Chapter 23: Cryopathic Hemolytic Anemia

INTRODUCTION

This type of anemia is caused by autoantibodies that bind red cells best at temperatures below 37°C, usually below 31°C.
It is mediated through two major types of “cold antibody”: cold agglutinins and Donath-Landsteiner antibodies.
Clinical features vary considerably, but in both types, the complement system plays a major role in red cell destruction.

COLD AGGLUTININ-MEDIATED AUTOIMMUNE HEMOLYTIC ANEMIA

Cold agglutinins are immunoglobulin M (IgM) autoantibodies that agglutinate red cells, optimally between 0°C and 5°C. Complement fixation occurs at higher temperatures.
This hemolytic anemia is classified as either primary (chronic cold agglutinin disease) or secondary (generally as a result of Mycoplasma pneumoniae infection or Epstein-Barr virus [EBV]–related infectious mononucleosis) (Table 23–1).
Peak incidence for the primary (chronic) syndrome is in persons older than 50 years.
This disorder characteristically has monoclonal IgM cold agglutinins and may be considered a symptomatic monoclonal gammopathy.
Some patients develop a B-cell lymphoproliferative disorder (eg, Waldenström macroglobulinemia).

TABLE 23–1AUTOIMMUNE HEMOLYTIC ANEMIA: COLD ANTIBODY TYPE*

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TABLE 23–1 AUTOIMMUNE HEMOLYTIC ANEMIA: COLD ANTIBODY TYPE*

Mediated by cold agglutinins
1. Idiopathic (primary) chronic cold-agglutinin disease (usually associated with clonal B-lymphocyte disease)
2. Secondary cold-agglutinin hemolytic anemia
  1. Postinfectious (eg, Mycoplasma pneumoniae or infectious mononucleosis)
  2. Associated with preexisting malignant B-cell lymphoproliferative disorder
Mediated by cold hemolysins
1. Idiopathic (primary) paroxysmal cold hemoglobinuria—very rare
2. Secondary
  1. Donath-Landsteiner hemolytic anemia, usually associated with an acute viral syndrome in children—relatively common
  2. Congenital or tertiary syphilis in adults—very rare

*Uncommonly, cases may have mixed cold and warm autoantibodies (eg, primary or idiopathic mixed autoimmune hemolytic anemia) or secondary mixed autoimmune hemolytic anemia associated with the rheumatic disorders, particularly systemic lupus erythematosus.

Source: Williams Hematology, 9th ed, Chap. 54, Table 54–1.

Pathogenesis

The specificity of cold agglutinins is usually against I/i antigens. I is expressed heavily in adult red cells, weakly on neonatal red cells. The reverse is true of the i antigen, which also may still be expressed on reticulocytes.
High proportions of IgM cold agglutinins with either anti-I or anti-i specificity have heavy-chain variable regions encoded by V_H4–34, a conserved immunoglobulin variable region gene.
Naturally occurring cold agglutinins are present in low titer (less than 1:32) in normal persons. Transient hyperproduction of less clonally restricted antibodies occurs in the recovery phase of infections, such as EBV, mycoplasma, or cytomegalovirus.
I/i antigens serve as mycoplasma receptors, which may lead to altered antigen presentation and to subsequent autoantibody production.
In B-cell lymphomas, cold agglutinins may be produced by the malignant lymphocytes.
The highest temperature at which antibodies can cause red cell agglutination is termed the thermal amplitude. The higher the thermal amplitude, the greater the risk of clinically significant hemolysis, depending on the ambient temperature.
Cold agglutinins bind to red cells in the superficial dermal vessels, where temperatures may be less than 37°C, impeding capillary flow, producing acrocyanosis.
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