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cold agglutinin syndrome (primary cold agglutinin disease)

Etiology: 1) autoimmune (IgM) 2) other disorders with IgM kappa monoclonal gammopathy a) chronic lymphocytic leukemia b) multiple myeloma c) B-cell non-Hodgkin's lymphoma d) Waldenstrom's macroglobulinemia e) IgM MGUS 3) disorders with anti-I specificity - Mycoplasma pneumoniae 4) disorders with anti-i specificity a) infectious mononucleosis b) cytomegalovirus infection c) lymphoma Epidemiology: 1) 15% of patients with autoimmune hemolytic anemia 2) peak incidence of onset: 51-60 years of age Pathology: 1) IgM autoantibody binds blood group I/i antigens 2) agglutination 3) small vessel occlusion 4) hemolytic anemia with extravascular hemolysis via complement fixation [2] 5) degree of hemolysis depends upon: a) thermal amplitude b) titer c) the higher the titer, the more likely to bind complement Clinical manifestations: 1) acrocyanosis of the ears, tip of nose, toes & fingers - all digits may be equally affected - skin color is dusky blue, then turns normal or blanches - NEJM Knowledge+ presents case with normal skin [7] 2) jaundice [2] 3) hepatomegaly &/or splenomegaly uncommon 4) symptoms of anemia: dyspnea, fatigue Laboratory: 1) cold agglutinin titer > 1:1000 2) direct antiglobulin test a) erythrocyte antibody is IgM b) complement C3d antibody in/on erythrocytes is positive c) optimal temperature for erythrocyte antibody binding is < 37 C [2] 3) complete blood count (CBC) a) mild to moderate normocytic anemia b) MCV may be spuriously elevated by agglutination - MCV may be > 130 fL [2] 4) peripheral blood smear a) agglutination (erythrocyte clumping rather than stacking <rouleaux>) b) agglutination disappears if smear is prepared at 37 C 5) reticulocyte count: reticulocytosis [2] 6) can lower hemoglobin A1c [6] 7) serum chemistries - serum lactate dehydrogenase is increased - bilirubin total in serum is increased - serum haptoglobin is decreased 8) protein electrophoresis with immunofixation - IgM kappa monoclonal gammopathy may be present 9) urinalysis - urine color: dark 10) see ARUP consult [3] Differential diagnosis: - Raynaud's phenomenon Management: 1) avoidance of cold temperatures 2) warming of infusion 2) primary cold agglutinin disease a) rituximab is treatment of choice [2] b) glucocorticoids less effective than in warm autoimmune hemolytic anemia c) splenectomy is generally ineffective d) some patients may respond to immunosuppressive agents - cyclophosphamide - chlorambucil - azathioprine - cyclosporin e) danazol f) IV immune globulin [2] g) plasmapheresis 1] not very effective 2] consider if patient is acutely ill because IgM is intravascular h) prognosis: chronic disorder 3) specific therapies for specific disorders

Related

cold agglutinin

General

cold antibody autoimmune hemolytic anemia syndrome

References

  1. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 415-16
  2. Medical Knowledge Self Assessment Program (MKSAP) 14, 16, 17, 18. 19. American College of Physicians, Philadelphia 2006, 2013, 2015, 2018, 2022.
  3. ARUP Consult: Cold Agglutinin Disease The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/cold-agglutinin-disease
  4. Berentsen S, Tjonnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012 May;26(3):107-15 PMID: 22330255
  5. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013 Aug 15;122(7):1114-21 PMID: 23757733
  6. Pant V HbA1c Below the Reportable Range. Lab Med. 2022;53(2):e44-e47. PMID: 34611711 https://www.medscape.com/viewarticle/970349
  7. NEJM Knowledge+ - Berentsen S. How I treat cold agglutinin disease. Blood. 2021 Mar 11;137(10):1295-1303. PMID: 33512410 Free article. Review.