Paroxysmal Cold Hemoglobinuria 

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

Background

Paroxysmal cold hemoglobinuria (PCH) has the distinction of being the first, albeit rarest, type of autoimmune hemolytic anemia (AIHA) to be identified. This condition was first described in 1854 as an abrupt onset of systemic symptoms including severe anemia and hemoglobinuria upon exposure to cold temperatures, occurring as a manifestation of massive intravascular hemolysis.

The pathophysiology of paroxysmal cold hemoglobinuria became apparent when Julius Donath and Karl Landsteiner discovered a unique "biphasic hemolysin" in blood that could be demonstrated in the laboratory. This antibody attaches to red blood cells (RBCs) in the cold and induces hemolysis when the RBCs are warmed due to complement activity. Together these investigators devised and published in 1904 what was to be the first immunohematologic test, referred to as the Donath-Landsteiner test.[1, 2, 3, 4] (See Lab Studies.)

In the latter half of the 19th century, the most common cause of paroxysmal cold hemoglobinuria was congenital or adult tertiary-stage syphilis. The ability to treat syphilis through antibiotic use resulted in the near elimination of this secondary cause to the chronic paroxysmal cold hemoglobinuria form. Currently, this condition commonly manifests as an abrupt onset and transitory process related to infections, usually representing a postviral episode. A study of children found that as many as 40% of immune hemolytic anemias were due to the Donath-Landsteiner (D-L) antibody.[5, 6]

Although most cases of paroxysmal cold hemoglobinuria occur as an acute event in children younger than 5 years, recurrent episodes have been reported.[6, 7, 8, 9, 10] Furthermore, because the D-L antibody does not necessarily occur with a specified cold exposure event, nor is it recurrent in nature, an alternative classification of Donath-Landsteiner hemolytic anemia was proposed.[11]

In the adult population, infections and neoplasms have been associated with the development of D-L antibody.[12] Reported neoplasms include solid organ carcinomas as seen with pulmonary small cell carcinoma and hematopoietic disorders such as non-Hodgkin lymphoma (NHL), chronic lymphocytic lymphoma (CLL), primary myelofibrosis with myeloid metaplasia, and in the presence of a monoclonal protein with Bence Jones proteinuria.[6, 11, 13, 14, 15, 16] With an underlying disease that is controllable or self-limited, the process may resolve spontaneously and quickly. Unfortunately, due to the transitory nature of paroxysmal cold hemoglobinuria, lack of awareness may lead to a failure in recognizing and diagnosing this uncommon syndrome.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

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Pathophysiology

Although paroxysmal cold hemoglobinuria shares similar antibody thermal activity range as cold hemagglutinin disease (CHD), the more common cold variant of autoimmune hemolytic anemia, the D-L antibody is not classified as a monophasic immunoglobulin M (IgM), but rather a biphasic, usually polyclonal, IgG. The D-L antibody is known to bind to various antigens such as I-, i-, p-, Pr-, on the RBC surface; yet, the glycosphingolipid P antigen is considered its primary target.[6]

This interaction sensitizes the erythrocytes to allow further interaction with the complement system. However, unlike cold hemagglutinin disease in which the IgM-complement interaction results in the cells' removal (via extravascular phagocytosis), paroxysmal cold hemoglobinuria occurs upon completion of complement lysis within the vascular circulation. Intravascular hemolysis occurs preferentially at 37°C, at which temperature the antibody has dissociated yet maintains maximal complement activity, providing the biphasic nature of the disease.

The exact etiology of the D-L antibody is unknown. There is a close relationship observed upon exposure to viral or bacterial agents and the development of paroxysmal cold hemoglobinuria within 2-3 weeks of upper respiratory or gastrointestinal symptoms. Young children are the most susceptible within the general population, developing a single, brief, postviral hemolytic episode.[2, 17]

The stimulus for production of this antibody is likely a form of molecular mimicry in which a microorganism's antigen shares structural similarity to the P antigen on human RBCs, resulting in immunogenic cross-reactivity.[3] Interestingly, the P antigen has been found on lymphocytes and skin fibroblasts; the latter is thought to be the reason for the development of urticaria in persons with paroxysmal cold hemoglobinuria.

Because complement-mediated injury to the RBC is an intravascular process, hemoglobinemia, hemoglobinuria, and, sometimes, renal failure may develop.[10, 18, 19, 20, 21, 22] Even after the acute event remits, the D-L antibody may persist for 1-8 months to several years.[23]

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Epidemiology

Frequency

United States

Paroxysmal cold hemoglobinuria is a rare disorder, with a prevalence rate that remains largely unknown within the United States population.

International

Sokol et al estimated the annual incidence of paroxysmal cold hemoglobinuria at 0.4 cases per 100,000 people.[7, 8] Unfortunately, due to the scarcity of subjects, European epidemiologic results have varied widely from as low as 1.6% to as high as 40% of autoimmune hemolytic anemia cases, with the latter value restricted to children.[6, 10, 23]

Mortality/Morbidity

  • When paroxysmal cold hemoglobinuria is promptly diagnosed and appropriately treated with supportive care, most patients recover spontaneously within days to a few weeks. Thus, the prognosis for this disorder is excellent.
  • Fatality is a rare event, more commonly attributed to severe anemia.

Race

No racial predisposition is recognized for paroxysmal cold hemoglobinuria.

Sex

There is a mild male sex predilection with paroxysmal cold hemoglobinuria; the male-to-female ratio is approximately 2:1 to 5:1.[10, 19]

Age

  • Acute paroxysmal cold hemoglobinuria is a disease that affects mostly young children, commonly following an acute viral or upper respiratory illness.
  • Chronic paroxysmal cold hemoglobinuria is commonly seen in the elderly. Contributory secondary causes are generally neoplastic in origin, followed by infections.
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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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