eMedicine Specialties > Pediatrics: General Medicine > Hematology

Donath-Landsteiner Hemolytic Anemia

Author: M Monica Gramatges, MD, Fellow in Pediatric Hematology/Oncology, Stanford University
Coauthor(s): Michael R Jeng, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology, Stanford University School of Medicine
Contributor Information and Disclosures

Updated: May 19, 2009

Introduction

Background

Two forms of cold antibody autoimmune hemolytic anemias are recognized: Donath-Landsteiner hemolytic anemia (DLHA) and cold agglutinin disease. Donath-Landsteiner hemolytic anemia is an intravascular hemolytic anemia caused by a cold-reacting immunoglobulin (Ig)G antibody directed specifically against the P antigen on the RBC surface. In contrast, cold agglutinin disease is due to a cold-reacting IgM antibody and is described in a separate eMedicine article (see Cold Agglutinin Disease).

Donath-Landsteiner hemolytic anemia was first clinically described in 1872. Donath and Landsteiner first characterized the causative antibody in 1904.¹   Previously, the disease had been referred to as paroxysmal hemoglobinuria and likely included various now known types of hemolytic disease. The discovery of the Donath-Landsteiner (D-L) antibody permits Donath-Landsteiner hemolytic anemia to be distinguished from other causes of hemoglobinuria such as cold agglutinin disease,² and the presence of this antibody is pathognomonic for the disease.

In most cases, Donath-Landsteiner hemolytic anemia is associated with a sudden onset of hemoglobinuria that may or may not be precipitated by exposure to cold. Of note, hemoglobinuria is not always observed and is not required for diagnosis of this disease.

Pathophysiology

The autoantibody responsible for Donath-Landsteiner hemolytic anemia is a cold-reacting polyclonal IgG known as the D-L autoantibody. The D-L autoantibody is a biphasic hemolysin capable of causing severe hemolysis, even when present in low titers. These antibodies are directed against the P antigen expressed on the RBC membrane. The antibody then activates a complement cascade, resulting in perforation of the RBC membrane and intravascular hemolysis.

The antibody attaches to RBC surfaces at cooler temperatures (<30ºC) in the peripheral circulation. Complement is activated, causing hemolysis, when the RBC travels to warmer temperatures (37ºC) in the central circulation. Therefore, the direct antiglobulin test (DAT) results are positive with anti-C3 but negative with anti-IgG, unless the test is performed at 4ºC and then incubated at 37ºC (see Laboratory Studies).³

The antibody typically appears a week after the onset of an illness and may persist for as long as 3 months.

Frequency

United States

Acute autoimmune hemolytic anemia is relatively rare, with an incidence of 1-3 cases per 100,000 population per year.³ However, Donath-Landsteiner hemolytic anemia is one of the most common causes of acute autoimmune hemolytic anemia in childhood, representing 30-40% of cases.⁴

Mortality/Morbidity

Most cases of Donath-Landsteiner hemolytic anemia resolve spontaneously. However, in rare cases, a severe acute drop in hemoglobin may be life-threatening and may present with shock and cardiac failure. Renal failure as a result of hemoglobinuria is also a concern. A chronic, mild hemolytic anemia has been observed.

Race

No race predilection is noted.

Sex

Donath-Landsteiner hemolytic anemia is more common in males (52 of 77 cases in 3 combined reviews), with a male-to-female ratio of 2.1:1.^5,6

Age

The acute form of Donath-Landsteiner hemolytic anemia is more common in children than adults. In a review of 52 patients identified as having D-L antibodies, the median age was 5 years (range, 1-82 y).⁷

Clinical

History

• The classic symptoms of Donath-Landsteiner hemolytic anemia (DLHA) include sudden onset of hemoglobinuria accompanied by pallor and mild jaundice.⁸  The hemoglobinuria resolves spontaneously, and a preceding history of upper respiratory infection or other viral infection is common, particularly in the younger age group. Preceding exposure to cold may be observed but may not be elicited from the patient history.³  In fact, only one in 52 cases of Donath-Landsteiner hemolytic anemia reported by Sokol et al occurred after exposure to cold.⁷
• Anemia may be mild or moderate; however, the fall in hemoglobin levels is often dramatic and severe, with approximately two thirds of patients requiring blood transfusion. Note that hemoglobinuria may not be present if the autoantibody level is not high enough to cause intravascular hemolysis.
• High fevers, chills, back or leg pain, and abdominal cramping may also be reported, along with headache, nausea and vomiting, and diarrhea; these symptoms resolve early on in the clinical course. Hepatosplenomegaly may be noted in 25% of patients.

Physical

• Symptoms of anemia include the following:
  • Pallor
  • Tachycardia
  • Fatigue
  • Dyspnea 
• Symptoms of hemolysis include the following:
  • Jaundice
  • Dark urine caused by hemoglobinuria 
• Systemic symptoms include the following:
  • Fever, rigors
  • Pain or cramps in the back, legs, or abdomen
  • Headache
  • Nausea, vomiting, diarrhea 
• Vasomotor symptoms include the following:
  • Cold urticaria
  • Cyanosis
  • Raynaud phenomenon

Causes

• Donath-Landsteiner hemolytic anemia may be either idiopathic or secondary, with the secondary type attributed to late stage or congenital syphilis in chronic cases. Acute cases may be idiopathic but are often presumed to be secondary and are preceded by a viral upper respiratory illness. However, a causative agent is rarely identified. 
• Viral infections that have been associated with acute Donath-Landsteiner hemolytic anemia include measles, mumps, Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella zoster virus, adenovirus, coxsackie A9, parvovirus, and influenza A. 
• Bacterial infection associations include Mycoplasma pneumoniae, Haemophilus influenza, Klebsiella pneumoniae, and Escherichia coli.³
• Donath-Landsteiner hemolytic anemia has also been rarely associated with non-Hodgkin lymphoma^9,10 and oat cell carcinoma.¹¹

• Search for CME/CE on This Topic »

• Cold Agglutinin Disease (Pediatrics: General Medicine)
• Hemoglobinuria, Paroxysmal Cold (Hematology)