Autoimmune Hemolytic Anemia

Descriptive text is not available for this imageBASICS

DESCRIPTION

  • Autoimmune hemolytic anemia (AIHA) is characterized by shortened red blood cell (RBC) survival caused by autoantibodies directed against cell surface antigens. In some cases, this process can involve participation of the complement system on the red cell membrane.
  • Natural history:
    • Acute disease
      • Rapid fall in hemoglobin with onset of symptoms over hours to days
      • Often complete resolution of disease within 3 to 6 months
      • Complete resolution more likely in children who present between 2 and 12 years of age
    • Chronic disease
      • May progress from acute disease, with persistence of hemolysis or intermittent relapses
      • More likely to be associated with underlying systemic illness in adolescents and children <2 years of age

EPIDEMIOLOGY

  • Less common in children than in adults
  • Incidence is 0.8 to 1.25 in 100,000 children per year.
  • Approximately half of cases in adolescents are associated with underlying systemic illness.

ETIOLOGY

  • Idiopathic (primary):
    • 40–50% of pediatric cases
    • Most cases are warm-reactive.
  • Secondary to an underlying disorder:
    • >50% of pediatric cases
    • Most cases are warm-reactive, except in the case of infections.
    • Infection
      • Viral (e.g., Epstein-Barr virus, hepatitis, HIV, SARS-CoV-2)
      • Bacterial (e.g., Mycoplasma, Streptococcus, Escherichia coli septicemia)
      • Typically, cold agglutinin disease or paroxysmal cold hemoglobinuria (PCH)
    • Drugs: antimalarials, antipyretics, penicillin, cephalosporins, erythromycin
    • Autoimmune disorders: systemic lupus erythematosus, Sjögren syndrome, juvenile rheumatoid arthritis, dermatomyositis, ulcerative colitis, type 1 diabetes mellitus, autoimmune lymphoproliferative syndrome (ALPS)
    • Immunodeficiencies: Wiskott-Aldrich syndrome, common variable immunodeficiency, 22q11.2 deletion syndrome
    • Malignancy:
      • Acute leukemia, Hodgkin lymphoma, myelodysplasia
      • Following hematopoietic stem cell transplant, due to alloimmunity and immunosuppression
      • Solid tumors: ovarian, carcinoma, thymoma, dermoid cyst
    • Following solid organ transplants: ABO incompatibility between donor and recipient

PATHOPHYSIOLOGY

  • Warm-reactive (~60–90% cases)
    • Preferential binding of in vitro antibody to RBC at 37°C
    • Usually immunoglobulin G (IgG)-mediated
    • IgG coated RBCs lead to extravascular hemolysis by macrophages, predominantly in the spleen.
  • Cold agglutinin disease (~10% of cases)
    • Immunoglobulin M (IgM) autoantibodies bind I/i antigens on RBC.
    • Binding preferentially occurs at temperatures between 0°C and 30°C.
    • Most commonly occurring after Mycoplasma pneumoniae or Epstein-Barr virus infection
    • Hemolysis is complement-mediated and occurs intravascularly.
  • PCH
    • IgG binds P antigen on RBCs, preferentially at colder temperatures.
    • Irreversible binding of complement, leading to intravascular hemolysis
    • Most frequently occurs in children, commonly after viral-like illness

Descriptive text is not available for this imageDIAGNOSIS

HISTORY

  • Symptoms of anemia: headache, dizziness, weakness, fatigue, anxiety, syncope, exercise intolerance
  • Signs of hemolysis: pallor, jaundice, painless dark urine (hemoglobinuria)
  • Symptoms of cold agglutinin disease: acrocyanosis on exposure to cold ambient temperatures that disappears upon warming
  • Nonspecific symptoms: abdominal pain, fever
    • Hemoglobinuria is suggestive of intravascular hemolysis, which is more typical of cold agglutinin disease or PCH.
  • History is important in helping to distinguish the presence of hemolysis rather than other causes of anemia (e.g., blood loss, hypoproduction).
  • Chief complaints can also help determine acuity and severity of anemia and/or hemolysis.
    • History of rapid deterioration of a child’s physical and/or mental state indicates an acute process.
    • Gradual onset of symptoms suggests that the child is compensated from a cardiovascular standpoint.
  • History of previous similar episodes or family history of immune disorders can be indicative of chronic or secondary AIHA.
  • Early age of onset of hemolytic symptoms may suggest a hereditary hemolytic disorder rather than autoimmunity as the cause.

PHYSICAL EXAM

  • Finding: Vital sign changes?
    • Tachycardia (common), hypotension (late), cardiac murmur
    • In chronic cases, these vital signs may have been compensated for and may not be as obvious.
  • Finding: Skin changes (pallor, jaundice, icterus)?
    • Pallor is nearly a universal finding in acute hemolysis. It can typically be identified in lips and eyelids if not obvious with skin.
    • Jaundice is more common in intravascular hemolysis.
    • Presence of ecchymoses or petechiae suggests concurrent thrombocytopenia (concerning for disseminated intravascular coagulation [DIC], thrombotic thrombocytopenic purpura [TTP]/hemolytic uremic syndrome (HUS), Evans syndrome).
  • Finding: Organomegaly (spleen, liver)?
    • Splenomegaly is the most common finding.
    • Hepatomegaly may be more pronounced if the child is in heart failure due to acute, severe anemia.
    • Significant lymphadenopathy should prompt a workup for an underlying cause such as lymphoproliferative disorders or malignancy.

