Donath-Landsteiner Hemolytic Anemia 

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

DLHA was first clinically described in 1872. Donath and Landsteiner demonstrated and 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 DLHA to be distinguished from other causes of hemoglobinuria such as cold agglutinin disease,^[2] and the presence of this 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 is not always observed 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, corticosteroid administration is also 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 risk of hemolysis with strenuous exercise should also be discussed.

The autoantibody responsible for Donath-Landsteiner hemolytic anemia (DLHA) 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 the antibody titer detected is low, because of its ability to detach from lysed RBCs and subsequently bind fresh erythrocytes with changes in temperature in the blood.

D-L antibodies are directed against the P antigen expressed on the RBC membrane. After binding in vivo, the D-L autoantibody activates the complement cascade, resulting in perforation of the RBC membrane (ie, intravascular hemolysis).

The antibody attaches to RBC surfaces in the peripheral circulation, where temperatures are cooler (< 30°C). Complement activation and resulting hemolysis occurs when the RBC subsequently 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, unless the test is begun at 4°C and subsequently incubated at 37°C (see Workup).^[3]

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

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. The causative agent is rarely identified.

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

• Measles
• Mumps
• Epstein-Barr virus (EBV)
• Cytomegalovirus (CMV)
• Varicella zoster virus
• Adenovirus
• Coxsackievirus A9
• Parvovirus
• Influenza A

Bacterial infections associated with acute Donath-Landsteiner hemolytic anemia include those caused by the following pathogens^[3] :

• Mycoplasma pneumoniae
• Haemophilus influenza
• Klebsiella pneumonia
• Escherichia coli

Oncologic associations also exist. Donath-Landsteiner hemolytic anemia has been rarely associated with non-Hodgkin lymphoma^{[4, 5]} and oat cell carcinoma.^[6]

Acute autoimmune hemolytic anemia is relatively rare, with an annual incidence of 1-3 cases per 100,000 population.^[3] The acute form of Donath-Landsteiner hemolytic anemia (DLHA) is more common in children than in adults. In childhood, the D-L autoantibody is one of the most common causes of acute autoimmune hemolytic anemia. It represents 30-40% of all pediatric cases.^[7] In one review of 52 patients with D-L antibodies, the median age was 5 years (range, 1-82 y).^[8]

DLHA is more common in males (52 of 77 cases in 3 combined reviews), with a male-to-female ratio of 2.1:1.^{[9, 10]}

No racial or ethnic predilection has been noted.

Although most patients recover without intervention, in rare cases, a severe acute drop in hemoglobin may be life threatening. Patients may present with hypovolemic shock and cardiac failure.

Another severe complication is acute tubular necrosis due to hemoglobinuria.

In general, however, prognosis in Donath-Landsteiner hemolytic anemia (DLHA) is very good, with most patients recovering spontaneously within 1 month of disease onset.^[11]

Occasionally, mild chronic hemolytic anemia has been observed, with the possibility of recurrence on exposure to cold.

Rarely, Donath-Landsteiner hemolytic anemia (DLHA) may be recurrent. One case of recurrent DLHA identified a Donath-Landsteiner (D-L) antibody to an antigen other than anti-P.^[12]

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