Le(a+b-) individuals have at least one functional Lewis gene (Le) but are homozygous for nonfunctional Secretor alleles (sese).  Thus, these individuals synthesize and secrete Le(a) antigen but lack Le(b) and type 1 chain ABH. [ 7 ]
Le(a-b+) individuals inherit both Le and Se alleles, leading to the synthesis of Le(a), Le(b), and type 1 chain ABH.  Most type 1 chain precursor is converted to Le(b), therefore these individuals appear as if they are Le(a-). [ 7 ]
Le(a+b+) phenotype is transiently observed in infants (Secretor activity increases with age). [ 7 ]   This phenotype is also encountered in 16% of Japanese individuals (who inherit a weak Secretor gene- Se(w)).


In absence of a functional Lewis gene (lele), neither Le(a) nor Le(b) are synthesized, leading to the Le(a-b-) phenotype. This phenotype is more common in persons of African descent. [ 7 ]


Two precursor oligosaccharides exist, type 1 and type 2.  Type 1 is found in secretions and in the serum.  Type 2 is found exclusively on the surface of red blood cells.  No type 1 oligosaccharide is found on RBCs.  Unbranched type 1 and 2 oligosaccharides represent  i antigen .  Branched type 1 and 2 oligosaccharides are  I antigens . [ 2 ]


In neonates,  i antigen  oligosaccharides predominate (high in cord blood samples).  Oligosaccharide branching increases with age, thus adults have mostly  I antigen . [ 2 ]


The H gene of the  ABO system  encodes a  fucosyltransferase  that adds fucose to type 2 precursor substances on the surface of RBCs to make H antigen.  The h allele is an amorphic form of the gene.  If no further modifications are made to the H antigen, the person is type O.  When the A gene product acts on the H antigen and adds an N-acetylgalactosamine, the A antigen results and the person is type A.  When the B gene product acts on the H antigen to add a galactose, the B antigen results and the person is type B. [ 2 ]


The Le gene encodes a fucosyltransferase that adds fucose to type 1 precursor substance (both free in serum and in secretions) to make the Le(a) antigen.  The le gene is an amorph.  The Lewis antigen produced on free type 1 precursor substance passively adsorbs onto the surfaces or red blood cells. [ 2 ]


The Se gene encodes a fucosyltransferase that adds fucose to type 1 precursor generating H antigen. After this step, the Le gene product (FUT3) can add another fucose producing Le(b) antigen.  Thus, individuals with the Le gene but no Se gene will have red blood cells bearing only the passively-adsorbed Le(a) but no Le(b).  Individuals with both the Le gene and the Se gene will have red blood cells bearing only the passively adsorbed Le(b) and no Le(a).  Individuals with no Le gene have neither Le(a) nor Le(b). [ 2 ]


In addition, the Se gene product is responsible for the presence of A, B and H substances in secretions. [ citation needed ]


Lewis antibodies are naturally occurring antibodies, almost always IgM type, found almost exclusively in Le(a-b-) individuals. [ 7 ]  Lewis antibodies may include a mixture of anti-Le(a), anti-Le(b) and anti-Le(a+). [ 7 ]


Lewis antibodies are almost always clinically insignificant because:


Therefore, it is not necessary to transfuse antigen-negative blood components for most patients.


Lewis antibodies are generally reactive at room temperature and only occasionally at 37 C and AHG phase (antihuman globulin).


Lewis antibodies are not a cause of  hemolytic disease of the fetus and newborn  (HDFN), as stated below.


Lewis antigens cannot be reliably detected until the 2nd birthday.  Lewis antibodies in a pregnant woman are essentially totally insignificant because they are IgM subtype (don't cross the placenta) and Lewis antigen is weakly expressed during pregnancy (Lewis Le(a-b-) phenotype is commonly seen during gestation). [ 2 ]   Most newborns will type as Le(a-b-). [ 7 ]


Lewis antigen is often decreased on RBCs during pregnancy with some women transiently typing as Le(a-b-). [ 7 ]  This is thought to be due in part to increased circulating plasma volume in pregnancy and increased lipoprotein. [ 5 ]


The Le(b) and H antigens are receptors for the bacteria  Helicobacter pylori , a  gram-negative  bacterium that can cause  gastritis  and has been implicated in  peptic ulcer disease ,  gastric adenocarcinoma , mucosa-associated lymphoma (or  mucosal associated lymphatic tissue lymphoma  – MALToma) and  idiopathic thrombocytopenic purpura  (ITP). [ 7 ] [ 8 ] [ 9 ]


Le(b) and type 1 H antigens are also receptors for Norwalk virus (common cause of acute gastroenteritis). [ 10 ]


The Le(a-b-) phenotype is associated with an increased susceptibility to infections by Candida and  uropathogenic  Escherichia coli . [ 7 ] [ 11 ] [ 12 ]


In patients with pancreatic adenocarcinoma and not harbouring a functional Lewis enzyme (Lea-b- genotype: 7%–10% of the population), levels of  CA 19-9  are typically undetectable or below 1.0 U/ml. [ 13 ]


The  LU domain  ( Ly-6 antigen / uPAR ) is an evolutionarily conserved protein domain of the  three-finger protein  superfamily. This domain is found in the  extracellular domains  of  cell-surface receptors  and in either  GPI-anchored  or  secreted   globular proteins , for example the Ly-6 family,  CD59 , and Sgp-2. [ 2 ] [ 3 ]


A variety of GPI-linked cell-surface glycoproteins are composed of one or more copies of a conserved LU domain of about 100 amino-acid residues. [ 4 ] [ 5 ]  Among these proteins, most contain only a single LU domain, though small numbers of exceptions are known; well-studied family member  uPAR  has three tandem LU domains. [ 3 ]


This domain folds into five antiparallel  beta sheets , a structure common to the  three-finger protein   family . The domain typically contains ten well- conserved   cysteine  residues involved in five  disulfide bonds , though some examples such as two of the three  uPAR  domains have fewer. [ 3 ]


Besides uPAR, other receptors with LU domains include members of the  transforming growth factor beta receptor  (TGF-beta) superfamily, such as the  activin type 2 receptor ; [ 6 ]  and  bone morphogenetic protein receptor, type IA . [ 7 ]  Other LU domain proteins are small globular proteins such as  CD59 antigen ,  LYNX1 ,  SLURP1 , and  SLURP2 . [ 2 ] [ 8 ]


ARS;        CD177 ;      CD59 ;       LY6D ;       LY6E ;       LY6H ;       LYNX1 ;
 LYPD2 ;      LYPD3 ;      LYPD4 ;      LYPD5 ;      LYPD6 ;   PLAUR ;      PSCA ;
 SLURP2 ;    SLURP1 ;     SPACA4 ;     TEX101 ;


Many LU domain containing proteins are involved in  cholinergic  signaling and bind  acetylcholine  receptors, notably linking their function to a common  mechanism  of 3FTx toxicity. [ 2 ] [ 3 ] [ 9 ]  Members of the Ly6/uPAR family are believed to be the evolutionary ancestors of the  three-finger toxin  (3FTx). [ 10 ]  Other LU proteins, such as the  CD59 antigen , have well-studied functions in regulation of the  immune system . [ 9 ]


The  Lutheran antigen systems  is a  classification of human blood  based on the presence of substances called Lutheran  antigens  on the surfaces of red blood cells. There are 19 known Lutheran antigens. [ 1 ]
The name Lutheran stems from a blood donor's misspelled last name, reportedly named Lutteran or Lutheran. [ 2 ] [ 3 ] [ 4 ] [ 5 ]
All of these antigens arise from variations in a gene called  BCAM (basal cell adhesion molecule) . The system is based on the expression of two codominant alleles, designated Lua and Lub. The antigens Aua and Aub, known as the  Auberger  antigens, were once thought to make up a separate blood group but were later shown to be Lutheran antigens arising from variations in the BCAM gene.


The  phenotypes  Lu(a+b−) and Lu(a+b+) are found at various frequencies within populations. The Lu(a−b+) phenotype is the most common in all populations, whereas the Lu(a−b−) phenotype is uncommon. Though present in the  fetus , it is seldom the cause of  erythroblastosis fetalis  or of transfusion reactions.


In  transfusion medicine ,  mixed-field agglutination  refers to mixed reactions during cell typing where two distinct cell populations are present: agglutinated cells admixed with many unagglutinated cells. The presence of two or more cell populations is known as  chimerism . Mixed-field agglutination is an important cause of ABO typing and genotype discrepancies. The cause of mixed field agglutinations should be sought prior to setting up blood for transfusion. [ 1 ]


By far the most common cause of mixed-field agglutination is false chimerism. There are several causes of false chimerism;


1) Transfusion of donor red cells. For example, a blood group B individual who has received a transfusion of group O donor red cells may show mixed field agglutination with anti-B sera. His own group B red cells are agglutinated by the anti-B sera while the group O donor red cells in his circulation are unagglutinated [ citation needed ]


2) After an ABO mismatched  stem cell transplant  for example a blood group O stem cell donor and a blood group A stem cell recipient. [ 2 ] [ 3 ]


3) Weak expression of the A or  B blood group  antigen [ citation needed ]


4) In some diseases, for example leukaemia [ citation needed ]


A true chimerism is a rare sporadic phenomenon whereby an individual has a dual cell population derived from more than one zygote. This may result from intrauterine exchange of erythrocyte precursors between twins (twin chimerism) or two fertilized eggs fuse into one individual. Twin chimerism results from mixing of blood between two twin fetuses through placental blood vessel anastomoses, leading to engraftment of hematopoietic stem cells from one twin within the marrow of the other. Each twin ends up with two distinct cell populations of varying proportions. [ citation needed ]


The  MNS antigen system  is a  human blood group system  based upon two genes ( glycophorin A  and  glycophorin B ) on  chromosome 4 .  There are currently 50  antigens  in the system, [ 1 ] [ 2 ] [ 3 ] [ 4 ]  but the five most important are called M, N, S, s, and U.


The system can be thought of as two separate groups: the M and N  antigens  are at one location on the  ECM  and S, s, and U are on a closely related location.  The two groups are very closely located together on  chromosome 4  and are inherited as a  haplotype .


