The clinical significance of blood group antibodies

purpose is to enable clinical decisions to be made regarding the management and blood transfusion support of patients with blood group antibodies that are not commonly encountered and for which antigen-negative blood is not available in the routine stock. Many of the antibodies described in this document are directed to high-frequency antigens and may create difficulties in obtaining compatible blood. Finding compatible blood should create no difficulty for patients with antibodies to antigens of lower frequency, but these antibodies may have to be considered when multiple specificities are present. Because antibodies to lower frequency antigens could have the potential to cause haemolytic disease of the newborn (HDN), the clinical significance of many of these antibodies is also described. It is not possible to provide a strict policy on whether or not antigen-negative blood is required for transfusion based purely on the specificity of the antibody. Other factors that need to be considered are:

1 how urgently blood is required; 2 the clinical diagnosis and the patient's bone marrow function; 3 whether the patient is immunologically compromised and unlikely to respond; 4 the strength and thermal amplitude of the antibody; 5 class and subclass of the immunoglobulin (Ig); 6 results of in vitro functional assays (e.g. a monocyte chemiluminescence assay, which may provide some indication of the potential clinical significance of the antibody); 7 in vivo red cell survival. (Results of studies are difficult to correlate with clinical outcome, as the behaviour of a small volume of labelled red cells may not accurately reflect response to transfusion of a large volume of red cells.)
Where British Committee for Standards in Haematology guidelines (BCSH, 1996) are provided for an antibody specificity, these should be followed. When an antibody is identified and considered to be of no clinical significance, particular care must be taken to ensure that it is not masking the presence of another, clinically significant, antibody. When compatible blood is not readily available, the following strategies should be considered:

1 correction of anaemia wherever possible; 2 autologous predeposit (for surgery); 3 cell salvage (for surgery); 4 calling up donors of known phenotype; 5 consultation of the National and International Frozen Blood Banks; 6 mass screening of donations; 7 transfusing serologically incompatible (or 'least incompatible') blood, with or without immunosuppression; 8 testing members of the patient's family, especially siblings; 9 consultation of the International Rare Donor Panel.
When antigen-positive blood is to be transfused, it is important to note that exceptionally strong examples of an antibody may behave atypically. Where possible, 'serologically least incompatible' units should be selected. Some of the antibodies listed are extremely rare, and little or nothing is known about their clinical significance. Absence of evidence of clinical significance does not mean that a transfusion of 'incompatible' blood will be uneventful. In these cases, ABOcompatible blood should be transfused with extra caution. Where appropriate, strategies for ameliorating the immunological response, such as the use of intravenous Ig and high-dose steroids, should be considered (Kohan et al., 1990; Woodcock et al., 1993). The transfusion should be performed at the slowest rate consistent with the clinical condition, and the patient should be observed closely throughout. Occasionally, clinical urgency requires that blood must be transfused before the antibody has been identified or before a tentative identification has been confirmed. Under these circumstances, ABO-compatible, serologically least incompatible blood should be transfused with extra caution. As discussed above, strategies for ameliorating the immunological response, such as the use of intravenous Ig and high-dose steroids, should be considered. Virtually all antibodies reactive in an indirect antiglobulin test (IAT) have been implicated in HDN (see BCSH (1996) for testing protocols). Whenever an IAT-reactive antibody is detected during pregnancy, a cord sample should be tested by a direct antiglobulin test (DAT), and, if positive, the haemoglobin and bilirubin levels should be monitored to diagnose HDN. Haemolysis caused by antibodies to red cell antigens of lower frequency is generally not sufficiently severe to require intrauterine transfusion, but blood may be required for neonatal transfusion.

