Red blood cell antigens and antibodies

INTRODUCTION — The surface of every red blood cell (RBC) is coated with antigens (sugars and proteins) that are integrally linked to membrane proteins or lipids. The clinical relevance of these antigens for blood component transfusion and tissue/organ transplantation lies in the ability of these surface molecules to incite an immune response, potentially causing a transfusion reaction or organ/tissue rejection. In addition, some RBC surface antigens have cellular functions with clinical relevance, and others are targets of immune attack in certain infections, as discussed below.

This topic will review clinically relevant RBC antigens and respective antibodies, and settings in which the RBC antigens may be important. Additional discussions of certain clinical issues are presented separately:

●Pretransfusion testing – (See "Pretransfusion testing for red blood cell transfusion" and "Red blood cell (RBC) transfusion in individuals with serologic complexity".)

●Hemolytic anemia – (See "Warm autoimmune hemolytic anemia (AIHA) in adults".)

●Hemolytic transfusion reactions – (See "Hemolytic transfusion reactions".)

●RhD hemolytic disease of the fetus and newborn (HDFN) – (See "RhD alloimmunization in pregnancy: Overview".)

●HDFN due to other alloantibodies – (See "Management of non-RhD red blood cell alloantibodies during pregnancy".)

TERMINOLOGY

●Blood group system – A blood group system is a collection of one or more antigens that are under the control of a single gene or a cluster of closely linked, homologous genes [1]. Forty-three blood group systems are recognized by the International Society for Blood Transfusion [2]. The major blood group systems with clinical significance are listed in the table (table 1) and discussed in more detail below. (See 'Clinically significant (common)' below.)

●Blood group antigen – A blood group antigen is a sugar or protein present on the surface of the RBC that is defined serologically by reagent antisera that react with the antigen and cause red cell agglutination (eg, blood group A cells are agglutinated by anti-A antibodies) (figure 1) [3]. In cases in which a single nucleotide difference results in two different antigens, the convention is for these to be designated with a superscript (eg, Fy^a, Fy^b). Every blood group antigen belongs to a blood group system. There are 343 RBC antigens recognized by the International Society for Blood Transfusion [2].

●RBC phenotype – RBC phenotype refers to the combination of antigens on the RBC surface; phenotyping refers to the laboratory-based process of detecting these antigens by serologic testing using reagent antisera [3].

●RBC genotype – RBC genotype refers to the genetic sequences at the loci for blood group antigens; genotyping refers to the use of DNA analysis to determine blood group antigens.

●Null phenotype – Null phenotype for a blood group system (possible for most blood group systems) refers to the absence of antigens for that system. The null phenotype may be due to inactivating mutations that prevent transcription of the gene product necessary for antigen expression [1].

SETTINGS IN WHICH BLOOD GROUPS PLAY A ROLE — Blood type is used clinically in pretransfusion testing, organ/tissue transplantation, evaluation of transfusion reaction, and determining the risk of hemolytic disease of the fetus and newborn (HDFN). Transfusion-associated hemolytic anemias are associated with certain blood group antigens.

Some blood group antigens (or their absence) appear to have been selected during evolution, such as antigen phenotypes that microorganisms cannot use to enter the RBC (see 'Resistance to RBC parasites' below). Additional information about historical contexts and specific blood groups is presented in several review articles [1,4].

Blood component transfusion — Safe transfusion of RBCs is possible because donor RBC units can be selected for their compatibility with the recipient's blood type. Transfused RBC units do not need to be phenotypically identical to the recipient's RBCs, but they do need to lack antigens that could provoke clinically significant hemolysis in the recipient (eg, a blood group A donor unit cannot be transfused to a blood group O recipient). If an individual develops an alloantibody to an RBC antigen, it is important to avoid transfusing RBCs with that specific antigen, indefinitely.

Antibodies to RBC antigens are considered to be clinically significant if they have been shown to lead to clinical events (acute hemolytic transfusion reactions, delayed hemolytic transfusion reactions, autoimmune hemolytic anemia, or hemolytic disease of the fetus and newborn). Generally, these antibodies are reactive at 37°C and are IgG, with the exception of IgM for ABO antibodies. Antibodies that have not been shown to lead to clinical events are considered clinically insignificant.

Incompatibility between a blood transfusion recipient and donor is a cause of potentially serious transfusion reactions. Routine pretransfusion testing for RBC, platelet, and plasma transfusion typically involves determination of ABO and RhD type (table 1).

●RBCs – For RBC transfusion, the patient’s RBCs are typed and the patient’s plasma is tested for the presence of antibodies that could cause hemolysis of the transfused blood, such as those directed against antigens in the ABO, Rh, Duffy, Kidd, Kell, MNS, and Lutheran blood groups. Antibodies to additional RBC antigens may be detected during compatibility testing (crossmatching) with a specific unit of blood. (See "Pretransfusion testing for red blood cell transfusion", section on 'Serologic testing (type and screen)'.)

●Platelets – Platelets express ABO (but not Rh) antigens on their surface; these ABO antigens are absorbed from the plasma onto the platelet surface. Rarely, an individual may have platelets that express high levels of ABO antigens [5,6]. Most transfusion services monitor platelet transfusions to limit the amount of ABO incompatible plasma administered with the platelet product, and some avoid giving platelets with high titers of anti-A and anti-B to A and B individuals. When RhD-negative women of childbearing age are given platelet transfusions, platelets from RhD-negative donors are used to avoid potential co-transfusion of a small amount of RhD-positive RBCs in the platelet product. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'ABO, Rh, and HLA matching'.)

●Plasma – Plasma contains antibodies to ABO antigens. Plasma for transfusion can either be from a donor who shares the same ABO type as the recipient (ABO identical or ABO matched) or it can be ABO compatible (eg, patient with type A blood can receive plasma from a donor who is type A or type AB, neither of which will contain antibodies to A). (See "Clinical use of plasma components", section on 'ABO matching'.)

Any individual with a history of a clinically significant antibody should receive blood that lacks the relevant antigen, even if the antibody is not detectable on subsequent testing. The rationale is that some antibodies may decrease to undetectable levels but may be boosted upon re-exposure to the antigen. Antibodies to Kidd blood group antigens (anti-Jk^a and anti-Jk^b) are one setting in which this phenomenon is seen. (See 'Kidd antibodies' below and "Pretransfusion testing for red blood cell transfusion".)

Hematopoietic stem cell and solid organ transplantation — Hematopoietic stem cells can be transplanted from a donor of any blood type to a recipient of any blood type, regardless of compatibility, because the donor hematopoietic stem cells will give rise to the new donor blood type and a new immune system that are compatible with each other.

Measures to reduce hemolysis of recipient and donor RBCs and improve platelet survival during the immediate post-transplant period (when donor and recipient blood cells and circulating antibodies in the plasma are both present) are outlined in the table (table 2) and discussed separately. (See "Red blood cell (RBC) transfusion in individuals with serologic complexity", section on 'Allogeneic hematopoietic stem cell transplantation recipients' and "Donor selection for hematopoietic cell transplantation", section on 'ABO and Rh status'.)

