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G.E. Linder and S.T. Chou
with the anti-e, we have cautiously transfused patients with e+ blood without evidence of a DHTR or anti-e re- appearance. In the future, RH genotype matched red cells would be the ideal choice.
The role of RH genotyping in blood donors and patients with SCD and genotype matching to prevent alloimmu- nization is currently under investigation. While systemat- ic RH genotyping of patients with SCD may aid in blood product selection and reduce the risk of alloimmunization in patients with variant RH alleles, a large pool of geno- typed Black donors would be needed as well. Universal RH genotyping is currently cost-prohibitive in most set- tings, but one study has shown that prophylactic RH matching based on genotype for patients with SCD is achievable but would require recruitment of double the number of Black blood donors as compared to those for serological matching.54
Inflammation and immune system regulation in alloimmunization
A subset of patients with SCD do not form alloantibod- ies despite repeated transfusions. Genetic modifiers and differences in immune regulation likely contribute to an individual’s risk. HLA molecules present foreign red cell antigens to T cells. Activated CD4+ T cells stimulate B-cell responses and differentiation into plasma cells. The class II HLA alleles HLA-DQ2, HLA-DQ3, and HLA-DQ5 are associated with lower risk of red cell alloimmunization, while HLA-DQ7, HLA-DRB1*04, and HLA-DRB1*15 may be associated with increased risk.65,66 Efforts to iden- tify genetic markers for alloimmunization in patients with SCD have demonstrated moderate associations but no strong predictors.67,68
Patients with high baseline levels of inflammation, such as those with autoimmune disease, have higher rates of alloimmunization.40 SCD is a chronic inflammatory state in which hemolysis results in elevated levels of circulating hemoglobin and free heme, activating neutrophils and macrophages and causing secretion of pro-inflammatory cytokines. Accordingly, patients with SCD have higher lev- els of pro-inflammatory cytokines, including interleukin-1, interleukin-6, and interferon-γ, as compared to the levels in healthy controls.69 Fasano and colleagues demonstrated that patients with SCD who received transfusions during inflammatory events such as ACS and vaso-occlusive episodes had an increased rate of alloimmunization.70
Chronic inflammation can lead to immune system dys- regulation. Several studies have shown that regulatory T cells, which control T-cell responses, display higher levels of inhibitory markers such as CTLA-4 and are dysfunc- tional in patients with SCD.71 Furthermore, regulatory B cells from alloimmunized patients with SCD have a decreased ability to suppress monocyte activation.72 Pal et al.73 demonstrated that hemolysis and cell-free heme typ- ically suppress B cells and plasma cell differentiation, but alloimmunized patients with SCD had altered B-cell inhi- bition. Further mechanistic studies are required to eluci- date the complex immunological pathways contributing to alloimmunization in SCD and to determine whether targeted reversal of immune dysregulation can reduce antibody formation.
Clinical impact of alloimmunization
Red cell alloimmunization in patients with SCD signif- icantly increases the risk of hemolytic transfusion reac-
tions, including hyperhemolytic reactions. Identifying compatible blood for patients with multiple alloantibod- ies or antibodies to high prevalence antigens can be chal- lenging or even impossible, potentially leading to transfu- sion delays and poor outcomes.
Additional complications of packed red blood cell transfusion
Delayed hemolytic transfusion reactions and hyperhemolysis
DHTR is a feared adverse outcome of transfusion in SCD.74 DHTR classically occurs after re-exposure to a red cell antigen that the patient had previously been immu- nized against. As many as 80% of alloantibodies in patients with SCD become undetectable.75 In patients with SCD, 30- 40% of DHTR are associated with no identifiable antibod- ies, and in one-third of cases, autoantibodies or antibodies of unclear specificity are the only detectable finding.76,77 The mechanisms of red cell destruction in antibody-negative DHTR have not been elucidated, however hypotheses include hyperactivated macrophages and red cells with increased membrane exposure of phosphatidylserine.78,79 Alternatively, the antibody may simply be difficult to detect. The most severe complication is hyperhemolysis, in which hemolysis of bystander autologous cells occurs, lead- ing to a hemoglobin level lower than pre-transfusion levels and often life-threatening anemia.
The reported incidence of DHTR in SCD is 4.8-7.7%.80,81 These rates may be underestimates, as many DHTR are misdiagnosed as vaso-occlusive episodes or go undetected. In one of the largest cohorts to date, the most common clin- ical manifestations of DHTR were hemoglobinuria, pain, and fever.76 Only 44% of patients had overt signs of anemia. Signs and symptoms of DHTR vary among individuals. The recent ASH guidelines define DHTR as a significant drop in hemoglobin within 21 days after transfusion in the presence of hemoglobinuria, newly detected alloantibodies, accelerated increase in HbS, significant change in reticulo- cyte percentage, or increase in lactate dehydrogenase level above baseline.2 Rapid decline in HbA concentration rela- tive to an early post-transfusion measurement is highly pre- dictive of DHTR. Risk factors include a history of alloim- munization, prior DHTR, and transfusion for acute compli- cations.76,80-82
High suspicion must be maintained when patients with SCD present with pain, fever, or worsening anemia in the days to weeks after transfusion. Habibi et al. reported that 92% of patients with DHTR were not immediately diag- nosed.76 Review of the transfusion history is required, and an antibody screen, direct antiglobulin test (DAT) with elu- tion, and hemoglobin electrophoresis should be performed if the patient has been recently transfused. Between 25- 60% of DHTR are associated with newly detected red cell antibodies, and approximately 80% of DHTR are DAT pos- itive.76,81,82 Time to DAT positivity is variable, and it is rec- ommended that the DAT and antibody screen are repeated 1-2 weeks after presentation in cases of DHTR that are ini- tially antibody-negative.
Additional transfusions may exacerbate hemolysis, par- ticularly when the antibody is not identified. Upon recogni- tion of a DHTR, further transfusion should be avoided if possible. If transfusion is necessary and no antibody speci- ficity has been identified, extended antigen matching for
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haematologica | 2021; 106(7)