal glycoprotein found on Ge-2,+3 erythrocytes.


The Ge2 epitope is antigenic only on glycophorin D and is a  cryptic antigen  in glycophorin C. It is located within exon 2 and is sensitive to  trypsin  and  papain  but resistant to  chymotrypsin  and  pronase . The Ge3 epitope is encoded by exon 3. It is sensitive to  trypsin  but resistant to  chymotrypsin ,  papain  and  pronase . It is thought to lie in the between amino acids 42-50 in glycophorin C (residues 21-49 in glycophorin D). Ge4 is located within the first 21 amino acids of glycophorin C. It is sensitive to trypsin, papain, pronase and  neuraminidase .


The relatively rare Leach phenotype is due either to a deletion in exons 3 and 4 or to a  frameshift mutation  causing a premature stop codon in the glycophorin C gene, and persons with this phenotype are less susceptible (~60% of the control rate) to invasion by  Plasmodium falciparum . Such individuals have a subtype of a condition called  hereditary elliptocytosis .
The abnormally shaped cells are known as elliptocytes or cameloid cells. The basis for this phenotype was first reported by Telen  et al. [ 11 ]  The phenotype is Ge:-2,-3,-4.


The Yussef (Yus)  phenotype  is due to a 57 base pair deletion corresponding to exon 2. The antigen is known as GPC Yus.


Glycophorin C mutations are rare in most of the Western world, but are more common in some places where malaria is endemic. In  Melanesia  a greater percentage of the population is Gerbich negative (46.5%) than in any other part of the world. The incidence of Gerbich-negative phenotype caused by an exon 3 deletion in the Wosera ( East Sepik Province ) and Liksul ( Madang Province ) populations of  Papua New Guinea  is 0.463 and 0.176 respectively. [ 12 ]


The rare Webb (Wb) antigen (~1/1000 donors), originally described in 1963 in  Australia , is the result of an alteration in  glycosylation  of glycophorin C: an A to G transition at nucleotide 23 results in an  asparagine  residue instead of the normal  serine  residue with the resultant loss of glycosylation. [ 13 ]  The antigen is known as GPC Wb.


The rare Duch (Dh) antigen was discovered in  Aarhus ,  Denmark  (1968) and is also found on glycophorin C. It is due to a C to T  transition  at  nucleotide  40 resulting in the replacement of  leucine  by  phenylalanine . [ 14 ]  This antigen is sensitive to trypsin but resistant to chymotrypsin and Endo F. [ 15 ]


The Lewis II (Ls(a); Ge-6) antigen has insert of 84 nucleotides into the ancestral GPC gene: the insert corresponds to the entire sequence of exon 3. [ 16 ]  Two subtypes of this antigen are known: beta Ls(a) which carries the Ge3 epitope and gamma Ls(a) which carries both the Ge2 and Ge3 epitopes. This antigen is also known as the Rs(a) antigen. [ 17 ]


The Ahonen (Ana) antigen was first reported in 1972. [ 18 ]
The antigen is found on glycophorin D. This antigen was discovered in a Finnish man on May 5, 1968, during post operative blood cross matching for an aortic aneurism repair. In Finland the incidence of this antigen was found to be 6/10,000 donors. In Sweden the incidence was 2/3266 donors. The molecular basis for the origin of this antigen lies within exon 2 where a G->T substitution in codon 67 (base position 199) converts an  alanine  to a  serine  residue. While this epitope exists within glycophorin C there it is a cryptantigen. It is only antigenic in glycophorin D because of the truncated N terminus.


A duplicated exon 2 has erythrocytes also been reported in Japanese blood donors (~2/10,000). This mutation has not been associated with a new antigen. [ 19 ]


Antibodies to the Gerbich antigens have been associated with transfusion reactions and mild  hemolytic disease  of the newborn.
In other studies naturally occurring anti-Ge antibodies have been found and appear to be of no clinical significance. Immunological tolerance towards Ge antigen has been suggested.


