Safety of red blood cell transfusion despite serologic incompatibility in autoimmune hemolytic anemia: A real-world multicenter study

Abstract Red blood cell transfusion in Autoimmune Hemolytic Anemia (AIHA) poses significant clinical challenges due to pan-reactive autoantibodies that interfere with cross-matching, often raising concerns regarding the safety of transfusing serologically “incompatible” blood. This retrospective multicenter study evaluated the frequency, management criteria, and safety profile of red blood cell transfusions in a cohort of adult patients affected by AIHA with a specific focus on transfusion management in the setting of serologic incompatibility. We analyzed 93 adult patients diagnosed with AIHA at two hematology referral centers in Palermo, Italy, between 2020 and 2025. Transfusion support was required in 31.2% ( N = 29) of patients. Decisions were mainly guided by a “double trigger” of low hemoglobin (mean 6.3 g/dL) and symptoms of tissue hypoxia, rather than by fixed hemoglobin thresholds. Notably, 61.1% of characterized units were serologically “incompatible” due to autoantibodies. Despite this, the adverse reaction rate was extremely low (1.2% per unit), with no hemolytic reactions recorded. This safety profile was likely supported by concomitant immunosuppressive therapy (89.6% of transfused patients), acting as “biological premedication”. Splenomegaly was identified as a marker for higher transfusion dependence (41.2% vs. 29.5%). Transfusion in AIHA is a safe and effective life-saving measure when managed with appropriate immunohematological oversight. Red blood cell transfusion in AIHA appears safe and effective when clinically indicated and managed with appropriate immunohematologic oversight, even in the presence of persistent serologic incompatibility. Transfusion support should not be delayed solely because of crossmatch incompatibility once clinically significant alloantibodies have been reasonably excluded.