Snapshot A 60-year-old man presents to his primary care physician with complaints of fatigue. His family is concerned that he looks very orange. He sometimes experiences shortness of breath with physical exertion. A peripheral smear comes back with some spherocytes as well as some smudge cells. His direct Coombs test comes back positive with anti-C3 and anti-IgG. Introduction Extrinsic hemolytic anemia caused by antibodies type II hypersensitivity Epidemiology peak incidence in 50s-80s Associated conditions thrombocytopenia (combination of AIHA and thrombocytopenia = Evans syndrome) other autoimmune diseases Characteristics Warm Agglutinin (IgG) Cold Aglutinin (IgM) Temperature at which antibodies are most reactive to RBC Body temperature Lower temperatures (39.2°F) Chronic vs acute Chronic Acute Complement-mediated Associated conditions SLE (most common) CLL Drugs (α-methyldopa and penicillin) Mycoplasma pneumonia Infectious mononucleosis (EBV) Epidemiology AIHA (most common) More common in women Mneumonic Warm weather is GGGreat Cold weather is for ice cream, yuMMM Presentation Symptoms warm agglutinin disease chronic hemolytic anemia cold agglutinin disease acrocyanosis (different from Raynaud's) painful and blue toes/fingers in the cold “colder” parts of the body numbness mottling symptoms resolve upon warming that part of the body acute hemolytic anemia Physical exam splenomegaly jaundice livedo reticularis Evaluation Two types of Coombs test direct (direct antiglobulin test, DAT) anti-IgG (Coombs reagent) added directly to patient's RBCs if RBCs coated with Ig (like in warm agglutinin disease), RBCs agglutinate RBC agglutination = + DAT can also use anti-C3 Coombs reagent indirect normal RBCs added to patient sample anti-IgG (Coombs reagent) is added to mixture if mixture has RBCs coated with Ig, RBCs agglutinate RBC agglutination = + indirect Coombs direct and indirect tells us the same thing, but indirect will tell us that there's more antibodies Characteristics Warm Agglutinin (IgG) Cold Aglutinin (IgM) Direct Coombs test + Direct Coombs test with anti-IgG Coombs reagent + Direct Coombs test (DAT) with anti-C3 Coombs reagent Indirect Coombs test + Indirect Coombs test (tests for IgG autoantibodies) - Indirect Coombs test Other tests RBCs spontaneously agglutinate at room temperature Most accurate test Cold agglutinin titer Complement level Normal C3 and C4 ↓ C3 and C4 Peripheral blood smear spherocytes (also seen in hereditary spherocytosis) no fragments RBC are destroyed in spleen or liver, not the vessels Serology showing hemolytic anemia ↑ LDH ↑ indirect bilirubin ↑ reticulocyte count ↓ haptoglobin Urinalysis hemoglobinuria hemosiderinuria Differential Cryoglobulinemia Lymphoma Raynaud's syndrome HIT Hereditary spherocytosis Treatment Warm agglutinin from best initial therapy to further steps in treatment ladder glucocorticoids IVIG splenectomy immunomodulators rituximab azathioprine cyclosporine Cold agglutinin keep extremities warm supportive therapy with folate rituximab plasmapheresis for those refractory to rituximab other immunosuppressants cyclosporine cyclophosphamide Prognosis, Prevention, and Complications Prognosis mortality rate 10% for most patients, prognosis is good Prevention for cold agglutinin disease keep warm Complications warm agglutinin lymphoproliferative disease venous thromboembolism cold agglutinin peripheral gangrene lymphoma