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Donath-Landsteiner Hemolytic Anemia

  • Author: Trisha Simone Tavares, MD, FAAP; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
 
Updated: Apr 07, 2014
 

Background

Two forms of cold antibody autoimmune hemolytic anemias are generally recognized: Donath-Landsteiner hemolytic anemia (DLHA) and cold agglutinin disease.

DLHA is an intravascular hemolytic anemia caused by a cold-reacting immunoglobulin (Ig). In the majority of patients, the antibody is directed specifically against the P or I antigen on the red blood cell (RBC) surface. Most cases are due to polyclonal IgG but IgM-induced DLHA has been described.[1, 2, 3]

In contrast to DLHA, cold agglutinin disease is always due to a cold-reacting IgM antibody. Cold agglutinin disease is described in a separate Medscape Reference article (see Cold Agglutinin Disease).

As early as 1865, it was known that exposure to cold may result in paroxysms of hemoglobinuria. Over the ensuing decades, the etiology of the condition was elucidated and a diagnostic test was developed.[4] In 1904, Donath and Landsteiner reported their characterization of the causative antibody.[5]

The discovery of the Donath-Landsteiner (D-L) antibody permits DLHA to be distinguished from other causes of hemoglobinuria,[6] and the presence of the D-L antibody is pathognomonic for the condition.

In most cases, DLHA is associated with a sudden onset of hemoglobinuria after exposure to cold temperature. It is important to note, however, that hemoglobinuria may be absent and is not required for diagnosis (see Workup). Furthermore, a history of cold exposure is not always obtained.

Treatment of DLHA depends on the severity of the signs and symptoms and the presence of an underlying cause. In children, the condition is usually transient and mild. In such cases, treatment consists of expectant management only. If the anemia is severe or rapidly progressive, however, supportive care with transfusions of packed red blood cells may be warranted. In select moderate or severe cases, medication administration is appropriate. (see Treatment).

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

Patient education

Teach patients to observe for signs and symptoms of anemia (eg, dyspnea, palpitations, fatigue, pallor) and to observe for signs of hemolysis (eg, jaundice, dark urine, pain). Instruct patients to avoid exposure to extreme cold, if possible. The possibility of hemolysis with strenuous exercise should also be discussed.

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Pathophysiology

The autoantibody responsible for Donath-Landsteiner hemolytic anemia (DLHA) is a cold-reacting immunoglobulin known as the D-L autoantibody. The D-L autoantibody is a biphasic hemolysin capable of causing severe hemolysis even when the titer detected is low. This is due to its ability to detach from lysed RBCs and subsequently bind intact erythrocytes with changes in temperature.

D-L antibodies are directed against antigens expressed on the RBC membrane. Most commonly, the target is the P antigen but I antigen specificity and others have been described.[3]

The antibody attaches to RBC surfaces in the peripheral circulation, where temperatures are cooler (< 30°C). After binding, the D-L autoantibody activates the complement cascade, resulting in perforation of the RBC membrane (ie, intravascular hemolysis). Complement activation and resulting hemolysis occur only after the RBC travels to an area of warmer temperature (37°C) in the central circulation.

Therefore, the direct antiglobulin test (DAT) results are positive with anti-C3 but negative with anti-IgG or anti-IgM, unless the test is begun at 4°C and subsequently incubated at 37°C (see Workup).[7]

The antibody typically appears days to weeks after the trigger and may persist for months.

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Etiology

Donath-Landsteiner hemolytic anemia (DLHA) may be either idiopathic or secondary to an identifiable cause. Historically, the secondary type is most closely associated with late-stage or chronic congenital syphilis. Acute cases are often deemed idiopathic but are generally presumed to be secondary to a preceding viral illness or to an immunization. A definitive causative agent is rarely identified.

Viral infections that have been associated with acute Donath-Landsteiner hemolytic anemia include the following:

Bacterial infections associated with acute DLHA include those caused by the following pathogens[7] :

Oncologic associations also exist. DLHA has been rarely associated with non-Hodgkin lymphoma[8, 9] and oat cell carcinoma.[10]

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Epidemiology

Acute autoimmune hemolytic anemia (AIHA) is relatively rare.[7]

Acute Donath-Landsteiner hemolytic anemia (DLHA) is more common in children than in adults. In children, the D-L autoantibody is a common cause of AIHA.

