Paroxysmal Cold Hemoglobinuria Differential Diagnoses

Updated: Jan 20, 2022
  • Author: Hira Latif, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Diagnostic Considerations

Cold hemagglutinin disease

Cold hemagglutinin disease manifests as an immune hemolytic anemia with acrocyanosis and, rarely, hemoglobinuria following cold exposure. In the same manner as paroxysmal cold hemoglobinuria, the cold hemagglutinin disease antibody, usually IgM, binds in colder areas of the body, allowing interaction with complement (ie, C3), followed by dissociation of the antibody upon circulating through warmer anatomic regions.

The complement remains attached to the erythrocyte and is degraded into its intermediate by-products (ie, C3b, iC3b). This is a decisive point that deviates from the paroxysmal cold hemoglobinuria pathway, as the cold hemagglutinin disease route results in the recognition and clearance of the complement-coated RBC by the reticuloendothelial system. Completion of the complement cascade, resulting in intravascular hemolysis, does not occur. Although laboratory analysis reveals a similar paroxysmal cold hemoglobinuria direct agglutinin test (DAT) positivity that is restricted to the monoclonal anti-C3, the D-L test is negative. [31]

Paroxysmal nocturnal hemoglobinuria (PNH)

PNH has similar presentation of hemoglobinuria, hemoglobinemia, and anemia secondary to intravascular hemolysis. However, paroxysmal nocturnal hemoglobinuria pathogenesis is dependent on a mutated cellular enzyme called phosphatidylinositol glycan A (PIG-A) that is required to anchor proteins known as glycophosphatidylinositols (GPIs) to the cellular membrane.

In addition, paroxysmal nocturnal hemoglobinuria characteristically manifests with persistent cytopenias and absent bone marrow iron. DAT results are negative, as are results from the D-L antibody test. Testing for paroxysmal nocturnal hemoglobinuria depends on the absence of the GPI antigens determined via various tests, including the highly sensitive flow cytometry and the bacterial toxin aerolysin assay. [32, 33, 34, 35, 36, 37]

Hemolytic transfusion reactions

Hemolytic transfusion reactions can result in life-threatening intravascular hemolysis and hemoglobinuria upon transmission of incompatible blood products. The recipient's preformed alloantibodies interact with the donor's RBCs, activating the complement sequence. Generally, these antibodies are IgG in origin, resulting in both polyclonal and monoclonal anti-IgG DAT positivity. Clinical history is important for identifying this condition and providing immediate therapeutic intervention.

Other conditions

Malaria caused by Plasmodium falciparum infection is a fulminating disease that may manifest with episodic, massive, intravascular hemolysis and hemoglobinuria, hepatosplenomegaly, icterus, fever and pain. Peripheral blood smears may identify the pathogens and serologic studies can confirm their presence.

Warm autoimmune hemolytic anemia (ie, direct Coombs-positive or warm antibody–induced hemolytic anemia) is caused by an antibody that binds to RBCs at 37°C, in contrast to the D-L antibody, which binds to RBCs in the cold. The antibody specificity in autoimmune hemolytic anemia is to the Rh system, and hemoglobinuria is uncommon. DAT results are positive, but the D-L antibody test is negative.

Myoglobinuria may be misinterpreted as hemoglobinuria at preliminary urine analysis. This condition is generally precipitated by exertion or trauma. Fever may be present, but icterus is rate. RBC hemolysis is not a feature of this disease.

Differential Diagnoses