Personalizing transfusion in sickle cell disease: where is the canary in the mine?

R ed blood cell (RBC) transfusion is the cornerstone of therapy for sickle cell disease (SCD). The genetic mutation in SCD results in the production of hemoglobin (Hb) S. HbS polymerizes when deoxygenated and deforms the shape of the RBC, leading to hemolysis with resultant anemia, inflammation, and endovascular activation. Prior to hemolysis, though, HbS RBCs have increased aggregation and decreased deformability compared to HbA RBCs, increasing the viscosity of the blood and decreasing flow through the microcirculation. The goal of chronic transfusion therapy is to increase the number of RBCs with HbA and decrease the quantity of RBCs with HbS, which not only increases the oxygen carrying capacity of the blood through correction of the patient’s anemia, but also improves flow through the microcirculation by decreasing aggregation and increasing the percentage of HbA RBCs with normal deformability. Most commonly, chronic transfusion is used as treatment for primary or secondary prevention of stroke in SCD. The neurocognitive complications of SCD are not surprising considering the high oxygen demand of the brain, requiring 20% of the cardiac output to fulfill its metabolic demand. Historically, approximately 10% of patients with HbSS disease had an overt stroke, associated with abnormalities on the bedside neurologic exam, by the age of 20 years. However, there is a 92% risk reduction with the initiation of chronic transfusion therapy for primary stroke prevention after identifying those at greatest stroke risk via screening transcranial Doppler ultrasound (TCD). Unfortunately, a high percentage of patients with SCD still suffer from silent cerebral infarctions (small strokes that are associated with cognitive deficits, but not with abnormalities on the neurologic exam) in the modern treatment era with TCD screening. Approximately 40% of children with HbSS disease develop a silent cerebral infarct by the age of 18 years without a plateau in prevalence. The Silent Cerebral Infarct Multi-Center Clinical Trial showed that chronic transfusion significantly decreased the risk of recurrent stroke, silent or overt, in patients with a history of silent infarct. Lastly, chronic transfusion therapy is occasionally used as treatment in patients with other complications of SCD, such as severe sickle cell hepatopathy, or recurrent acute chest syndrome, vasoocclusive episodes, or priapism. The benefits from chronic transfusion therapy in SCD are partially offset by the side effects of this intervention. Even though automated exchange transfusions decrease iron burden when compared to simple transfusion or manual exchange, many patients still require chelation with potentially toxicmedications for hemosiderosis. Alloimmunization remains a significant risk of chronic transfusion even in the setting of matching for Rh, D, E and K antigens and utilizing RBCs from African American donors, with up to 7%-59% of chronically transfused patients becoming alloimmunized. Approximately 1/3 of new alloantibodies in this setting are associated with a delayed hemolytic transfusion reaction. In this issue of TRANSFUSION, Kamyszek et al report the results of a retrospective cohort study investigating the association between HbA decrement between RBC exchange procedures with SCD-related clinical events in 21 adult SCD patients receiving chronic transfusion therapy for a variety of clinical indications. Within this cohort, they found that the subgroup of patients with increased SCD-related complications resulting in an emergency department visit or hospitalization had a significantly greater HbA decrement between exchange procedures compared to those with fewer complications of their disease. Kamyszek’s study of HbA decrement may have important clinical implications, but further investigation will be required. The vast majority of research on chronic transfusion therapy for SCD has focused on monitoring HbS between transfusions. One other group, Yee and colleagues investigated the decrement of HbA in chronically transfused pediatric patients with SCD. However, this study focused on the relationship between HbA decrement, prior alloimmunization, and donor-recipient minor RBC antigen mismatches, rather than on the relationship between HbA decrement and clinical outcomes. The work of Kamyszek et al reiterates the positive impact of chronic transfusion therapy on themultitude of clinical complications associated with SCD, and together, these two studies highlight our lack of understanding of factors influencing survival of transfused RBCs, the best algorithms for monitoring chronic transfusion therapy, and the optimal transfusion goals required for this population, which receives a single therapeutic intervention for a variety of clinical indications. Current guidelines for chronically transfusing patients with SCD recommend targeting a pre-transfusion HbS less than 30%, with a post-transfusion Hb < 10 g/dL. This recommendation was based on landmark trials, including the Stroke Prevention Trial in Sickle Cell Anemia (STOP), Stroke With Transfusions Changing to Hydroxyurea (SWiTCH), Silent Cerebral Infarct Multi-Center Clinical Trial (SIT), and TCD With Transfusions Changing to Hydroxyurea (TWiTCH), all of doi:10.1111/trf.15453 © 2019 AABB TRANSFUSION 2019;59;2493–2495