Sections

Presentation

History

The initial inciting event to Donath-Landsteiner (D-L) antibody synthesis remains unknown. However, paroxysmal cold hemoglobinuria frequently occurs shortly after upper respiratory or gastrointestinal infections.^[27]

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.^{[6, 8, 9, 28]}The development of the D-L antibody has also been reported following measles immunization. Other associations include solid organ and hematopoietic neoplasms .^[13]

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.^[29]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.

Physical Examination

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 red blood cell 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. A clinical examination (to rule out lymphadenopathy and/or splenomegaly) is obligatory.

Another feature can be sequelae of microthrombosis, but generally it is rare.^[30]

Other constitutional symptoms are likely related to an underlying secondary pathologic process.

Differential Diagnoses

Paroxysmal Cold Hemoglobinuria. National Organization for Rare Disorders. Available at https://rarediseases.org/rare-diseases/paroxysmal-cold-hemoglobinuria/. 2012; Accessed: January 20, 2022.
Donath J, Landsteiner K. Uber paroxysmale haemoglobinurie. Munchen Medicine Wochenschr. 1904. 51:1590-3.
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. [QxMD MEDLINE Link].
Eder AF. Review: acute Donath-Landsteiner hemolytic anemia. Immunohematology. 2005. 21(2):56-62. [QxMD MEDLINE Link].
Kypson AP, Warner JJ, Telen MJ, Milano CA. Paroxysmal cold hemoglobinuria and cardiopulmonary bypass. Ann Thorac Surg. 2003 Feb. 75(2):579-81. [QxMD MEDLINE Link].
Bunch C, Schwartz FC, Bird GW. Paroxysmal cold haemoglobinuria following measles immunization. Arch Dis Child. 1972 Apr. 47(252):299-300. [QxMD MEDLINE Link]. [Full Text].
Taylor CJ, Neilson JR, Chandra D, Ibrahim Z. Recurrent paroxysmal cold haemoglobinuria in a 3-year-old child: a case report. Transfus Med. 2003 Oct. 13(5):319-21. [QxMD MEDLINE Link].
Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis associated with Donath-Landsteiner antibodies. Acta Haematol. 1982. 68(4):268-77. [QxMD MEDLINE Link].
Sokol RJ, Hewitt S, Stamps BK, Hitchen PA. Autoimmune haemolysis in childhood and adolescence. Acta Haematol. 1984. 72(4):245-57. [QxMD MEDLINE Link].
Win N, Stamps R, Knight R. Paroxysmal cold haemoglobinuria/Donath-Landsteiner test. Transfus Med. 2005 Jun. 15(3):254. [QxMD MEDLINE Link].
Vaglio S, Arista MC, Perrone MP, et al. Autoimmune hemolytic anemia in childhood: serologic features in 100 cases. Transfusion. 2007 Jan. 47(1):50-4. [QxMD MEDLINE Link].
Slemp SN, Davisson SM, Slayten J, Cipkala DA, Waxman DA. Two case studies and a review of paroxysmal cold hemoglobinuria. Lab Med. 2014 Summer. 45 (3):253-8; quiz e92. [QxMD MEDLINE Link]. [Full Text].
Breccia M, D'Elia GM, Girelli G, et al. Paroxysmal cold haemoglobinuria as a tardive complication of idiopathic myelofibrosis. Eur J Haematol. 2004 Oct. 73(4):304-6. [QxMD MEDLINE Link].
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. 1998 Dec. 20(6):373-5. [QxMD MEDLINE Link].