The  MN blood group  in humans is under the control of a pair of  co-dominant   alleles , L M  and L N . Most people in the  Inuit  population are M/M, while this genotype is rare among  Aborigines . In fact, they tend to possess the opposite genotype (N/N). [ citation needed ]


The MN blood group system is under the control of an  autosomal  locus found on chromosome 4, with two alleles designated L M  and L N . The blood type is due to a  glycoprotein  present on the surface of a red blood cell (RBC), which behaves as a native  antigen .  Phenotypic  expression at this locus is  codominant  because an individual may exhibit either one or both antigenic substances. Frequencies of the two  alleles  vary widely among human populations. [ 5 ]


M+ and N+ RBCs are common (75% of population) and M+N+ cells are the most common genotype (50% of population).  These antigens were an early discovery and are some of the oldest blood antigens known after the  ABO system .  They were first described by  Karl Landsteiner  and  Philip Levine  in 1927.  Anti-M and anti-N antibodies are usually  IgM  and are rarely associated with  transfusion reactions . [ citation needed ]


Anti-N is sometimes seen in  dialysis  patients due to cross-reactions with the residual  formaldehyde  from sterilizing the equipment.  This is usually irrelevant for transfusion since this variant of the antibody does not react at body temperature. [ citation needed ]


The S antigen is relatively common (~55% of the population) and the s antigen is very common (~89% of the population).  Anti-S and anti-s can cause  hemolytic transfusion reactions  and  hemolytic disease of the newborn .The U antigen is a high incidence antigen, occurring in more than 99.9% of the population. The U was originally short for "Universal", though this is not the case. U negative RBCs can be found in people of  African  descent.  This mutation in red cell surface structure also makes the RBCs S- and s-.  Anti-U has been associated with both hemolytic transfusion reactions and hemolytic disease of the newborn. [ citation needed ]


The other 41 identified antigens in the MNS group are low incidence, such as He (0.8% of the population) or  high incidence, such as EN a  (>99.9% of the population).


Antigens of the MNS system are located on one of two glycoproteins: glycophorin A (GPA, CD235A) and glycophorin B (GPB, CD235B). [ 6 ]   Each glycoprotein crosses the membrane once and has an external N-terminal domain (varying in length from 44 amino acids for GPB to 72 amino acids in length for GPA) [ 6 ]  as well as a C-terminal cytosolic domain (GPB, 8 amino acids in length; GPA, 36 amino acids in length). [ 6 ]


Neonatal alloimmune thrombocytopenia  ( NAITP ,  NAIT ,  NATP  or  NAT ) is a  disease  that affects babies in which the  platelet count is decreased  because the mother's immune system attacks her  fetus ' or newborn's  platelets . A low platelet count increases the risk of bleeding in the fetus and newborn.  If the bleeding occurs in the brain, there may be long-term effects.


Platelet  antigens  are inherited from both mother and father.   NAIT  is caused by antibodies specific for platelet antigens inherited from the father but which are absent in the mother. [ 1 ]   Fetomaternal transfusions (or fetomaternal hemorrhage) results in the recognition of these antigens by the mother's immune system as non-self, with the subsequent generation of allo-reactive antibodies which cross the placenta.  NAIT , hence, is caused by transplacental passage of maternal platelet-specific  alloantibody  and rarely  human leukocyte antigen  ( HLA ) allo-antibodies [ 2 ]  (which are expressed by platelets) to fetuses whose platelets express the corresponding antigens.


NAIT  occurs in somewhere between 1/800 [ 3 ]  and 1/5000 [ 4 ]  live births. More recent studies of  NAIT  seem to indicate that it occurs in around 1/600 live births in the Caucasian population. [ 5 ]


The diagnosis of NAIT is usually made after an incidental finding of a low platelet count on a blood test or because of bleeding complications ranging from bruising or  petechiae  to  intracranial hemorrhage  in the fetus or newborn. [ 6 ]


Frequently, the reduction in platelet count is mild and the affected neonates remain largely asymptomatic. [ 6 ]   NAIT is the commonest cause of a very low platelet count, and the commonest cause of intracranial haemorrhage in the term neonate. [ 6 ] [ 7 ]


In case of severe thrombocytopenia, the neonates may exhibit bleeding complications at or a few hours after delivery. The most serious complication is intracranial hemorrhage, leading to death in approximately 10% of symptomatic babies [ 6 ]  or neurologic sequelae in 20% of cases. 80% of intracranial hemorrhages occur before birth. [ 6 ]  After birth the greatest risk of bleeding is in the first four days of life. [ 6 ]


Immune thrombocytopenic purpura  ( ITP ), sometimes called  idiopathic thrombocytopenic purpura  is a condition in which autoantibodies are directed against a patient's own platelets, causing platelet destruction and thrombocytopenia.  Anti-platelet autoantibodies in a pregnant woman with  immune thrombocytopenic purpura  will attack the patient's own platelets and will also cross the placenta and react against fetal platelets.  Therefore,  ITP  is a significant cause of fetal and neonatal immune thrombocytopenia.  Approximately 10% of newborns affected by  ITP  will have platelet counts <50,000 μL −1  and 1% to 2% will have a risk of intracerebral hemorrhage comparable to infants with  NAIT . [ 1 ] [ 8 ]


Mothers with thrombocytopenia or a previous diagnosis of  ITP  should be tested for serum anti-platelet antibodies.  A woman with symptomatic thrombocytopenia and an identifiable anti-platelet antibody should be started on therapy for their  ITP  which may include steroids or  IVIG .  Fetal blood analysis to determine the platelet count is not generally performed as  ITP -induced thrombocytopenia in the fetus is generally less severe than  NAIT . Platelet transfusions may be performed in newborns, depending on the degree of thrombocytopenia. [ 1 ]


Other conditions that can cause a low platelet count in the neonate include bacterial and viral infection,  disseminated intravascular coagulation  and other rare congenital conditions associated with a low platelet count. [ 6 ]


Platelets have many proteins on their surface. Each person has a different set of proteins, which are inherited from their parents. These different platelet proteins make different platelet groups, just like different proteins on  red blood cells  make different  blood groups . These differences do not affect how the platelets work. However, if a baby inherits a protein that is found on the father's platelets but is absent from the mother's platelets, the mother may respond to this foreign protein by developing an antibody that fights against it. [ citation needed ]


This antibody may pass from the mother's blood into the baby's blood and attach to the baby's platelets. This antibody destroys the baby's platelets and suppresses production of fetal platelets, they are also thought to weaken the blood vessel walls (vascular integrity) and affect production of new blood vessels ( angiogenesis ). [ 9 ]  This results in an increased risk of bleeding for the baby, and this can lead to the baby's death. [ 9 ]  The mother's antibodies can remain in the baby's bloodstream for weeks, and bleeding can occur in the baby before birth (fetal), during birth or after birth (neonatal). [ 9 ]


A number of different proteins can cause NAIT, about 80% of cases are caused by antibodies against platelet antigen  HPA -1a , 15% by anti- HPA -5b , and 5% by other antibodies (e.g.  HPA -1b ,  HPA -15,  HPA -3 and  HPA -9b). [ 10 ] [ 11 ]   HPA -1a is present in 98% of the population of the United States, suggesting that approximately 2% of women who are  HPA -1a negative may be at risk for  NAIT  during pregnancy. [ 1 ] [ 12 ]  Of course, the antigen expression of the father must also be taken into account - in most cases the father is  HPA -1a/1a or 1a/1b and the mother is  HPA -1b/1b with anti- HPA -1a antibodies.  In women of Asian descent,  HPA -4 antigens are the most frequently implicated. [ 13 ]


Studies have shown a relationship between maternal  HLA  type DRw52a (DRB3* 0101) and the development of anti- HPA -1a. [ 14 ] [ 15 ] [ 16 ] [ 17 ]


The offending antibodies are IgG subtype and therefore capable of crossing the placenta and entering the fetal circulation. [ citation needed ]


Unlike  hemolytic disease of the fetus and newborn ,  NAIT  occurs during the first pregnancy in up to 50% of cases, [ 1 ]  and the affected fetuses may develop severe thrombocytopenia (<50,000 μL −1 ) very early during pregnancy (as early as 20 weeks gestation, consistent with the development of platelet antigens, [ 1 ]  and the majority of the time  in utero [ 18 ] ). Usually, the thrombocytopenia increases as gestation progresses. During the first pregnancy,  NAIT  is often not detected until birth when the newborn presents with classic symptoms of thrombocytopenia including  petechiae , bruising or intracranial hemorrhage. [ 1 ]  In utero intracranial hemorrhage occurs in about 10% to 30% of affected cases (and  NAIT  is thought to be the underlying cause in the majority of cases of intracranial hemorrhage due to thrombocytopenia- greater than all other causes of thrombocytopenia combined). The risk of hemorrhage is inversely related to the platelet count with the greatest risk when the platelet count is below 100,000 μL −1 . [ 1 ]


The recurrence of  NAIT  has been estimated to be more than 80% in subsequent pregnancies in which the fetus also carries the target platelet antigen. [ 6 ]   Subsequent cases of  NAIT  may be equivalent or more severe. [ 6 ]


The fetal response to  NAIT  is variable and may include compensatory extramedullary hematopoiesis.  Rarely, fetal hydrops may develop.  Fetal anemia (in presence of red cell incompatibility) may also occur. [ 1 ]


Doctors may consider a diagnosis of NAIT if they notice bleeding or bruising in a baby, or low platelet counts on a blood test after birth, or neurologic symptoms. Some babies may have a specific pinpoint rash called “ petechiae ”. If a diagnosis of NAIT is suspected, then the baby should be treated as if it had NAIT until the diagnosis is confirmed. [ 19 ] [ 20 ]


The diagnosis is confirmed by taking blood samples from the baby's parents, and sometimes the baby. Maternal and paternal platelet antigen phenotyping and screening of the maternal serum for anti-platelet antibodies can be performed. [ 12 ]  Additionally, platelet antigen  genotyping  can be performed on the maternal and paternal blood to determine the exact nature of the incompatibility. [ citation needed ]


Neonatal platelet counts on laboratory testing are typically under 20,000 μL −1 .  Higher counts may suggest a different diagnosis, such as maternal  immune thrombocytopenic purpura . [ 21 ]


Even in mildly affected babies, it is important to fully investigate and diagnose the baby because the results can be critical for the effective management of any future pregnancies. [ 6 ]


Antenatal management only occurs if a mother has had a previously affected baby or a family member has had an affected baby. [ 9 ]


Interventions can be classified as invasive or non-invasive. [ citation needed ]


A review of the evidence has shown that invasive management resulted in a relatively high complication rate (mainly preterm emergency  cesarean section ) of 11% per treated pregnancy. [ 9 ]  Noninvasive management was also shown to be effective, but without the relatively high rate of adverse outcomes seen with invasive management. [ 9 ]  They concluded that first-line antenatal management in NAIT should be non-invasive with weekly  intravenous immunoglobulin  administration, with or without the addition of  corticosteroids . [ citation needed ]


Recent international guidelines have now recommended non-invasive management of NAIT. [ 19 ] [ 20 ]  Previously there had been no international consensus on the optimal antenatal management of NAIT, [ 9 ]  and numerous strategies had been used in different centers that specialized in antenatal treatment. [ 9 ]


Fetal blood sampling from the umbilical cord and intrauterine platelet transfusion was the first antenatal treatment for NAIT to prevent intracerebral hemorrhage. [ 9 ]  However, this is no longer recommended routinely because of the serious risk of harms. [ 9 ] [ 19 ]   Cordocentesis  in the presence of a low platelet count may lead to serious complications, these included slowing of the baby's heart (fetal bradycardia),  tamponade  of the cord, and bleeding complications in the baby, including  exsanguination .  Fetal blood sampling is estimated to cause death of the baby in 1.3% of procedures, however the incidence varies significantly from center to center. [ 22 ]  With an overall risk of death of the fetus due to the repeated procedures of about 3% (17 deaths out of 485 pregnancies). [ 9 ]