HDN potential ABO system Anti-A, -B and -A,B severe intravascular HTRs Anti-A1 - rarely active at 37 C - Not clinically significant. Plasma with high-titre ABO antibodies MNS system Anti-M and N not detected by IAT at 37 C can be ignored. anti-M or -N active at 37 C capable of causing transfusion reactions. anti-M active by IAT at 37 C anti-N active by IAT at 37 C Anti-S and -s cause HTRs Anti-U high-freq Ag cause immediate and delayed HTRs. Occasionally, anti-N in U patient reacts by IAT at 37 C with all red cells, except N U phenotype. high-frequency MNS antigens a En family Rare ?cause severe HTR low-frequency MNS antigens a w anti-Mi (incl anti-Mur & -V ) can cause immediate and delayed HTRs P1 system P1 antibodies not usually reactive >25 C do not cause HTRs. rare anti-P1 reactive at 37 C cause severe immediate or delayed HTRs. IAT compatible M blood anti-M rarely Ag negative IAT-compatible

Donor frequency

only to group O

22% M 28% N

IAT-compatible Ag negative U blood Also S- sN U blood Anti-S and -s may Anti-U may

45% S 11% s U blood is usually only Africans

IAT-compatible blood, if possible, IAT-compatible blood (most donors)

severe HDN

severe HDN.

Anti-P1 not been implicated in HDN.

rare in Europeans / but relatively common in Orientals 20% P1 (P2)

Duffy system

Anti-Fy and -Fy cause immediate and delayed HTRs. Anti-Fy3 rare Ab detecting antigens on all red cells, except those of the Fy(a b ) phenotype. cause immediate and delayed HTRs Anti-Fy5 rare antibody similar to anti-Fy3 does not react with Fy(a b ) or Rhnull cells. cause delayed HTRs

Ag-negative blood Fy(a b ) blood Fy(a b ) blood

potential to cause HDN.

32% Fy(a ) and 20% Fy(b )

Anti-Fy3 and Fy5 no severe HDN.

Fy(a b ) rare Caucasians very common in Africans

Rh system

All Rh antibodies should be considered potentially capable of causing HTRs Rh antibody reactive in IAT (majority) Antibodies to high-frequency Rh antigens Rare *anti-Rh29, made by immunized Rhnull * anti-Hr0 (-Rh17) * related antibodies that detect epitopes on the RhCcEe protein *anti-Hr, -Hr , -Rh46 and -MAR (-Rh51). Anti-hr and -hr resemble anti-e may be found in patients of African origin not clinically significant particularly potent example might cause problems. Pt may be stimulated to produce Ab to a B high-frequency antigen (anti-Hr or -Hr ) or anti-E. Anti-C relatively common no report of transfusion reaction many low-frequency antigens w a a Anti-E , -Go , -Be , -Evans, -Tar and -JAL have all been implicated in HDN.
w S B B

Ag negative

only Rhnull blood (v rare)

All Rh antibodies should be considered potentially capable of causing HDN.

Rhnull D Related phenot = DcE/DcE (R2R2) cells should be compatible But

IAT-compatible blood

HDN reported. all considered to have potential not implicated in severe HDN.

97% are C

Lutheran system

Anti-Lu and -Lu cause mild delayed HTRs anti-Lu anti-Lu

a b

8% Lu(a+) over 99% Lu(b+).

IAT-compatible Ag-negative Lunull blood The dominant, In(Lu)-type of Lunull is rare but is the most readily available type of Lunull.

Anti-Lu3 very rare antibody produced by immunized recessive Lunull (Lu(a b )) antibodies to Lutheran system highfrequency antigens not clinically significant Lewis system Lewis antibodies not generally considered clinically significant anti-Le , -Le and -Le Kidd system
a b a b a+b

Lunull blood for strong examples of the antibody. not been implicated in severe HDN. IAT at 37 C Ag ve blood Kidd antibodies do not usually cause HDN, but there is one report of severe HDN caused by a anti-Jk .

Anti-Jk and -Jk are dangerous antibodies often difficult to detect common cause of delayed HTRs Jk antibodies cause immediate HTRs Anti-Jk3 very rare antibody reacts with all red cells, except Jk(a b ) can cause immediate and delayed HTRs
a

24% Jk(a ) and 27% Jk(b ).

Jk(a b ) blood.

