Cold Agglutinin Disease

Patient History 62 year old female who presented to clinic with a one month history of worsening fatigue and subjective fevers.

Physical Exam/Labs Jaundice and scleral icterus Labs: Date Hgb Haptoglobin LDH TBili CBili 10/30/13 6.1 1151 5.9 <8 847 4.9 0.4 10/31/13 5.7 717 3.9

Labs - Previous 4/2012 Presented with exertional fatigue, jaundice, and dark urine and laboratory evidence of hemolysis Antibody screen (pre-warmed): negative Antibody screen (room temperature): positive Direct antiglobulin test (Coomb’s) was positive (+4) for complement fixation and negative for IgG The cold agglutinin titer at 4C is 1:512. The thermal amplitude is 30 C The specificity of the cold agglutinin is anti I.

Labs- Previous 12/2012 Antibody screen was performed on prewarmed plamsa was negative A cold agglutinin titer showed: anti-I titer at 37 degrees C is 0 anti-I titer at 30 degrees C is 1:256 the anti-I titer at 4 degrees C is 1:32768 A DAT was perfomed and was positive for complement (4+) and negative for IgG.

Labs - Current Cold (IgM) antibody at a titer of 1:4096 The patient's blood type is B positive. The reverse type is discrepant, likely due to high cold agglutinin titer. Antibody screen was negative A direct antiglobulin test (DAT) was negative for IgG and positive for complement (4+).

Cold Agglutinin Disease 15% of AIHAs Usually presents in 7th decade of life, F>M 90% of cases - IgM antibodies react with RBC antigens at temperatures below core body temperature IgM can span the distance between RBCs, thus producing in vitro agglutination

Diagnosis Signs/symptoms of hemolysis DAT: Titer and thermal activity +C3d, - IgG (classically) Both C3d and IgG in ~20% Titer and thermal activity >512 is clinically significant, but hemolysis can occur in lower titers

CAD, hemolysis Once IgM binds to RBC, complement activation occurs C3b binds to cell surface in periphery RBC travels to body coreIgM dissociates Can lead to extravascular or intravascular hemolysis Can be polyclonal or monoclonal Polyclonal – postinfectious (Mycoplasma, EBV, legionella) Monoclonal – underlying lymphoproliferative d/o (clonal light chain predominance in 90%, trisomies 3, 12 and t(8:22); )

Monoclonal Those that bind to the I/i antigens have heavy chains encoded by V4.34 gene segment 10% of all mature B cells use this gene segmentwhy normal subjects can have low-titers

Treatment Supportive Corticosteroids, cytotoxic agents, purine analogs Rituximab Plasmapheresis

References Swiecicki PL, Hegerova LT, and Gertz MA. Cold Agglutinin Disease. BLOOD, 15 AUGUST 2013 x VOLUME 122, NUMBER 7 Gertz MA. Cold Hemolytic Syndrome. Hematology 2006