In addition, given the short life span of transfused platelets, transfusions are needed regularly, increasing the overall risk of death of the baby. If intrauterine platelet transfusions are performed, they are generally repeated weekly (platelet lifespan after transfusion is approximately 8 to 10 days).   Platelets administered to the fetus must be negative for the culprit antigen (often  HPA -1a, as stated above).  Many blood suppliers (such as  American Red Cross ;  NHS Blood and Transplant ;  United Blood Services ) have identified  HPA -1a and 5b negative donors.  An alternative donor is a mother who is, of course, negative for the culprit antigen.  However, she must meet general criteria for donation and platelets received from the mother must be washed to remove the offending alloantibody and irradiated to reduce the risk of  graft-versus-host disease .  If platelet transfusions are needed urgently, incompatible platelets may be used, with the understanding that they may be less effective and that the administration of any blood product carries risk. [ 1 ]


Any administered cellular blood products must be irradiated to reduce the risk of  graft-versus-host disease  in the fetus. Additionally, all administered blood products should be  CMV  reduced-risk ( CMV  seronegative and leukoreduced are considered essentially equivalent for the purposes of  CMV  risk reduction). [ 1 ]


The use of  Intravenous immunoglobulin  ( IVIG ) during pregnancy and immediately after birth has been shown to help reduce or alleviate the effects of  NAIT  in infants and reduce the severity of thrombocytopenia.  The most common treatment is weekly  IVIG  infusions at a dosage of 1 g/kg beginning at 12 to 16 weeks of pregnancy in women who have had a previously affected child with an intracranial hemorrhage. [ 19 ]  For all other pregnancies, use of IVIG should be discussed, and, if indicated, should be started before 24 weeks of pregnancy and continued until the birth of the child. [ 19 ] [ 23 ] [ 24 ] [ 9 ] [ 25 ]  In some cases this dosage is increased to 2 g/kg and/or combined with a course of  prednisolone   depending on the exact circumstances of the case. [ 9 ] [ 19 ]


In a review they found that giving IVIG alone during pregnancy prevented intracranial hemorrhage in 98.7% of treated pregnancies (4 cases occurred in 315 pregnancies). [ 9 ]  This is a similar estimate to a previous review that only assessed the evidence within randomised controlled trials. [ 25 ]  They also found no consistent benefit of adding steroids to IVIG. [ 9 ]


The goal of both  IVIG  and platelet transfusion is to avoid hemorrhage.  Ultrasound monitoring to detect hemorrhage in the fetus is not recommended as detection of intracranial hemorrhage generally indicates permanent brain damage (there is no intervention that can be performed to reverse the damage once it has occurred). [ citation needed ]


Before delivery, the fetal platelet count may not be known, due to the high risks associated with cordocentesis (see above). [ 19 ]   If the platelet count is not known then assisted forms of delivery, for example  forceps  or  ventouse , should be avoided to reduce the risk of harm. [ 19 ]  If the delivery has been planned then antigen negative platelets should be available in case the infant's platelet count is low on a cord blood sample. [ 19 ]


The most rapidly effective treatment in infants with severe hemorrhage and/or a very low platelet count (<30,000  μL −1 ) is the transfusion of compatible platelets (i.e. platelets from a donor who, like the mother, lacks the causative antigen). [ 20 ]  If  antigen negative platelets are unavailable, then standard neonatal platelet transfusions should be given until antigen negative platelets become available. [ 20 ] [ 19 ]  If a platelet transfusion is not available immediately then the infant can be given IVIG (1g/kg) however, this will have no effect on the platelet count before 24 to 72 hours. [ 19 ]


A platelet transfusion is required immediately if there is severe or life-threatening bleeding. [ 19 ] [ 20 ]  If life-threatening bleeding occurs, for example an  intracranial hemorrhage , then the platelet count needs to be increased to decrease the risk of further bleeding (> 100,000  μL −1 ). [ 19 ] [ 20 ]


Any infant with suspected NAIT should have an ultrasound of the head within the first 24 hours after birth to make sure that there is no evidence of an  intracranial hemorrhage . [ 19 ]


If the infant has a platelet count >30,000  μL −1  and no evidence of bleeding, then the baby can be monitored with blood counts until the blood counts return to normal, without the need for any additional treatment. [ 19 ]  In the past, infusions of  IVIG  (1 g/kg/day for two days) have been given to the infant and have been shown to rapidly increase the  platelet count . [ 6 ]  However, IVIG and platelet transfusions are also associated with harm and therefore should be avoided if they are not necessary. [ 19 ]


After a first affected pregnancy, if a mother has plans for a subsequent pregnancy, then the mother and father should be typed for platelet antigens and the mother screened for alloantibodies.  Testing is available through reference laboratories (such as  ARUP ).   DNA  testing of the father can be used to determine zygosity of the involved antigen and therefore risk to future pregnancies (if homozygous for the antigen, all subsequent pregnancies will be affected, if heterozygous, there is an approximate 50% risk to each subsequent pregnancy).  During subsequent pregnancies, the genotype of the fetus can also be determined using amniotic fluid analysis or maternal blood as early as 18 weeks gestation to definitively determine the risk to the fetus. [ 1 ]


NHS Blood and Transplant   is an executive  special health authority  of the United Kingdom's  Department of Health and Social Care .
It was established on 1 October 2005 to take over the responsibilities of two separate NHS agencies: UK Transplant (now renamed Organ Donation and Transplantation), founded by  Dr. Geoffrey Tovey  in 1972, [ 3 ]  and the National Blood Service [ 4 ]  (now renamed Blood Donation). Its remit is to provide a reliable, efficient supply of blood, organs and associated services to the NHS. Since NHSBT was established, the organisation has maintained or improved the quality of the services delivered to patients, stabilised the rising cost of blood, and centralised a number of corporate services.


It has the responsibility for optimising the supply of blood, organs and tissues and raising the quality, effectiveness and efficiency of blood and  transplant  services. Its roles are stated to include: [ 5 ]


In 2009/10 its strategic objectives were focused on the efficient provision of a safe and sustainable supply of blood and its components, the identification and referral of more organ donors and the establishment of NHSBT as an effective and responsive organisation, focused on the needs of donors and patients. The year saw a record high in organ donation and transplantation together with an increase in the number of people signing up to donate blood. [ 6 ]


The Core System Modernisation Programme which was meant to modernise the organisation’s information technogy systems was abandoned in 2018 with costs of £26 million written off. [ 7 ]


The National Blood Service, now renamed NHS  Blood Donation , is the organisation for England which collects blood and other tissues, tests, processes, and supplies all the hospitals in England. Other official blood services in the United Kingdom include the  Northern Ireland Blood Transfusion Service ,  Scottish National Blood Transfusion Service  and the  Welsh Blood Service . [ citation needed ]


The National Blood Service was formed in 1946 as the National Blood Transfusion Service of England and Wales (NBTS). The National Blood Authority was established as a Special Health Authority in 1993 and assumed control of the 12 English Regional Transfusion Centres in 1994. The National Blood Service became a nationally coordinated body in 1996. The service operates out of fifteen centres, and collects around 2.1 million donations per year and supplies 8,000 units of blood every day. Service directors proposed a reconfiguration and centralisation strategy in 2006, based on the closure of most local processing and testing labs, and subsequent operation out of just three large 'supercentres' to serve the same geographical area. [ 8 ]  Staff opposed this strategy. [ 9 ]  In July 2015 it was decided to shut the blood supply chain manufacturing facilities in Sheffield and Newcastle in 2017 and transfer their work to Manchester. [ 10 ]


Blood donation vehicles are allowed the use of  blue lights and sirens  (known commonly " blues and twos ") for the use of emergency blood transports. In some cases this will also require the use of a police escort for the transporting vehicle in order to safely and quickly navigate major road junctions. Escort is normally provided by several motorbike units.


The service depends entirely on voluntary donations from the public. Originally, blood was collected from various donor clinics located over the country. In 1994, the first mobile session was held in Elstree, hosted by  The Joely Bear Appeal . In the South West from 1946 and since the formation of the NHS the service was primarily a mobile collection service visiting all parts of the mainly rural community. Originally Local Organisers called up the Donors from their own lists; this only changed in the 1990s. This link with the Local Organisers was inherited from the Wartime Red Cross (mainly) and St. Johns blood collection teams.  These mobile teams continue to collect, but two centres – Bristol and Plymouth (Derriford) – have static bases in local venues. Currently, blood donation sessions are set up throughout the country and take place in many diverse venues, from village halls, workplaces and mobile collection units (known as  Bloodmobiles ). Donors are generally required to be fit and healthy, weigh 50 kilograms (110 lb; 7 st 12 lb) and aged between 17 and 60. However, regular (healthy) donors are permitted to donate past the age of 60 as long as they remain healthy. Donors are encouraged to give blood up to three times a year (once every 16 weeks). Since February 2012, male donors have been allowed to donate up to four times a year. [ 11 ]   In 2013–14 1,986 people complained they had been turned away from walk-in sessions. 1,949 said they did not have their blood taken even when they had made an appointment. [ 12 ]


Besides the main blood donations, known as "whole blood",  platelets  are also collected. As platelets can only be stored for a few days, regular and frequent donors are in great demand and that is why platelet donors are asked to attend at least 8–10 times per year.


Organ Donation and Transplantation ensures that organs donated for transplant are matched and allocated to patients in a fair and unbiased way. Matching, particularly in the case of kidneys, is so important that donation and allocation needs to be organised nationally. The larger the pool of organs, the better the likelihood there is of a good match. Unlike some other NHS organisations, it does not have a direct relationship with patients and do not provide "hands on" care. However, in providing support to transplantation services across England, everything it does affects the quality of service delivered to individual patients. [ citation needed ]


In 1968, the National Tissue Typing and Reference Laboratory was established at  Southmead Hospital  in Bristol. [ 4 ] [ 13 ] [ 14 ]  The National Organ Matching and Distribution Service  was founded in 1972 and the two organisations merged in 1979 to form the UK Transplant Service. [ citation needed ]


In 1991 the UK Transplant Service became an NHS special health authority and was renamed the United Kingdom Transplant Support Service Authority. It moved to purpose-built accommodation at  Stoke Gifford , in the northern suburbs of Bristol, in 1993. In July 2000, UK Transplant was formed with a new, extended remit to increase organ donation rates. In October 2005 UK Transplant merged with the National Blood Service and the  Bio Products Laboratory  to form NHS Blood and Transplant. [ citation needed ]


In 2010, the Bio Products Laboratory became a  limited company  owned directly by the Department of Health. The Department of Health partly privatised it in 2013, selling a significant majority stake to Bain Capital. The business benefited from investment and growth, enabling full privatisation, achieved when a group controlled by Creat Group Corporation acquired it in 2016.


