Red Blood Cell Alloimmunization Is Influenced By Recipient Inflammatory State At Time Of Transfusion In Patients With Sickle Cell Disease

Red blood cell (RBC) alloimmunization occurs at a much higher rate in patients with sickle cell disease (SCD) compared to other multiply transfused populations. Reasons for this include: altered immunologic responses, frequent transfusions during times of elevated inflammatory states, and disparate donor/recipient RBC antigens. Providing Rh and Kell matched RBCs has been shown to decrease but not eliminate RBC alloimmunization in patients with SCD. Although it has been shown in murine models that recipient inflammatory state at time of transfusion has the ability to regulate alloimmunization, direct clinical evidence for this effect is lacking in SCD patients.

With IRB approval, medical records of alloimmunized pediatric SCD patients were retrospectively reviewed to determine the influence of SCD-related complications often considered to be pro-inflammatory, at time of transfusion on RBC alloimmunization. The degree of antigen matching, age, and additive solution of each RBC unit were also assessed. Potential pro-inflammatory states were classified as: acute chest syndrome (ACS), acute stroke, acute febrile illness in the absence of another sickle-co morbidity, splenic sequestration, aplastic crisis, priapism, VOC with and without leukocytosis (WBC count ≥ 20k/μL) and elective surgery. Initial alloantibody detection dates were ascertained from blood bank records. Clinical events at time of transfusion were compared between transfusions resulting in a new alloantibody (AlloAb) and transfusions that did not. Univariable analysis was performed using Wilcoxon rank sum and Pearson’s Chi square test. Logistic regression modeling was used to estimate adjusted effects of stated variables on alloimmunization.

A total of 3166 prestorage leukoreduced RBC transfusions (mean age 19.3 days) were provided to 52 SCD patients; 128 transfusions resulted in RBC alloantibodies; 3038 transfusions did not. On univariable analysis, 14.1% of transfusions during any inflammatory event resulted in a new AlloAb compared to 1.4% of transfusions in the absence of inflammation (p<.0001); ACS and VOC with elevated WBC count showed the strongest association. Twenty percent and 27% of transfusions during ACS and VOC with elevated WBC resulted in AlloAbs respectively versus 2% and 4% of transfusions in the absence of these events (p<.0001). On multivariable analysis, the presence of an inflammatory event at time of transfusion was associated with increase risk for AlloAbs (OR: 8.9; 95%CI 5.9-13.5; p<.0001) with ACS showing the highest association (OR: 13.2; 95%CI 8.4-20.8; p<.0001). Any degree of antigen matching beyond ABO/Rh was associated with a significant protective effect on AlloAb formation (OR: 0.24; 95%CI: 0.13-0.46). Multivariable analysis for adjusted unit age effect demonstrated that both fresh and older units exhibited a trend toward reduced probability of alloimmunization; however, there was a paucity of units transfused at the shelf life extremes to allow definitive continuous variable analysis. There was no significant association between the additive solution of the units and AlloAb formation.

We provide clinical evidence in SCD patients that recipient pro-inflammatory state (most notably ACS) at time of transfusion directly impacts RBC alloimmunization. These results offer indirect evidence that different types of inflammatory states within the recipient induce qualitatively different immunologic processes, which may or may not promote alloimmunization, thereby substantiating previously published mouse model findings. Further investigation of the immunologic processes involved in various pro-inflammatory states, especially ACS, is warranted. Additional data are needed to determine if the age of the RBCs influences the likelihood of alloimmunization.

Fasano:ApoPharma: Honoraria.