Anemia and Hashimoto Thyroiditis

Caroline Cromwell, MD and Marc J. Kahn, MD, MBA

Dr. Cromwell: Icahn School of Medicine, New York, NY
Dr. Kahn: Tulane University School of Medicine, New Orleans, LA

Copyright of the American Society of Hematology, 2013. ISSN: 1931-6860.


Autoimmune hemolytic anemias (AIHA)

Autoimmune hemolytic anemias (AIHA) are anemias caused by antibodies directed against antigens on the red blood cell surface. They can be due to a number of antibodies of different immunoglobulin classes. Autoimmune hemolysis can be associated with a number of underlying disorders. Typical findings are:
  • Anemia
  • Increased LDH
  • Low haptoglobin (in severe disease) due to haptoglobin's ability to bind serum free hemoglobin, which in turn leads to clearance of haptoglobin from the circulation
  • Increased indirect (unconjugated) bilirubin
  • Reticulocytosis
  • Positive direct antiglobulin test (Coombs test).

Warm and Cold Antibodies

The direct antiglobulin test (DAT) or Coombs test helps us identify the type of antibody present on the red cell.

The antibodies responsible can be referred to as "warm" or "cold." Warm AIHA is due to IgG antibodies, which have maximal activity at body temperature. When IgG binds to the RBC antigen, these red cells are then phagocytized by the spleen via the Fc receptors found on splenic macrophages. A bit of antibody-coated red cell membrane is pinched off by the reticuloendothelial cells in the spleen, causing the red cell to have a decreased membrane-to-intracellular volume ratio, leading to the development of spherocytes (see image below). It is important to note that patients with warm antibody hemolytic anemia DO NOT have fragmented cells or schistocytes on their peripheral smear. These are found in microangiopathic hemolytic anemias such as hemolytic-uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP). Some patients with warm antibody hemolysis also have complement (C3) on their red cells in addition to IgG.

Cold antibodies, typically IgM, have maximal activity at colder temperatures, activate complement, and bind to the red cell membrane. These red blood cells are cleared by the hepatic Kupffer cells. Patients with cold agglutinin disease typically have a Coombs test positive for complement, as IgM does not remain on the red cells for much time. The peripheral smear in cold agglutinin disease typically shows agglutinated red cells due to the fact that the smear is made at room temperature. As such, the cells may have a very large reported MCV (112+ fL) on the Coulter counter, due to measurement of red cell aggregates.

Other Types of Hemolytic Anemia

There are also two less common subtypes of hemolytic anemia:

  • Chronic cold agglutinin disease: This is a disorder in which IgM antibodies occur in patients with lymphoproliferative disorders, including CLL, Waldenströms, and bind complement.
  • Paroxysmal cold hemoglobinuria: PCH is caused by an IgG antibody (known as the Donath Landsteiner antibody) that activates complement in the cold and causes intravascular hemolysis. It is usually seen in the setting of viral syndromes and syphilis. It primarily affects children.

The direct antiglobulin test (DAT) aids in the diagnosis of autoimmune hemolytic anemia. The patient's red blood cells are mixed with anti-human IgG or C3. Agglutination of the patient's red blood cells means a positive test. Agglutination with anti-IgG means warm AIHA. Agglutination with anti-C3 DAT occurs in cold AIHA.

Coombs Test

Coombs testing

Although AIHA is often idiopathic, one should always look for the cause or associated disorder. AIHA can precede or follow other diseases such as lymphoma. AIHA can occur in the setting of autoimmune disease (such as Hashimoto thyroiditis), pregnancy, HIV infection, and lymphoproliferative diseases such as chronic lymphocytic leukemia or non-Hodgkin lymphoma. Cold agglutinin disease can occur following infectious mononucleosis or mycoplasma pneumoniae. Patients with cold agglutinin disease have a particularly high incidence of non-Hodgkin lymphoma.

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