The NHS Organ Donor Register is a national, confidential list of people who are willing to become donors after their death. It can be quickly accessed to see whether an individual has registered a willingness to be an organ donor. [ citation needed ]


NHSBT operates the largest blood processing facility in Europe, capable of processing 1 million units a year. [ 15 ] [ 16 ]  The site also houses the International Blood Group Reference Laboratory, one of the world’s leading laboratories in rare blood identification. [ 17 ]


Northfield Laboratories Inc.  (former NASDAQ:  NFLD ) was the maker of  PolyHeme , a  hemoglobin-based oxygen carrier  (HBOC).  The company was based in  Evanston, Illinois , with Dr. Steven A. Gould as its  chief executive officer .  As of May 31, 2005, the company had 68 employees.


It was founded in 1985 and has since been a mainly  research and development  company.  Northfield's only product was PolyHeme, an oxygen-carrying  blood substitute , which failed to receive  Food and Drug Administration  (FDA) regulatory approval.  On May 9, 2009, after being informed by the FDA the product's risks outweighed the benefits, the company shut down operations. During their operations, they incurred losses of about 220 million dollars. [ 1 ]  The corporation was also criticized for some design elements of its clinical trials related to the need to perform critical care and resuscitation while patients were in grave clinical conditions due to the mechanisms of injury incurred and the consequent inability of patients to provide informed consent for treatment. [ 2 ]


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


This United States corporation or company article is a  stub . You can help Wikipedia by  expanding it .


In  Osborn v. Irwin Memorial Blood Bank , 5 Cal.App.4th 234 (1992), the  Court of Appeals of California  considered certain questions pertaining to whether a  blood bank  could be held liable for  negligence  or  negligent misrepresentation  after a patient contracted  HIV/AIDS  as a result of a  blood transfusion .


In 1983, Michael Osborn, an infant, underwent surgery to repair a  congenital heart defect .  During that surgery, Osborn received a blood transfusion.  At the time of the transfusion, donated blood was not routinely tested for  human immunodeficiency virus , because the cause of  AIDS  had not definitively been identified yet.


Fearing that AIDS could be transmitted by blood, the Osborns had requested to make  directed blood donations  specifically earmarked for use by Michael.  They first contacted the surgeon, who informed them that they needed to contact the blood bank.  The receptionist at the blood bank, however, said that directed donations were not allowed, and so the surgery proceeded using blood from the public supply.  He subsequently was diagnosed with  acquired immune deficiency syndrome  (AIDS).


The patient and his family sued the University of California (where the surgery occurred) and the  Irwin Memorial Blood Bank  (which supplied the blood) for multiple  causes of action .  A jury trial took place.  The blood bank introduced evidence that its safety procedures were at least as good as those generally prevailing at the time.  The blood bank also sought to introduce evidence that, because the patient was  type A negative , he could not receive any donations from members of his family, as a result of which only a small amount of blood (or no blood at all) would have been able to be provided by means of  directed donation , but the judge did not allow defendants to present this evidence to the jury.


At the conclusion of the evidence the trial judge granted the defendants' motions for  nonsuit  on several of the causes of action, and  directed a verdict  in favor of the university on the remaining causes of action.  Thus, only the blood bank remained as a defendant, and the following questions were submitted to the jury:


The jury returned a general verdict in favor of the plaintiffs and awarded them a total of $750,000.  The blood bank moved for  judgment notwithstanding the verdict  and also moved for an amended judgment on the grounds that the damages awarded were in excess of those allowed under the  Medical Injury Compensation Reform Act  (MICRA).  The trial court acknowledged that it had erred when it had held that MICRA did not apply, and the blood bank moved for a new trial.


The court granted the blood bank's motion for  judgment notwithstanding the verdict  as to the counts of negligence and intentional  misrepresentation  and, conditioned on the plaintiffs' acceptance, reduced the award to $416,307.  Both sides appealed.


There were three issues on appeal:


The California Court of Appeals ruled in favor of defendants on the count of negligence, held that the defendants were entitled to a new trial on the issue of negligent misrepresentation, and ruled in favor of the university.


P1PK  (formerly: P) is a  human blood group system  ( International Society of Blood Transfusion  system 003) based upon the  A4GALT  gene on  chromosome 22 . The P antigen (later renamed P1) was first described by  Karl Landsteiner  and  Philip Levine  in 1927. [ 1 ]  The P1PK blood group system consists of three  glycosphingolipid  antigens: P k , P1 and NOR. [ 2 ] [ 3 ]  In addition to glycosphingolipids, terminal Galα1→4Galβ structures are present on complex-type N-glycans. [ 4 ]  The GLOB antigen (formerly P) is now the member of the separate GLOB (globoside) blood group system.


The P1PK antigens are carbohydrate antigens that include P k  (Gb3), P1 and NOR1, NOR int  and NOR2. All are synthesized by Gb3/CD77 synthase (α1,4-galactosyltransferase, P1/P k  synthase). [ 5 ]


The presence or absence of P1 antigen depends on the  A4GALT  transcript level. It was found that differential binding of transcription factors  early growth response 1  (EGR1) and  runt-related transcription factor 1  (RUNX1) to the SNP rs5751348 [ 9 ]  genomic region with the different genotypes in the  A4GALT  gene leads to differential activation of  A4GALT  expression, leading to two genotypes: P 1  and P 2 . [ 10 ] [ 11 ]


P1PK phenotypes are defined by reactivity to antibodies to anti-P 1 , anti-P, anti-P k  anti-PP 1 P k . and anti-NOR antibodies.


Anti-P1P k  antibodies are not usually detected with routine laboratory methods.  It is possible to detect them using the Donath-Landsteiner test.  This test is performed on 2 vials of blood at two different temperatures: 4 °C and 37 °C (body temperature).  A test is interpreted as positive only after a patient's red blood cells have been incubated at both temperatures and subsequently hemolyzed. [ 17 ]


Pathogen reduction using riboflavin and UV light  is a method by which infectious  pathogens  in  blood for transfusion  are inactivated by adding  riboflavin  and irradiating with  UV light . [ 1 ] [ 2 ] [ 3 ]  This method reduces the infectious levels of disease-causing agents that may be found in donated blood components, while still maintaining good quality blood components for transfusion. This type of approach to increase blood safety is also known as “pathogen inactivation” in the industry.


Despite measures that are in place in the developed world to ensure the safety of blood products for transfusion, a risk of disease transmission still exists.  Consequently, the development of pathogen inactivation/reduction technologies for blood products has been an ongoing effort in the field of transfusion medicine. A new procedure for the treatment of individual units of single-donor (apheresis) or whole blood–derived, pooled, platelets has recently been introduced. This technology uses riboflavin and light for the treatment of platelets and plasma.


This pathogen reduction process involves adding riboflavin (vitamin B2) to the blood component, which is then placed into an illuminator where it is exposed to UV light for about five to ten minutes. Exposure to UV light activates riboflavin and when it is associated with  nucleic acids  ( DNA  and  RNA ), riboflavin causes a chemical alteration to functional groups of the nucleic acids thereby making pathogens unable to replicate. [ 1 ] [ 4 ] [ 5 ]  In this way the process prevents viruses, bacteria, parasites and white blood cells, from replicating and causing disease. [ 6 ] [ 7 ]


This method using riboflavin and UV light renders pathogens harmless by using a non-mutagenic, non-toxic method. Riboflavin and its photoproducts are already present in the human body and do not need to be removed from blood products prior to transfusion. [ 1 ]


The riboflavin and UV light method for pathogen reduction of platelets and plasma is in routine use in multiple countries throughout Europe. [ 10 ] [ 11 ] [ 12 ] [ 13 ]  This same process is currently in development for the treatment of whole blood, resulting in pathogen reduction of the three components (RBCs, platelets and plasma).


Plasma frozen within 24 hours after phlebotomy , commonly called  FP24 , [ 1 ]   PF‑24 , or similar names, is a frozen human  blood plasma  product used in  transfusion medicine . It differs from  fresh-frozen plasma  (FFP) in that it is frozen within 24 hours of blood collection, whereas FFP is frozen within 8 hours. The phrase "FFP" is sometimes used to refer to any frozen blood plasma product intended for transfusion.


PF24 is stored, thawed, and infused with the same procedures used for FFP. Although it is technically a different product, most healthcare providers continue to refer to FFP when the actual component is PF24.


The production of PF24 began in response to an increase in reported cases of  transfusion-related acute lung injury , or TRALI. The proposed mechanism of TRALI involves antibodies from donor blood components (predominantly plasma) that are directed against  human leukocyte antigens  (HLA). [ 2 ]  These antibodies are most numerous in women who have been pregnant more than once. Thus, removing these women from the donor pool for frozen plasma was proposed as a solution to the TRALI problem (the women's plasma could still be used for production of other components, including cryoprecipitate). However, removing roughly half of the donor pool was not a viable alternative, given the increasing need for plasma transfusion. [ citation needed ]


The PF24 approach was pioneered in the United Kingdom beginning in 2004 [ 3 ]  and in the United States beginning in 2007. [ 4 ]  The use of PF24 has been accompanied by a decrease in the incidence of TRALI—a roughly 50% reduction in reported cases. [ 3 ]   Long-term studies on the effectiveness of PF24 in massive transfusion have not been conducted.


This does not address the question of risk from plasma in other components, particularly  apheresis   platelets . Removing multiparous women from this limited donor pool would likely cause too great a shortage of platelets, resulting in more deaths (due to hemorrhage) than are seen due to TRALI after platelet infusion. [ citation needed ]


PF24 has roughly 70% of the blood coagulation-factor activity of FFP. Given the fact that there is typically an overabundance of coagulation factors in normal plasma, the decrease noted in PF24 is not thought to be clinically significant. [ citation needed ]


Much of the donor blood supply is obtained at "remote" blood donation events, such as blood drives at colleges, community events, etc., rather than at dedicated donation centers. The time required for transportation and processing often precludes production of FFP in such cases; that is the plasma cannot be separated and frozen within 8 hours of collection. However, the (male) donor blood can be separated into packed red blood cells and plasma within 24 hours (and usually less). [ citation needed ]


Plasmapheresis  (from the  Greek  πλάσμα,  plasma , something molded, and ἀφαίρεσις  aphairesis , taking away) is the removal, treatment, and return or exchange of  blood plasma  or components thereof from and to the  blood circulation . It is thus an  extracorporeal therapy , a medical procedure performed outside the body. [ 1 ]


Three general types of plasmapheresis can be distinguished:


Plasmapheresis of the autologous and exchange types is used to treat a variety of disorders, including those of the  immune system , such as  Goodpasture's syndrome , [ 3 ]   Guillain–Barré syndrome ,  lupus ,  myasthenia gravis , [ 4 ] [ 5 ]  and  thrombotic thrombocytopenic purpura .