DIFFERENTIAL DIAGNOSIS

  • Nonimmune causes of hemolytic anemia (hemolysis with negative direct antiglobulin test)
    • Defects intrinsic to RBC:
      • Membrane defects (e.g., hereditary spherocytosis, elliptocytosis)
      • Enzyme defects (e.g., glucose-6-phosphatase deficiency, pyruvate kinase deficiency)
      • Hemoglobin defects (e.g., sickle cell disease, thalassemia)
    • Defects extrinsic to RBC:
      • Hypersplenism
      • Microangiopathies
        • TTP/HUS
        • DIC
      • Mechanical damage (e.g., artificial heart valves, Kasabach-Merritt phenomena)
      • Paroxysmal nocturnal hemoglobinuria
      • Hemolytic transfusion reaction, blood group incompatibility, hemolytic disease of the newborn
  • Nonhematologic causes of jaundice:
    • Liver disease (e.g., Gilbert syndrome)
  • Nonhematologic causes of painless dark urine:
    • March hemoglobinuria
    • Myoglobinuria
    • Dehydration

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (screening, lab, imaging)

  • Complete blood count
    • Anemia, often severe (e.g., hemoglobin <7 g/dL)
    • Other cell lines usually normal
      • If low, consider Evans syndrome or ALPS.
      • If globally abnormal, should consider bone marrow failure syndromes and/or malignancies
    • Mean corpuscular volume may be normal or increased due to RBC agglutination.
    • Mean corpuscular hemoglobin concentration may be increased from spherocytosis.
  • Reticulocyte count
    • Useful to determine whether bone marrow is responding appropriately to anemia
    • Can help determine hemolytic anemia versus another etiology (e.g., RBC hypoproduction)
      • Typically elevated in hemolytic anemia, although can be decreased in severe cases if reticulocyte bears target antigen
  • Peripheral blood smear
    • Spherocytes predominate in warm AIHA.
    • Polychromasia reflects increased circulating reticulocytes.
    • Howell-Jolly bodies can be present with accelerated erythropoiesis.
    • Agglutination of RBCs suggests cold reactive AIHA.
  • Direct antiglobulin test (DAT; Coombs test)
    • Single most important test: positive in ~95% of cases
    • Detects antibodies or complement fragments present on the patient’s RBCs
    • Indirect antiglobulin test detects antibodies in the patient’s serum that can bind normal RBCs.
    • Strength of antibody correlates with severity of hemolysis.
    • Warm AIHA will be anti-IgG ± anti-C3 positive.
    • In severe, rapid hemolysis, Coombs test can be negative, as most coated cells have already been cleared from circulation; if clinical suspicion remains high, can use radiolabeled Coombs test of enzyme immunoassays for more sensitive diagnosis
    • Cold AIHA and paroxysmal cold hemoglobinuria will be anti-C3 positive and anti-IgG negative.
      • In this case, serum should be tested for IgG Donath-Landsteiner autoantibodies.
  • Antigen specificity
    • Patients require extended typing to find compatible blood if the need for transfusion arises.
    • Pan-reactive antibodies lead to difficulty finding fully compatible blood, and alloantibodies can lead to major transfusion reactions. Knowledge of antigen specificity can predict intravascular lysis caused by complement activation on initiation of blood transfusion.
  • Serum markers of hemolysis
    • Indirect hyperbilirubinemia due to accelerated RBC destruction
    • Elevated lactate dehydrogenase
    • Haptoglobin level decreased (bound by free plasma hemoglobin)
  • Blood urea nitrogen (BUN) and/or creatinine: Hemolysis can lead to renal insufficiency.
  • Urinalysis
    • Hemoglobinuria is present in intravascular hemolysis; established by a urine dipstick positive for heme with no intact red cells microscopically
    • Myoglobinuria can also give this picture.
  • Bone marrow aspiration when there is concern for malignancy or bone marrow failure

