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.

References
  1. Donath J, Landsteiner K. Uber paroxysmale haemoglobinurie. Munchen Medicine Wochenschr. 1904;51:1590-3.

  2. Gottsche B, Salama A, Mueller-Eckhardt C. Donath-Landsteiner autoimmune hemolytic anemia in children. A study of 22 cases. Vox Sang. 1990;58(4):281-6. [Medline].

  3. Eder AF. Review: acute Donath-Landsteiner hemolytic anemia. Immunohematology. 2005;21(2):56-62. [Medline].

  4. Kypson AP, Warner JJ, Telen MJ, Milano CA. Paroxysmal cold hemoglobinuria and cardiopulmonary bypass. Ann Thorac Surg. Feb 2003;75(2):579-81. [Medline].

  5. Bunch C, Schwartz FC, Bird GW. Paroxysmal cold haemoglobinuria following measles immunization. Arch Dis Child. Apr 1972;47(252):299-300. [Medline]. [Full Text].

  6. Taylor CJ, Neilson JR, Chandra D, Ibrahim Z. Recurrent paroxysmal cold haemoglobinuria in a 3-year-old child: a case report. Transfus Med. Oct 2003;13(5):319-21. [Medline].

  7. Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis associated with Donath-Landsteiner antibodies. Acta Haematol. 1982;68(4):268-77. [Medline].

  8. Sokol RJ, Hewitt S, Stamps BK, Hitchen PA. Autoimmune haemolysis in childhood and adolescence. Acta Haematol. 1984;72(4):245-57. [Medline].

  9. Win N, Stamps R, Knight R. Paroxysmal cold haemoglobinuria/Donath-Landsteiner test. Transfus Med. Jun 2005;15(3):254. [Medline].

  10. Vaglio S, Arista MC, Perrone MP, et al. Autoimmune hemolytic anemia in childhood: serologic features in 100 cases. Transfusion. Jan 2007;47(1):50-4. [Medline].

  11. Breccia M, D'Elia GM, Girelli G, et al. Paroxysmal cold haemoglobinuria as a tardive complication of idiopathic myelofibrosis. Eur J Haematol. Oct 2004;73(4):304-6. [Medline].

  12. Papalia MA, Schwarer AP. Paroxysmal cold haemoglobinuria in an adult with chicken pox. Br J Haematol. May 2000;109(2):328-9. [Medline].

  13. Lippman SM, Winn L, Grumet FC, Levitt LJ. Evans' syndrome as a presenting manifestation of atypical paroxysmal cold hemoglobinuria. Am J Med. May 1987;82(5):1065-72. [Medline].

  14. Rosse WF, Hillmen P, Schreiber AD. Immune-mediated hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2004;48-62. [Medline]. [Full Text].

  15. Sharara AI, Hillsley RE, Wax TD, Rosse WF. Paroxysmal cold hemoglobinuria associated with non-Hodgkin's lymphoma. South Med J. Mar 1994;87(3):397-9. [Medline].

  16. Sivakumaran M, Murphy PT, Booker DJ, et al. Paroxysmal cold haemoglobinuria caused by non-Hodgkin's lymphoma. Br J Haematol. Apr 1999;105(1):278-9. [Medline].

  17. Wynn RF, Stevens RF, Bolton-Maggs PH, Schwe K, Will AM. Paroxysmal cold haemoglobinuria of childhood: a review of the management and unusual presenting features of six cases. Clin Lab Haematol. Dec 1998;20(6):373-5. [Medline].

  18. Bell CA, Zwicker H, Rosenbaum DL. Paroxysmal cold hemoglobinuria (P.C.H.) following mycoplasma infection: anti-I specificity of the biphasic hemolysin. Transfusion. May-Jun 1973;13(3):138-41. [Medline].

  19. Rausen AR, LeVine R, Hsu TC, Rosenfield RE. Compatible transfusion therapy for paroxysmal cold hemoglobinuria. Pediatrics. Feb 1975;55(2):275-8. [Medline].

  20. Bird GW, Wingham J, Martin AJ, et al. Idiopathic non-syphilitic paroxysmal cold haemoglobinuria in children. J Clin Pathol. Mar 1976;29(3):215-8. [Medline]. [Full Text].