Kell system

Kell system antibodies always considered potentially significant Anti-k cause severe immediate HTRs Anti-Kp cause delayed HTRs Anti-Js cause delayed HTRs Anti-Ku Ab produced by immunized K0 individuals can cause a severe HTR antibodies to high-frequency Kell antigens very rare. None is reported to have caused an HTR Kell antigens of lower frequency, a anti-K and -Js anti-Kp , -Ul and -K17 not been reported to cause HTRs,
a a b b

Antigennegative blood k blood

have the potential to cause severe HDN.

K+k

02%.

Kp(b ) blood Js(b ) blood

Kp(a+b ) 001%. Js(a+b ) v. rare in most white pop K0 v. rare

If possible, K0 blood Ag-negative if possible (mostly only K0 available) Ag-negative IAT-compatible Antigennegative blood Anti-Di has been implicated in severe HDN.
a

Diego system

Anti-Di detects antigen very rare in Caucasians but polymorphic in the people of eastern Asia and in Native Americans a no firm evidence that anti-Di causes HTR a but anti-Di has haemolytic potential. Anti-Di rare antibody detects an antigen of very high frequency. b no clear evidence anti-Di caused an HTR Anti-Wr relatively common antibody to a very lowfrequency antigen cause HTRs Anti-Wr rare alloAb to a very high-frequency antigen. b no report anti-Wr causing an HTR or HDN.
b a b

Antigennegative blood IAT-compatible blood must be selected. If possible, for strong Abs Ag-negative blood . IAT-compatible (most donors) Yt(a ) blood is not required But if strong Ab IAT-compatible blood IAT-compatible blood

implicated in HDN. Anti-Wr has caused severe HDN. Wr(b ) blood is extremely rare
a

Other antibodies of the Diego system antigens of very low frequency none caused an HTR Yt system Anti-Yt detects antigen of frequency about 997%. rarely been responsible for an HTR Anti-Yt antigen frequency of about 8%. Xg system Anti-Xg antigen with a frequency of 66% M/89% F no report of an HTR
a b a

anti-ELO (-DI8)& -BOW (-DI15) severe HDN not cause HDN. no report of causing HDN not been implicated in HDN.

Scianna system

Anti-Sc1 and -Sc3 antigens of very high frequency (rare). no report of HTR or HDN. antibodies are IgG and usually potent evidence of clinical significance is limited anti-Sc3 Anti-Sc2 antigen of low frequency not been reported to cause an HTR or HDN.

Ag-negative if possible

Sc: 1,2,3 may be available but is extremely rare. Sc: 1, 2, 3 no donors

least incomp. IAT-compatible

Dombrock system

Anti-Do and -Do cause immediate and delayed HTRs in sera of multiple antibodies finding compatible blood could be complicated by the presence of the other antibodies. In most instances, typed donors are not available. IAT-compatible blood should be selected for transfusion. About 34% of donors are Do(a ) and 18% Do(b ). a a Anti-Gy , -Hy and -Jo are rare antibodies that detect antigens of very high frequency. There is one report of anti-Hy causing an HTR, but, because of the rarity of the antibodies, evidence of clinical significance is limited. Antigen-negative blood is not usually required for transfusion but is recommended for strong examples of the antibody. No Dombrock antibody has caused HDN. Colton system a Anti-Co detects an antigen of high frequency and causes delayed HTRs and severe HDN. Co(a ) blood (about 02% of donors) should be selected for transfusion. b Anti-Co is a rare antibody that detects an antigen with a frequency of about 85%. One b case of a mild HTR due to anti-Co has been reported. IAT-compatible blood (90% of b donors) should be selected. Anti-Co has not been implicated in HDN. Anti-Co3 is a very rare antibody detecting an antigen of very high frequency. Anti-Co3 has caused a mild HTR and HDN. Ideally, Co(a b ) blood should be selected for compatibility testing but is extremely rare. Serologically least incompatible blood may be given with extra caution. LW system a ab Anti-LW and -LW detect antigens of very high frequency. There is no report of either antibody causing an HTR. Antigen-negative blood is not required for transfusion, but D blood should be selected (unless anti-c is present in an R1R1 LW(a ) patient). b Anti-LW , which detects an antigen of low frequency, has not been reported to cause an HTR. IAT-compatible blood (most donors) should be selected. No LW antibody has been implicated in HDN.