Descriptive text is not available for this imageTREATMENT

  • Cold agglutinin disease and PCH typically have self-limited courses that do not require pharmacologic interventions.
    • Mainstays of treatment are to keep the patient warm, avoid exposure to cold fluids, and treat the underlying cause (if applicable).
    • In cases of severe, symptomatic anemia, treatment with immunosuppression may be indicated (see “2nd-line therapies” below).
    • RBC transfusion is reserved for life-threatening anemia with cardiovascular compromise (see “Additional Therapies”).
  • Warm-reactive AIHA
    • 1st-line therapy is corticosteroids.
      • Shown to interfere with macrophage Fc and C3b receptors responsible for RBC destruction
      • Can induce remission in 70–80% of warm-reactive AIHA cases
      • Typically not effective in cold agglutinin disease
      • Dose: methylprednisolone IV 0.5 to 1 mg/kg/dose every 6 to 8 hours for severe anemia, prednisone PO 2 mg/kg/24 h for mild to moderate anemia
      • Tapering of corticosteroids should begin after a therapeutic response is achieved (based on normalization of hemoglobin and markers of hemolysis). Taper may take several weeks or even months. Taper to the lowest necessary dose to maintain normal hemoglobin level with tolerable side effects. Relapse is common if taper is done too quickly. If relapse occurs, restart on lowest dose that was previously effective.
      • Common adverse effects include weight gain, increased appetite, mood changes, and hypertension—all of which are reversible on discontinuation of steroids.
    • 2nd-line therapies: rituximab (anti-CD20): targets and depletes B cells
      • 1st-line for refractory warm-reactive AIH; may be used in conjunction with steroids; response rate is 40–100%.
      • Dose: 375 mg/m2 weekly for 2 to 4 weeks.
      • Must check immunoglobulins prior to giving, as could be harmful if underlying immunodeficiency is present
      • Adverse effects: infusion associated fever, chills, rigors, hypertension, bronchospasm; rare risk of viral infections, hypogammaglobulinemia
    • 3rd-line therapies:
      • Immunosuppressive agents (e.g., mycophenolate mofetil, sirolimus); indicated when there is a clinically unacceptable degree of hemolysis that is refractory to 1st- and 2nd-line agents; may be used in conjunction with corticosteroids; some have been effective in cold agglutinin disease; dose: adjusted to maintain white blood cell (WBC) >2,000, absolute neutrophil count (ANC) >1,000, and platelet count 50,000 to 100,000/mcL
      • IV immunoglobulin (IVIg) may be useful in selected cases of immune hemolytic anemia unresponsive to steroids. Effect is usually temporary, and retreatment may be required every 3 to 4 weeks; complications: aseptic meningitis, theoretic risk of transfusion-transmitted viral infection, and large doses of IVIg have been associated with hemolytic anemia; dose: 1 g/kg/24 h for up to 5 days
      • Plasmapheresis/exchange transfusion may slow the rate of hemolysis in severe disease, especially if IgM-mediated; indicated if TTP cannot be excluded; effect is usually short term.
      • Alemtuzumab (anti-CD52) may be effective in refractory AIHA, particularly in cases that are secondary to B-cell chronic lymphocytic leukemia (B-CLL).

ADDITIONAL THERAPIES

Blood transfusion:

  • Indicated only in cases with evidence of physiologic compromise from severe anemia and brisk hemolysis
  • The blood bank may be unable to find compatible blood. In IgG-mediated disease, autoantibody is usually pan-reactive; therefore, you must use the “least incompatible” unit of blood.
  • In cold agglutinin disease, blood should be warmed prior to infusion to decrease IgM binding.
  • Close monitoring for acute hemolysis during transfusion is imperative.

SURGERY/OTHER PROCEDURES

Splenectomy

  • Removes main sites of both autoantibody production and RBC destruction
  • Indicated for patients who are unresponsive to medical management, who require high maintenance doses of steroids, or who develop steroid intolerance during treatment
  • Not effective in cold agglutinin disease
  • Adverse effects: surgical risks, lifelong increased risk of infection by encapsulated bacterial organisms
  • Response rate is 50–70%, with many partial remissions.

Descriptive text is not available for this imageONGOING CARE

FOLLOW-UP RECOMMENDATIONS

  • During initial presentation and treatment:
    • Hemoglobin level every 4 to 12 hours (depending on severity) until stable
    • Reticulocyte count: daily
    • Evaluation of spleen size: daily
    • Hemoglobinuria: daily
    • Coombs test: weekly
    • Markers of hemolysis (e.g., lactate dehydrogenase [LDH], bilirubin) can be trended throughout treatment.
  • Once remission has been reached, patients should still be monitored for at least 1 year, as risk of relapse is greatest during this time.
    • Hemoglobin level, reticulocyte count, Coombs test, LDH, bilirubin at least monthly for the 1st year
    • Spleen size should be checked at each visit.
    • DAT may remain weakly positive despite the evidence of hemolysis resolving. If strong positivity persists, it should prompt an autoimmune workup, particularly in adolescents.

COMPLICATIONS

  • May be an increased risk of venous thrombosis in patients with AIHA
  • May be associated with a predisposition to lymphoproliferative disorders
  • Chronic hemolysis can lead to episodes of cholelithiasis and cholecystitis.

CODES

ICD 10

  • D59.1 Other autoimmune hemolytic anemias
  • D59.0 Drug-induced autoimmune hemolytic anemia

FAQ

  • Q: Is this condition contagious?
  • A: No. Another child may acquire the same viral illness; however, the body’s response to produce an autoantibody is dependent on the individual patient.
  • Q: Will this happen again?
  • A: Unfortunately, it is hard to define with certainty which patients will have complete resolution of disease and which will relapse. The risk of relapse is highest in the 1st year of presentation.

Authors

Manpreet Kochhar, MD, MS


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