In solid organ/tissue transplantation, antibodies to blood group antigens that are expressed on the transplanted organ can mediate organ rejection and graft loss. Routine transplantation practice involves the use of organs that are ABO identical with the recipient. Compatibility for other (non-ABO) blood group antigens is not performed. Non-ABO identical transplants can be performed (eg, group O donor organ transplanted to group A, B, or AB recipient).

In selected cases, transplantation of an ABO incompatible organ can be performed (eg, from a living kidney donor; for fulminant hepatic failure), often using desensitization and immunosuppression protocols [7,8]. This subject and other exceptions are discussed separately. (See "Liver transplantation in adults: Deceased donor evaluation and selection", section on 'ABO compatibility' and "Kidney transplantation in adults: ABO-incompatible transplantation", section on 'Pretransplant ABO desensitization'.)

In some cases, transient hemolysis of recipient RBCs may be observed due to the presence of passenger lymphocytes from the donated organ. (See "Pretransfusion testing for red blood cell transfusion", section on 'Transplant recipients'.)

ABO compatibility is not required for transplantation of tissues such as cornea, bone, or tendon. These tissues do not contain appreciable RBCs, and ABO compatibility has not been correlated with transplant outcomes [9,10].

Hemolytic disease of the fetus and newborn (HDFN) — HDFN is a potentially fatal alloimmune reaction in which maternal antibodies directed against fetal RBC antigens can cross the placenta and cause hemolytic anemia in the fetus or during the neonatal period (maternal antibodies persist in fetal plasma for several weeks). Maternal antibodies that could potentially react with fetal antigens inherited from the father may have developed in response to prior exposures to the antigens. Examples include exposure of an RhD-negative mother to an RhD-positive fetus during a previous pregnancy or exposure of a Kell-negative mother to Kell antigen through a previous blood transfusion.

A more comprehensive list of RBC antibodies implicated in HDFN, as well as approaches to patient evaluation, prevention, and management of HDFN, are presented separately. (See "RhD alloimmunization in pregnancy: Overview" and "RhD alloimmunization in pregnancy: Management" and "Management of non-RhD red blood cell alloantibodies during pregnancy" and "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management".)

Autoimmune hemolytic anemia — Autoantibodies to self-RBC antigens play a role in hemolytic anemias. Common examples include autoimmune hemolytic anemia (AIHA) due to antibodies to the I antigen that develop following certain infectious illnesses (eg, mycoplasma), and paroxysmal cold hemoglobinuria resulting from autoantibodies to the P antigen of the Glob blood group. (See "Warm autoimmune hemolytic anemia (AIHA) in adults" and 'Lewis, P1P(K), GLOB, and I blood group systems' below and "Paroxysmal cold hemoglobinuria".)

Resistance to RBC parasites — Some blood groups appear to have been selected during evolution for their role in protection against invading organisms that use RBC surface antigens as receptors for entry into RBCs.

Malaria is the best known example. Blood group systems for which certain antigens appear to provide partial protection include ABO, MNS, Gerbich, and Knops (for Plasmodium falciparum) and Duffy (for P. vivax and P. knowlesi). (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'RBC surface proteins'.)

Disease predisposition (including COVID-19) — A variety of disease predispositions have been reported with various blood group phenotypes, although the implications of these associations for patient management are often unclear. As examples:

●Venous thromboembolism – Individuals with blood group O have approximately 20 to 30 percent lower levels of von Willebrand factor (VWF) than those with types A, B, or AB, which may be due to increased clearance of VWF from the circulation [11]. Type O individuals as a result may have a lower risk for venous thromboembolic disease [12-14]. (See "Overview of the causes of venous thrombosis", section on 'Factor VIII' and "Factor V Leiden and activated protein C resistance", section on 'Other genetic variants' and "Pathophysiology of von Willebrand disease", section on 'Clearance and control of plasma VWF levels'.)

●COVID-19 – Disease severity in individuals with coronavirus disease 2019 (COVID-19) and likelihood of infection with the SARS-CoV-2 virus were initially reported to vary with ABO blood type, with group A and AB individuals appearing to be at greater risk and group O at lower risk [15-19]. However, the choice of control groups was questioned, and mortality did not appear to vary by blood group [20]. A 2022 meta-analysis of >60 studies (nearly 2 million participants) concluded that O blood group was associated with a lower risk of COVID-19 (odds ratio [OR] 0.88, 95% CI 0.82–0.94) [21]. There were slight differences in mortality with different blood groups that may have related to demographic characteristics rather than blood group.

One hypothesis suggests that the presence of anti-A antibodies, rather than blood type, could be responsible for a difference in rates of infection or disease severity [22]. Another study suggests that it may be the ABH antigen on tissues such as the lung that contributes to differences in infection susceptibility [23]. Using the variant of the A antigen present on respiratory epithelial cells (which differs slightly in its carbohydrate structure from the A antigen on RBCs) investigators demonstrated that the receptor binding domain (RBD) of the virus has high affinity for the structure of the A antigen on respiratory epithelium, possibly enhancing viral entry into respiratory cells. Ongoing research is required to further elucidate the contributions of these mechanisms to SARS-CoV-2 pathogenicity as it relates to ABO blood type [24].

●Cancer – Certain malignancies have been reported to be more likely in individuals with certain blood groups. Gastric cancers appear to be more prevalent in group A individuals, gastric and duodenal ulcers occur more often in those who are group O, and pancreatic cancers appear to be more common in those who are of non-O blood types (A, AB, or B) [25-28]. (See "Epidemiology and nonfamilial risk factors for exocrine pancreatic cancer", section on 'Other inherited risk factors' and "Risk factors for gastric cancer", section on 'Blood group'.)

●Complement – Individuals with null phenotypes for certain blood groups may be missing a cellular protein that has important functions on other cells in the body, such as the Chido-Rodgers null phenotype associated with absence of a complement component and associated abnormalities. (See 'Chido-Rodgers blood group' below and "Inherited disorders of the complement system", section on 'C4 deficiency'.)

In all of these examples, other patient characteristics and risk factors are likely to impact disease risk to a much greater degree than that of blood group antigens. Connections between other blood groups and various clinical findings are described in the following sections.

CLINICALLY SIGNIFICANT (COMMON) — The blood group systems in the following sections are considered clinically significant in one or more settings.

ABO and Rh are generally the most familiar, because they define the blood type. (See "Pretransfusion testing for red blood cell transfusion", section on 'Blood type (ABO and RhD type)'.)

ABO blood group system

ABO antigens — The ABO blood group system is responsible for four major RBC phenotypes: A, B, O, and AB (table 1). The distribution of phenotypes varies by race and ethnicity; an example of estimated frequencies among donors in the United States is shown in the table (table 3).

The A and B antigens are defined by the immunodominant sugars (n-acetylgalactosamine for the "A" antigen and d-galactose for the "B" antigen); these are carbohydrates that are added on top of the carbohydrate backbone known as the "H" antigen. The glycosyltransferase enzymes responsible for adding these sugars are encoded by the ABO gene. In group O individuals, a variant in the ABO gene causes a frameshift and production of a protein incapable of modifying the H antigen. In A and B individuals, one or more sugars are added onto the H backbone depending on the combination of alleles inherited.

