Practice Essentials
Two forms of cold antibody autoimmune hemolytic anemias are generally recognized: Donath-Landsteiner hemolytic anemia (DLHA) and cold agglutinin disease.
DLHA, also known as paroxysmal cold hemoglobinuria, 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] (Whipple et al reported a case of autoimmune hemolytic anemia in which paroxysmal cold hemoglobinuria was caused by an IgA Donath-Landsteiner [D-L] antibody. [4] )
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. [5] In 1904, Donath and Landsteiner reported their characterization of the causative antibody. [6]
The discovery of the D-L antibody has permitted DLHA to be distinguished from other causes of hemoglobinuria, [7] and the presence of the D-L antibody is pathognomonic for the condition.
Signs and symptoms of Donath-Landsteiner hemolytic anemia
The classic signs of DLHA include a sudden onset of hemoglobinuria accompanied by pallor and mild jaundice. [8] Patients and their caretakers may report dark, brown, black, or otherwise abnormally colored urine.
High fevers, chills, back or leg pain, and abdominal cramping may also be reported, along with headache, nausea, vomiting, or diarrhea.
Diagnosis and management of Donath-Landsteiner hemolytic anemia
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.
Laboratory testing is crucial to making the diagnosis of DLHA. Tests include complete blood count (CBC) and peripheral smear. The peripheral blood smear exhibits spherocytosis, polychromasia, nucleated red blood cells (RBCs), anisocytosis, poikilocytosis, and sometimes erythrophagocytosis by neutrophils. [8, 9]
Blood typing should be performed on all patients even if anemia is mild. This is important because the hemoglobin may fall acutely and transfusion may be needed.
The direct antiglobulin test (DAT) with anti-immunoglobulin (anti-Ig) G usually produces negative results because of dissociation of IgG from the RBC surface at warm temperatures.
The indirect antiglobulin test, if performed, must be carried out at a cold temperature. The Donath-Landsteiner bithermic hemolytic test is a hemolytic assay in which the patient's serum is incubated with normal RBCs and complement at 0-4°C to allow the early components of complement to be fixed. Subsequently, the specimen is incubated at 37°C in order to allow the later components of complement to be activated. The membrane attack complex lyses the RBCs.
Other tests include blood chemistry and serology, as well as urinalysis. On serologic testing, results for syphilis, mycoplasmal infection, or viruses (eg, influenza A, measles, mumps, adenovirus, cytomegalovirus, varicella, Epstein-Barr virus [EBV]) may be positive, depending on the underlying cause.
Definitive diagnosis requires performance of the Donath-Landsteiner test. There are several methods of performing this test, and sensitivity varies between assays; false-negative results may occur. [10]
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.
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). [11]
The antibody typically appears days to weeks after the trigger and may persist for months.
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:
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Adenovirus
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Coxsackievirus A9
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Parvovirus
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Influenza A
Respiratory syncytial virus (RSV) has been reported to have caused paroxysmal cold hemoglobinuria in a child, while Leibrandt et al reported the first documented case in which RSV caused the disease in an adult. [12, 13]
Bacterial infections associated with acute DLHA include those caused by the following pathogens [11] :
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Klebsiella pneumonia
Oncologic associations also exist. DLHA has been rarely associated with non-Hodgkin lymphoma [14, 15] and oat cell carcinoma. [16]
Epidemiology
Acute autoimmune hemolytic anemia (AIHA) is relatively rare. [11]
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. However, the condition can occur in patients of all ages, and the diagnosis should be considered when the clinical and laboratory presentations are suggestive of the disorder. [17, 18]
A literature review by Jacobs et al indicated that the epidemiology of DLHA has changed since the mid-20th century. Although currently DLHA generally arises in children, following acute infection, most often upper respiratory infection and gastroenteritis, the investigators reported that between 1950 and 1970, syphilis was present in 53% of patients diagnosed with DLHA. Individuals with DLHA during this 20-year period had a median age of 31 years, with the median age of those whose disease was secondary to syphilis being 42 years. The epidemiology of DLHA is thought to have been impacted by the widespread employment of antitreponemal therapy. [19]
In one review of 52 patients with D-L antibodies, the median age was 5 years (range, 1-82 y). [20] Due to under-diagnosis, the true incidence is unknown but DLHA may represent 30-40% of all pediatric AIHA cases cases. [21]
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. [22, 23] Estimates differ, however, with the study by Jacobs and colleagues reporting the male-to-female ratio to be nearly equal, at 1.17:1, and the ratio in children aged 5 years or under to be 1.25:1. [19]
No racial or ethnic predilection has been noted.
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. [24]
Mild chronic hemolytic anemia has been observed in several children with the possibility of recurrence on exposure to cold or with illness. [17]
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. [25, 3]
Chronic syphilis-associated DLHA resolves with appropriate treatment of the underlying disease.
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Blood smear showing spherocytosis, polychromatophilia, and erythrophagocytosis by neutrophils.
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Blood smear showing spherocytosis, polychromatophilia, and erythrophagocytosis by neutrophils.
