Ideal donors, imperfect results in sickle cell disease

In this issue of Blood, Chou et al report findings from an observational study of alloimmunization in patients with sickle cell disease (SCD) receiving blood transfusions from ethnically matched donors.¹ 

An impressive array of Rh allelic variants in African Americans is provided, some of which were associated with clinically significant delayed transfusion reaction (DTR). Of the 182 patients who were transfused in this single institution study, 80 developed alloantibodies. The investigators sought to characterize factors associated with alloimmunization in sickle cell patients, who are of African descent and who were transfused with antigen-matched blood predominantly from African-American donors. They described the antigen specificity of antibodies identified, including extensive high-resolution Rh genotyping. Clinical events, such as DTR, were described in relationship to total red blood cell exposure and RHD and RHCE genotypes. The authors report rates of alloimmunization of 58% and 15% among patients on chronic transfusions and episodic transfusions, respectively. Rates of sensitization to C, E, and Kell in particular were still high, despite extended matching for these antigens.

It is estimated that more than half of all children and 90% of adults with SCD have received ≥1 transfusion in their lifetime.²  Acute or episodic transfusions can relieve severe symptomatic anemia or improve oxygen-carrying capacity, and chronic transfusions are effective in both primary stroke prevention in children with abnormal transcranial Doppler cerebral blood flow velocities and secondary stroke prophylaxis following overt cerebrovascular events.³  Even as the indications for transfusions continue to expand, serious hazards of transfusions such as alloimmunization can create almost insurmountable challenges for some patients. Strategies to avoid or manage this risk are desperately needed.

Studies have demonstrated that antibodies against C, E, and Kell antigens account for >50% of alloantibodies identified in patients with SCD and that extended antigen matching to include C, E, and Kell can decrease the development of new antibodies in this population by 40% to 90%.^2,4  Although academic medical centers are more likely to provide extended antigen matching,⁵  a recent North American survey indicated two-thirds of institutions continue to only match for ABO and D in nonalloimmunized patients with SCD.⁶  There are also significant global variations in transfusion practices in SCD.^7,8 

To date, this is the largest cohort of SCD patients who have been supported over an extended period almost exclusively with blood collected from self-identified African-American donors. Ethnic disparity has often been cited as the major contributor to allosensitization in SCD throughout Europe and North America, where the donor population is predominantly nonblack. Diversity of the blood supply in an increasingly global, multiethnic nation is important, whether planning for national disasters or insuring safe and adequate resources for routine procedures.⁹  African Americans, in particular, continue to be underrepresented in community blood donation programs. Strategies to enhance matching by focused recruitment of African-American blood donors or establishing directed donor programs for children with SCD have long been advocated as potential solutions to this very serious transfusion-related complication.

The incorporation of DNA-based methods into standard transfusion practices for determining RBC genotype is becoming more feasible, particularly for polymorphic antigens in most blood group systems.⁸  The Rh system, however, has been a notable exception, primarily due to its complexities as demonstrated by Chou et al. The wide diversity of Rh variants among their patients (and presumably their donors) suggests that additional or alternate approaches may be needed to improve matching and reduce alloimmunization.

The authors identify a very relevant concern for hematologists and for patients with sickle cell disease. Racial differences alone do not explain the increased propensity of patients with SCD to develop allo- and autoantibodies. Patients with hemoglobinopathies and most non-European ethnic groups are among the populations that pose exceptional challenges in blood banking as identified by the 2007 National Heart, Lung, and Blood Institute Working Group on Transfusions Epidemiology and Recipient Outcomes Research and in whom more research is needed.¹⁰  The paper by Chou et al provides some very critical insights to a problem for which as yet there does not appear to be an easy solution.