Diagnostic Considerations

Donath-Landsteiner hemolytic anemia (DLHA) may be difficult to diagnose. It can be confused with cold agglutinin disease, with mixed type autoimmune hemolytic anemia and with warm-antibody autoimmune hemolytic anemia.^[21]

In general, cold agglutinin disease is characterized by the presence of very high cold agglutinin titers and the absence of hemoglobinuria, while warm-antibody autoimmune hemolytic anemia is typically diagnosed by positive results on the anti-IgG direct antiglobulin test.

Donath-Landsteiner (D-L) autoantibody is present only in DLHA and is therefore specific. The sensitivity of this test, however, is low. Many patients with the condition are undiagnosed. The D-L test is often negative in patients who have the condition if the antibody titer is low.

A number of more sensitive assays exist. The use of RBCs from patients with paroxysmal nocturnal hemoglobinuria (PNH) increases the sensitivity of the standard D-L test because PNH RBCc are more sensitive to the lysing ability of complement. This modification increases the ability to detect patients with the condition. The most sensitive diagnostic assay for DLHA uses radiolabeled antibody.^[26]

Go to Pediatric Chronic Anemia, Anemia of Prematurity, Fanconi Anemia, Pediatric Acute Anemia, and Pediatric Megaloblastic Anemia for complete information on these topics.