The H antigen is a fucosyltransferase encoded by the FUT1 gene. There are several unusual phenotypes within the ABO system resulting from a lack or alteration of fucosyltransferase activity:

●Bombay phenotype – In the Bombay phenotype, fucosyltransferase activity is lacking. Since the H antigen is required for the addition of the A and B antigens, A and B also cannot be produced, regardless of the ABO genotype. In these individuals, RBCs lack A, B, and H antigens, and antibodies to A, B, and H are produced. As a result, these individuals are at risk for a severe hemolytic transfusion reaction (HTR) if transfused with RBCs of any ABO type other than Bombay. Crossmatching of blood from an individual with this phenotype will show hemolysis with all group O screening cells and panel cells, alerting the blood bank to the need for further investigation.

The Bombay phenotype is found almost exclusively in individuals from India, with an incidence of 1/10,000 [29]. The incidence is approximately 1/1,000,000 in individuals of European descent [30].

Individuals with the Bombay phenotype can only be transfused with blood from other individuals with the Bombay phenotype (typically, a relative), or they may use autologous blood that has been donated prior to a procedure. If an individual with the Bombay phenotype needs blood in an acute emergency and blood from a Bombay phenotype donor is not available, artificial blood could be used instead. (See "Oxygen carriers as alternatives to red blood cell transfusion", section on 'Categories of oxygen carriers'.)

●Weak subgroups – Altered enzyme activity of the glycosyltransferases may lead to qualitative and/or quantitative differences in antigen expression. Weak subgroups are relatively rare, but when encountered they may make determination of ABO type uncertain. In such cases, it is advisable to transfuse group O RBCs.

●Acquired B antigen – Certain bacteria (eg, Escherichia coli K-12, Clostridium tertium) can produce and release a deacetylase enzyme into the circulation that converts the A1 antigen into a B-like antigen. Thus, individuals with A1 (which accounts for 80 percent of A phenotypes) are at risk for the acquired B antigen phenotype in the setting of expansion of these bacterial populations, as may occur in the setting of a necrotic tumor or bowel obstruction. Once the infection is successfully treated, the patient's ABO group will return to group A1 [31].

Individuals with the acquired B antigen should never be transfused with AB or B blood, because their naturally occurring anti-B alloantibody (see 'ABO antibodies' below) is likely to clear the transfused cells from the circulation at a rapid rate. However, this anti-B does not react with the patient's own RBCs with the acquired B antigen.

ABO antibodies — The ABO blood group system is also defined by the presence or absence of naturally occurring alloantibodies, also referred to as "isohemagglutinins." These antibodies are directed against the A and/or B antigens that are missing from the individual's RBCs. Antibodies to ABO antigens generally appear in the blood by four to six months of age following exposure to bacterial antigens that are similar in structure to the A and B antigens (eg, molecular mimicry) as the gut becomes colonized in early infancy [32].

●Group A individuals will have anti-B antibodies

●Group B individuals will have anti-A antibodies

●Group O individuals will have both anti-A and anti-B antibodies

●Group AB individuals will have neither anti-A nor anti-B antibodies

These antibodies are detected as RBC agglutinins during pretransfusion antibody testing (also called reverse typing). (See "Pretransfusion testing for red blood cell transfusion", section on 'Antibody screen'.)

Absence of the expected anti-A or anti-B might occur under the following circumstances [33-36]:

●Weak ABO subgroup where the patient appears to be group O yet does not have both anti-A and anti-B.

●Hematopoietic cell transplantation from a donor with a different ABO type.

●Hypogammaglobulinemia such as seen in certain immunodeficiency states, with globally decreased antibody production.

●Fraternal twin with in-utero mixing of RBCs through the circulation, leading to induction of tolerance (eg, group O twin exposed to group A cells does not form anti-A).

Higher-than-normal titers of anti-A or anti-B may be seen following pregnancy, recent vaccination, or ingestion of high doses of live bacteria (eg, probiotic therapy). Infusion of plasma-containing blood products such as platelets or Frozen Plasma (FP) from donors with extremely high anti-A or anti-B titers may result in severe hemolytic transfusion reactions in recipients, even if the amounts of plasma are small [37]. Because of this potential problem, some medical centers obtain alloantibody titers on all group O platelets to determine whether the anti-A and anti-B titers exceed an institutionally defined threshold before deciding if products can be given to non-group O recipients.

ABO incompatibility can cause acute hemolytic transfusion reactions (AHTR), hemolytic disease of the fetus and newborn (HDFN), and solid organ transplant rejection (table 1):

●AHTR – Historically, AHTRs as a consequence of ABO incompatible blood transfusion were the leading cause of deaths from blood transfusion, typically due to clerical errors.

Following the 1999 Institute of Medicine report focusing on preventable harm, quality and regulatory organizations responsible for patient care practice, including transfusion, mandated improved processes for patient identification and blood specimen collection to mitigate errors in transfusion and risk for AHTR [38].

Various measures, including technologies promoting positive patient identification as well as robust training of health care team members on transfusion practice, starting with specimen collection through final blood product administration, are required. These measures have dramatically reduced but not eliminated ABO incompatible transfusion events. Mistransfusion due to clerical errors persists, contributing to the overall risk for fatal ABO-incompatible AHTR at 1 per 7.1 million units transfused [38].

●HDFN – In contrast with the life-threatening effects of a severe AHTR, most cases of HDFN associated with maternal anti-ABO antibodies tend to be relatively mild in nature, since the A and B antigens are not well developed at birth. An exception is a group B African-American or Black, non-Hispanic newborn of a group O mother. The B antigen appears to be more developed at birth in this ethnic group, and HDFN can be of a more severe nature, sometimes requiring exchange transfusion. (See "Management of non-RhD red blood cell alloantibodies during pregnancy", section on 'ABO' and "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Postnatal management'.)

●Organ rejection – The presence of ABO antigens on epithelial and endothelial cells in transplanted organs accounts for the higher likelihood of graft rejection/failure with ABO incompatible transplants and provides the rationale for matching organs to recipient ABO type. (See 'Hematopoietic stem cell and solid organ transplantation' above.)

Rh blood group system

Rh antigens — The Rh antigens are located on non-glycosylated transmembrane proteins that are integral to the RBC membrane (figure 1). More than 45 serologically defined antigens have been recognized within the Rh system [39]. The most common include D, C, c, E, and e (there is no "d" antigen) [40]. The antigens are encoded by two separate but closely linked genes, RHD and RHCE. The RhAG and Rh proteins appear to function as ammonia/ammonium transporters [41].

The following Rh phenotypes warrant attention in pretransfusion testing and prenatal care:

●Rh-negative – Individuals whose RBCs do not express the RhD antigen are frequently referred to as Rh-negative. This phenotype is the result of either an absence of the RHD gene or alterations in the RHD gene resulting in gene inactivation [3]. Prevention of alloimmunization is important in RhD-negative women of childbearing potential because these individuals are at risk of HDFN if they have an RhD-positive pregnancy. (See 'Rh antibodies' below and "RhD alloimmunization: Prevention in pregnant and postpartum patients".)

