Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is a rare type of hemolytic anemia characterized by antibody production against self RBCs, leading to destruction of these cells in the spleen and other reticuloendothelial tissues. The disease is generally categorized as warm or cold, depending on the thermal reactivity of the autoantibodies. The etiology is diverse and includes infections, autoimmune diseases, lymphoproliferative disorders, and drugs. The diagnosis is based on laboratory evidence of hemolysis (elevated LDH, indirect bilirubin, reduced haptoglobin) in association with a positive direct antiglobulin test (DAT) or Coombs test. Management involves supportive care, removal of the inciting agent, use of steroids and immunosuppressive agents, and splenectomy in refractory cases.

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Overview

Definition

Autoimmune hemolytic anemia (AIHA) is hemolysis or premature destruction of RBCs due to autoantibodies. There are 2 categories of AIHA based on the thermal reactivity of autoantibodies:

  • Warm AIHA
  • Cold AIHA

Epidemiology

  • 1–3 cases per 100,000 population per year
  • Slightly more likely to occur in females than in males
  • Secondary cause present in 20%–80% of reported cases
  • Warm AIHA:
    • 70%–80% of AIHAs
    •  Seen in children 0–4 years old and in adults > 40 years old
  • Cold AIHA: peak incidence in adults > 60 years old

Etiology

Warm AIHA:

  • Idiopathic/primary: no underlying condition or medication 
  • Secondary: associated with an underlying condition (50%–60% of cases)
    • Lymphoproliferative disorders 
    • Autoimmune disorders 
    • Malignancy
    • Immunodeficiency
    • Infections
    • Pregnancy
    • Drugs 
    • Allogeneic hematopoietic stem cell transplantation (HSCT): usually 2–6 months after engraftment

Cold AIHA:

  • Idiopathic/primary (cold agglutinin disease)
  • Cold agglutinin syndrome:
    • Lymphoproliferative disorders
    • Infections
    • Autoimmune disease
    • Malignancy 
  • Paroxysmal cold hemoglobinuria (PCH) (seen almost exclusively in children):
    • Idiopathic
    • Secondary (can be acute transient or chronic)

Mixed-type AIHA:

  • Idiopathic
  • Secondary (lymphoproliferative disorders, autoimmune disorders)

Specific causes of AIHAs

Table: Specific causes of warm AIHA (antibody type mostly IgG)
TypeSpecific cause
PrimaryIdiopathic
SecondaryViral infectionHIV
Other disease/condition
  • Malignancy
  • Lymphoproliferative disorders (e.g., CLL)
  • Autoimmune disorders (e.g., systemic lupus erythematosus)
  • HSCT
  • Pregnancy
Drugs
  • Penicillin
  • Ceftriaxone
  • Methyldopa
Table: Specific causes of cold AIHA (antibody type mostly IgM)
TypeSpecific cause
PrimaryPrimary cold agglutinin disease (CAD)
SecondaryViral infection
  • EBV
  • CMV
  • PCH commonly presents after viral infection in children.
Bacterial infection
  • Mycoplasma pneumoniae
  • PCH also associated with Klebsiella, Escherichia coli, and syphilis (congenital and tertiary)
Other conditions
  • Lymphoproliferative disorders
  • Malignancy
  • Autoimmune disorders
DrugLenalidomide (rare)

Pathophysiology

Warm AIHA

  • Warm autoantibodies are responsible for the majority of AIHA cases.
  • Antibodies (predominantly IgG) interact with Rhesus factor (Rh) complex antigens or glycoprotein antigens.
  • Warm autoantibodies react more strongly at 37°C.
  • Pathogenesis:
    • In most cases, hemolysis (facilitated by phagocytic cells) occurs extravascularly.
    • RBC destruction occurs where macrophages are abundant, mostly in the spleen (also in liver and bone marrow):
      • Fc portion (antibody) is recognized by Fc receptor of phagocytes → phagocytosis of heavy chain of IgG and part of the cell membrane → spherocyte formed
      • Cytotoxic T cells in the spleen → cell-mediated cytotoxicity → RBC hemolysis
      • Liver macrophages recognize complement C3 fragments → RBCs with complements are phagocytosed.
  • Over 95% of warm AIHA cases have a positive direct antiglobulin test (DAT) or Coombs test.
Drug-induced hemolytic anemia

Drug-induced autoimmune hemolytic anemia (AIHA):
Drugs can cause AIHA by:
Top: Binding to specific proteins of a drug that remain on the surface of RBCs and are recognized as new antigens by IgG (penicillin)
Middle: Complement activation induced by immune complexes formed by a drug (quinidine)
Bottom: Alteration of the Rhesus factor (Rh) molecule or a cell membrane component by a drug, thus making it immunogenic for IgG even after the drug is discontinued (methyldopa)

Image by Lecturio.