During plasmapheresis,  blood , which consists of  blood cells  and a clear liquid called  blood plasma , is initially taken out of the body through a needle or previously implanted  catheter . Plasma is then removed from the blood by a cell separator. Three procedures are commonly used to  separate  the plasma from the blood cells, with each method having its own advantages and disadvantages: [ 6 ]


After plasma separation, the blood cells are returned to the person undergoing treatment, while the plasma, which contains the  antibodies , is first treated and then returned to the patient in traditional plasmapheresis. Rarely, other replacement fluids, such as  hydroxyethyl starch , may be used in individuals who object to blood transfusion but these are rarely used due to severe side-effects. Medication to keep the blood from clotting (an  anticoagulant ) is given to the patient during the procedure. [ 1 ]


Plasmapheresis is used as a therapy in particular  diseases . It is an uncommon treatment in the United States, but it is more common in Europe and particularly Japan. [ 7 ]


An important use of plasmapheresis is in the therapy of  autoimmune disorders , where the rapid removal of disease-causing  autoantibodies  from the circulation is required in addition to other medical therapy. It is important to note that plasma exchange therapy in and of itself is useful to temper the disease process, while simultaneous medical and  immunosuppressive therapy  is required for long-term management. Plasma exchange offers the quickest short-term answer to removing harmful autoantibodies; however, the production of autoantibodies by the immune system must also be suppressed, usually by the use of medications such as  cyclophosphamide ,  cyclosporine ,  mycophenolate mofetil ,  prednisone ,  rituximab , or a mixture of these. [ 8 ]


Other uses are the removal of blood  proteins  where these are overly abundant and cause  hyperviscosity syndrome . [ 9 ]


There is weak evidence that therapeutic plasma exchange (TPE) might be of benefit in severe cases of  COVID-19 . [ 10 ]


Though plasmapheresis is helpful in certain medical conditions, like any other therapy, there are potential risks and complications. Insertion of a rather large  intravenous  catheter can lead to bleeding, lung puncture (depending on the site of catheter insertion), and, if the catheter is left in too long, it can get infected. [ 16 ]


Aside from placing the catheter, the procedure itself has complications. When patient blood is outside of the body passing through the plasmapheresis machine, the blood has a tendency to clot. To reduce this tendency, in one common protocol, [ which? ]   sodium citrate  is infused while the blood is running through the circuit. Citrate binds to  calcium  in the blood, calcium being essential for blood to clot. Citrate is very effective in preventing blood from clotting; however, its use can lead to life-threateningly low calcium levels. This can be detected using the  Chvostek's sign  or  Trousseau's sign . To prevent this complication, calcium is infused intravenously while the patient is undergoing the plasmapheresis; in addition, calcium supplementation by mouth may also be given. [ 17 ]


Other complications include:


Donating plasma is similar in many ways to  whole blood donation , though the end product is used for different purposes.  Most plasmapheresis is for  fractionation  into other products; other blood donations are transfused with relatively minor modifications.  Plasma that is collected solely for further manufacturing is called Source Plasma. [ 18 ]


Plasma donors undergo a screening process to ensure both the donor's safety and the safety of the collected product.  Factors monitored include  blood pressure ,  pulse , temperature, total protein,  protein electrophoresis , health history screening similar to that for whole blood, as well as an annual physical exam with a licensed physician or an approved physician substitute under the supervision of the physician. Donors are screened at each donation for viral diseases that can be transmitted by blood, sometimes by multiple methods.  For example, donations are tested for  HIV  by  ELISA , which shows if they have been exposed to the disease, as well as by nucleic acid methods ( PCR  or similar) to rule out recent infections that the ELISA test might miss and are also screened for  hepatitis B  and  hepatitis C . Industry standards require at least two sets of negative test results before the collected plasma is used for injectable products.  The plasma is also treated in processing multiple times to inactivate any virus that was undetected during the screening process. [ 19 ]


In a few countries, plasma (like blood) is donated by unpaid volunteers. In others, including the United States, Austria, Germany and some Canadian facilities plasma donors are paid for their donations. [ 20 ]  Standards for donating plasma are set by national regulatory agencies such as the  U.S. Food and Drug Administration  (FDA), [ 21 ]  the  European Union , and by a professional organization, the Plasma Protein Therapeutics Association (or PPTA), [ 22 ]  which audits and accredits collection facilities. A  National Donor Deferral Registry  (NDDR) is also maintained by the PPTA for use in keeping donors with prior positive  viral   antibody  test results from donating at any facility.


Almost all plasmapheresis in the US is performed by automated methods. [ 23 ]  In some cases, automated plasmapheresis is used to collect plasma products like  fresh frozen plasma  for direct transfusion purposes, often at the same time as  plateletpheresis . These procedures are performed at facilities such as  community blood centers . [ 24 ]


Since returning  red cells  causes the body to replace plasma more rapidly, a donor can provide up to a liter of plasma at a time and can donate with only a few days between donations, unlike the 56-day deferral for blood donation. The amount allowed in a donation varies vastly from country to country, but generally does not exceed two donations, each as much as a liter (one-third of the total plasma volume), per seven-day period. If a significant amount of red blood cells cannot be returned, the donor may not donate for 56 days, just as if they had donated a unit of blood.  Depending on the collection system and the operation, the removed plasma may be replaced by  saline .  The body typically replaces the collected volume within 24 hours, and donors typically donate up to twice a week, though this varies by country. [ 25 ]


The collected plasma is promptly frozen at lower than -20 °C (-4 °F) and is typically shipped to a processing facility for fractionation. This process separates the collected plasma into specific components, such as  albumin  and  immunoglobulins , most of which are made into medications for human use. Sometimes the plasma is thawed and transfused as Fresh Frozen Plasma (FFP), much like the plasma from a normal blood donation. [ 26 ]


Plasmapheresis was originally described by doctors Vadim A. Yurevick and Nicolay Rosenberg of the  Imperial Medical and Surgical Academy of Saint Petersburg  in 1913. [ 30 ]  and John Abel and  Leonard Rowntree  of  Johns Hopkins Hospital  in 1914. [ 31 ]  Both studies carried out on animals, are considered precedent to subsequent studies held in humans and offered the first description of the technique. The first studies of the effects of plasmapheresis on humans were undertaken during the WWII period, and the results were reported in a study over six plasma donors presented by doctors Co Tui, F.C. Bartter and A.M. Wright in 1944. [ 32 ]


Aware of the rising demand for plasma for transfusion, Dr.  Josep Antoni Grífols-Lucas  conducted the first systematic study of the application of plasmapheresis in a series of plasma donors. Performed in 1951, this was the most exhaustive study to date of the medium-term effects on the human body, and involved more than 320 plasmapheresis procedures. Grifols-Lucas concluded that it was possible for donors to undergo plasmapheresis on a weekly basis without the quality of their plasma suffering, while the method also made it possible to obtain a larger quantity of plasma when compared to the conventional method of whole blood donation. The results of the study were presented at the 4th International Congress of Blood Transfusion in Lisbon (1951), and were published in 1952 in the  British Medical Journal [ 33 ]  and Medicina Clínica in Spain. [ 34 ]


At the Lisbon congress, Grifols-Lucas met  Edwin Cohn . While Grifols-Lucas was presenting a safe technique for obtaining large quantities of plasma from healthy donors, Cohn presented a plasma fractionator, a device that separated out the proteins contained in plasma. These two major contributions marked the birth of a new industry: plasma fractionation to obtain plasma products. [ 35 ]  In 1955, further data were presented at the 5th Congress of the European Hematology Society, in Freiburg, Germany, based on the ongoing performance of plasmapheresis over a five-year period. In 1956 Grifols-Lucas presented the results at the 6th Congress of the International Hematology Society in Boston, US. [ 35 ]


Michael Rubinstein was the first to use plasmapheresis to treat an immune-related disorder when he saved the life of an adolescent boy with  thrombotic thrombocytopenic purpura  (TTP) at the  Cedars of Lebanon Hospital  in Los Angeles in 1959. [ 36 ]  The modern plasmapheresis process itself originated in the U.S.  National Cancer Institute  between 1963 and 1968, where investigators drew upon an old dairy creamer separation technology first used in 1878 and refined by  Edwin Cohn 's centrifuge marketed in 1953. [ 36 ]


In 1965, Dr. Víctor Grifols-Lucas, brother of Josep Antoni Grifols-Lucas, patented the device, along with the procedure for performing plasmapheresis  in situ , [ 37 ]  that is, with the donor present. This replaced a fragmented, manual process with a continuous automatic method which enabled blood components to be extracted, separated and returned to the donor in a single procedure. The new device made plasmapheresis faster and simpler, and also made it safer for donors. [ 38 ]


Platelets  or  thrombocytes  (from  Ancient Greek     θρόμβος  ( thrómbos )  'clot' and    κύτος  ( kútos )  'cell') are a  blood  component whose function (along with the  coagulation factors ) is to react to  bleeding  from  blood vessel  injury by clumping, thereby initiating a  blood clot . [ 1 ]  Platelets have no  cell nucleus ; they are fragments of  cytoplasm  derived from the  megakaryocytes [ 2 ]  of the  bone marrow  or lung, [ 3 ]  which then enter the circulation. Platelets are found only in mammals, whereas in other  vertebrates  (e.g.  birds ,  amphibians ), thrombocytes circulate as intact  mononuclear cells . [ 4 ] : 3


One major function of platelets is to contribute to  hemostasis : the process of stopping bleeding at the site of interrupted  endothelium . They gather at the site and, unless the interruption is physically too large, they plug the hole. First, platelets attach to substances outside the interrupted endothelium:  adhesion . Second, they change shape, turn on receptors and secrete  chemical messengers :  activation . Third, they connect to each other through receptor bridges:  aggregation . [ 5 ]  Formation of this  platelet plug  (primary hemostasis) is associated with activation of the  coagulation cascade , with resultant  fibrin  deposition and linking (secondary hemostasis). These processes may overlap: the spectrum is from a predominantly platelet plug, or "white clot" to a predominantly fibrin, or "red clot" or the more typical mixture. Berridge adds  retraction  and  platelet inhibition  as fourth and fifth steps, [ 6 ]  while others would add a sixth step,  wound repair . [ citation needed ]  Platelets participate in both innate [ 7 ]  and adaptive [ 8 ]  intravascular immune responses.


In addition to facilitating the clotting process, platelets contain  cytokines  and  growth factors  which can promote wound healing and regeneration of damaged tissues. [ 9 ] [ 10 ]


The term  thrombocyte  (clot cell) came into use in the early 1900s and is sometimes used as a synonym for platelet; but not generally in the scientific literature, except as a root word for other terms related to platelets (e.g.  thrombocytopenia  meaning low platelets). [ 4 ] : v3   The term thrombocytes are proper for mononuclear cells found in the blood of non-mammalian vertebrates: they are the functional equivalent of platelets, but circulate as intact cells rather than cytoplasmic fragments of bone marrow megakaryocytes. [ 4 ] : 3


In some contexts, the word  thrombus  is used interchangeably with the word  clot , regardless of its composition (white, red, or mixed). In other contexts it is used to contrast a normal from an abnormal clot:  thrombus  arises from physiologic hemostasis,  thrombosis  arises from a pathologic and excessive quantity of clot. [ 11 ]  In a third context it is used to contrast the result from the process:  thrombus  is the result,  thrombosis  is the process.


