Autoimmune Hemolytic Anemias (AIHAs)

These are the most common acquired hemolytic anemia (excluding malaria). They are due to true auto-antibodies against RBC antigens and can be either primary or secondary.

• Warm AIHA: IgG antibodies which react with RBC surface antigens at body temperature, leading to extravascular hemolysis
• Cold AIHA: IgM antibodies which fix complement, resulting in intravascular hemolysis

Clinical Presentation

AIHA is typically abrupt in onset (days) and can lead to severe anemia, jaundice, and splenomegaly. Spherocytes are the characteristic finding on smear.

DAT positivity is typically the defining features of AIHA; DAT-negative AIHA is very rare

Lab Presentation

• normo-/macrocytic anemia, raised reticulocyte count, raised unconjugated bilirubin, reduced haptoglobin, and blood smear with polychromasia or more specific features, such as spherocytes or agglutination
• Although the typical pattern is presented, none of these tests are fully sensitive or specific for hemolysis. For example, liver disease can increase lactate dehydrogenase (LDH) and reduce haptoglobin. The bilirubin may be normal with milder hemolysis, and spherocytes are not always visible.
• Reticulocytopenia can occur in AIHA, secondary to bone marrow infiltration by a lymphoproliferative disorder or to parvovirus B19 infection. However, reticulocytopenia is also observed in a significant minority of patients at presentation (20% in 1 series1 ), despite erythroid hyperplasia in the marrow. This may be caused by immune attack on late-stage erythroid precursors or reflect a lag in marrow responsiveness, but it can sometimes persist and predict a more severe clinical course.2
• A significantly raised LDH, red cell fragments on smear, or the presence of urinary hemosiderin suggests a predominant intravascular component to the hemolytic process. There are fewer causes of intravascular hemolysis; therefore, these can be very useful for subsequent investigations

Approach to Etiology/Classification

Warm AIHA (65%)

• More common, autoantibody reacts best at body core temperature (37 C), and reacts with most RBCs, but usually Rh-specific.
• DAT positive for IgG only or when DAT is positive for C3d ± IgG
• Can be isolated or part of another systemic disorder:
  • Idiopathic
  • SLE
  • CLL
  • Post-BMT
  • Post-organ transplant with immunosuppression
  • Post-immune checkpoint inhibitor

Cold Agglutinin Disease

Chronic condition in contrast to the acute onset of warm antibody AIHA. Caused by an underlying lymphoproliferative bone marrow disorder. Hemolysis is caused by IgM antibodies that are most active in vitro at low temperatures. In vivo, these antibodies bind red cells in the cooler peripheral circulation, causing agglutination that leads to acrocyanosis or Raynaud’s disease in some patients. Clinically significant cold agglutinin can be excluded if saline-suspended normal red cells are not agglutinated by the patient’s serum after incubation at room temperature for 30 to 60 minutes. CAD can be diagnosed in patients with AIHA and a DAT positive for C3d ± IgG, with a consistent clinical picture and a high-titer cold reactive antibody (titer ≥ 1:64 at 4°C).

Mixed AIHA

Mixed AIHA is caused by a combination of a warm IgG antibody and a cold IgM antibody. The DAT is usually positive for IgG and C3d. Cold-associated symptoms rarely appear, and the cold antibody may have a low antibody titer (eg, <1:64) but with a thermal amplitude up to 30 to 37°C. It can be diagnosed with a DAT positive for IgG and C3d, a cold antibody with a thermal amplitude ≥ 30°C, and an appropriate clinical picture.

Paroxysmal Cold Hemoglobinuria

Paroxysmal cold hemoglobinuria (PCH) usually occurs in children. The hemolysis can be severe and intravascular but is typically transient following infection. PCH is caused by a biphasic IgG antibody that binds to red cells at low temperature and causes complement-mediated lysis as the temperature is increased. It can be diagnosed in patients with AIHA and a positive Donath-Landsteiner test. Testing should be considered in patients with AIHA and a DAT positive for C3d ± IgG (the DAT is sometimes negative), when CAD has been excluded, and there is hemoglobinuria, cold-associated symptoms, atypical serological features, or patients younger than 18 years old.

Treatment of AIHA

Primary AIHA

1. Treat the identified underlying cause
2. Provide folate supplementation to match the demands of increased erythropoiesis
3. Thromboprophylaxis with low-molecular-weight heparin is recommended for in-patients with an acute exacerbation of hemolysis and should be considered in ambulatory patients during severe exacerbations (hemoglobin < 85 g/L).

Cold Agglutinin Disease

1. In CAD patients, intravascular hemolysis can be triggered by bacterial or other febrile illnesses and should be treated promptly.
2. Avoid exposure to cold weather and dress to protect the distal extremities.
3. Patients should not receive cold fluids IV, and use of an in-line blood warmer is recommended.

Patients on Steroids

1. antacid therapy is recommended in patients on steroids with additional risk factors (previous PUD, age ≥60, concomitant NSAID/ASA/anticoagulant, thrombocytopenia)
2. fracture risk modification

Primary Warm AIHA

1. First-line prednisone 1 mg/kg ± RTX
2. Second-line splenectomy or RTX
3. Third-line: MMF, AZA, CsA, etc.

Primary CAD

1. Patients with mild asymptomatic anemia can be monitored without specific treatment, which should be reserved for symptomatic anemia, severe circulatory symptoms, or transfusion dependence. Because exacerbations can be transient, a period of support with transfusion may be useful before determining the need for pharmacological intervention.
2. First-line pharm: RTX
3. Second-line: bendamustine, bortezomib
4. Acute therapy: steroids, PLEX, eculizumab

Secondary AIHA

In adults, the most common associations are hematological malignancy, infection, and autoimmune disorders. A broad strategy is to treat the underlying condition according to best practice. Successful treatment may also improve the AIHA, but that is not always the case because the strength of the association varies.

If the associated condition does not require treatment, AIHA can usually be approached in a similar fashion to primary AIHA, although treatment decisions must be individualized.

References

1. Hemolytic Anemias | Harrison's Principles of Internal Medicine, 20e | AccessMedicine | McGraw-Hill Medical (mcmaster.ca)
2. How I treat autoimmune hemolytic anemia | Blood | American Society of Hematology (ashpublications.org)
3. Autoimmune hemolytic anemia | Hematology, ASH Education Program | American Society of Hematology