Peritransfusional C1-inhibitor (C1-INH) demonstrated its ability to temporarily reduce complement activation but failed to suppress hemolytic activity in severe transfusion-dependent complement-mediated autoimmune hemolytic anemia (CM-AIHA) such as cold agglutinin disease (CAD), according to a study published in Blood Advances.

For this prospective, single-center, phase 2 open-label trial, the authors recruited 10 patients with established CM-AIHA and indication for the transfusion of 2 red blood cell (RBC) units. The participants received 4 intravenous C1-INH doses (6000, 3000, 2000, and 1000 U) with 12-hour interim periods around RBC transfusion.

Next, the researchers analyzed the serial blood samples for hemolytic activity, RBC opsonization, complement activation, and inflammation markers.

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According to the results, C1-INH administration amplified plasma C1-INH antigen and activity, peaking at 48 hours after the first dose, as well as reduced RBC C3d deposition. The levels of hemoglobin slightly increased after transfusion but returned to baseline within 48 hours.

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In general, markers of hemolysis, inflammation, and complement activation were unchanged. Five grade 3 and one grade 4 adverse events occurred but the authors did not believe these were related to the study medication.

Treatment with C1-INH had no direct effect on the markers of hemolysis, inflammation, and complement activation. The researchers also reported 5 cases of grade 3 and 1 case of grade 4 adverse events, which were considered not related to the experimental treatment.

“An interesting novel finding was the strong increase in inflammatory markers in our cohort compared to healthy controls, which may be relevant for clinical correlations to the thrombotic risk and deserve further study,” De Boer and colleagues noted. “These data do not support the clinical use of C1-INH in the tested dose in patients with severe CM-AIHA, but adds to the increasing experience with proximal complement inhibitors in this patient population.”

It is unclear whether the post-transfusion hemolytic activity would have been even higher without C1-INH. However, the effectiveness of this therapeutic approach for severe CM-AIHA patients is yet to be determined.


De Boer ECW, Jalink M, Delvasto-Nuñez L, et al. C1-inhibitor treatment in patients with severe complement-mediated autoimmune hemolytic anemia. Blood Adv. Published online March 15, 2023. doi:10.1182/bloodadvances.2022009402