Structurally the platelet can be divided into four zones, from peripheral to innermost: [ citation needed ]


Circulating inactivated platelets are biconvex discoid (lens-shaped) structures, [ 12 ] [ 4 ] : 117–118   2–3 μm in greatest diameter. [ 13 ]  Activated platelets have cell membrane projections covering their surface.


In a first approximation, the shape can be considered similar to  oblate spheroids , with a semiaxis ratio of 2 to 8. [ 14 ]  This approximation can be used to model the hydrodynamic and optical properties of a population, as well as to restore the geometric parameters of individual measured platelets by  flow cytometry . [ 15 ]  More accurate biophysical models of platelet surface morphology that model its shape from first principles, make it possible to obtain a more realistic platelet geometry in a calm and activated state. [ 16 ]


The fundamental function of platelets is to clump together to stop acute bleeding. This process is complex, as more than 193 proteins and 301 interactions are involved in platelet dynamics. [ 5 ]   Despite much overlap, platelet function can be modeled in three steps:


Thrombus  formation on an intact  endothelium  is prevented by  nitric oxide , [ 19 ]   prostacyclin , [ 20 ]  and  CD39 . [ 21 ]


Endothelial cells  attach to the subendothelial  collagen  by  von Willebrand factor  (VWF), which these cells produce. VWF is also stored in the  Weibel-Palade bodies  of the endothelial cells and secreted constitutively into the blood. Platelets store vWF in their alpha granules.


When the endothelial layer is disrupted, collagen and VWF anchor platelets to the subendothelium. Platelet  GP1b-IX-V  receptor binds with VWF; and GPVI receptor and integrin α2β1 bind with collagen. [ 22 ]


The intact endothelial lining  inhibits  platelet activation by producing  nitric oxide , endothelial- ADPase , and  PGI 2  (prostacyclin). Endothelial-ADPase degrades the platelet activator  ADP . [ citation needed ]


Resting platelets maintain active calcium  efflux  via a  cyclic AMP -activated calcium pump. Intracellular calcium concentration determines platelet activation status, as it is the  second messenger  that drives platelet conformational change and degranulation. Endothelial  prostacyclin  binds to  prostanoid  receptors on the surface of resting platelets. This event stimulates the coupled  Gs  protein to increase  adenylate cyclase  activity and increases the production of cAMP, further promoting the efflux of calcium and reducing intracellular calcium availability for platelet activation. [ citation needed ]


ADP on the other hand binds to  purinergic receptors  on the platelet surface. Since the thrombocytic purinergic receptor  P2Y12  is coupled to  Gi  proteins, ADP reduces platelet adenylate cyclase activity and cAMP production, leading to accumulation of calcium inside the platelet by inactivating the cAMP calcium efflux pump. The other ADP-receptor  P2Y1  couples to Gq that activates phospholipase C-beta 2 ( PLCB2 ), resulting in  inositol 1,4,5-trisphosphate  (IP3) generation and intracellular release of more calcium. This together induces platelet activation. Endothelial ADPase degrades ADP and prevents this from happening.  Clopidogrel  and related antiplatelet medications also work as purinergic receptor  P2Y12   antagonists . [ citation needed ]  Data suggest that ADP activates the  PI3K/Akt  pathway during a first wave of aggregation, leading to thrombin generation and  PAR‐1  activation, which evokes a second wave of aggregation. [ 23 ]


Platelet activation begins seconds after adhesion occurs. It is triggered when  collagen  from the subendothelium binds with its receptors ( GPVI  receptor and integrin α2β1) on the platelet. GPVI is associated with the Fc receptor gamma chain and leads via the activation of a tyrosine kinase cascade finally to the activation of PLC-gamma2 ( PLCG2 ) and more calcium release. [ citation needed ]


Tissue factor  also binds to  factor VII  in the blood, which initiates the extrinsic  coagulation  cascade to increase  thrombin  production. Thrombin is a potent platelet activator, acting through Gq and G12. These are  G protein-coupled receptors  and they turn on calcium-mediated  signaling pathways  within the platelet, overcoming the baseline calcium efflux. Families of three G proteins (Gq, Gi, G12) operate together for full activation. Thrombin also promotes secondary fibrin-reinforcement of the platelet plug. Platelet activation in turn degranulates and releases  factor V  and  fibrinogen , potentiating the coagulation cascade. Platelet plugging and coagulation occur simultaneously, with each inducing the other to form the final fibrin-crosslinked thrombus. [ citation needed ]


Collagen-mediated GPVI signalling increases the platelet production of  thromboxane A2  (TXA2) and decreases the production of  prostacyclin . This occurs by altering the metabolic flux of platelet's  eicosanoid  synthesis pathway, which involves enzymes  phospholipase A2 ,  cyclo-oxygenase 1 , and  thromboxane-A synthase . Platelets secrete thromboxane A2, which acts on the platelet's own  thromboxane receptors  on the platelet surface (hence the so-called "out-in" mechanism), and those of other platelets. These receptors trigger intraplatelet signaling, which converts  GPIIb/IIIa  receptors to their active form to initiate  aggregation . [ 5 ]


Platelets contain  dense granules , lambda granules, and  alpha granules . Activated platelets secrete the contents of these granules through their canalicular systems to the exterior. Bound and activated platelets degranulate to release platelet  chemotactic  agents to attract more platelets to the site of endothelial injury. Granule characteristics:


As shown by flow cytometry and  electron microscopy , the most sensitive sign of activation, when exposed to platelets using ADP, are morphological changes. [ 24 ]  Mitochondrial hyperpolarization is a key event in initiating morphology changes. [ 25 ]  Intraplatelet calcium concentration increases, stimulating the interplay between the microtubule/actin filament complex. The continuous changes in shape from the unactivated to the fully activated platelet are best seen via  scanning electron microscopy . The three steps along this path are named  early dendritic ,  early spread,  and  spread . The surface of the unactivated platelet looks similar to the surface of the brain–a wrinkled appearance from numerous shallow folds that increase the surface area;  early dendritic , an octopus with multiple arms and legs;  early spread , an uncooked frying egg in a pan, the "yolk" is the central body; and the  spread , a cooked fried egg with a denser central body.


These changes are all brought about by the interaction of the microtubule/actin complex with the platelet cell membrane and open canalicular system (OCS), which is an extension and invagination of that membrane. This complex runs just beneath these membranes and is the chemical motor that pulls the invaginated OCS out of the interior of the platelet, like turning pants pockets inside out, creating the dendrites. This process is similar to the mechanism of contraction in a  muscle cell . [ 26 ]  The entire OCS thus becomes indistinguishable from the initial platelet membrane as it forms the "fried egg". This dramatic increase in surface area comes about with neither stretching nor adding phospholipids to the platelet membrane. [ 27 ]


Platelet activation causes its membrane surface to become negatively charged. One of the signaling pathways turns on  scramblase , which moves negatively charged  phospholipids  from the inner to the outer platelet membrane surface. These phospholipids then bind the  tenase  and  prothrombinase  complexes, two of the sites of interplay between platelets and the coagulation cascade. Calcium ions are essential for the binding of these coagulation factors.


In addition to interacting with vWF and fibrin, platelets interact with thrombin, Factors X, Va, VIIa, XI, IX, and prothrombin to complete formation via the coagulation cascade. [ 28 ] [ 29 ]  Human platelets do not express  tissue factor . [ 28 ]  Rat platelets do express tissue factor protein and carry both tissue factor pre-mRNA and mature mRNA. [ 30 ]


Platelet aggregation begins minutes after activation, and occurs as a result of turning on the  GPIIb/IIIa  receptor, allowing these receptors to bind with  vWF  or  fibrinogen . [ 5 ]  Each platelet has around 60,000 of these receptors. [ 31 ]  When any one or more of at least nine different platelet surface receptors are turned on during activation, intraplatelet signaling pathways cause existing GpIIb/IIIa receptors to change shape — curled to straight — and thus become capable of binding. [ 5 ]


Since fibrinogen is a rod-like protein with nodules on either end capable of binding GPIIb/IIIa, activated platelets with exposed GPIIb/IIIa can bind fibrinogen to aggregate. GPIIb/IIIa may also further anchor the platelets to subendothelial vWF for additional structural stabilisation.


Classically it was thought that this was the only mechanism involved in aggregation, but three other mechanisms have been identified which can initiate aggregation, depending on the velocity of blood flow (i.e. shear range). [ 32 ]


Platelets have a central role in  innate immunity , initiating and participating in multiple inflammatory processes, directly binding and even destroying pathogens. Clinical data show that many patients with serious bacterial or viral infections have  thrombocytopenia , thus reducing their contribution to inflammation. Platelet-leukocyte aggregates (PLAs) found in circulation are typical in  sepsis  or  inflammatory bowel disease , showing the connection between thrombocytes and immune cells. [ 33 ]


The platelet cell membrane has receptors for collagen. Following rupture of the blood vessel wall, platelets are exposed and adhere to the collagen in the surrounding tissue.


As hemostasis is a basic function of thrombocytes in mammals, it also has its uses in possible infection confinement. [ 7 ]  In case of injury, platelets, together with the coagulation cascade, provide the first line of defense by forming a blood clot. Hemostasis and host defense were thus intertwined in evolution. For example, in the  Atlantic horseshoe crab  (estimated to be over 400 million years old), the only blood cell type, the  amebocyte , facilitates both the hemostatic function and the encapsulation and phagocytosis of  pathogens  by means of  exocytosis  of intracellular granules containing  bactericidal  defense molecules. Blood clotting supports immune function by trapping the bacteria. [ 34 ]


Although thrombosis, blood coagulation in intact blood vessels, is usually viewed as a pathological immune response, leading to obturation of lumen of blood vessel and subsequent hypoxic tissue damage, in some cases, directed thrombosis, called immunothrombosis, can locally control the spread of an infection. The thrombosis is directed in concordance of platelets,  neutrophils  and  monocytes . The process is initiated either by immune cells by activating their pattern recognition receptors (PRRs), or by platelet-bacterial binding. Platelets can bind to bacteria either directly through thrombocytic PRRs [ 33 ]  and bacterial surface proteins, or via plasma proteins that bind both to platelets and bacteria. [ 35 ]  Monocytes respond to bacterial  pathogen-associated molecular patterns  (PAMPs), or  damage-associated molecular patterns  (DAMPs) by activating the extrinsic pathway of coagulation. Neutrophils facilitate the blood coagulation by  NETosis , while platelets facilitate neutrophils' NETosis. NETs bind tissue factor, binding the coagulation centers to the location of infection. They also activate the intrinsic coagulation pathway by providing its negatively charged surface to the factor XII. Other neutrophil secretions, such as proteolytic enzymes which cleave coagulation inhibitors, also bolster the process. [ 7 ]


In case of imbalance throughout the regulation of immunothrombosis, this process can become aberrant. Regulatory defects in immunothrombosis are suspected to be a major factor in pathological thrombosis in forms such as  disseminated intravascular coagulation  (DIC) or  deep vein thrombosis . DIC in sepsis is a prime example of both the dysregulated coagulation process as well as an undue systemic inflammatory response, resulting in a multitude of microthrombi of similar composition to that in physiological immunothrombosis — fibrin, platelets, neutrophils and NETs. [ 7 ]


Platelets rapidly deploy to sites of injury or infection, and potentially modulate inflammatory processes by interacting with  leukocytes  and secreting  cytokines ,  chemokines , and other inflammatory mediators. [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ]  Platelets also secrete  platelet-derived growth factor  (PDGF).