Chido/Rodgers system Chido/Rodgers antibodies detect antigens on C4 that become attached to the red cell surface in vivo. No Chido/Rodgers antibody has caused an HTR, and antigen-negative blood is not required for transfusion. (Use serum neutralized with AB serum for compatibility testing.) H system Anti-H is always present in the serum of individuals with the Oh (Bombay) phenotype (red cell H-deficient, nonsecretor). Like anti-A and -B, anti-H is likely to cause a severe immediate HTR. Blood of the Oh (Bombay) phenotype must be selected for transfusion. Anti-H has caused severe HDN. Some nonsecretors of A or B genotype have very low levels of red cell H and have the 'para-Bombay' Ah or Bh phenotype. These individuals usually have anti-H in their serum, though this is rarely of high titre. Little information exists on the clinical significance of anti-H in Ah or Bh individuals. Ideally, Oh (Bombay) phenotype should be selected, but if not available, red cells of the appropriate ABO group (A for Ah, B for Bh) may be used. Anti-HI is present in the serum of individuals with some para-Bombay phenotypes (red cell H-deficient, secretor) and is occasionally found in group A1, A1B and B individuals. Anti-HI is not usually active at 37 C, and ABO-identical blood, compatible at 37 C, can be used for transfusion. If the antibody is active at 37 C, blood of the ABO group of the patient should be used. Group O and A2 blood should not be used. Kx system Anti-Kx is a rare antibody found in the serum of immunized individuals with McLeod syndrome, usually together with anti-Km. Anti-Kx + anti-Km has caused severe HTRs. If possible, antigen-negative (McLeod phenotype) blood should be selected. Gerbich system Anti-Ge2, -Ge3 and -Ge4 detect antigens of very high frequency. There is no firm evidence that any of these antibodies has caused an HTR, and antigen-negative blood is not usually required for transfusion. None of the Gerbich antibodies to low-frequency antigens has caused an HTR. The Gerbich antibodies have not been implicated in HDN. Cromer system There is no firm evidence that any of the rare antibodies to the Cromer system higha a a a frequency antigens (anti-Cr , -Tc , -Dr , -Es , b -IFC, -WES and -UMC) has caused an HTR, and the evidence from functional cellular assays is equivocal. Antigen-negative blood is not usually required for transfusion but should be considered for strong examples of the antibody. None of the antibodies to lowfrequency antigens has caused an HTR. No Cromer antibody has been implicated in HDN.

Knops system and the COST antibodies a a a a a Anti-Kn , -McC , -Sl , -Yk and -Cs detect antigens of relatively high frequency; antib b b Kn , -McC , -Vil and -Cs detect antigens of relatively low frequency. All these antibodies can be considered to be of no clinical significance and can be ignored when selecting blood for transfusion. Use of least incompatible blood will reduce the hazard of masking other, clinically significant, antibodies. No Knops antibody has caused HDN.

