Page 39 - 2021_07-Haematologica-web

Red cell transfusion and alloimmunization in SCD
transfusion parameters of hemoglobin <10-11 g/dL and HbS percentage <30% prior to autologous stem cell mobilization and transplantation.39 The optimal transfu- sion modality and timing peri-transplant are important areas of further study.
Alloimmunization in sickle cell disease
Alloantigen specificity and donor/recipient antigen discrepancies
Alloimmunization, or formation of antibodies to non- self antigens, is a major adverse effect of transfusion. Alloimmunization increases the risk of hemolytic transfu- sion reactions and leads to delays in identification of compatible red cell units. While multicenter, registry- based studies have identified a prevalence of red cell alloimmunization of 2-5% in the general population, the prevalence in patients with SCD ranges from 5-75%.40-42 The pathophysiology of alloimmunization in SCD is complex and is associated with level of antigen matching, Rh blood group system diversity, and immune factors (Figure 1).
Antibodies to Rh system antigens C and E and to the Kell system antigen K historically accounted for up to two-thirds of alloantibodies in SCD.43,44 Rh and Kell sys- tem antigens are among the most immunogenic. Thus, a primary driver behind alloimmunization is recipient- donor mismatch of Rh and K antigens. The majority of Blacks lack C and E antigens (73% and 78%, respective- ly), and only 2% express the K antigen.45 In the predomi- nantly white blood donor populations in the USA and Europe, the frequencies of C, E, and K are higher, leading to recipient-donor mismatch.43,45 Other clinically relevant antigens, including Jkb in the Kidd system, Fya in the Duffy system, and S in the MNS system are also more common in individuals of European descent. Several studies report a lower prevalence of alloimmunization when the blood donor and SCD patient populations share greater antigenic similarity, but an important caveat is the low transfusion burden of the patients in these reports.46-48 Differences in red cell antigens among patient and donor populations have led to efforts to recruit Black donors to support transfusion of SCD populations.49,50
Red cell antigen matching
The British Society for Haematology guidelines, the ASH 2020 guidelines, and the National Institutes of Health Expert Panel recommend prophylactic matching for Rh (C, E or C/c, E/e), and K in addition to ABO and D in patients with SCD.2-4,51 Transfusion of red cells matched for Rh and K decreases the rate of alloimmunization from 1.7-3.9 antibodies per 100 units transfused to 0.26-0.50 antibodies per 100 units transfused.41 Additional antigen matching extended for Fya/Fyb, Jka/Jkb, M/N, S/s, Lea/Leb, and P antigens further reduces the rate of alloantibody formation to 0.1-0.3 per 100 units transfused, but finding sufficient compatible units becomes significantly more challenging.52-54
An extended red cell antigen profile should be obtained in all patients with SCD at the earliest opportunity.2 Extended antigen identification has traditionally been performed by manual serological phenotyping methods. As most blood group antigens are due to single nucleotide polymorphisms, high throughput genotyping systems
can identify Rh, Kell, Kidd, Duffy, MNS, Lutheran, Diego, Dombrock, and Colton blood group system antigens.55 DNA-based red cell typing is more accurate than serolog- ical phenotyping and provides additional information, such as whether a patient has a GATA mutation in the ACKR1 gene and is, therefore, not at risk of forming anti- Fyb antibodies.56 Genotyping methods also provide increased accuracy for C antigen expression in this popu- lation, predict antigen expression when no antisera is available, and should be used over serological phenotyp- ing if the patient has been transfused in the preceding 3 months. Several studies have utilized molecular genotyp- ing to support extended antigen matching between blood donors and patients with SCD.57,58
RH diversity and the role of RH genotyping
Despite serological matching for D and C, E or C/c, E/e antigens, Rh alloimmunization persists due to RH genetic diversity in individuals of African descent.49,59 The RHD and RHCE genes are located on chromosome 1, arose through gene duplication, and encode D and C, c, E, e antigens, respectively.60 The two loci are highly homolo- gous, leading to many gene recombination events result- ing in variant RHD and RHCE alleles that encode altered antigens.45,60 Rh variant antigens are difficult to distinguish serologically and require RH genotyping for identifica- tion. While RH variants can result in weak (decreased antigen density) or partial (missing epitopes) antigen expression, Blacks typically carry alleles in the latter cate- gory and are at risk of alloantibody formation when exposed to the epitopes they lack via transfusion, preg- nancy, or transplantation. High suspicion must be main- tained when apparent autoantibodies with Rh specificity or unexplained Rh antibodies are detected in patients with SCD, and further investigation with RH genotyping
should be pursued.
Most patients with SCD have one or more RH allele vari-
ants.49,54,59 Two common variants in Blacks, RHD*DAU0 and RHCE*ce48C, have not been shown to encode Rh proteins lacking epitopes and are considered “altered” antigens.54 RHD*D 4.0, *DIVa, *DAU3, and *DIIIa are frequently detected variants in patients with SCD and result in partial D antigen expression.61,62
The hybrid RHD*DIIIa-CE(4-7)-D allele results from RHCE exons 4 through 7 replacing the corresponding exons of RHD. This allele encodes a partial C antigen and no D antigen. Individuals with RHD*DIIIa-CE(4-7)-D who lack conventional RHCE*Ce or *CE alleles serologi- cally type as C positive but are at risk of developing allo- anti-C if exposed to conventional C antigen.63 Variant RhCE antigens resulting in partial c and e antigens are par- ticularly common in Blacks. Individuals with homozy- gous ce variants often make allo-anti-e antibodies and may also lack the high frequency hrB and hrS antigens.64 Formation of alloantibodies against hrB and hrS, present on the red cells of 98% of individuals, can pose a challenge to identification of compatible donor units.45 Anti-hrB and -hrS may initially appear as having an anti-e specificity. Knowledge of the patient’s RH genotype, which identifies those who are hrB and hrS negative, can facilitate proper antibody evaluation and distinguish these antibodies from anti-e. E-e+ patients with partial e antigens who form allo-anti-e are at risk of anti-E if transfused with E+e- red cells. While each clinical scenario requires indi- vidual decision-making, if there was no associated DHTR
haematologica | 2021; 106(7)
1809