Platelets modulate neutrophils by forming platelet-leukocyte aggregates (PLAs). These formations induce upregulated production of αmβ2 ( Mac-1 ) integrin in neutrophils. Interaction with PLAs also induces degranulation and increased phagocytosis in neutrophils.


Platelets are the largest source of soluble  CD40L  which induces production of  reactive oxygen species  (ROS) and upregulate expression of adhesion molecules, such as  E-selectin ,  ICAM-1 , and  VCAM-1 , in neutrophils, activates macrophages and activates cytotoxic response in  T  and  B lymphocytes . [ 33 ]


Mammalian platelets lacking nucleus are able to conduct autonomous locomotion. [ 41 ]  Platelets are active scavengers, scaling walls of blood vessels and reorganising the thrombus. They are able to recognize and adhere to many surfaces, including bacteria, and can envelop them in their open canalicular system (OCP), leading to a proposal to name the process as  covercytosis  (OCS) rather than phagocytosis, as OCS is merely an invagination of outer plasma membrane. These platelet-bacteria bundles provide an interaction platform for neutrophils that destroy bacteria using the NETosis and phagocytosis.


Platelets also participate in chronic inflammatory disease, such as  synovitis  or  rheumatoid arthritis . [ 42 ]  Platelets are activated by collagen receptor  glycoprotein IV  (GPVI). Proinflammatory platelet microvesicles trigger constant cytokine secretion from neighboring  fibroblast-like synoviocytes , most prominently  Il-6  and  Il-8 . Inflammatory damage to the surrounding extracellular matrix continuously reveals more collagen, maintaining microvesicle production.


Activated platelets are able to participate in  adaptive immunity , interacting with  antibodies . They are able to specifically bind  IgG  through  FcγRIIA , a receptor for IgG's constant fragment (Fc). When activated and bound to IgG  opsonised  bacteria, platelets release reactive oxygen species (ROS), antimicrobial peptides,  defensins , kinocidins and  proteases , killing the bacteria directly. [ 43 ]  Platelets also secrete proinflammatory and procoagulant mediators such as inorganic  polyphosphates  or  platelet factor 4  (PF4), connecting innate and adaptive immune responses. [ 43 ] [ 44 ]


Spontaneous and excessive bleeding can occur because of platelet disorders. This bleeding can be caused by deficient numbers of platelets, dysfunctional platelets, or platelet densities over 1 million/microliter. (The excessive numbers create a relative von Willebrand factor deficiency due to sequestration.) [ 45 ] [ 46 ]


Bleeding due to a platelet disorder or a coagulation factor disorder can be distinguished by the characteristics and location of the bleeding. [ 4 ] : 815, Table 39-4   Platelet bleeding involves bleeding from a cut that is prompt and excessive, but can be controlled by pressure; spontaneous bleeding into the skin which causes a purplish stain named by its size:  petechiae ,  purpura ,  ecchymoses ; bleeding into mucous membranes causing bleeding gums, nose bleed, and gastrointestinal bleeding; menorrhagia; and intraretinal and intracranial bleeding.


Excessive numbers of platelets, and/or normal platelets responding to abnormal vessel walls, can result in  venous thrombosis  and  arterial thrombosis . The symptoms depend on the thrombosis site.


Platelet concentration in the blood (i.e. platelet count), can be measured manually using a  hemocytometer , or by placing blood in an automated platelet analyzer using particle counting, such as a  Coulter counter  or optical methods. [ 47 ]  Most common  blood testing methods  include platelet count in their measurements, usually reported as  PLT . [ 48 ]


Platelet concentrations vary between individuals and over time, with the population average between 250,000 and 260,000 cells per mm 3  (equivalent to per microliter), but the typical laboratory accepted normal range is between 150,000 and 400,000 cells per mm 3  or 150–400 × 10 9  per liter. [ 48 ] [ 47 ]


On a stained  blood smear , platelets appear as dark purple spots, about 20% of the diameter of red blood cells. The smear reveals size, shape, qualitative number, and  clumping . A healthy adult typically has 10 to 20 times more red blood cells than platelets.


Bleeding time  was developed as a test of platelet function by Duke in 1910. [ 49 ]  Duke's test measured the time taken for bleeding to stop from a standardized wound in the ear lobe that was blotted every 30 seconds, considering less than 3 minutes as normal. [ 50 ]  Bleeding time has low sensitivity and specificity for mild to moderate platelet disorders and is no longer recommended for screening. [ 51 ]


In  multiple electrode aggregometry , anticoagulated whole blood is mixed with saline and a platelet agonist in a single-use cuvette with two pairs of electrodes. The increase in impedance between the electrodes as platelets aggregate onto them, is measured and visualized as a curve. [ 52 ] [ 53 ]


In light transmission aggregometry (LTA),  platelet-rich plasma  is placed between a light source and a  photocell . Unaggregated plasma allows relatively little light to pass through. After adding an agonist, the platelets aggregate, increasing light transmission, which is detected by a photocell. [ 56 ]


Whole blood impedance aggregometry (WBA) measures the change in electrical impedance between two electrodes when platelet aggregation is induced by an agonist. Whole blood lumiaggregometry may increase the test sensitivity to impairment of platelet granule secretion. [ 57 ]


The  PFA-100  (Platelet Function Assay — 100) is a system for analysing platelet function in which citrated whole blood is aspirated through a disposable cartridge containing an aperture within a membrane coated with either collagen and epinephrine or collagen and ADP. These agonists induce platelet adhesion, activation and aggregation, leading to rapid occlusion of the aperture and cessation of blood flow termed the closure time (CT). An elevated CT with EPI and collagen can indicate intrinsic defects such as  von Willebrand disease ,  uremia , or circulating platelet inhibitors. A follow-up test involving collagen and ADP is used to indicate if the abnormal CT with collagen and EPI was caused by the effects of acetyl sulfosalicylic acid (aspirin) or medications containing inhibitors. [ 58 ]  The PFA-100 is highly sensitive to von Willebrand disease, but is only moderately sensitive to defects in platelet function. [ 59 ]


Low platelet concentration is called  thrombocytopenia , and is due to either decreased production or increased destruction. Elevated platelet concentration is called  thrombocytosis , and is either  congenital , reactive (to  cytokines ), or due to unregulated production: one of the  myeloproliferative neoplasms  or certain other myeloid  neoplasms . A disorder of platelet function is called a  thrombocytopathy  or a platelet function disorder. [ 4 ] : vii


Normal platelets can respond to an abnormality on the vessel wall rather than to hemorrhage, resulting in inappropriate platelet adhesion/activation and  thrombosis : the formation of a clot within an intact vessel. This type of thrombosis arises by mechanisms different from those of a normal clot: extending the fibrin of  venous thrombosis ; extending an unstable or ruptured arterial plaque, causing  arterial thrombosis ; and microcirculatory thrombosis. An arterial  thrombus  may partially obstruct blood flow, causing downstream  ischemia , or may completely obstruct it, causing downstream  tissue death .: [ 4 ] : vii


The three broad categories of platelet disorders are "not enough", "dysfunctional", and "too many". [ 4 ] : vii


Some drugs used to treat inflammation have the unwanted side effect of suppressing normal platelet function. These are the  non-steroidal anti-inflammatory drugs  (NSAIDS).  Aspirin  irreversibly disrupts platelet function by inhibiting  cyclooxygenase -1 (COX1), and hence normal hemostasis. The resulting platelets are unable to produce new cyclooxygenase because they have no DNA. Normal platelet function does not return until the use of aspirin has ceased and enough of the affected platelets have been replaced by new ones, which can take over a week.  Ibuprofen , another  NSAID , does not have such a long duration effect, with platelet function usually returning within 24 hours, [ 66 ]  and taking ibuprofen before aspirin prevents the irreversible effects of aspirin. [ 67 ]


These drugs are used to prevent thrombus formation.


Platelet transfusion  is most frequently used to correct unusually low platelet counts, either to prevent spontaneous bleeding (typically at counts below 10×10 9 /L) or in anticipation of medical procedures that necessarily involve some bleeding. For example, in patients undergoing  surgery , a level below 50×10 9 /L is associated with abnormal surgical bleeding, and  regional anaesthetic  procedures such as  epidurals  are avoided for levels below 80×10 9 /L. [ 68 ]  Platelets may also be transfused when the platelet count is normal but the platelets are dysfunctional, such as when an individual is taking aspirin or  clopidogrel . [ 69 ]  Finally, platelets may be transfused as part of a  massive transfusion protocol , in which the three major blood components (red blood cells, plasma, and platelets) are transfused to address severe  hemorrhage . Platelet transfusion is contraindicated in  thrombotic thrombocytopenic purpura  (TTP), as it fuels the  coagulopathy .  Platelet transfusion is generally ineffective, and thus contraindicated, for prophylaxis in  immune thrombocytopenia  (ITP), because the transfused platelets are immediately cleared; however, it is indicated to treat bleeding. [ 70 ]


Platelets are either isolated from collected units of whole blood and pooled to make a therapeutic dose, or collected by  platelet apheresis : blood is taken from the donor, passed through a device which removes the platelets, and the remainder is returned to the donor in a closed loop. The industry standard is for platelets to be tested for bacteria before transfusion to avoid septic reactions, which can be fatal. Recently the AABB Industry Standards for  Blood Banks  and Transfusion Services (5.1.5.1) has allowed use of pathogen reduction technology as an alternative to bacterial screenings in platelets. [ 71 ]


Pooled whole-blood platelets, sometimes called "random" platelets, are separated by one of two methods. [ 72 ]  In the US, a unit of whole blood is placed into a large  centrifuge  in what is referred to as a "soft spin". At these settings, the platelets remain suspended in the plasma. The  platelet-rich plasma  (PRP) is removed from the red cells, then centrifuged at a faster setting to harvest the platelets from the plasma. In other regions of the world, the unit of whole blood is centrifuged using settings that cause the platelets to become suspended in the " buffy coat " layer, which includes the platelets and the white blood cells. The "buffy coat" is isolated in a sterile bag, suspended in a small amount of red blood cells and plasma, then centrifuged again to separate the platelets and plasma from the red and white blood cells. Regardless of the initial method of preparation, multiple donations may be combined into one container using a sterile connection device to manufacture a single product with the desired therapeutic dose.