High expression of glycophorin C has been associated with a poor prognosis for acute lymphoblastic leukaemia in Chinese populations. [ 20 ]


Glycophorin C is the receptor for the protein erythrocyte binding antigen 140 (EBA140) of  Plasmodium falciparum . [ 21 ]  This interaction mediates a principal invasion pathway into the erythrocytes. The partial resistance of erythrocytes lacking this protein to invasion by  P. falciparum  was first noted in 1982. [ 22 ]  The lack of Gerbich antigens in the population of Papua New Guinea was noted in 1989. [ 23 ]


Influenza A and B bind to glycophorin C. [ 24 ]


A  granulocyte transfusion  is a medical procedure in which  granulocytes  are infused into a person's blood. Granulocytes are a category of  white blood cell  that includes  neutrophils ,  eosinophils , and  basophils . [ 1 ] : 99   Granulocyte transfusions were historically used to prevent and treat infections in people with  neutropenia  (an abnormally low level of  neutrophils ), but the practice declined in popularity in the 1980s. Interest in the procedure increased in the 1990s due to the development of more effective methods for harvesting granulocytes and a growing population of people with severe neutropenia from  chemotherapy . However, the treatment's efficacy remains poorly understood and its use is controversial. [ 2 ] [ 3 ] [ 4 ]


Granulocytes are most often collected through  leukapheresis , a process that separates the donor's white blood cells from their  red blood cells  and  plasma . Donors may be given  corticosteroids  or  granulocyte colony-stimulating factor  to increase their granulocyte count prior to the blood collection. Granulocytes have a short shelf life and it is recommended that they are transfused within hours of collection. Adverse effects from granulocyte transfusions include  fever ,  chills ,  respiratory  symptoms,  transfusion-transmitted infections , and the development of  antibodies  against  human leukocyte antigens , which can interfere with subsequent transfusions. [ 2 ]


Neutrophils are the most common type of granulocyte in normal blood, [ 5 ] : 82   and they play a major role in defending against infections, especially those caused by  fungi  and  bacteria . [ 6 ]  People with severe  neutropenia , a low neutrophil count, have an increased risk of developing serious infections. One of the approaches to preventing and treating infections in people with neutropenia is to increase the neutrophil count, which is commonly done using drugs like  G-CSF  to stimulate the production of neutrophils in the  bone marrow . [ 6 ]  However, another approach is to directly transfuse granulocytes from a donor into the person's blood. [ 2 ]


As of 2015, there is some evidence that granulocyte transfusions may help to prevent  bacteremia  and  fungemia  in adults who have neutropenia caused by  chemotherapy  or  hematopoietic stem cell transplantation . However, it is unclear whether this has any impact on  mortality  or major adverse events, [ 7 ]  and the use of granulocyte transfusions to prevent infections is considered controversial because of the potential for serious  side effects . [ 2 ]  Although the studies performed to date have been low-quality, a 2016 review suggested that granulocyte transfusion may not be effective for treating infections in adults with neutropenia. [ 8 ]  In both cases, the treatment is considered  investigational . [ 7 ] [ 8 ]


Granulocyte transfusion is still used in some cases, such as in cases of severe neutropenia and where the patient has a life-threatening infection that does not respond to  antimicrobial treatment . [ 2 ]  The treatment has also been studied in people with  aplastic anemia  (a condition in which a person's bone marrow does not produce enough blood cells) and  chronic granulomatous disease  (a disorder in which a person has a normal number of neutrophils, but they do not function correctly). Newborn babies who have neutropenia and  sepsis  are sometimes given granulocyte transfusions, [ 2 ]  although a 2011 study found that there was insufficient evidence to determine whether or not this practice is effective. [ 9 ]


Prior to donating granulocytes, potential donors must undergo screening and testing procedures. They are required to meet the general criteria for  blood donation . [ 2 ]  Because the granulocyte concentrate also contains  red blood cells , the donor's  ABO blood type  is usually matched to the recipient's. [ note 1 ]  If the recipient has  antibodies  against  human leukocyte antigens  (HLA), proteins found on the surface of  white blood cells , the donor's cells need to be tested for compatibility, because antibodies against donor granulocytes can reduce the effectiveness of the transfusion and cause  transfusion reactions . [ 10 ] : 630


In order to collect enough granulocytes for the transfusion to be effective, donors are frequently given drugs to increase their neutrophil count prior to the blood collection. The treatment typically includes  corticosteroids  or G-CSF, often in combination. [ 3 ] [ 10 ] : 627   Donors may experience minor side effects from steroid and G-CSF treatment, including headaches, bone and joint pain,  insomnia  and  fatigue . [ 2 ]