●Partial or weak D – Several D variants exist, referred to as partial D, weak D, Rh mod, D(u), and D(el). In some cases, these cells may type as RhD-positive by all available serologic reagents, and in some cases they may not. Patients with these variants are potentially at risk for developing antibodies to D, and their blood may lead to the formation of anti-D antibodies in D-negative recipients [42]. Genotyping may be used to resolve such complex serologic results. (See "Red blood cell (RBC) transfusion in individuals with serologic complexity", section on 'RBC genotyping'.)  

The implications of weak D in pregnant women are discussed separately. (See "RhD alloimmunization in pregnancy: Overview", section on 'D variants'.)

The rare weak D antigen DEL, found primarily in Japanese and Chinese populations, is exceedingly difficult to detect, particularly when using monoclonal Rh reagents. Data suggest that a DEL-positive donor unit is extremely unlikely to cause primary immunization in an Rh-negative recipient, although it may prompt a secondary response in already immunized Rh-negative patients [43,44].

●RhCE variants – Certain individuals have variants that give rise to altered C or E antigens that may not be detected by routine serologic antigen typing. As a consequence, these individuals may be at risk for alloimmunization when transfused with RBCs that are Rh matched using standard phenotypic testing. This is especially true and concerning in individuals with sickle cell disease (SCD) due to their high rate of alloimmunization [45]. This observation has prompted calls for the use of molecular genotyping to guide transfusion in SCD [46]. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Transfusion techniques'.)

●Rh-null – In contrast with Rh-negative, which refers to lack of the RhD antigen, Rh-null refers to absence of any Rh antigens (absence of RhD, RhC, and RhE). The Rh-null phenotype is rare. It is most commonly associated with mutations in the RHAG gene, which encodes the Rh-associated glycoprotein (RhAG; different from RhG discussed below). RhAG is required for targeting Rh antigens to the RBC membrane [41]. RHAG mutation can also be associated with a form of hereditary stomatocytosis. These individuals can have chronic, mild, compensated hemolytic anemia, increased osmotic fragility of RBCs, and stomatocytes on the peripheral blood smear (see "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)", section on 'Genetics'). The Rh-null phenotype can also be caused by simultaneous RHD and RHCE variants associated with absence of antigen expression.

When transfused, individuals with Rh null phenotypes may form one or more antibodies to high frequency Rh antigens, which makes it extremely difficult to procure compatible blood.

●RhG – The RhG antigen is expressed on red cells bearing the C or D antigen. Antibodies directed against the G antigen appear as anti-C plus anti-D. It is clinically important to distinguish anti-G from anti-C plus anti-D in pregnant women to ensure proper prenatal monitoring and appropriate administration of RhD immune globulin (individuals with anti-G can receive anti-D immune globulin, whereas individuals with anti-RhD should not) [47]. (See "RhD alloimmunization in pregnancy: Overview", section on 'G'.)

Rh antibodies — The majority of antibodies to Rh antigens arise in the setting of exposure to blood from another individual (eg, from transfusion or pregnancy) and subsequent alloimmunization. Rarely, naturally occurring IgM antibodies have been reported that are directed at E and Cw (a replacement antigen at the Cc locus). All of these antibodies are capable of causing significant hemolysis leading to severe HTR and HDFN (table 1). (See 'Settings in which blood groups play a role' above.)

In the extremely unlikely event that an RhD-negative woman of childbearing potential is inadvertently exposed to RhD-positive RBCs, either through clerical error involving RBC transfusion or through transfusion of platelets from an RhD-positive donor, there is a risk of alloimmunization. In one series of 130 RhD-negative individuals who received one or more units of RhD-positive platelets, none formed anti-RhD antibodies [48]. Administration of prophylactic anti-D immune globulin (also called Rho[D] immune globulin) may be used in this setting. Consultation with transfusion medicine physician or blood bank specialist with expertise in this area may be helpful. Additional information about this issue is presented separately. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'ABO, Rh, and HLA matching'.)

●HDFN – Anti-RhD, the antibody originally described as anti-Rh, causes the most severe form of hemolytic disease of the fetus and newborn (HDFN), sometimes resulting in hydrops fetalis and occasionally fetal demise. The use of anti-D immune globulin in RhD-negative women during pregnancy has greatly reduced the frequency of HDFN due to maternal anti-D. As a result, HDFN due to anti-c and anti-E may be more commonly seen. (See "RhD alloimmunization in pregnancy: Overview" and "Management of non-RhD red blood cell alloantibodies during pregnancy" and "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Postnatal management'.)

●HTR – Alloantibodies to Rh antigens are a frequent cause of hemolytic transfusion reactions (HTR), especially delayed HTRs. Since Rh antibodies rarely if ever bind complement, RBC destruction is mediated almost exclusively via splenic trapping.

As noted above, individuals with sickle cell disease (SCD) who have certain variants at the e locus may develop anti-E and an anti-e-like antibody that may make transfusion especially challenging. Molecular matching of donors with patients known to have variant Rh antigens is being promoted as a method to improve compatibility testing in this setting [46]. (See 'Rh antigens' above.)

●AIHA – Autoantibodies with Rh system specificity have been demonstrated in a high percentage of cases of autoimmune hemolytic anemia (AIHA), with anti-e being most commonly seen. Anti-e reacts with 98 percent of random donor RBC units, presenting a problem in identifying compatible units. In the absence of hemolysis, Rh(e)-negative blood need not be given; Rh(e)-negative blood should be reserved for patients who have formed allo anti-Rh(e). Anti-Rh(C) can be difficult to detect but has been reported to cause hemolysis and hemoglobinuria. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Stabilization and transfusion for severe anemia'.)

Duffy blood group system

Duffy antigens — The Duffy blood group antigens reside on an integral RBC membrane glycoprotein known as the Duffy antigen receptor for chemokines (DARC); other names for this protein include atypical chemokine receptor 1 (ACKR1), Fy glycoprotein, and CD234. DARC is encoded by the ACKR1 gene. Individuals may express any combination of Fy^a and Fy^b; those who are Fy(a-b-) are also referred to as being homozygous for the Fy allele. This allele results from a polymorphism in the ACKR1 promoter that disrupts transcription factor binding and blocks expression in erythroid cells.

DARC is a multi-pass membrane glycoprotein that acts as a chemokine receptor for certain proinflammatory cytokines (IL-8, monocyte chemotactic protein-1, RANTES) [49,50]. Duffy antigens are also used by malaria parasites (Plasmodium vivax and P. knowlesi) to enter the RBC. As a result, approximately 70 percent of Black people from West Africa are Fy(a-b-), which is protective against invasion of these malaria species. The merozoites can attach to Fy(a-b-) RBCs but cannot enter the cell and eventually detach, leaving the RBC markedly deformed [51]. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Duffy blood group system'.)

