A genome-wide association study of alloimmunization in the TOPMed OMG-SCD cohort identifies a locus on chromosome 12.

BACKGROUND: Red cell alloimmunization after exposure to donor red cells is a very common complication of transfusion for patients with sickle cell disease (SCD), resulting frequently in accelerated donor red blood cell destruction. Patients show substantial differences in their predisposition to alloimmunization, and genetic variability is one proposed component. Although several genetic association studies have been conducted for alloimmunization, the results have been inconsistent, and the genetic determinants of alloimmunization remain largely unknown. STUDY DESIGN AND METHODS: We performed a genome-wide association study (GWAS) in 236 African American (AA) SCD patients from the Outcome Modifying Genes in Sickle Cell Disease (OMG-SCD) cohort, which is part of Trans-Omics for Precision Medicine (TOPMed), with whole-genome sequencing data available. We also performed sensitivity analyses adjusting for different sets of covariates and applied different sample grouping strategies based on the number of alloantibodies patients developed. RESULTS: We identified one genome-wide significant locus on chr12 (p = 3.1e-9) with no evidence of genomic inflation (lambda = 1.003). Further leveraging QTL evidence from GTEx whole blood and/or Jackson Heart Study PBMC RNA-Seq data, we identified a number of potential genes, such as ARHGAP9, STAT6, and ATP23, that may be driving the association signal. We also discovered some suggestive loci using different analysis strategies. DISCUSSION: We call for the community to collect additional alloantibody information within SCD cohorts to further the understanding of the genetic basis of alloimmunization in order to improve transfusion outcomes.

Use of a novel configuration of ports for patients needing intermittent long-term apheresis.

PURPOSE: In patients with a need for frequent but intermittent apheresis, vascular access can prove challenging. We describe the migration of the use of a Vortex LP dual lumen port (Angiodynamics, Latham, NY) to one Powerflow and one ClearVUE power injectable port (Becton Dickinson, Franklin Lakes, NJ) in a series of patients undergoing intermittent apheresis. MATERIALS AND METHODS: All patients had a need for long-term intermittent apheresis. Eight had double lumen Vortex port (pre) and were exchanged for one Powerflow port and one conventional subcutaneous venous port with 90° needle entry (post) while 12 did not have any port in place and received the same configuration. IRB approval was granted. We recorded the treatment time, flow rate, and tissue plasminogen activator (tPA) use for five treatment sessions after placement. When available, we compared five treatments with the Vortex port and the new configuration. RESULTS: The mean treatment time is reduced with the new configuration (P = 0.0033). The predicted mean treatment time, adjusting for gender, race, BMI and age and accounting for correlations within a patient is 91.18 min pre and 77.96 min post. The flow rate is higher with the new configuration (P < 0.0001). The predicted mean flow rate in mL/min is 61.59 for the Vortex port and 71.89 for the new configuration. tPA use was eliminated in the population converted from Vortex ports and had a 48% reduction when compared to all other configurations in the study. CONCLUSION: The introduction of a novel device configuration of venous access ports for intermittent apheresis resulted in higher flow rates and less total time for treatment. Use of tPA was greatly reduced. These results suggest that the new configuration could result in less expense for the hospital and better throughput in a busy pheresis practice. Clinical trial registration with ClinicalTrials.gov: NCT04846374.

The global role of G6PD in infection and immunity.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans. G6PD is an essential enzyme in the pentose phosphate pathway (PPP), generating NADPH needed for cellular biosynthesis and reactive oxygen species (ROS) homeostasis, the latter especially key in red blood cells (RBCs). Beyond the RBC, there is emerging evidence that G6PD exerts an immunologic role by virtue of its functions in leukocyte oxidative metabolism and anabolic synthesis necessary for immune effector function. We review these here, and consider the global immunometabolic role of G6PD activity and G6PD deficiency in modulating inflammation and immunopathology.

Bleeding recurrence risk among hospitalized patients undergoing therapeutic plasma exchange: a multi-center study.

BACKGROUND: In hospitalized patients undergoing therapeutic plasma exchange (TPE), it is not known how TPE-associated bleeding risk is impacted by a prior bleeding episode. Therefore, to assess the prevalence and predictors of bleeding recurrence, we analyzed data from the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III). MATERIALS AND METHODS: Using a retrospective cross-sectional analysis of REDS-III public use files, we identified hospitalized adults who had a major bleeding episode prior to their first TPE procedure. Patients were classified into two cohorts based on bleeding recurrence (no-recurrence vs recurrence). After identifying potential predictors, we used multiple imputation by chained equations to impute variables with <30% missing data. Variable selection was optimized using a 10-fold cross validated least absolute shrinkage and selection operator. Final predictors were identified by fitting a logistic regression model. RESULTS: In 310 patients with major bleeding prior to TPE initiation, bleeding recurred in 121 (39.0%). We identified the following seven unique predictors: 1) >10 TPE procedures (OR 2.23); 2) intensive care unit stay (OR 1.35); 3) thrombocytopenia (OR 1.26); 4) surgery (OR 1.22); 5) hepatic disease (OR 1.21); 6) 6-10 TPE procedures (OR 1.04); and 7) Asian race (OR 1.01). We also identified the following five interactions: 1) surgery and therapeutic anticoagulation (OR 1.50); 2) 6-10 TPE procedures and therapeutic anticoagulation (OR 1.05); 3) 6-10 TPE procedures and antiplatelets (OR 1.02); 4) >10 TPE procedures and antiplatelets (OR 1.00); and 5) albumin-only TPE and antiplatelets (OR 0.53). When assessed for adjusted performance, the prediction model had a C-statistic of 0.617 (95% CI 0.613-0.619) and Brier Score of 0.342 (95% CI 0.340-0.347). DISCUSSION: In this study assessing predictors of bleeding recurrence among hospitalized patients undergoing TPE, we identified seven variables and five interactions. These findings should be validated in future studies.