Medical Care
The mainstay of treatment for paroxysmal cold hemoglobinuria is supportive care and the avoidance of cold exposure. Patients require hospitalization to monitor and treat complications associated with severe anemia secondary to massive hemolysis.
During inpatient treatment maintain the patient's cardiorespiratory function and hydration status. Daily laboratory evaluation of anemia should include complete blood cell counts, lactate dehydrogenase (LDH) levels, and reticulocyte counts. Hemoglobinuria is monitored with routine urinalysis. Once hemolysis is suspected, folic acid 1 mg/d orally should be instituted to help with erythropoiesis. Folic acid is lost via the hemolytic process and hence needs to be replenished.
Transfuse warmed, packed red blood cells (RBCs) for life-threatening hemolysis and symptomatic anemia. Utilizing washed RBC units has not been proven to improve transfusion safety, but this can be done if the patient's condition remains refractory to standard warmed products.
As most of the blood supply is P-antigen positive, finding phenotypic p, also called Tj(a-), blood may not be feasible. However, the antibody should not interfere with donor cell survival, nor should it be problematic with pretransfusion and compatibility testing, as the pathogenic immunoresponse does not occur at normal body temperatures. Treat the uncommon chronic form with RBC transfusions only when severe exacerbation occurs.
Plasma exchange therapy with 5% albumin fluid replacement has been successfully employed. [38] Normal use of plasmapheresis for removal of IgG-induced processes is not as effective due to rebound of immunoglobulin as it shifts from the extravascular to the intravascular compartment. However, due to the low titer and limited production period of the Donath-Landsteiner (D-L) antibody, the process can be effectively controlled. Another theory is that the antibody preferentially binds to the RBC, shifting the antibody equilibrium to the intravascular component, allowing for ease in its removal. [47]
Secondary causes of paroxysmal cold hemoglobinuria should be evaluated (eg, with viral and bacterial serologic and culture assays, imaging studies). Treat underlying secondary conditions with appropriate medical therapy.
Hydration, alkalinization of the urine, and other measures may become necessary to prevent kidney failure. Symptoms of cold urticaria may be ameliorated by antihistamines.
No pharmaceutical agents have consistently shown benefit for reversal of paroxysmal cold hemoglobinuria. Case reports describe use of corticosteroids, rituximab, intravenous IgG, and eculizumab. [50, 51] Steroids are commonly employed, but these agents have not been shown to shorten the clinical course of paroxysmal cold hemoglobinuria. Eculizumab led to rapid and complete resolution of acute paroxysmal cold hemoglobinuria in a 4-year-old boy, which should encourage further investigation into complement-directed therapies in this setting. [51] However, in an adult patient with chronic paroxysmal cold hemoglobinuria, eculizumab substantially improved intravascular hemolysis improved substantially but anemia persisted, presumably due to extravascular hemolysis. [52]
Consultations
A hematologist-oncologist and an infectious diseases expert may be helpful for the proper diagnosis and treatment of paroxysmal cold hemoglobinuria. A nephrologist may also be consulted as needed to assist in the care of affected patients.
The support of an experienced laboratory/blood bank is essential for all the serologic testing.
Diet
Folic acid supplements may be useful in the chronic form of paroxysmal cold hemoglobinuria. Encourage patients to eat fresh fruits and vegetables rich in folate.
Activity
Patients with paroxysmal cold hemoglobinuria should limit activities while severely anemic or if complications such as renal insufficiency are present. Avoid activities in the outdoors that are likely to result in cold exposure. Patients with the chronic form of the disease must wear proper clothes and garments to protect the extremities from becoming chilled.
Prevention
In patients with the chronic form of paroxysmal cold hemoglobinuria, avoiding exposure to cold is essential to prevent recurrent episodes of hemolysis. These patients should avoid activities that would increase their likelihood of being chilled, such as jogging outside in cold weather and handling of cold objects that can alter the body's peripheral thermal property.
Long-Term Monitoring
When the acute phase of paroxysmal cold hemoglobinuria is over, several follow-up visits for assessment of blood counts to ensure recovery may be all that is necessary, with instructions to patients to avoid cold exposure. Confirming that the D-L antibody test result is no longer positive may be valuable on subsequent regular checkups; however, note that low titers of the antibody may persist for several years after an acute episode. Appropriate treatment and follow-up care for syphilis or other infections are needed until the conditions are deemed cured or in remission.
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A Donath-Landsteiner test result is seen here, showing the appearance of a negative tube (no hemolysis in the supernatant) and a positive tube (red color in the supernate, implying the presence of free hemoglobin).
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Workup for hemolytic anemia. Abbreviations: LDH, lactate dehydrogenase; DAT, direct antiglobulin; AIHA, autoimmune hemolytic anemia; WAIHA, warm autoimmune hemolytic anemia; CAIHA, cold autoimmune hemolytic anemia; PCH, paroxysmal cold hemoglobinuria; Ab, antibody.