Fy(a-b-) individuals also may have a reduced baseline neutrophil count. When the absolute neutrophil count (ANC) is below the lower limit of normal (<1500 cells/microL), the patient is said to have Duffy-null associated neutrophil count (DANC, formerly referred to as constitutional neutropenia, benign ethnic neutropenia [BEN], or benign familial neutropenia). The mechanism is not completely understood, but it might be related to reduced clearance of cytokines by RBCs. Approximately 10 to 15 percent of Fy(a-b-) individuals have an ANC <1500/microL.

Additional information about ACKR1 and malaria is presented separately. (See "Gene test interpretation: ACKR1 (Duffy blood group gene)" and "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Duffy blood group system'.)

Duffy antibodies — A number of antibodies to Duffy antigens have been characterized [52]. Individuals who have anti-Fy^a should not be transfused with RBCs expressing Fy^a, and individuals who have anti-Fy^b should not receive RBCs expressing Fy^b.

Anti-Fy3 is an alloantibody that reacts with all RBCs except those that are Fy(a-b-), including Rh-null cells. Anti-Fy5 is an alloantibody that will react with any Duffy phenotype except Fy(a-b-), but not with Rh-null cells. Individuals who are Fy(a-b-) may occasionally become alloimmunized by transfusion and develop anti-Fy5; in contrast, anti-Fy3 is rarely seen [53]. Individuals with anti-Fy3 or anti-Fy5 should be transfused with Fy(a-b-) units. These units can be readily located by screening Black donors with ancestry from African countries, 70 percent of whom are Fy(a-b-).

●Anti-Fy^a can cause significant HTR and HDFN.

●Anti-Fy^b occasionally causes HTR and rarely causes HDFN, and when HDFN does occur it is usually mild.

●Anti-Fy3 has caused significant HTR.

●Anti-Fy5 caused a mild HTR in one reported case.

Kell blood group system

Kell antigens — The Kell system includes a number of antigens that are located on a highly folded membrane glycoprotein encoded by the KEL gene. This protein is a metalloendopeptidase that may have a role in activating and/or inactivating bioactive peptides. The most readily recognized antigens in this system are K (also called KEL1) and its alternate allele k (also called Cellano or KEL2); Kp^a (KEL3) and Kp^b (KEL4); and Js^a (KEL6) and Js^b (KEL7). Microbial infection will sometimes cause transient depression of Kell system antigens (particularly Kp^b). The Kell proteins require intact disulfide bonds to maintain antigenic integrity.

Expression of the Kell antigens also requires the XK protein (figure 1), encoded by a separate XK gene. The XK gene appears to be closely linked with the locus for X-linked chronic granulomatous disease (CGD) in males; however, there is no evidence to suggest a pathophysiologic role. XK is a transmembrane transporter that is linked to Kell by a disulfide bond.

●McLeod – The McLeod phenotype is associated with uniformly weak K system antigens due to mutations in XK, the gene product of which is required for appropriate membrane anchoring of the glycoprotein carrying the Kell antigens as noted above (figure 1). Individuals with this phenotype have compensated hemolytic anemia and profound acanthocytosis on the peripheral blood smear [54]. Mutations in the XK gene, can be associated with the McLeod syndrome, a rare X-linked syndrome characterized by chorea, other neurologic deficits, and myopathy [55]. (See "Burr cells, acanthocytes, and target cells: Disorders of red blood cell membrane", section on 'Blood group abnormalities' and "Neuroacanthocytosis", section on 'Mcleod syndrome'.)

●Kmod – Point mutations or missense mutations in the K gene can result in a phenotype called Kmod, in which there is marked reduction of all Kell system antigens (only detectable via adsorption/elution techniques).

●K₀ – The Kell-null (also called K₀) phenotype results in no production of K system antigens. K₀ individuals may produce an antibody known as anti-Ku, which is broadly reactive to all but K₀ RBCs.

Patients who are treated with the monoclonal antibody daratumumab (eg, for multiple myeloma) may have panagglutination in a pretransfusion antibody screen, and enzyme treatment is sometimes used to circumvent this problem. It is important to note that this enzyme treatment can destroy Kell system antigens, and care must be taken to select K1-negative units for transfusion in this setting. (See "Red blood cell (RBC) transfusion in individuals with serologic complexity", section on 'Anti-CD38 (daratumumab, isatuximab)'.)

Kell antibodies — Anti-K is capable of causing severe HTR and HDFN. Bacteria can elicit production of anti-K, probably due to cross-reactive antigens. Anti-k is one of the most common antibodies directed against high frequency antigens (the population frequency of k-negative individuals is approximately 1/500). Anti-Js^b is seen primarily in African Americans. Anti-Js^a and anti-Kp^a are directed against low frequency antigens in the random donor population.

●HTR – Antibodies to Kell antigens can cause HTR. In individuals who have CGD and the McLeod phenotype, transfusion can induce the production of an anti-Km alloantibody. These individuals can receive McLeod or K₀ blood. Patients who have the CGD and McLeod phenotype can also form an alloantibody called anti-KL, which consists of anti-Km and anti-Kx (Kx is an antigen on the XK protein). These individuals can only be transfused with blood from ABO compatible donors who also have the McLeod phenotype. Individuals who are K-null or Kmod can also produce an antibody called anti-Ku. These individuals must receive only K₀ blood, which is exceedingly rare and can only be procured through donor centers connected with rare donor registries.

Anti-k, anti-Js^b, anti-Js^a, anti-Kp^a, and anti-Kp^b can cause mild to moderate HTR as well. Formation of anti-Js^a in individuals with sickle cell disease (SCD) who are receiving blood primarily from Black donors may reduce the available donor pool by approximately 30 percent (the frequency of the Js^a antigen in Black people). Because of the scarcity of reagent grade anti-Js^a, the patient's serum may need to be used for finding Js^a-negative donor units, providing the antibody is reactive stronger than 1+ in the antiglobulin phase of testing.

●HDFN – Anti-K is capable of causing severe HDFN and is responsible for a relatively large portion of clinically significant non-Rh HDFN. The K antigen is produced early in fetal development and is expressed on bone marrow erythroid progenitor cells; thus, antibodies to K can cause suppression of normal erythropoiesis in addition to hemolysis of mature RBCs. This bone marrow suppression is thought to account for the severity of anemia in Kell-associated HDFN. Anti-k, anti-Js^b, anti-Js^a, anti-Kp^a, and anti-Kp^b can cause mild to moderate HDFN. (See "Management of non-RhD red blood cell alloantibodies during pregnancy", section on 'KEL' and "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Postnatal management'.)

●AIHA – Approximately 1 in 250 patients with warm-reacting AIHA will have autoantibody directed against Kell blood group system antigens. Sometimes patients with AIHA who express the Kp^b antigen can have transient depression of antigen expression (eg, due to concurrent infection), making an autoantibody to Kp^b "appear" to be an alloantibody. This can create a dilemma as to whether the patient should receive Kp(b-) blood. Radiochromium red cell survival studies may be useful in determining the antibody's clinical significance at a particular point in time. (See "Red blood cell survival: Normal values and measurement".)

