In Reply: Diagnostic challenges in severe autoimmune hemolysis

We appreciate Dr. Rizwan’s thoughtful and relevant comments. The key message is that a strong clinical suspicion for autoimmune hemolytic anemia warrants consideration of immunoglobulin A warm-antibody autoimmune hemolytic anemia even in the setting of a variable or negative direct antiglobulin test.

The diagnostic steps outlined in our article¹ provide a practical algorithm that can be applied both in settings with and without access to a reference laboratory. Step 1 emphasizes the basic laboratory evaluation needed to confirm hemolytic anemia. Step 2 highlights the direct antiglobulin test as a widely used and easily performed screening assay for autoimmune hemolytic anemia, recognizing that the direct antiglobulin test may be negative in 3% to 10% of patients with autoimmune hemolytic anemia, depending on the testing methodology used.^2,3

Step 3 is performed in laboratories with transfusion services, with the recommendation to proceed to step 4 in the setting of “ongoing hemolysis with a negative eluate.” This phrasing is meant to encompass scenarios in which eluate testing is either negative or not performed.

Step 4 appropriately recommends extended direct antiglobulin testing when clinical suspicion for autoimmune hemolytic anemia remains high and underscores the critical point to still “consider Coombs negative autoimmune hemolytic anemia if all standard assays are negative.” This statement acknowledges that all available testing may fail to identify an autoantibody despite clear clinical evidence of autoimmune hemolytic anemia. Extended direct antiglobulin testing for autoimmune hemolytic anemia subtype can have a turnaround time of 72 hours.

When available, extended direct antiglobulin testing can be diagnostically definitive and should be considered in patients with persistent hemolytic anemia. This testing can be pursued early following a negative standard direct antiglobulin test. Our stepwise approach remains clinically applicable when autoimmune hemolytic anemia is highly suspected, as the last step suggests that even when extended direct antiglobulin testing is negative (which implies unavailable or delayed), clinical judgment dictates treatment. We have summarized the treatment of warm autoimmune hemolytic anemia.

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