Bell CA, Zwicker H, Rosenbaum DL. Paroxysmal cold hemoglobinuria (P.C.H.) following mycoplasma infection: anti-I specificity of the biphasic hemolysin. Transfusion. 1973 May-Jun. 13(3):138-41. [QxMD MEDLINE Link].
Rausen AR, LeVine R, Hsu TC, Rosenfield RE. Compatible transfusion therapy for paroxysmal cold hemoglobinuria. Pediatrics. 1975 Feb. 55(2):275-8. [QxMD MEDLINE Link].
Bird GW, Wingham J, Martin AJ, et al. Idiopathic non-syphilitic paroxysmal cold haemoglobinuria in children. J Clin Pathol. 1976 Mar. 29(3):215-8. [QxMD MEDLINE Link]. [Full Text].
Petz LD, Garratty G. Acquired Immune Hemolytic Anemias. New York, NY: Churchill Livingstone; 1980. 37-50.
Dacie J. The Haemolytic Anaemias. 3rd ed. New York, NY: Churchill Livingstone; 1992. 210-362.
Gertz MA. Cold hemolytic syndrome. Hematology Am Soc Hematol Educ Program. 2006. 19-23. [QxMD MEDLINE Link]. [Full Text].
Papalia MA, Schwarer AP. Paroxysmal cold haemoglobinuria in an adult with chicken pox. Br J Haematol. 2000 May. 109(2):328-9. [QxMD MEDLINE Link].
Lippman SM, Winn L, Grumet FC, Levitt LJ. Evans' syndrome as a presenting manifestation of atypical paroxysmal cold hemoglobinuria. Am J Med. 1987 May. 82(5):1065-72. [QxMD MEDLINE Link].
Rosse WF, Hillmen P, Schreiber AD. Immune-mediated hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2004. 48-62. [QxMD MEDLINE Link]. [Full Text].
Sharara AI, Hillsley RE, Wax TD, Rosse WF. Paroxysmal cold hemoglobinuria associated with non-Hodgkin's lymphoma. South Med J. 1994 Mar. 87(3):397-9. [QxMD MEDLINE Link].
Sivakumaran M, Murphy PT, Booker DJ, et al. Paroxysmal cold haemoglobinuria caused by non-Hodgkin's lymphoma. Br J Haematol. 1999 Apr. 105(1):278-9. [QxMD MEDLINE Link].
Stefanizzi C, Breccia M, Santopietro M, et al. Unusual association of paroxysmal cold hemoglobinuria as the first sign of disease in myelodysplastic patient. Int J Hematol. 2009 Jun. 89(5):720-1. [QxMD MEDLINE Link].
Berentsen S. Role of Complement in Autoimmune Hemolytic Anemia. Transfus Med Hemother. 2015 Sep. 42 (5):303-10. [QxMD MEDLINE Link]. [Full Text].
Ziman A, Hsi R, Goldfinger D. Transfusion Medicine Illustrated: Donath-Landsteiner antibody-associated hemolytic anemia after Haemophilus influenzae infection in a child. Transfusion. 2004 Aug. 44(8):1127-8. [QxMD MEDLINE Link].
Vergara LH, Mota MC, Sarmento Ada G, Duarte CA, Barbot JM. [Acute renal failure secondary to paroxysmal cold hemoglobinuria] [Spanish]. An Pediatr (Barc). 2006 Mar. 64(3):267-9. [QxMD MEDLINE Link]. [Full Text].
Kim GM, Kim CH, Kim BS. Multiple cerebral infarction and microbleeds associated with adult-onset paroxysmal cold hemoglobinuria. J Clin Neurosci. 2009 Feb. 16(2):348-9. [QxMD MEDLINE Link].
Sinha A, Richardson G, Patel RT. Cold agglutinin related acrocyanosis and paroxysmal haemolysis. Eur J Vasc Endovasc Surg. 2005 Nov. 30(5):563-5. [QxMD MEDLINE Link].
Chrobak L. Paroxysmal nocturnal hemoglobinuria (membrane defect, pathogenesis, aplastic anemia, diagnosis). Acta Medica (Hradec Kralove). 2000. 43(1):3-8. [QxMD MEDLINE Link].
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. 1968 Feb. 31(2):151-65. [QxMD MEDLINE Link]. [Full Text].
