Blood group genotyping and evaluation of RBC alloimmunization risk by functional analyses and clinical interpretation of variant alleles in patients with Sickle Cell Disease

Abstract

Sickle Cell Anemia is the most prevalent hereditary disease in Brazil, affecting approximately 30,000 Brazilians. The main therapy used to prevent and treat the acute and chronic complications associated with sickle cell disease is the transfusion of packed red blood cells. However, the occurrence of antibodies against transfused red blood cells is one of the serious complications of transfusion therapy in these patients with an incidence ranging from 10 to 60% depending on the region studied. The presence of alloantibodies besides making it difficult to obtain compatible blood for these patients can lead to hemolytic transfusion reactions and the formation of autoantibodies. We could say that we have the perfect storm: a disease that affects predominantly Afro-descendant individuals with a distinct erythrocyte antigen profile, scarcity of compatible donors and possibly the main risk group for erythrocyte alloimmunization due to a chronic inflammation state secondary to the recurrence of vaso occlusion-reperfusion phenomena. Nonetheless, with advances made throughout the century, the survival of patients with sickle cell disease has increased noticeably. Thirty years ago, we could not imagine that today we would be dealing with elderly patients in a sea of different variants of the Rh blood group system. We could not have envisioned in performing molecular compatibility in situations where this is possibly the only solution. We could not have conjectured that we would evaluate the risk of alloimmunization and the clinical significance of variants and antibodies in order to attain transfusion safety. But this is what we are wanting to do. Thus, in this project we intend to validate a protocol of next generation sequencing for the analysis of 17 blood group genes and to evaluate its usefulness and clinical application in patients with sickle cell disease. We also intend to investigate hybrid RH genes that lead to variant Rh phenotypes and to evaluate the potential effect of allelic variants in proteins to improve transfusion management, thereby increasing the level of compatibility between donors and sickle cell patients who are at risk of alloimmunization or hemolytic transfusion reactions thus transforming the blood transfusion into one of the most personalized and controlled processes in clinical practice in such a way as to face the perfect storm. (AU)