Stella Chou and co-authors published a very interesting and somewhat disquieting paper in the August 8, 2013 edition of Blood (abstract), "High prevalence of RBC immunization in sickle cell disease despite transfusion from Rh-matched minority donors." This paper is an essential read for anyone in transfusion medicine taking care of these patients and is also of interest for its illustration of the unintended consequences of a seemingly rational policy.
The appropriate strategy to transfuse sickle cell patients to prevent alloimmunization has been controversial for several decades. My place has maintained a policy of not providing phenotypically-matched RBCs for SCD patients. My personal experience is probably similar to most in that most of the time, it's not a problem. But when one these patients starts developing antibodies, especially to high-frequency antigens, it becomes a nightmamedicine.
The authors' transfusion protocol included transfusion of HbS-negative, leukoreduced, irradiated RBCs less than 21 days' old prospectively antigen-matched for D, C, E, and K antigens from ethnically-matched RBCs units through a donor program in which donors could self-identify as "African-American" and designate their donation to support children with SCD.
It is interesting, first, to compare the distribution of alloantibodies with those in the seminal study from Vichinsky et al published in NEJM in 1990.
Of 182 transfused patients, 15% of patients undergoing "episodic" transfusions and 58% of chronically transfused patients developed alloimmunization. 55% of chronically transfused and 12% of episodically transfused patients were Rh-immunized despite prophylactic Rh antigen matching. In fact, anti-D developed in 30 patients, 29 of whom were phenotypically D-positive! Overall, 20/50 Rh alloantibodies developed in patients POSITIVE for the corresponding antigen and 8/29 Rh antibodies were found in antigen-negative patients who received antigen-negative blood.
Perhaps the most interesting part of this study is the molecular testing that was performed to identify specific RH and RHCE genotypes in the transfused patients. The reader is referred to the paper for more details but here's a couple of salient points:
- There was no significant difference in delayed hemolytic transfusion reaction incidence between D+ patients lacking conventional RHD and those with 1 or more conventional RHD alleles.
- The persistence of anti-D was not significantly different based on the presence of 1 or more conventional RHD alleles or the occurrence of delayed HTR and most were undetectable after 1 to 3 months. Conversely, anti-D developing in D-negative patients persisted for long periods following detection.
- No significant difference was found in the incidence of Rh alloimmunization in 123 chronically transfused patients with only variant RH alleles, variant and conventional alleles, or only conventional alleles.
- Despite a policy of transfusing D-, C-, and E- ethnically-matched RBCs, 1 out of 6 D-negative patients made anti-D, 17 of 87 C-negative patients made anti-C, and 13 of 104 E-negative patients made anti-E.
I focused some of my time and attention on molecular immunohematology at the recent annual AABB meeting. This paper, however, shows the limitations of molecular testing in either predicting an alloantibody response or preventing alloimmunization in this important group of transfused patients with SCD. While diversity in the RH gene contributes to Rh alloimmunization, the pathophysiology of alloimmunization appears far more complex.