Paroxysmal Cold Hemoglobinuria Clinical Presentation

  • Author: Corinne Goldberg, MD; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Nov 22, 2011
 

History

The initial inciting event to the predisposition of D-L antibody synthesis remains unknown. However, there does appear to be an indirect correlation to an infectious source, as paroxysmal cold hemoglobinuria can occur soon after developing upper respiratory and gastrointestinal symptoms.

Once strongly linked with syphilis, paroxysmal cold hemoglobinuria is now associated with numerous infectious agents. Identified pathogens have included the following: measles, mumps, influenza, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, parvovirus B19, Coxsackie A9, Haemophilus influenzae, Mycoplasma pneumoniae, and Klebsiella pneumoniae.[5, 7, 8, 24] The development of the D-L antibody has also been reported following measles immunization. Other associations include solid organ and hematopoietic neoplasms.[11]

Within minutes to a few hours of exposure to cold temperatures, the patient develops a combination of the following: sudden onset of back and abdominal pain, headache, leg cramps, fever, rigors, chills, nausea, vomiting, diarrhea, and esophageal spasms. The hemoglobinuria can be severe enough to alter the urine to a dark red-brown color, although hematuria is generally minimal or absent. Oliguria or anuria can develop upon renal dysfunction. Cold urticaria and jaundice may also occur.[25] These generalized symptoms are likely attributed to the release of large quantities of hemoglobin from lysed RBCs, which then act as an irritant to various tissues.

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Physical

Patients who present with paroxysmal cold hemoglobinuria are in acute distress, with obvious pain and elevation of body temperature.

  • Symptoms associated with respiratory infection are the most common initial presentation.
  • Physical signs of massive RBC hemolysis include pallor, icterus, and urticarial dermal eruption. Severe hemoglobinuria is commonly detected during the acute event, resulting in a red-brown discoloration to the urine.
  • Hepatosplenomegaly can be attributed to an underlying lymphoproliferative or other neoplastic process, but it has also been observed as a reactive process in 25% of paroxysmal cold hemoglobinuria cases.
  • Another feature can be thrombosis, which results in high morbidity and mortality.[26]
  • Other constitutional symptoms are likely related to an underlying secondary pathologic process.
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Causes

  • Known risk factors for paroxysmal cold hemoglobinuria are attributed to underlying pathogenic states, including infectious diseases and neoplasms (see History).
  • In most cases, the P antigen must be present on the RBCs for paroxysmal cold hemoglobinuria to develop. As most people express P antigen on their erythrocytes, nearly the entire population is susceptible to reactivity by the D-L antibody.
  • The degree and duration of hypothermia that is required to precipitate hemolysis depends on the temperature requirement of the antibody-RBC reaction and on the concentration availability of complement.
  • Male sex appears to be a risk factor in at least 1 study.[19]
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Contributor Information and Disclosures
Author

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

Disclosure: Nothing to disclose.

Coauthor(s)

Ronald A Sacher, MB, BCh, MD, FRCPC  Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC 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, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Specialty Editor Board

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 Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences

Disclosure: Nothing to disclose.

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

Disclosure: Medscape Salary Employment

Ronald A Sacher, MB, BCh, MD, FRCPC  Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC 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, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Mark Cooper, MBBS, PhD, FRACP  Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, 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 College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors gratefully acknowledge the contributions of previous authors, Rajalaxmi McKenna , MD , FACP,  Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems, and Harry L Messmore, Jr, MD, Professor, Department of Medicine, Division of Hematology/Oncology, Loyola University Stritch School of Medicine, to the development and writing of this article.

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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).
 
 
 
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