Indian (In) system b b Anti-In is a rare antibody that recognizes an antigen of very high frequency. There is one reported case of anti-In causing an HTR. In(b ) blood is not usually required for transfusion but should be considered for strong examples of the antibody. a Anti-In is a rare antibody that detects an antigen, which is rare in populations of European origin, but with a frequency of a about 3% in Indians and 10% in Arabs. Anti-In has not been reported to be clinically significant. IAT-compatible red cells should be selected for transfusion. a b Anti-In and -In have not been implicated in HDN. Ok system a Only two examples of anti-Ok are known: both were in Japan, and neither was transfused. In vivo survival tests and a cellular functional assays suggest that anti-Ok is clinically significant. Ok(a ) blood is extremely rare. When Ok(a ) a blood is not available, serologically least incompatible blood may be given with extra caution. Anti-Ok has not been implicated in HDN. JMH system Anti-JMH detects an antigen of high frequency, and JMH is usually an acquired phenotype. Anti-JMH is not considered clinically significant, so serologically least incompatible blood may be used for transfusion. Anti-JMH has not been implicated in HDN. I Anti-I is always present as an alloantibody in the serum of individuals with the rare adult phenotype I i+, although it is more commonly found as an autoantibody in cold haemagglutinin disease (CHAD) patients. I+ blood transfused to patients with alloanti-I has caused increased destruction of cells, and I blood should be considered if anti-I is active at 37 C. I blood is not required when autoanti-I is present. Anti-I has not been implicated in HDN. Er a b Anti-Er and -Er are rare antibodies, detecting antigens of high and low frequency, respectively. There is no evidence that they are clinically significant, but the antibodies are extremely rare, and little clinical data are available. Serologically a b least incompatible blood should be used with extra caution. Anti-Er and -Er have not been implicated in HDN. k P, 'P,P1,P ', LKE k k Anti-P and -P,P1,P are antibodies always present in individuals with the rare P and p phenotypes, respectively. Both antibodies can react at 37 C, be strongly haemolytic and can cause an HTR. Antigen-negative red cells must be k k selected. Both antibodies are compatible with p cells; anti-P is also compatible with P cells. Neither anti-P nor -P,P1,P has been reported to cause HDN, but there is a high rate of early spontaneous abortion. k Anti-LKE detects an antigen of high frequency absent from P and p cells. LKE antibodies are generally only active at low temperature, and there is no report of an HTR. Serologically least incompatible blood may be used. Antibodies to antigens of low frequency (700 series) Antibodies to low-frequency antigens do not present a transfusion problem, as compatible blood is readily available. Some of the antibodies in this series have caused HDN. These are anti-JFV, -Kg, -JONES, -HJK and -REIT. Antibodies to antigens of high frequency (901 series) All the antibodies in this section detect antigens of very high frequency. Anti-VelOften complement-activating IgM antibodies that cause severe immediate HTRs. Vel blood must be selected. There is no report of anti-Vel causing HDN. Anti-LanOne example is reported to have caused an immediate HTR. Lan blood is not usually required for transfusion but should be considered for strong examples of the antibody. There is no report of anti-Lan causing HDN. a Anti-At Reported to have caused a transfusion reaction. At(a ) blood is not usually required for transfusion but should a be considered for strong examples of the antibody. There is one report of anti-At causing mild HDN. a a Anti-Jr There is little evidence that anti-Jr has caused an HTR, and there is no report of HDN. Jr(a ) blood is not usually required for transfusion but should be considered for strong examples of the antibody. Anti-EmmOnly five examples are known, and there is no evidence of clinical significance. Serologically least incompatible blood can be used. Anti-AnWjThis antibody has caused severe HTRs, and hence IAT-compatible blood must be selected. Red cells of the Lunull (dominant In(Lu) type) phenotype have very low expression of AnWj and are suitable for transfusion. There is no report of anti-AnWj causing HDN. Anti-PELOnly two examples of anti-PEL and two anti-PEL-like antibodies are known. In vivo survival studies suggest that anti-PEL would not cause an HTR. Serologically least incompatible blood should be used. Anti-ABTIOnly three examples are known, and there is little information on their clinical significance. Serologically least incompatible blood should be used. Anti-MAMFour known examples are potent IgG antibodies. Anti-MAM has not caused an HTR, but it has caused severe HDN. MAM blood is not available, and serologically least incompatible blood with immunosuppressive therapy may be necessary. Sd a a a Anti-Sd detects an antigen with a frequency of about 91%. The strength of Sd is very variable. Although anti-Sd is not generally considered a transfusion hazard and Sd(a ) red cells are not required for transfusion, serologically least incompatible red cells should be selected (avoid Sd(a+++) cells).
a