Apheresis platelets are collected using a mechanical device that draws blood from the donor and centrifuges the collected blood to separate out the platelets and other components to be collected. The remaining blood is returned to the donor. The advantage to this method is that a single donation provides at least one therapeutic dose, as opposed to the multiple donations for whole-blood platelets. This means that a recipient is exposed to fewer donors and has less risk of transfusion-transmitted disease and other complications. Sometimes a person such as a  cancer  patient who requires routine transfusions of platelets receives repeated donations from a specific donor to minimize risk. Pathogen reduction of platelets using for example,  riboflavin and UV light treatments  can reduce the infectious load of pathogens contained in donated blood products. [ 73 ] [ 74 ]  Another photochemical treatment process utilizing amotosalen and UVA light has been developed for the inactivation of viruses, bacteria, parasites, and leukocytes. [ 75 ]  In addition, apheresis platelets tend to contain fewer contaminating red blood cells because the collection method is more efficient than "soft spin" centrifugation.


Platelets collected by either method have a typical shelf life of five days. This results in supply shortages, as testing donations often requires up to a full day. No effective preservative solutions have been devised for platelets.


Platelets are stored under constant agitation at 20–24 °C (68–75 °F). Units cannot be refrigerated as this causes platelets to change shape and lose function. Storage at room temperature provides an environment where any introduced bacteria may proliferate and subsequently cause  bacteremia . The United States requires products to be tested for the presence of bacterial contamination before transfusion. [ 76 ]


Platelets do not need to belong to the same A-B-O blood group as the recipient or be cross-matched to ensure immune compatibility between donor and recipient unless they contain a significant amount of red blood cells (RBCs). The presence of RBCs imparts a reddish-orange color to the product and is usually associated with whole-blood platelets. Some sites may type platelets, but this is not critical.


Prior to issuing platelets to the recipient, they may be irradiated to prevent  transfusion-associated graft versus host disease  or they may be washed to remove the plasma.


The change in the recipient's platelet count after transfusion is termed the "increment" and is calculated by subtracting the pre-transfusion platelet count from the post-transfusion count. Many factors affect the increment including body size, the number of platelets transfused, and clinical features that may cause premature destruction of the transfused platelets. When recipients fail to demonstrate an adequate post-transfusion increment, this is termed  platelet transfusion refractoriness .


Platelets, either apheresis-derived or random-donor, can be processed through a volume reduction process. In this process, the platelets are spun in a centrifuge and plasma is removed, leaving 10 to 100 mL of platelet concentrate. Such volume-reduced platelets are normally transfused only to neonatal and pediatric patients when a large volume of plasma could overload the child's small circulatory system. The lower volume of plasma also reduces the chances of an adverse transfusion reaction to plasma proteins. [ 77 ]  Volume reduced platelets have a shelf life of four hours. [ 78 ]


The blood clot is only a temporary solution to stop bleeding; tissue repair is needed. Small interruptions in the endothelium are handled by physiological mechanisms; large interruptions by a trauma surgeon. [ 79 ]  The fibrin is slowly dissolved by the fibrinolytic enzyme,  plasmin , and the platelets are cleared by  phagocytosis . [ 80 ]


Platelets release  platelet-derived growth factor  (PDGF), a potent  chemotactic  agent; and  TGF beta , which stimulates the deposition of  extracellular matrix ;  fibroblast growth factor ,  insulin-like growth factor 1 , platelet-derived  epidermal growth factor , and  vascular endothelial growth factor . Local application of these factors in increased concentrations through  platelet-rich plasma  (PRP) is used as an adjunct in wound healing. [ 81 ]


Instead of platelets, non-mammalian vertebrates have nucleated thrombocytes, which resemble  B lymphocytes  in morphology. They aggregate in response to thrombin, but not to ADP, serotonin, nor adrenaline, as platelets do. [ 82 ] [ 83 ]


Platelet concentrates  are products containing platelet enriched blood, which are used for  platelet transfusions


Platelets can be isolated from whole blood using three methods, the platelet rich plasma method, the buffy coat method and with apheresis. Platelets are normally stored at room temperature (20 to 24 °C) in order to preserve their ability to circulate after transfusion. [ 1 ]  However, platelets can be stored at other temperatures, including refrigeration and cryopreservation for use in specific instances.


When stored at room temperature, the platelet concentrates are gently agitated at a speed of 60 strokes per minutes, so that the platelets to remain in suspension. Platelets can be stored for up to seven days with maintenance of their function in patients. [ 2 ]  Due to their storage at room temperature, platelet concentrates are at risk of bacterial outgrowth if a unit is contaminated. Therefore, measures have been taken to prevent this. Bacterial screening within 24 to 36 hours after blood collection can be performed, pathogen inactivation can be performed, or the storage time can be shortened to 3 to 5 days.


During storage, platelet mainly metabolize glucose. Oxidative metabolism leads to the formation of carbon dioxide, and anaerobic metabolism leads to the formation of lactic acid. Both types of metabolism occur simultaneously. Both carbon dioxide and lactic acid acidify the storage medium, and the lowering of the pH of the storage medium affects the quality of the platelets. Below pH 6.2, the damage to the platelets is irreversible, and platelets do not circulate when transfused. [ 3 ]  Platelets are therefore stored in gas-permeable containers with a large volume-to-surface ratio, in order to expel carbon dioxide, which elevates the pH. Also, these containers allow for the entry of oxygen, favoring oxidative metabolism.


Originally, platelets were stored in the donor’s own plasma. Nowadays, many blood banks have switched to using platelet additive solution to store platelets. Typically, when platelets are isolated from whole blood, not all plasma is removed, as platelets need to be in a certain volume of plasma in order to have a clear separation from other cells. Platelet additive solution is added to bring the platelets to a concentration that sustains five to seven day storage. Consequently, platelets are typically stored in approximately one-third plasma and two-thirds platelet additive solution.


Platelet additive solutions contain nutrients to support platelet metabolism during their storage. Acetate is often used as nutrient. When acetate is metabolized, an hydroxy-ion is consumed, which elevates the pH. [ 4 ]  Platelet additive solutions may additionally contain a buffer to keep the pH above 6.2. Potassium and magnesium may be added to prevent untimely platelet activation. [ 5 ]  Due to the dilution of plasma, allergic reactions to plasma antigens are less frequent. [ 6 ]  Also, ABO antibody titers are fourfold lower, making ABO-incompatible transfusions easier.


Platelet transfusion , is the process of infusing platelet concentrate into the body via vein, to prevent or treat the  bleeding  in people with either a  low platelet count  or  poor platelet function . [ 1 ]  Often this occurs in people receiving  cancer chemotherapy . [ 1 ]  Preventive transfusion is often done in those with platelet levels of less than 10 x 10 9 /L. [ 2 ]  In those who are bleeding transfusion is usually carried out at less than 50 x 10 9 /L. [ 2 ]  Blood group matching ( ABO ,  RhD ) is typically recommended before platelets are given. [ 2 ]  Unmatched platelets, however, are often used due to the unavailability of matched platelets. [ 3 ]  They are given by  injection into a vein . [ 4 ]


Side effects can include  allergic reactions  such as  anaphylaxis ,  infection , and  lung injury . [ 2 ]   Bacterial infections  are relatively more common with platelets as they are stored at warmer temperatures. [ 2 ]  Platelets can be produced either from  whole blood  or by  apheresis . [ 1 ]  They keep for up to five to seven days. [ 1 ]


Platelet transfusions came into medical use in the 1950s and 1960s. [ 1 ] [ 5 ]  It is on the  World Health Organization's List of Essential Medicines . [ 6 ] [ 7 ]  Some versions of platelets have had the  white blood cells  partially removed or been  gamma irradiated  which have specific benefits for certain populations. [ 8 ]


International guidelines recommend that platelets transfusions are given to people with reversible bone marrow failure to reduce the risk of spontaneous bleeding when the platelet count is less than 10 x 10 9 /L. [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ]  If the person is well using a higher platelet count threshold does not reduce the risk of bleeding further. [ 14 ]


A review in people with  blood cancers  receiving intensive  chemotherapy  or a  stem cell transplant  found that overall giving platelet transfusions when the platelet count is less than 10 x 10 9 /L reduced the number of bleeding events and days with significant bleeding. [ 15 ]  However, this benefit was only seen in certain patient groups, and people undergoing an autologous  stem cell transplant  derived no obvious benefit. [ 15 ]  Despite prophylactic platelet transfusions, people with blood cancers often bleed, and other risk factors for bleeding such as inflammation and duration of thrombocytopenia should be considered. [ 13 ]


There is little evidence for the use of preventive platelet transfusions in people with chronic bone marrow failure, such as  myelodysplasia  or  aplastic anemia . [ 16 ]  Multiple guidelines recommend prophylactic platelet transfusions are not used routinely in people with chronic bone marrow failure, and instead an individualised approach should be taken. [ 11 ] [ 10 ] [ 13 ]


Several studies have now assessed the benefit of using preventive platelet transfusions in adults with dengue who have profound thrombocytopenia (platelet count < 20 x 10 9 /L. [ 17 ]  There is no evidence that this reduce the risk of bleeding, but there is evidence that they increase the risk of harm due to the platelet transfusion (increased risk of a transfusion reaction including  anaphylaxis ). [ 17 ]


Two reviews in people with  blood cancers  receiving intensive  chemotherapy  or a  stem cell transplant  found that overall giving platelet transfusions when the platelet count is less than 10 x 10 9 /L compared to giving platelet transfusions when the platelet count is less than 20 or 30 x 10 9 /L had no effect on the risk of bleeding. [ 14 ] [ 18 ]


Higher platelet transfusion thresholds have been used in premature neonates, but this has been based on limited evidence. [ 19 ]  There is now evidence that using a high platelet count threshold (50 x 10 9 /L) increases the risk of death or bleeding compared to a lower platelet count threshold (25 x 10 9 /L) in premature neonates. [ 20 ]


A review in people with  blood cancers  compared different platelet transfusion doses. [ 21 ]  This review found no difference in the number of people who had clinically significant bleeding between platelet transfusions that contained a small number of platelets (low dose – 1.1 x 10 11 /m 2 ) and those that contained an intermediate number of platelets (intermediate dose – 2.2 x 10 11 /m 2 ).  This review also found no difference in the number of people who had clinically significant bleeding between platelet transfusions that contained a small number of platelets and those that contained a large number of platelets (high dose – 4.4 x 10 11 /m 2 ). [ 21 ]  One of the review's included studies reported on transfusion reactions. This study's authors suggested that a high-dose platelet transfusion strategy may lead to a higher rate of transfusion-related adverse events. [ 22 ]


In people with a low platelet count, prophylactic platelet transfusions do not need to be given prior to procedures that have a low risk of causing bleeding. [ 10 ] [ 13 ] [ 9 ]  Low-risk procedures include surgical sites that do not contain many blood vessels e.g. cataract surgery, [ 13 ]  or minor procedures. [ 10 ] [ 13 ]  The evidence is very uncertain about the effect of platelet transfusions prior to surgery for people with a low platelet count on the all-cause mortality, the number of participants with bleeding events after surgery, serious surgery-related or transfusion-related adverse events. [ 23 ]


Guidelines recommend that it is safe to perform  central venous catheter  insertion when the platelet count is 20 x 10 9 /L or above. [ 9 ] [ 13 ]  The evidence for this is based on observational studies in which bleeding occurred due to procedure error rather than due to the platelet count. [ 13 ] [ 24 ]