Differential Diagnoses

Workup

Hayashi H, Yasutomi M, Hayashi T, et al. Paroxysmal cold hemoglobinuria caused by an IgM-class Donath-Landsteiner antibody. Pediatr Int. 2013 Oct. 55(5):664-6. [QxMD MEDLINE Link].
Karafin MS, Shirey RS, Ness PM, King KE, Keefer J. A case study of a child with chronic hemolytic anemia due to a Donath-Landsteiner positive, IgM anti-I autoantibody. Pediatr Blood Cancer. 2012 Nov. 59(5):953-5. [QxMD MEDLINE Link].
Ogose T, Wakata Y, Kaneko M, Shinahara K, Takechi T, Kotani H. A case of recurrent paroxysmal cold hemoglobinuria with the different temperature thresholds of Donath-Landsteiner antibodies. J Pediatr Hematol Oncol. 2007 Oct. 29(10):716-9. [QxMD MEDLINE Link].
Whipple NS, Moreau DA, Moulds JM, Hankins JS, Wang WC, Nottage KA. Paroxysmal cold hemoglobinuria due to an IgA Donath-Landsteiner antibody. Pediatr Blood Cancer. 2015 Nov. 62 (11):2044-6. [QxMD MEDLINE Link].
Lichtman MA, Spivak JL, eds. Ueber paroxysmale Haemoglo- binurie [Concerning paroxysmal hemoglobinuria]. Hematology: Landmark Papers of the Twentieth Century. San Diego, Calif: Academic Press; 2000. 21.
Donath J LK. Uber paroxysmale Hamoglobinurie. Munchener Medizinische Wochenschrift. 1904. 51:1590-3.
Bird GW. Paroxysmal cold haemoglobinuria. Br J Haematol. 1977 Oct. 37(2):167-71. [QxMD MEDLINE Link].
Heddle NM. Acute paroxysmal cold hemoglobinuria. Transfus Med Rev. 1989 Jul. 3(3):219-29. [QxMD MEDLINE Link].
Hernandez JA, Steane SM. Erythrophagocytosis by segmented neutrophils in paroxysmal cold hemoglobinuria. Am J Clin Pathol. 1984 Jun. 81(6):787-9. [QxMD MEDLINE Link].
Kilty M, Ipe TS. Donath-Landsteiner test. Immunohematology. 2019 Jan. 35 (1):3-6. [QxMD MEDLINE Link].
Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol. 2002 Apr. 69(4):258-71. [QxMD MEDLINE Link].
Santos Malave C, Shardy DL, Hartman SK, Sampayo EM. Paroxysmal cold hemoglobinuria in a child with RSV: an underrecognized cause of hemolytic anemia. Am J Emerg Med. 2016 Nov. 34 (11):2252.e5-.e6. [QxMD MEDLINE Link].
Leibrandt R, Angelino K, Vizel-Schwartz M, Shapira I. Paroxysmal Cold Hemoglobinuria in an Adult with Respiratory Syncytial Virus. Case Rep Hematol. 2018. 2018:7586719. [QxMD MEDLINE Link]. [Full Text].
Sivakumaran M, Murphy PT, Booker DJ, Wood JK, Stamps R, Sokol RJ. Paroxysmal cold haemoglobinuria caused by non-Hodgkin's lymphoma. Br J Haematol. 1999 Apr. 105(1):278-9. [QxMD MEDLINE Link].
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].
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].
Prince SD, Winestone LE, Nance SJ, Friedman DF. Recurrent Donath-Landsteiner hemolytic anemia: a pediatric case report. Transfusion. 2017 Jun. 57 (6):1401-6. [QxMD MEDLINE Link]. [Full Text].
Voulgaridou A, Kalfa TA. Autoimmune Hemolytic Anemia in the Pediatric Setting. J Clin Med. 2021 Jan 9. 10 (2):[QxMD MEDLINE Link].
Jacobs JW, Figueroa Villalba CA, Booth GS, Woo JS, Stephens LD, Adkins BD. Clinical and epidemiological features of paroxysmal cold hemoglobinuria: a systematic review. Blood Adv. 2023 Jun 13. 7 (11):2520-7. [QxMD MEDLINE Link]. [Full Text].
Sokol RJ, Booker DJ, Stamps R. Erythropoiesis: Paroxysmal Cold Haemoglobinuria: A Clinico-Pathological Study of Patients with a Positive Donath-Landsteiner Test. Hematology. 1999. 4(2):137-164. [QxMD MEDLINE Link].
Petz LD. Cold antibody autoimmune hemolytic anemias. Blood Rev. 2008 Jan. 22(1):1-15. [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].
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].
Wolach B, Heddle N, Barr RD, Zipursky A, Pai KR, Blajchman MA. Transient Donath-Landsteiner haemolytic anaemia. Br J Haematol. 1981 Jul. 48(3):425-34. [QxMD MEDLINE Link].
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].
Rosse WF, Hillmen P, Schreiber AD. Immune-mediated hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2004. 48-62. [QxMD MEDLINE Link].
Zeller MP, Arnold DM, Al Habsi K, et al. Paroxysmal cold hemoglobinuria: a difficult diagnosis in adult patients. Transfusion. 2017 Jan. 57 (1):137-43. [QxMD MEDLINE Link]. [Full Text].
Win N, Stamps R, Knight R. Paroxysmal cold haemoglobinuria/Donath-Landsteiner test. Transfus Med. 2005 Jun. 15(3):254. [QxMD MEDLINE Link].
[Guideline] Gibson BE, Todd A, Roberts I, et al. Transfusion guidelines for neonates and older children. Br J Haematol. 2004 Feb. 124(4):433-53. [QxMD MEDLINE Link]. [Full Text].
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].
Murakhovskaya I. Rituximab Use in Warm and Cold Autoimmune Hemolytic Anemia. J Clin Med. 2020 Dec 13. 9 (12):[QxMD MEDLINE Link]. [Full Text].
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].

Media Gallery

Blood smear showing spherocytosis, polychromatophilia, and erythrophagocytosis by neutrophils.
Blood smear showing spherocytosis, polychromatophilia, and erythrophagocytosis by neutrophils.

of 2

Author

Trisha Simone Natanya Tavares, MD Contract Clinical Hematologist and Oncologist, Department of Pediatric Hematology and Oncology, Presbyterian Healthcare; Volunteer Hematology/Oncology Physician, St Vincent de Paul Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Lawrence C Wolfe, MD Associate Chief for Hematology and Safety, Division of Pediatric Hematology-Oncology, Cohen Children's Medical Center

Lawrence C Wolfe, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association of Blood Banks, American Society of Hematology, Children's Oncology Group, Eastern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

M Monica Gramatges, MD, PhD Associate Professor, Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine

M Monica Gramatges, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group

Disclosure: Nothing to disclose.

Acknowledgements

Nicolas A Camilo, MD Consulting Staff, Division of Pediatric Hematology-Oncology, Mountain States Tumor Institute, St Luke's Regional Medical Center

Nicolas A Camilo, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology