Autoimmune hemolytic anemia

Last updated: January 28, 2022

Summarytoggle arrow icon

Autoimmune hemolytic anemias (AIHAs) are a collection of disorders characterized by the destruction of RBCs through antibody-mediated hemolysis (extravascular and/or intravascular). There are two broad types, categorized by the temperature at which the antigen-antibody reactions maximally occur: cold agglutinin hemolytic anemia (cold AIHA) and warm agglutinin hemolytic anemia (warm AIHA). AIHAs can be either idiopathic or secondary to another disease e.g., infectious, lymphoproliferative, or autoimmune diseases. Cold AIHA and warm AIHA share some characteristics, e.g., they can both present with clinical signs of anemia and laboratory signs of hemolysis, and produce symptomatic anemia severe enough to require blood transfusion. However, their pathophysiology, etiology, epidemiology, clinical and diagnostic features, and targeted treatments all have key differences. Careful clinical and diagnostic evaluation (including direct Coombs testing, antibody titers, and peripheral blood smear) can help distinguish between the types, however, occasionally patients may have a mixed-type AIHA or unusual clinical presentations and laboratory findings. Management depends on the clinical presentation, etiology, and subtype, and is typically performed in consultation with a hematologist. Treatments include stabilization with blood transfusion and temporizing measures (e.g., plasmapheresis, plasma exchange), systemic immunomodulators (e.g., glucocorticoids, rituximab), treatment of underlying conditions, supportive care, and in warm AIHA, splenectomy.

Typical distinguishing features of autoimmune hemolytic anemias [1][2]
Clinical features


Acute therapy
Long-term management

Typical biochemical findings in hemolysis include haptoglobin, LDH concentration, indirect bilirubin concentration, peripheral blood smear abnormalities (e.g., reticulocytes, schistocytes, spherocytes, polychromasia), and urinalysis abnormalities (e.g., hemoglobinuria, hemosiderinuria, and urobilinogen).

Background [3][4][5]

Pathophysiology [4]

Etiology [4]

Cold weather is MMMMiserable: Cold (IgM) AIHA is seen in Malignancy (CLL), Mycoplasma pneumonia, and Mononucleosis.

Clinical features

Diagnostics [4][6][9]

Spherocytes may be seen in both cold AIHA and warm AIHA. However, abundant spherocytosis is characteristic of warm AIHA.

Management [5][9][10]


The goal is to reduce cold-induced symptoms, control hemolysis, and improve anemia. Hematology consult is advised.

  • Compensated hemolysis and mild or absent circulatory symptoms : close surveillance
  • Significant clinical manifestations: Start acute therapy.
  • CAD: Consider chronic therapy (systemic immunomodulatory).
  • CAS: Treat the underlying condition
  • Advise all patients to avoid exposure to the cold.
  • Consider folic acid supplementation in all patients.
  • Manage disease complications: Venous thromboembolism (VTE) [11]

Spontaneous remission is rare in CAD but is common in CAS secondary to infection (e.g., Mycoplasma) and typically occurs within a few weeks of onset. [4][6]

Acute therapy

Long-term therapy

Splenectomy is not recommended for cold AIHA. It is not effective as most extravascular hemolysis occurs in the liver.

Background [5][7][12][13]

Pathophysiology [15]

Warm weather is Great”: Warm AIHA is IgG mediated.


Clinical features

Diagnostics [10]

Consider warm AIHA in patients with severe anemia for whom the blood bank is unable to find crossmatch-compatible blood units.

Management [5][10][14]


The goal is to control hemolysis and improve anemia. Early specialist consultation is advised (e.g., hematology, intensive care).

  • Manage severe disease acutely.
  • Address potential secondary causes (see “Etiology”). [17]
    • Hold any potentially causative medications.
    • Identify and manage underlying conditions.
  • Consider the need for chronic systemic immunomodulators.
  • Observation without immunosuppressive interventions may be appropriate for patients with mild asymptomatic anemia.
  • Manage disease complications: e.g., VTE
  • Monitor for relapses and consider repeated therapeutic intervention.

Acute therapy

Do not delay a potentially life-saving blood transfusion in unstable patients with severe anemia, even if crossmatched blood is unavailable. Use type-specific uncrossmatched blood in close consultation with the blood bank. [14]

Long-term therapy

References: [5][7][12][13]

  1. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013; 122 (7): p.1114-1121. doi: 10.1182/blood-2013-02-474437 . | Open in Read by QxMD
  2. Berentsen S. New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia. Frontiers in Immunology. 2020; 11 . doi: 10.3389/fimmu.2020.00590 . | Open in Read by QxMD
  3. Hill A, Hill QA. Autoimmune hemolytic anemia. Hematology. 2018; 2018 (1): p.382-389. doi: 10.1182/asheducation-2018.1.382 . | Open in Read by QxMD
  4. Berentsen S, Röth A, Randen U, Jilma B, Tjønnfjord GE. Cold agglutinin disease: current challenges and future prospects. J. Blood Med. 2019; Volume 10 : p.93-103. doi: 10.2147/jbm.s177621 . | Open in Read by QxMD
  5. Barcellini W, Fattizzo B. The Changing Landscape of Autoimmune Hemolytic Anemia. Frontiers in Immunology. 2020; 11 . doi: 10.3389/fimmu.2020.00946 . | Open in Read by QxMD
  6. Packman CH. The Clinical Pictures of Autoimmune Hemolytic Anemia. Transfusion Medicine and Hemotherapy. 2015; 42 (5): p.317-324. doi: 10.1159/000440656 . | Open in Read by QxMD
  7. Hansen DL, Möller S, Andersen K, Gaist D, Frederiksen H. Increasing Incidence and Prevalence of Acquired Hemolytic Anemias in Denmark, 1980–2016. Clinical Epidemiology. 2020; Volume 12 : p.497-508. doi: 10.2147/clep.s250250 . | Open in Read by QxMD
  8. Sigbjørn Berentsen. How I manage patients with cold agglutinin disease. Br J Haematol. 2018; 181 (3): p.320-330. doi: 10.1111/bjh.15109 . | Open in Read by QxMD
  9. Hill QA, Stamps R, Massey E, et al. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol. 2016; 176 (3): p.395-411. doi: 10.1111/bjh.14478 . | Open in Read by QxMD
  10. Sonikpreet Sonikpreet, Gulshan Oberoi and Sarwan Kumar. Case Report: Autoimmune Hemolytic Anemia with Venous Thromboembolism, a Common Complication of a Rare Disease. Blood. 2014 .
  11. Charles H. Packman. The Clinical Pictures of Autoimmune Hemolytic Anemia. Transfusion Medicine and Hemotherapy. 2015 .
  12. Autoimmune hemolytic anemia, warm agglutinin disease, cold agglutinin disease. . Accessed: May 17, 2019.
  13. Brodsky RA. Warm Autoimmune Hemolytic Anemia. N Engl J Med. 2019; 381 (7): p.647-654. doi: 10.1056/nejmcp1900554 . | Open in Read by QxMD
  14. Kalfa TA. Warm antibody autoimmune hemolytic anemia. Hematology. 2016; 2016 (1): p.690-697. doi: 10.1182/asheducation-2016.1.690 . | Open in Read by QxMD
  15. Schrier SL, Brugnara C. Pathogenesis of autoimmune hemolytic anemia: Warm agglutinins and drugs. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. updated: September 19, 2018. Accessed: February 7, 2019.
  16. Hill QA, Stamps R, Massey E, et al. Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia. Br J Haematol. 2017; 177 (2): p.208-220. doi: 10.1111/bjh.14654 . | Open in Read by QxMD
  17. Red Blood Cell Transfusion: a pocket guide for the clinician.
  18. Flores G, Cunningham-Rundles C, Newland AC, Bussel JB. Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: Results in 73 patients. Am J Hematol. 1993; 44 (4): p.237-242. doi: 10.1002/ajh.2830440404 . | Open in Read by QxMD
  19. Go RS, Winters JL, Kay NE. How I treat autoimmune hemolytic anemia. Blood. 2017; 129 (22): p.2971-2979. doi: 10.1182/blood-2016-11-693689 . | Open in Read by QxMD

3 free articles remaining

You have 3 free member-only articles left this month. Sign up and get unlimited access.
 Evidence-based content, created and peer-reviewed by physicians. Read the disclaimer