Kidd blood group system

Kidd antigens — The Kidd blood group system is defined by two alleles, Jk^a and Jk^b, controlled by the KIDD gene. The carrier molecule for the Kidd antigens is a urea transporter. It protects RBCs from osmotic stress in the kidney by transporting urea into the RBC as it enters the renal medulla and then transporting urea back out of the RBC as it exits the renal medulla [56].

The Jk(a-b-) phenotype, also known as Jk(3-), is seen in approximately 1 percent of Polynesians and a high proportion of Filipinos, and has been described in individuals of African and subcontinental Indian descent [57].

Lysis of RBCs in 2 molar (M) urea is used in some automated hematology analyzers to remove RBCs prior to counting white blood cells (WBC) and platelets [58]. Jk(a-b-) RBCs are resistant to 2M urea lysis, which could potentially result in a spuriously high WBC or platelet count. Inability to lyse red cells in 2M urea has been used as a screening test for the Jk(a-b-) phenotype [58]. Jk(a-b-) individuals are also unable to maximally concentrate their urine due to reduced urea transport in renal cells [59].

Kidd antibodies

HTR – Anti-Jk^a, and to a lesser extent anti-Jk^b, are responsible for a great percentage of serious HTRs, including acute and delayed reactions that may be severe. These antibodies are usually IgG and can bind complement and cause hemolysis.

Another important feature of anti-Kidd antibodies is that they may be difficult to detect because they tend to decline rapidly to undetectable levels in plasma. This lack of detection during pretransfusion testing may account for their role in delayed HTR, which is due to an anamnestic response induced by the Kidd-positive RBCs in the transfusion. Individuals with antibodies to Kidd should also wear a Medic Alert bracelet stating this information.

●HDFN – Despite causing hemolysis, anti-Kidd antibodies are only rarely implicated in HDFN. HDFN is usually mild if it does occur, although severe hemolysis has been reported. (See "Management of non-RhD red blood cell alloantibodies during pregnancy".)

Lewis, P1P(K), GLOB, and I blood group systems

Lewis, P1P(K), GLOB, and I antigens — The Lewis, P1P^K, GLOB, and I blood group antigens are structurally related to the ABO antigens in being defined by small carbohydrate epitopes on glycoproteins and glycolipids. Similar to the ABO system, the antigens are created through the actions of specific glycosyltransferases.

●Lewis – The Lewis blood group system is controlled by the FUT3 gene, which encodes a fucosyltransferase. The Lewis antigen is passively adsorbed onto RBCs. The Lewis antigen on gastric mucosa is thought to be the receptor for Helicobacter pylori, although this has been questioned [60,61]. (See "Pathophysiology of and immune response to Helicobacter pylori infection", section on 'Bacterial attachment'.)

●P1 and P^K – The P1 and P^k blood group system controlled by the A4GALT gene, which encodes a galactosyltransferase. The P1 and P^K antigens are receptor sites for certain strains of E. coli. Individuals with the P-null phenotype are resistant to infection with these strains. (See "Bacterial adherence and other virulence factors for urinary tract infection", section on 'Adhesins'.)

●GLOB – The GLOB blood group system is controlled by the B3GALNT1 gene, which encodes a galactosyltransferase. The P antigen, a member of the GLOB blood group system, is a receptor for parvovirus B19. Like P1 and P^k antigens, it can serve as an adhesion site for uropathogenic E. Coli [62].

●I – The I blood group system is controlled by the GCNT2 gene, which encodes an n-acetylglucosaminyltransferase. The function of the I antigen is unknown. The I-negative adult phenotype (also called i-positive) occurs in less than 1 percent of the population. These individuals will develop naturally occurring anti-I, which often has an increased thermal range (ability to bind at a wider range of temperatures). Its clinical significance is variable, and specialized RBC survival studies are needed in deciding whether I-negative RBCs are required for transfusion in this setting. An association has been described between the I-negative (i-positive) phenotype and congenital cataracts [63].

Lewis, P1P(K), GLOB, and I antibodies

●Anti-Lewis – Lewis antibodies are formed primarily in individuals who type as Le(a-b-). These antibodies are often seen in these individuals during pregnancy and postpartum. These antibodies rarely, if ever, cause transfusion reactions.

•Anti-Le^b does not cause clinical issues. Anti-Le^a may have clinical significance; in such cases, hemolysis correlates with the ability to demonstrate hemolysis in vitro, and crossmatch-compatible donor units can be used.

•The rare instance of hemolytic or IgG reactive anti-Le^a and anti-Le^b in a group O Le(a-b-) individual who requires a large number of RBC units presents a special problem. Rather than attempting to obtain Le(a-b-) units, which are found in only 6 percent of the random donor population, in vivo neutralization of the anti-Le^b may be a viable option [64].

Lewis antibodies do not cause HDFN.

●Anti-P1P^K – Anti-P1 is generally considered to be of little clinical significance. It is often naturally occurring. On rare occasions, the antibody may show a broad thermal range, particularly in pigeon breeders who are P1 negative, or in patients with hydatid or echinococcus cysts. Transfusion of P1-negative blood may be advisable in such instances, or when the antibody is IgG in nature. Anti-P1 does not cause HDFN.

●Anti-P – Auto anti-P is often the causative antibody in paroxysmal cold hemoglobinuria (PCH), where it acts as a biphasic hemolysin, the classical Donath-Landsteiner antibody [65]. This cold reactive IgG antibody binds to RBCs at reduced temperatures and causes complement mediated hemolysis as the serum/cell mixture is warmed to body temperature. (See "Paroxysmal cold hemoglobinuria", section on 'Pathophysiology'.)

●Anti-I – Most anti-I antibodies are IgM and have a low thermal amplitude (ie, they are reactive at or below room temperature); these antibodies rarely cause problems from a transfusion standpoint. Rare I-negative (i-positive) individuals will have increased RBC destruction when transfused with random donor RBC units. Anti-i is rare.

Mycoplasma pneumoniae has been reported to cause acute self-limiting hemolysis in some individuals. The organism is capable of modifying the I antigen on the patient’s RBCs, making it more immunogenic. This causes an increase in the titer and thermal range of the patient's naturally occurring autoantibody to I. When the infection is successfully treated, the patient's I antigen reverts to normal and the previously increased levels of anti-I destroy a portion of the patient's own RBCs until the antibody level has diminished.

In rare instances of patients with autoantibodies to I with an increased thermal range (ie, >31°C), a blood warmer may be required. The patient's core body temperature should be maintained as close to 37°C as possible to avoid cold-induced exacerbation of hemolysis. (See "Cold agglutinin disease", section on 'Management'.)

Anti-I does not cause HDFN.

MNS blood group system

MNS antigens — The MNS (also called MNSs) blood group system contains a number of antigens [66]. These include M and N, which are located on glycophorin A; and S and s, located on glycophorin B, as well as many high prevalence antigens, the most notable of which is U. MN and Ss are closely linked, and antigens in this system generally will be inherited together.

