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

Workup

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Media Gallery

A Donath-Landsteiner test result is seen here, showing the appearance of a negative tube (no hemolysis in the supernatant) and a positive tube (red color in the supernate, implying the presence of free hemoglobin).
Workup for hemolytic anemia. Abbreviations: LDH, lactate dehydrogenase; DAT, direct antiglobulin; AIHA, autoimmune hemolytic anemia; WAIHA, warm autoimmune hemolytic anemia; CAIHA, cold autoimmune hemolytic anemia; PCH, paroxysmal cold hemoglobinuria; Ab, antibody.

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Author

Hira Latif, MD Assistant Professor, Division of Hematology/Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center

Hira Latif, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, International Society on Thrombosis and Haemostasis, Pakistan Medical and Dental Council

Disclosure: Nothing to disclose.

Coauthor(s)

Michael F Matheney, MD Fellow in Hematology/Oncology, MedStar Washington Hospital Center

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MD, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Paul Schick, MD † Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Neetu Radhakrishnan, MD Medical Oncologist, Kettering Cancer Care

Neetu Radhakrishnan, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Acknowledgements

Corinne Goldberg, MD Fellow in Transfusion Medicine/Blood Banking, Transfusion Medicine Department, Hoxworth Blood Center, University of Cincinnati

Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Harry L Messmore, Jr, MD Professor, Department of Medicine, Division of Hematology/Oncology, Loyola University Stritch School of Medicine

Harry L Messmore, Jr, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Angiology, American College of Physicians, American Heart Assocation, American Society of Hematology, and Phi Beta Kappa

Disclosure: Nothing to disclose.