Table 1.

Unanswered questions and future considerations relevant to DHTRs

Unanswered questions	Future considerations
Are there particular characteristics of antigen/antibody binding in and of themselves that determine whether a severe DHTR will occur?	• IgG subtype studies • IgG glycosylation studies • Antigen density studies • Contribution of IgM • Are there blood donor–specific considerations beyond RBC antigen expression?
Are there inherent differences affecting the complement cascade in patients with recurrent DHTRs with bystander hemolysis?	• In-depth studies of patients with recurrent DHTRs • Measurement of complement breakdown products, including factor Bb • Consideration of genetic testing
How can we determine the optimal treatment of DHTRs with hyperhemolysis?	• Could a multicenter clinical trial of anticomplement treatment (or other immunomodulatory therapy) be feasible? • Might other complement inhibitors beyond those targeting C5 be feasible in the setting of DHTR?
What is the pathophysiology of antibody-negative DHTRs with hyperhemolysis?	• Develop a registry of patients with antibody-negative DHTRs for translational immunologic and genetic studies
How do we prevent future DHTRs in patients with a history of severe DHTRs (especially antibody-negative DHTRs) who need RBC transfusion?	• Prospective multicenter studies of patients with recurrent DHTRs • Preclinical and translational studies are needed for a better mechanistic understanding
How can we work together in the United States to create an RBC antibody registry?	• Consideration of an accrediting agency making this mandatory as a patient safety initiative • Consideration of collaborating with blood bank information software companies, with participation in an antibody registry being a benefit to hospital clients and an incentive for future clients

IgG, immunoglobulin G; IgM, immunoglobulin M.