With its unique anatomy and location amidst the circulatory system, the spleen allows an intimate contact between its resident cells and blood passing through the organ. Senescent and damaged red cells are primarily sequestered in the splenic red pulp and consumed by its macrophages. 1 Consequently, this route facilitates the presentation of non-self antigens of transfused red cells to splenic immune cells as a first and essential step in red cell alloimmunization. Indeed, the splenic microenvironment has been demonstrated to play a prominent role in red cell alloimmunization in mice. 2, 3 Contrasting these animal studies, some observational studies in thalassemia patients suggested splenectomy to be associated with increased red cell alloimmunization, 4, 5 while others did not find any association. 6, 7

In the study herein, we assessed the association between the anatomic absence of the spleen and (transfusion-related) red cell alloantibody induction in our multicenter case-control Risk Factors for Alloimmunization to Red Blood Cell Transfusion (R-FACT) study cohort. This cohort includes 505 alloimmunized cases and 1,010 non-alloimmunized matched controls among a primarily Caucasian source population of 24,063 patients receiving their first and subsequent red cell transfusions between January 2005 and December 2013 at one of six participating hospitals in the Netherlands, as described earlier. 8 A detailed description of our case-control cohort and the methodology used has been published recently. 9