Subbarayan PR, Shichishima T, Yoshida H, Maruyama Y, Naiki M. Report on a patient with paroxysmal cold hemoglobinuria. Int J Hematol. 1997 Feb. 65(2):165-7. [QxMD MEDLINE Link].
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. 2000 Sep. 106(5):689-96. [QxMD MEDLINE Link]. [Full Text].
Brodsky RA, Mukhina GL, Li S, et al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol. 2000 Sep. 114(3):459-66. [QxMD MEDLINE Link].
Garratty G. Erythrophagocytosis on the peripheral blood smear and paroxysmal cold hemoglobinuria. Transfusion. 2001 Aug. 41(8):1073-4. [QxMD MEDLINE Link].
Roy-Burman A, Glader BE. Resolution of severe Donath-Landsteiner autoimmune hemolytic anemia temporally associated with institution of plasmapheresis. Crit Care Med. 2002 Apr. 30(4):931-4. [QxMD MEDLINE Link].
Lechner K, Jäger U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010 Sep 16. 116(11):1831-8. [QxMD MEDLINE Link].
Chandrashekar V, Soni M. Florid erythrophagocytosis on the peripheral smear. J Lab Physicians. 2012 Jan. 4(1):59-61. [QxMD MEDLINE Link]. [Full Text].
Peña VN, Naik RP. Paroxysmal cold hemoglobinuria: a unique constellation of peripheral smear findings. Blood. 2020 Jan 30. 135 (5):393. [QxMD MEDLINE Link]. [Full Text].
Mukhopadhyay S, Keating L, Souid AK. Erythrophagocytosis in paroxysmal cold hemoglobinuria. Am J Hematol. 2003 Nov. 74(3):196-7. [QxMD MEDLINE Link]. [Full Text].
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. 1984 Mar. 73(2):258-62. [QxMD MEDLINE Link].
Lindgren S, Zimmerman S, Gibbs F, Garratty G. An unusual Donath-Landsteiner antibody detectable at 37 degrees C by the antiglobulin test. Transfusion. 1985 Mar-Apr. 25(2):142-4. [QxMD MEDLINE Link].
Nordhagen R. Two cases of paroxysmal cold hemoglobinuria with a Donath-Landsteiner antibody reactive by the indirect antiglobulin test using anti-IgG. Transfusion. 1991 Feb. 31(2):190-1. [QxMD MEDLINE Link].
Thomas AT. Autoimmune hemolytic anemias. Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md: Williams & Wilkins; 1999. 1233-63.
Gertz MA. Management of cold haemolytic syndrome. Br J Haematol. 2007 Aug. 138(4):422-9. [QxMD MEDLINE Link].
Zeller MP, Arnold DM, Al Habsi K, Cserti-Gazdewich C, Delage G, Lebrun A, et al. Paroxysmal cold hemoglobinuria: a difficult diagnosis in adult patients. Transfusion. 2017 Jan. 57 (1):137-143. [QxMD MEDLINE Link].
Hothi DK, Bass P, Morgan M, et al. Acute renal failure in a patient with paroxysmal cold hemoglobinuria. Pediatr Nephrol. 2007 Apr. 22(4):593-6. [QxMD MEDLINE Link].
Koppel A, Lim S, Osby M, Garratty G, Goldfinger D. Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria. Transfusion. 2007 Oct. 47(10):1902-4. [QxMD MEDLINE Link].
Lau-Braunhut SA, Stone H, Collins G, Berentsen S, Braun BS, Zinter MS. Paroxysmal cold hemoglobinuria successfully treated with complement inhibition. Blood Adv. 2019 Nov 26. 3 (22):3575-3578. [QxMD MEDLINE Link]. [Full Text].
Gregory GP, Opat S, Quach H, Shortt J, Tran H. Failure of eculizumab to correct paroxysmal cold hemoglobinuria. Ann Hematol. 2011 Aug. 90(8):989-90. [QxMD MEDLINE Link].

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.

Paroxysmal Cold Hemoglobinuria Clinical Presentation

History

Physical Examination

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