  21. Petz LD, Garratty G. Acquired Immune Hemolytic Anemias. New York, NY: Churchill Livingstone; 1980:37-50.

  22. Dacie J. The Haemolytic Anaemias. 3rd ed. New York, NY: Churchill Livingstone; 1992:210-362.

  23. Gertz MA. Cold hemolytic syndrome. Hematology Am Soc Hematol Educ Program. 2006;19-23. [Medline]. [Full Text].

  24. Ziman A, Hsi R, Goldfinger D. Transfusion Medicine Illustrated: Donath-Landsteiner antibody-associated hemolytic anemia after Haemophilus influenzae infection in a child. Transfusion. Aug 2004;44(8):1127-8. [Medline].

  25. Vergara LH, Mota MC, Sarmento Ada G, Duarte CA, Barbot JM. [Acute renal failure secondary to paroxysmal cold hemoglobinuria] [Spanish]. An Pediatr (Barc). Mar 2006;64(3):267-9. [Medline]. [Full Text].

  26. van Bijnen ST, van Heerde WL, Muus P. Mechanisms and Clinical Implications of Thrombosis in Paroxysmal Nocturnal Hemoglobinuria. J Thromb Haemost. Nov 12 2011;[Medline].

  27. Sinha A, Richardson G, Patel RT. Cold agglutinin related acrocyanosis and paroxysmal haemolysis. Eur J Vasc Endovasc Surg. Nov 2005;30(5):563-5. [Medline].

  28. Chrobak L. Paroxysmal nocturnal hemoglobinuria (membrane defect, pathogenesis, aplastic anemia, diagnosis). Acta Medica (Hradec Kralove). 2000;43(1):3-8. [Medline].

  29. Prasad AS, Berman L, Tranchida L, Poulok MD. Red cell hypoplasia, cold hemoglobinuria and M-type gamma G serum paraprotein and Bence Jones proteinuria in a patient with lymphoproliferative disorder. Blood. Feb 1968;31(2):151-65. [Medline]. [Full Text].

  30. Subbarayan PR, Shichishima T, Yoshida H, Maruyama Y, Naiki M. Report on a patient with paroxysmal cold hemoglobinuria. Int J Hematol. Feb 1997;65(2):165-7. [Medline].

  31. Chen R, Nagarajan S, Prince GM, et al. Impaired growth and elevated fas receptor expression in PIGA(+) stem cells in primary paroxysmal nocturnal hemoglobinuria. J Clin Invest. Sep 2000;106(5):689-96. [Medline]. [Full Text].

  32. Brodsky RA, Mukhina GL, Li S, et al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol. Sep 2000;114(3):459-66. [Medline].

  33. Garratty G. Erythrophagocytosis on the peripheral blood smear and paroxysmal cold hemoglobinuria. Transfusion. Aug 2001;41(8):1073-4. [Medline].

  34. Roy-Burman A, Glader BE. Resolution of severe Donath-Landsteiner autoimmune hemolytic anemia temporally associated with institution of plasmapheresis. Crit Care Med. Apr 2002;30(4):931-4. [Medline].

  35. Mukhopadhyay S, Keating L, Souid AK. Erythrophagocytosis in paroxysmal cold hemoglobinuria. Am J Hematol. Nov 2003;74(3):196-7. [Medline]. [Full Text].

  36. Nordhagen R, Stensvold K, Winsnes A, Skyberg D, Storen A. Paroxysmal cold haemoglobinuria. The most frequent acute autoimmune haemolytic anaemia in children?. Acta Paediatr Scand. Mar 1984;73(2):258-62. [Medline].

  37. Lindgren S, Zimmerman S, Gibbs F, Garratty G. An unusual Donath-Landsteiner antibody detectable at 37 degrees C by the antiglobulin test. Transfusion. Mar-Apr 1985;25(2):142-4. [Medline].

  38. Nordhagen R. Two cases of paroxysmal cold hemoglobinuria with a Donath-Landsteiner antibody reactive by the indirect antiglobulin test using anti-IgG. Transfusion. Feb 1991;31(2):190-1. [Medline].

  39. Thomas AT. Autoimmune hemolytic anemias. In: Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md: Williams & Wilkins; 1999:1233-63.

  40. Gertz MA. Management of cold haemolytic syndrome. Br J Haematol. Aug 2007;138(4):422-9. [Medline].

  41. Hothi DK, Bass P, Morgan M, et al. Acute renal failure in a patient with paroxysmal cold hemoglobinuria. Pediatr Nephrol. Apr 2007;22(4):593-6. [Medline].

  42. Röth A, Dührsen U. Treatment of paroxysmal nocturnal hemoglobinuria in the era of eculizumab. Eur J Haematol. Dec 2011;87(6):473-9. [Medline].

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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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