Snapshot A 57-year-old woman recently moved from Florida to Maine over the summer. She presents in November as a new patient, looking to establish a primary care relationship. She complains that ever since the temperature dropped, she develops painful, numb, blue fingers, and toes. They return back to normal once she warms up indoors. However, this happens every time her fingers and toes are cold. Her nose sometimes turns blue too. On closer questioning, a few weeks ago, she felt fatigued and had a “long cold,” with sore throat and swollen lymph nodes. She shows a photo of her lymph nodes at the time. Introduction Extrinsic hemolytic anemia caused by antibodies type II hypersensitivity Epidemiology peak incidence in 50s-80s Characteristics Warm Agglutinin (IgG) Cold Aglutinin (IgM) Temperature at which antibodies are most reactive to RBC Body temperature Lower temperatures (<37°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 Mnemonic Warm weather isGGGreat Cold weather is for ice cream, yuMMM Presentation Symptoms warm agglutinin disease chronic hemolytic anemia cold agglutinin disease acrocyanosis (different from Raynaud) painful and blue toes/fingers in the cold “colder” parts of the body symptoms resolve upon warming that part of the body acute hemolytic anemia with the cold Physical exam splenomegaly jaundice 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 serum if serum has anti-IgG, RBCs agglutinate when you add anti-IgG 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 results + Direct Coombs test with anti-IgG Coombs reagent + Direct Coombs test (DAT) with anti-C3 Coombs reagent Indirect Coombs test results + Indirect Coombs test (tests for IgG autoantibodies) - Indirect Coombs test (tests for IgG autoantibodies, not performed with IgM antibodies) Other tests RBCs spontaneously agglutinate at room temperature Most accurate test Cold agglutinin titer Complement levels Normal ↓ C3 and C4 Peripheral blood smear spherocytes (also seen in hereditary spherocytosis) Urinalysis hemoglobinuria hemosiderinuria Differential Diagnosis Raynaud's syndrome HIT Hereditary spherocytosis Treatment Warm agglutinin from best initial therapy to further steps in treatment ladder glucocorticoids IVIG splenectomy immunosuppressants Cold agglutinin keep extremities warm supportive therapy with folate rituximab plasmapheresis for those refractory to rituximab 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