In one review of 52 patients with D-L antibodies, the median age was 5 years (range, 1-82 y).[11] Due to under-diagnosis, the true incidence is unknown but DLHA may represent 30-40% of all pediatric AIHA cases cases.[12]

DLHA appears to be more common in males (52 of 77 cases in 3 combined reviews), with a male-to-female ratio of 2.1:1.[13, 14]

No racial or ethnic predilection has been noted.

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Prognosis

Most patients with Donath-Landsteiner hemolytic anemia (DLHA) do not require intervention. In rare cases, a severe acute drop in hemoglobin may be life threatening. These children may develop hypovolemic shock and cardiac failure.

Another potential complication of DLHA is acute tubular necrosis due to hemoglobinuria.

In general, however, prognosis in DLHA is very good, with most patients recovering spontaneously within 1 month of disease onset.[15]

Mild chronic hemolytic anemia has been observed in several children with the possibility of recurrence on exposure to cold or with illness.

Analysis of cases of recurrent DLHA suggests that repeated episodes of hemolysis may be likely when the child has a D-L antibody to an antigen other than anti-P.[16, 3]

Chronic syphilis-associated DLHA resolves with appropriate treatment of the underlying disease.

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Contributor Information and Disclosures
Author

Trisha Simone Tavares, MD, FAAP Attending Physician, Department of Pediatrics, Section of Hematology/Oncology, Cardon Children's Medical Center

Trisha Simone Tavares, MD, FAAP is a member of the following medical societies: Children's Oncology Group

Disclosure: Nothing to disclose.

Coauthor(s)

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

M Monica Gramatges, MD 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.

Chief Editor

Max J Coppes, MD, PhD, MBA Executive Vice President, Chief Medical and Academic Officer, Renown Heath

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

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

Disclosure: Nothing to disclose.

Gary D Crouch, MD Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences

Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology

Disclosure: Nothing to disclose.

Michael R Jeng, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology, Stanford University School of Medicine

Michael R Jeng, MD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Histiocyte Society

Disclosure: Nothing to disclose.

Gary R Jones, MD Associate Medical Director, Clinical Development, Berlex Laboratories

Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Thomas W Loew, MD Clinical Professor of Pediatrics, Division Director of Pediatric Hematology/Oncology, University of Missouri Children's Hospital

Thomas W Loew, MD is a member of the following medical societies: American Academy of Pediatrics, American Academy of Pediatrics, American College of Physician Executives, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Children's Oncology Group

Disclosure: Genzyme Grant/research funds Independent contractor; Genzyme Honoraria Speaking and teaching; Amicus Grant/research funds Independent contractor; Purdue Pharmaceuticals Grant/research funds Independent contractor

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
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  2. 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. [Medline].

  3. 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. [Medline].

  4. 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.

  5. Donath J LK. Uber paroxysmale Hamoglobinurie. Munchener Medizinische Wochenschrift. 1904. 51:1590-3.

  6. Bird GW. Paroxysmal cold haemoglobinuria. Br J Haematol. 1977 Oct. 37(2):167-71. [Medline].

  7. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol. 2002 Apr. 69(4):258-71. [Medline].

  8. 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. [Medline].

  9. 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. [Medline].

  10. 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. [Medline].

  11. 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. [Medline].

  12. Petz LD. Cold antibody autoimmune hemolytic anemias. Blood Rev. 2008 Jan. 22(1):1-15. [Medline].

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  14. 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].

  15. 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. [Medline].

  16. 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. [Medline].

  17. Heddle NM. Acute paroxysmal cold hemoglobinuria. Transfus Med Rev. 1989 Jul. 3(3):219-29. [Medline].

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

  19. Hernandez JA, Steane SM. Erythrophagocytosis by segmented neutrophils in paroxysmal cold hemoglobinuria. Am J Clin Pathol. 1984 Jun. 81(6):787-9. [Medline].

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

  21. [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. [Medline]. [Full Text].

  22. 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. [Medline].

  23. 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. [Medline].

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