Cold AIHA

Cold-sensitive autoantibodies react more strongly at 0–4℃.

  • Cold agglutinins:
    • Antibodies (predominantly IgM) interact with RBC I antigen or i antigen below normal core temperature:
      • I antigen: present in 99% of the population
      • i antigen: noted in < 1% 
    • After binding RBCs, IgM autoantibodies activate the classic complement cascade (C1 → C3b).
    • RBCs coated with C3b undergo phagocytosis extravascularly (in the reticuloendothelial system, mostly by Kupffer cells in the liver)
    • Results in extravascular hemolysis
    • Upon warming, IgM dissociates, but C3b remains and is, thus, detected on DAT.
  • Donath-Landsteiner antibodies: 
    • Recognize RBC antigens (often the P antigen) in cold temperature and fix complement, leading to hemolysis 
    • Intravascular hemolysis → hemoglobinuria and anemia
    • Found in PCH

Clinical Presentation

  • Anemia:
    • Shortness of breath
    • Tachycardia
    • Fatigue
    • Pallor
    • Palpitations
  • Extravascular hemolysis:
    • Jaundice 
    • Gallstones
    • Splenomegaly
    • Hepatomegaly
    • Lymphadenopathy 
  • Intravascular hemolysis:
    • Dark urine (hemoglobinuria)
    • Transient renal failure

Cold AIHA:

  • Acrocyanosis:
    • Dark gray or purple discoloration of toes, fingers, ears, or nose on exposure to cold 
    • Can result in gangrene in severe cases
  • Raynaud phenomenon
  • Livedo reticularis: skin with bluish or violaceous reticulated pattern that blanches
Gangrenous change and acrocynosis

Acrocyanosis of the hands:
Acrocyanosis with gangrene (A) and resolution of acrocyanosis (B)

Image: “Gangrenous change and acrocynosis” by Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan. License: CC BY 4.0

Diagnosis

Initial laboratory evaluation

Diagnosis is with evidence of hemolysis and positive DAT.

  • CBC: 
    • Anemia
    • MCV varies with reticulocyte count
    • Usually normal leukocyte and platelet counts
  • Reticulocyte count: usually increased
  • Peripheral blood smear:
    • Polychromasia (due to high reticulocyte counts)
    • Spherocytes
    • Schistocytes
    • Nucleated RBCs
    • RBC clumps
  • DAT:
    • Establishes the diagnosis
    • Identifies the presence of antibodies and/or complement bound on RBCs
    • Strength of positive test correlates with severity of hemolysis.
    • Warm AIHA:
      • Positive at  37°C for anti-IgG 
      • Anti-C3 may or may not be positive. 
    • Cold AIHA: positive for anti-C3 and negative for anti-IgG
  • Serum markers of hemolysis:
    • ↑ Indirect bilirubin
    • ↑ LDH 
    • ↑ AST and ALT  
    • Low serum haptoglobin 
  • C3 and C4 levels reduced in cold AIHA 
  • Cold agglutinin titer: high titer in cold AIHA

Additional evaluation

  • Urinalysis, both dipstick and microscopic:
    • Hemoglobinuria → dipstick positive for blood but absence of RBCs
    • Urinalysis normal in extravascular hemolysis
  • BUN/creatinine: renal impairment in intravascular hemolysis
  • Review possible secondary causes:
    • Underlying conditions 
    • Recent infections (i.e., serologic testing positive for Mycoplasma pneumoniae)
    • Medications
    • Transfusion 
  • Bone marrow aspiration on relevant indications (i.e., to exclude CLL)

Management

Principles of management

  • Stabilization of the patient:
    • Assess severity of anemia and associated symptoms (i.e., dyspnea or those associated with cardiac ischemia).
    • Hemodynamic and ventilatory support as needed
    • Determine need for transfusion (transfuse when necessary).
    • Discontinue suspected offending drug.
  • Treatment of underlying condition, if present, is recommended.
  • Hemolysis will continue for up to 3 weeks (equivalent to the half-life of autoantibodies).

Warm AIHA

  • Folic acid supplementation: Folate deficiency can develop with chronic hemolysis.
  • Glucocorticoids +/– rituximab:
    • May start with both as initial treatment, OR
    • Initiate rituximab if no response with glucocorticoids after 2–3 weeks
  • Intravenous immunoglobulin (IVIG)
  • Refractory disease:
    • Immunosuppressants: mycophenolate, cyclophosphamide, or azathioprine
    • Splenectomy

Cold AIHA

  • Avoid cold.
  • Folic acid supplementation
  • Immunosuppressants: rituximab-containing regimens (i.e., rituximab with bendamustine)
  • Plasmapheresis in cases of severe hemolysis

Complications and prognosis

Warm AIHA:

  •  ↑ Risk of venous thromboembolism:
    • Rule out deep vein thrombosis if D-dimer positive.
    • Rule out pulmonary embolism if dyspnea is disproportionate to anemia.
  • Evans syndrome: 
    • 2 or more immune cytopenias occur concurrently.
    • AIHA can present with immune-mediated thrombocytopenic purpura (ITP).
    • Associated with higher mortality rate
  • Majority of cases respond to therapy in 2–3 weeks.
  • Relapse is possible, and patients should be educated to seek medical care if symptoms recur.

Cold AIHA:

  • Survival similar to that of age-matched populations
  • In viral-associated PCH affecting children, recovery is seen within 2 weeks.
  • Recurrent episodes are more often seen in adults.

Differential Diagnosis

  • Hemolytic anemia: group of anemias that are due to destruction or premature clearance of RBCs. Hemolysis can be either intravascular or extravascular (in the spleen). The etiology of premature erythrocyte destruction is diverse and can be due to conditions such as RBC membrane defects, erythrocyte enzymatic defects, immune destruction of erythrocytes, mechanical injury, and hypersplenism. In non-autoimmune causes of hemolytic anemia, the DAT is characteristically negative.
  • System lupus erythematosus (SLE): chronic, autoimmune, inflammatory condition that causes immune complex deposition in organs, resulting in systemic manifestations. This disease overwhelmingly affects women, particularly those of African American descent. Notable clinical features include a malar rash, nondestructive arthritis, lupus nephritis, serositis, cytopenias, thromboembolic disease, seizures, and/or psychosis. The diagnosis is made by meeting clinical criteria, which includes antinuclear antibodies, SLE-specific antibodies, and specific clinical findings.
  • Chronic lymphocytic leukemia: most common leukemia in adults. Chronic lymphocytic leukemia is a monoclonal B-cell proliferation that infiltrates the bone marrow or lymph nodes. The B cells arrest before maturation, and thus these patients have agammaglobulinemia, resulting in recurrent infections. Chronic lymphocytic leukemia is mainly found incidentally on blood work showing lymphocytosis. Peripheral smears show smudge cells. Chronic lymphocytic leukemia is a leading secondary cause of both warm and cold AIHA and should be considered in cases of AIHA associated with massive splenomegaly or lymphadenopathy.
  • Cryoglobulinemia: disorder due to immunoglobulins (cryoglobulins) that precipitate in cold temperatures (below 37℃). Cryoglobulinemia is associated with arthralgias, glomerulonephritis, purpura, or peripheral neuropathy. Patients can also exhibit cold-induced Raynaud phenomenon. History of infection (usually hepatitis C virus) is associated with cryoglobulinemia. Patients will not have cold agglutinin on laboratory testing, and most do not have AIHA.

References

  1. Brugnara, C., Barcellini,W. (2021). Paroxysmal cold hemoglobinuria. UpToDate. Retrieved April 19, 2021, from https://www.uptodate.com/contents/paroxysmal-cold-hemoglobinuria
  2. Brugnara, C., Brodsky, R.A. (2021). Warm autoimmune hemolytic anemia (AIHA) in adults. UpToDate. Retrieved April 14, 2021, from https://www.uptodate.com/contents/warm-autoimmune-hemolytic-anemia-aiha-in-adults
  3. Luzzatto, L. (2018). Hemolytic anemias. Jameson, J., Fauci A.S., Kasper D.L., Hauser S.L., Longo D.L., Loscalzo J. (Eds.),  Harrison’s Principles of Internal Medicine, 20th ed. New York: McGraw-Hill.
  4. Ware, R.E., Despotovic, J.M. (2021). Autoimmune hemolytic anemia in children: classification, clinical features, and diagnosis. UpToDate. Retrieved April 14, 2021, from https://www.uptodate.com/contents/autoimmune-hemolytic-anemia-in-children-classification-clinical-features-and-diagnosis
  5. Ware, R.E., Despotovic, J.M. (2021). Autoimmune hemolytic anemia in children: Treatment and outcome. UpToDate. Retrieved April 14, 2021, from https://www.uptodate.com/contents/autoimmune-hemolytic-anemia-in-children-treatment-and-outcome
  6. Schick, P.  (2019). Hemolytic anemia. Medscape. Retrieved April 14, 2021, from https://reference.medscape.com/article/201066-overview

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