On the other side, splenectomy (currently reserved for patients with marked symptoms related to hypersplenism) and hypo-functional spleen as a disease complication play a significant role in immune system modifications (with a significantly high absolute lymphocytic count and low level of IgM memory B cells), leading to an increased risk to complicated infections in thalassemia (even if it was not reported in our cohort, evidencing the efficacy of SARS-CoV-2 vaccination) [30,31,32,33,34]. This evidence concerns the gene CD40LG and infection.