311 Autoimmune hemolytic anemia with complement activation mimicking aHUS

A boy of 5 years was admitted into the Division for Pediatric Hematology and Oncology due to severe anemia. Initial complete blood count showed severe macrocytic anemia (Hb 44 g/L, Htc 14.9%, MCV 112.6 fL), elevated Rtc count (34.7%, 158.7/1000 erythrocytes), and slightly reduced platelet count (110 x109). The boy had hemolysis (low haptoglobin level (<0.10 g/L), elevated bilirubin, and LDH, with complement activation (C4 0.72 g/L, C3 0.02 g/L, CH50 13%). Urea (3.3 mmol/L) and creatinine (19 umol/L) were within reference values. Exclusion diagnostics: malignant hematological disorders (bone marrow biopsy), folate deficiency anemia, and vitamin B12 deficiency. Immunohematological analysis: autoimmune hemolytic anemia with positive both direct and indirect antiglobulin (Coombs) test. The erythrocytes were coated with warm IgG autoantibodies and IgM class autoantibodies in a wide temperature range (4 – 37°C) without erythrocyte specificity alongside activated complement components while the platelets were coated with IgM autoantibodies. ADAMTS13 activity was decreased (38%), but not deficient alongside low C1q antigen, low Factor H antigen (84 mg/L, ref. range 250-880 mg/L) and low sC5b-9 (terminal complement complex) (301 ng/mL, ref. range 110-252 ng/mL) Treatment: intravenous methylprednisolone (6 mg/kgBW/14 consecutive days) with periodical erythrocyte and platelet concentrate transfusions, rituximab once weekly (5 doses in total); plasmapheresis (6 cycles in total, with side effects which included increased tendency clotting). These therapeutic strategies showed no therapeutic benefit, and the child was dependant on periodic RBC and platelet transfusions. The therapy was switched to IVIg (4,7g/kg/5 days) and vitamin B12 (1000mcg/daily/7 days), with significant improvement of RBC and platelet count. Genetic analysis: a heterozygous mutation for a rare intronic variation (c.600-14C>T) and heterozygous for the Y402H polymorphism of the CFH gene. c.600-14C>T mutation is located near the 5’ end of exon 6 in the gene encoding the complement C3 protein (C3). This rare variation was described previously in one patient with aHUS, in one patient with glomerulonephritis, in one subject suffering from C3-deficiency, and one patient with age-related macular degeneration. This rare variation was also identified in healthy subjects with a relatively low frequency (0.04-1.1%), but no functional studies were performed on its possible role. Conclusion We believe that the underlying disease was autoimmune hemolytic anemia with both cold and warm autoantibodies complicated with complement activation on predisposing genetic background.