C1-inhibitor treatment in patients with severe complement-mediated autoimmune hemolytic anemia

Abstract

Complement-mediated autoimmune hemolytic anemia (CM-AIHA) is characterized by destruction of red blood cells (RBCs) by autoantibodies that activate the classical complement pathway. These antibodies also reduce transfusion efficacy via lysis of donor RBCs. Since C1-inhibitor (C1-INH) is an endogenous regulator of the classical complement pathway, we hypothesized that peritransfusional C1-INH in patients with severe CM-AIHA reduces complement activation and hemolysis, and thus enhance RBC transfusion efficacy. We conducted a prospective, single center, phase 2 open-label trial (EudraCT2012-003710-13). Patients with confirmed CM-AIHA and indication for the transfusion of two RBC units were eligible for inclusion. Four intravenous C1-INH doses (6000, 3000, 2000 and 1000 U) were given with 12 h intervals around RBC transfusion. Serial blood samples were analyzed for hemolytic activity, RBC opsonization, complement activation and inflammation markers. Ten patients were included in the study. C1-INH administration increased plasma C1-INH antigen and -activity, peaking at 48 h after the first dose, accompanied by a significant reduction of RBC C3d deposition. Hemoglobin levels increased briefly after transfusion but returned to baseline within 48 h. Overall, markers of hemolysis, inflammation and complement activation remained unchanged. Five grade 3 and one grade 4 adverse event occurred, but were considered unrelated to the study medication. In conclusion, peritransfusional C1-INH temporarily reduced complement activation. However, C1-INH failed to halt hemolytic activity in severe transfusion-dependent CM-AIHA. We cannot exclude that posttransfusional hemolytic activity would have been even higher without C1-INH. The potential of complement inhibition on transfusion efficacy in severe CM-AIHA remains to be determined.

Case report: Autoimmune hemolytic anemia caused by warm and cold autoantibodies with complement activation—etiological and therapeutic issues

“…In cold agglutinin disease, the levels of complement C3 and, in particular, C4 are often reduced, reflecting continuous consumption ( 20 ). Reduction of C3 and C4 levels may also be caused by infection-related consumption ( 4 ). In addition, heterozygous gain-of-function C3 mutations can increase the formation of C3bBb ( 21 ).…”

“…Complement blockade therapy (CBT) with C1 inhibitor Berinert revealed an immediate effect (increase in hemoglobin levels) by C3d deposit reduction. However, it failed to decrease hemolytic activity, stabilize transfusion efficacy, or reduce systemic complement activation ( 4 , 31 ). Sutimlimab (anti-C1-humanized monoclonal antibody) inhibits the classical complement system by binding to complement protein subcomponent 1 (sC1).…”

“…Complement overactivation and overconsumption should be reserved for devastating, life-threatening complement-related multiorgan failure with the need for short- or long-term complement blockade ( 6 ). Some authors believe that patients with severe AIHA who successfully respond to CBT may require long-term treatment ( 4 ). This was precisely why we looked at underground genetics, which may or may not support long-term CBT.…”

“…Prior to treatment, a bone marrow biopsy was performed to exclude malignant hematological disorders. As we were aware of the simultaneous presence of warm and cold AIHA autoantibodies, immunosuppressive therapy was started alongside periodic packed RBC and platelet substitutes, avoiding such substitution as much as possible ( 3 , 4 ). The first-line treatment consisted of intravenous methylprednisolone [4 mg/kg/body weight for the first 72 h (q12 h), followed by 2 mg/kg body weight for 21 consecutive days and very slow steroid reduction until plasmapheresis (PLEX)].…”

“…Approximately 1–1.5 plasma volume was swapped with normal saline and fresh frozen plasma. Periodic packed RBC and platelet transfusions were administered as needed ( 4 , 5 ). We maintained the hemoglobin count at 70–80 g/L and the platelet count at 30–50 × 109 to avoid giving too much “fuel” to the hemolysis ( 4 , 6 ).…”