Glycophorin A and B are both sialoglycoproteins. The sialic residues are the primary determinant of the net negative charge of the RBC membrane. Glycophorin A associates with band 3 in the RBC membrane. Glycophorin A has a sialic acid-dependent site for Plasmodium falciparum invasion and a receptor for certain viruses and E. coli species. Glycophorin A also can act as a complement receptor. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'MNS blood group system (glycophorins A and B)'.)

Notable MNS antigen phenotypes include the following:

●The extremely rare En(a-) phenotype results from the absence of glycophorin A. It is seen more frequently in Finland.

●S-negative, s-negative, U-negative phenotype is a rare phenotype arising in most instances from a homozygous deletion of the coding region of the glycophorin B locus. It results in the absence of glycophorin B. It is seen in 2 percent of Black individuals.

●The exceedingly rare Mk/Mk phenotype results in the absence of both glycophorin A and B. These RBCs are severely deficient in sialic acid residues but do not undergo hemolysis.

●The Mur antigen is among the collection of low prevalence antigens within the MNS system. It occurs in <1 percent of most populations, including White individuals. However, the prevalence is 6, 7, and 9 percent in individuals with ancestry from China, Taiwan, and Thailand, respectively [67].

MNS antibodies

●Anti-M – Anti-M can be naturally occurring. It is usually an IgM or cold reactive IgG antibody and will sometimes react better if the patient's serum is acidified. The antibody rarely causes a transfusion reaction, unless it is reactive at body temperature. HDFN due to anti-M has only rarely been reported [68].

●Anti-N – Anti-N is generally considered to have little if any clinical significance. It may be found as an autoantibody in patients undergoing hemodialysis when the equipment was sterilized with formaldehyde. The antibody is almost always IgM.

●Anti-En(a) – Anti-En^a can occur in the extremely rare case of the En(a-) phenotype (complete absence of glycophorin A). Anti-En^a can cause severe HTRs and HDFN.

●Anti-Mur – Anti-Mur is an antibody directed against the low frequency antigen MUR; it has been reported to cause mild and severe HDFN. The gene encoding MUR antigen is more common in Asian people; thus, cases of otherwise unexplained HDFN in a newborn with ancestry from Asia should be examined for evidence of MUR incompatibility between the mother and father of the newborn [67].

●Anti-S and anti-s – Anti-S will frequently be found as an underlying alloantibody in patients with warm autoantibodies. Both anti-S and anti-s can cause HTR, although the majority are mild to moderate in severity. Anti-S and anti-s are mainly IgG, and thus can cross the placenta and cause HDFN, although severe cases are rare.

●Anti-U – Anti-U can present as a relatively common serologic problem, especially in Black individuals, who have a higher incidence of the U-negative phenotype (absence of glycophorin B). Anti-U can cause both severe HTRs and severe HDFN.

CLINICALLY SIGNIFICANT (RARE) — Information on additional blood groups including Chido-Rodgers, Colton, Diego, Er, Gerbich, Globoside (P and Pk), Lutheran, and Vel, is presented in the following sections.

Chido-Rodgers blood group — The Chido-Rodgers blood group is controlled by the C4A and C4B genes, which encode the C4 component of complement (see "Complement pathways"). The blood group antigens are located on the C4d fragment, which is liberated upon cleavage of C4 during complement activation and becomes adsorbed from the surrounding plasma onto the RBC surface. Both antigens (Chido and Rodgers) are found in over 90 percent of the population. The antigens are inactivated by proteolytic enzymes but not by DTT.

The null phenotype for the Chido-Rodgers blood group is associated with a possible predisposition to certain infections (eg, bacterial meningitis) as well as autoimmune conditions such as systemic lupus erythematosus and autoimmune hepatitis [69,70].

Antibodies to Chido and Rodgers antigens demonstrate fragile agglutination (and easy dissipation) at the indirect antiglobulin stage of the pretransfusion antibody screen. These antibodies are neutralized by the addition of pooled plasma, and they both react strongly with C4d-coated RBCs prepared in vitro.

Colton blood group system — The Colton blood group system, controlled by the AQP1 locus, consists of two alleles, Co^a and Co^b. AQP1 encodes aquaporin 1, a water channel (previously called CHIP28). (See "Red blood cell membrane: Structure and dynamics", section on 'Aquaporin-1'.)

Co^a is very common (present in over 99 percent of the population); Co^b is seen in approximately 8 to 11 percent of individuals, most commonly in those of European ancestry. The Colton antigens are resistant to enzymatic digestion, and both anti-Co^a and anti-Co^b react better with enzyme-treated RBCs. However, reagents for determining anti-Co^b are not widely available.

Antibodies to Co^a and Co^b can cause HTR, and anti-Co^a can cause HDFN. Anti-Co^b is rarely seen as an isolated alloantibody; it usually is formed in the setting of other alloantibodies.

Diego blood group system — The Diego blood group system is based on two alleles of the SLC4A1 gene, which encodes band 3, also called the anion exchanger AE1. Band 3/AE1 is an integral component of the RBC membrane-cytoskeleton linkage, as well as an ion transporter that allows RBCs to exchange bicarbonate and chloride ions. Mutations in band 3/AE1 that affect its interactions with the cytoskeleton and/or ion exchange function have been associated with hereditary spherocytosis, Southeast Asian ovalocytosis, and hereditary stomatocytosis. (See "Hereditary spherocytosis", section on 'Band 3 deficiency due to SLC4A1 variants' and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)", section on 'Genetics'.)

There are multiple Diego antigens on the extracellular portions of the band 3/AE1 protein. Most are relatively rarely expressed. An exception is Di^a, which is expressed in up to 35 percent of South American Indians and Native Americans. Another pair of Diego antigens are the Wright (Wr) antigens. Wr^a is uncommon, whereas Wr^b is very common.

Antibodies to Di^a and Di^b can cause HTR and HDFN. Naturally occurring antibodies to Wr^a are often seen, and anti-Wr^a can cause severe HTR and HDFN. Alloantibodies to Wr^b are extremely rare, but autoantibodies to Wr^b are sometimes seen in patients with AIHA.

Er blood group system — The Er system is encoded by the PIEZO1 gene. PIEZO1 encodes a mechanosensitive channel that controls RBC volume; pathogenic variants in the gene can cause hereditary stomatocytosis or xerocytosis. (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)", section on 'Genetics'.).

The Er blood group includes the antigens Er^a, Er^b, Er3, Er4, and Er5 [71]. It may have a role in hemolytic transfusion reactions and hemolytic disease of the fetus and newborn (HDFN), although further data are needed.

Gerbich blood group system — The Gerbich blood group is based on variations in the GYPC gene, which encodes glycophorin C (GPC) and glycophorin D (GPD). These proteins interact with the RBC cytoskeleton. GPC appears to be used by some strains of Plasmodium falciparum malaria as a receptor for entry into the RBC.

Gerbich-null RBCs (ie, cells that completely lack GPC and GPD), also known as the Leach phenotype or as Ge(2-3-4-), are somewhat resistant to malaria and have an elliptocytic shape, without hemolysis [72]. This phenotype is common in individuals with Mexican and Melanesian (from certain Pacific Islands) ancestry. (See "Hereditary elliptocytosis and related disorders", section on 'Glycophorin C variants (GYPC gene)'.)

Naturally occurring alloantibodies to Ge2 have been reported. Antibodies to certain Gerbich antigens including anti-Ge2 and anti-Ge3 have been reported to cause HTR, some of which have been associated with severe intravascular hemolysis. In the United States, these antibodies are seen in individuals with Mexican and Melanesian ancestry. It is important when using frozen Ge-negative RBC units to test for compatibility using frozen sample segments before thawing and deglycerolizing the entire unit, because certain "Gerbich-negative" RBCs can still contain certain Gerbich antigens.

Gerbich antigens have not been implicated in HDFN.

Autoantibodies to Gerbich antigens have been reported in some cases of autoimmune hemolytic anemia (AIHA); however, a pathogenic role in the AIHA has been questioned [73-75].

Lutheran blood group system — The Lutheran system, encoded at the locus, includes a number of antigens on two glycoproteins, with Lu^a and Lu^b being the most commonly recognized. The glycoproteins are adhesion molecules and may have a role in migration of mature RBCs out of the bone marrow; they are linked to the RBC cytoskeleton through an interaction with spectrin [76,77]. Lu^a occurs in approximately 8 percent of European and African populations, while Lu^b is very common worldwide. Lutheran antigens are resistant to enzyme treatment (ficin or papain), but are inactivated by the sulfhydryl reagent dithiothreitol (DTT).

In a patient with antibodies to Lu^a, incubation with Lu^a-positive cells shows a characteristic "mixed field" appearance (mixture of agglutinated and unagglutinated cells); anti-Lu^a is associated with mild delayed hemolytic transfusion reactions (HTRs) and mild hemolytic disease of the fetus on newborn (HDFN).

Antibodies to Lu^b can cause mild HTR; HDFN associated with anti-Lu^b has not been reported.

Antibodies known as anti-Lu3 can occur in patients with the null type Lu(a-b-). No concrete data are available on the clinical significance of anti-Lu3.

Vel blood group system — The Vel system, encoded by the SMIM1 gene, contains only the Vel antigen. This antigen is a high prevalence antigen, present in over 99.98 percent of the population. The rare Vel-negative individual can be immunized against the Vel antigen following exposure to RBCs through transfusion or pregnancy. Anti-Vel is often a mix of IgG and IgM antibodies that can bind complement; hence, transfusion of Vel-positive blood to a patient with anti-Vel can cause a severe HTR. This is potentially important because donors with weak Vel expression can be mistyped as Vel-negative.

Anti-Vel can cause HDFN (rarely), but it is thought to be mild since fetal cells do not express high levels of the Vel antigen.

LIMITED OR NO CLINICAL SIGNIFICANCE

Cartwright (Yt) blood group system — The Cartwright blood group system is controlled by the ACHE gene, which encodes acetylcholinesterase. The two Cartwright (Yt) antigens are Yt^a and Yt^b. The majority of individuals express Yt^a, and approximately 8 percent express Yt^b.

Anti-Yt^a often presents as a weak antibody on pretransfusion testing and has variable clinical significance. Yt^a has not been reported to cause hemolytic disease of the fetus and newborn (HDFN), likely because it is not well developed at birth.

Anti-Yt^b is rarely seen and has not been reported to cause hemolytic transfusion reactions (HTRs) or HDFN.

Knops blood group system — The Knops blood group system is controlled by the CR1 gene, which encodes complement receptor 1, also called CD35.

Certain Knops antigens (so-called African Knops antigens) may be somewhat protective against Plasmodium falciparum malaria and Mycobacterium tuberculosis [78]. (See 'Resistance to RBC parasites' above.)

Antibodies to Knops antigens are not known to cause HTRs or HDFN.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transfusion and patient blood management".)

SUMMARY

●Definition – A blood group system is a collection of one or more antigens that are under the control of a single gene or a cluster of closely linked, homologous genes. Forty-three blood group systems are recognized by the International Society for Blood Transfusion. The major blood group systems with clinical significance are listed in the table (table 1). A blood group antigen is a sugar or protein present on the surface of the red blood cell (RBC) that is defined serologically by an antibody (figure 1). (See 'Terminology' above.)

●Relevance for transfusion – Any individual with a history of a clinically significant RBC alloantibody should receive blood that lacks the relevant antigen, whether the antibody is detectable on subsequent testing, to avoid hemolytic transfusion reactions. Hematopoietic stem cell donors and recipients can have different blood types. In solid organ/tissue transplantation, routine practice uses organs that are ABO identical with the recipient. (See 'Blood component transfusion' above and 'Hematopoietic stem cell and solid organ transplantation' above and "Red blood cell (RBC) transfusion in individuals with serologic complexity", section on 'Allogeneic hematopoietic stem cell transplantation recipients'.)

●Relevance for obstetrics – Hemolytic disease of the fetus and newborn (HDFN) is an alloimmune reaction in which maternal antibodies directed against fetal RBC antigens cross the placenta and cause hemolysis in the fetus or during the neonatal period (maternal antibodies persist in fetal plasma for several weeks); it is potentially fatal and requires close monitoring in case interventions are needed. (See "RhD alloimmunization in pregnancy: Overview" and "RhD alloimmunization in pregnancy: Management" and "Management of non-RhD red blood cell alloantibodies during pregnancy".)

●Disease predisposition – Certain RBC antigens and antibodies may be associated with autoimmune hemolytic anemia, resistance to RBC parasites, and certain disease predispositions, possibly including coronavirus disease 2019 (COVID-19), although other patient characteristics and risk factors are likely to impact disease risk to a much greater degree than that of blood group antigens. (See 'Autoimmune hemolytic anemia' above and 'Resistance to RBC parasites' above and 'Disease predisposition (including COVID-19)' above and "Protection against malaria by variants in red blood cell (RBC) genes".)

●Listing of clinically important blood groups – Information about antigens and antibodies in clinically important blood group systems is discussed above:

Common:

•ABO and Rh – (See 'ABO blood group system' above and 'Rh blood group system' above.)

•Duffy – (See 'Duffy blood group system' above.)

•Kell – (See 'Kell blood group system' above.)

•Kidd – (See 'Kidd blood group system' above.)

•Lewis, P1P^K, GLOB, and I – (See 'Lewis, P1P(K), GLOB, and I blood group systems' above.)

•MNS – (See 'MNS blood group system' above.)

Rare:

•Chido-Rodgers – (See 'Chido-Rodgers blood group' above.)

•Colton – (See 'Colton blood group system' above.)

•Diego – (See 'Diego blood group system' above.)

•Er – (See 'Er blood group system' above.)

•Gerbich – (See 'Gerbich blood group system' above.)

•Lutheran – (See 'Lutheran blood group system' above.)

•Vel – (See 'Vel blood group system' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges extensive contributions of Arthur J Silvergleid, MD to earlier versions of this and many other topic reviews.

UpToDate staff would also like to acknowledge David W Cohen, MA, MT(ASCP)SBB, who contributed to earlier versions of this topic review.