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Pediatrics: General Medicine > Hematology
Paroxysmal Cold Hemoglobinuria
Article Last Updated: Aug 10, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Thomas W Loew, MD, Director, Clinical Associate Professor of Pediatrics, Pediatric Hematology/Oncology Subspecialty Training Program, University of Iowa Hospitals and Clinics
Thomas W Loew is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Clinical Oncology, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Coauthor(s):
Nicolas A Camilo, MD, Consulting Staff, Mountain States Tumor Institute, Division of Pediatric Hematology-Oncology, St Luke's Regional Medical Center
Editors: Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Author and Editor Disclosure
Synonyms and related keywords:
Donath-Landsteiner syndrome, PCH, cryopathic hemolytic syndrome, Donath-Landsteiner hemolytic anemia, cold-induced immune hemolytic anemia, autoimmune hemolytic anemia, AIHA, intravascular hemolysis, anemia, blood disorder, blood disease, cold exposure, biphasic hemolysin
Background
Paroxysmal cold hemoglobinuria (PCH), also known as Donath-Landsteiner syndrome, is characterized by a sudden onset of hemoglobinuria either spontaneously or after exposure to cold. PCH is one type of cryopathic hemolytic syndrome, which includes 2 types of autoimmune hemolytic anemias due to cold-reacting autoantibodies. The second type, cold agglutinin disease, is described in a separate eMedicine article (see Cold Agglutinin Disease).
Pathophysiology
The autoantibody responsible for PCH is a cold-reacting polyclonal immunoglobulin G (IgG) known as the Donath-Landsteiner autoantibody. The event triggering autoantibody formation may be a microorganism antigen that induces antibodies that cross-react with the P antigen in the red blood cell (RBC) membrane. The P antigen is a glycosphingolipid globoside that is similar to glycolipids in many microorganisms. The Donath-Landsteiner autoantibody is a biphasic hemolysin capable of causing severe hemolysis even when present in low titers. The autoantibody binds to the RBCs at cooler temperatures. Complement lysis occurs at warmer temperatures. Occasionally, the autoantibody may be monophasic; it may have a wide thermal amplitude and be able to bind the RBCs at warmer temperatures, when complement activity is possible. The hemolysis is due to complement fixation and is intravascular.
Frequency
United States
PCH may be responsible for more than 40% of autoimmune hemolytic anemias in children younger than 5 years.
Race
No race predilection exists.
Sex
No predilection exists for either sex.
Age
The acute transient form of PCH is more common in children than adults.
History
The classic symptom of PCH is a sudden onset of hemoglobinuria following exposure to cold, even for a few minutes. Symptoms may occur minutes to hours following exposure to cold. Hemoglobinuria is not always present because, in some persons with PCH, the autoantibody level is not high enough to cause intravascular hemolysis. In other individuals with PCH, hemolysis may occur spontaneously without exposure to cold. Anemia may range from mild to severe. A recent respiratory or other viral infection is common.
- Symptoms of anemia
- Pallor
- Fatigue
- Dyspnea
- Poor feeding
- Symptoms of hemolysis
- Jaundice
- Dark urine caused by hemoglobinuria
- Systemic symptoms
- Fever, rigors
- Pain or cramps in the back, legs, or abdomen
- Headache
- Nausea, vomiting, diarrhea
- Vasomotor symptoms
- Cold urticaria
- Tingling of the hands and feet
- Cyanosis
- Raynaud phenomenon
- Gangrene
Physical
- A fever as high as 40°C is common.
- Signs of anemia include pallor and tachycardia.
- Signs of congestive heart failure or shock are rare but may be present when anemia is severe.
- Signs of hemolysis include jaundice and splenomegaly.
- Vasomotor signs include cyanosis, Raynaud phenomenon, and gangrene.
Causes
The 3 main causes of PCH are congenital or tertiary syphilis, a postinfectious and/or postvaccination etiology, and idiopathic and/or autoimmune causes. PCH associated with chronic syphilis was previously common but now is observed rarely. Acute transient postinfectious PCH is more common. Chronic idiopathic and/or autoimmune PCH is rare.
- PCH associated with chronic congenital or tertiary syphilis
- Acute transient postinfectious and/or postvaccination PCH
- Viral infections, including measles, mumps, influenza A, adenovirus, varicella, cytomegalovirus, and Epstein-Barr virus
- Bacterial infections, including Haemophilus influenzae and Mycoplasma pneumoniae
- Vaccines, including measles vaccine
- Chronic idiopathic and/or autoimmune PCH
Anemia, Acute
Anemia, Chronic
Cold Agglutinin Disease
Evans Syndrome
Lymphoproliferative Disorders
Mononucleosis and Epstein-Barr Virus Infection
Non-Hodgkin Lymphoma
Syphilis
Systemic Lupus Erythematosus
Other Problems to be Considered
Autoimmune hemolytic anemia due to warm antibodies
Hemolytic anemia
Other causes of hematuria, including renal disorders
Lab Studies
- Hematology
- Anemia may be mild, moderate, or severe. Anemia is usually normocytic normochromic. However, the mean corpuscular volume (MCV) may be elevated when reticulocytosis is present.
- Reticulocytopenia is often present in the early stages. Eventually, reticulocytosis develops.
- Leukopenia may be present early. The leukocyte count is usually normal or high. Leukocytosis may be present during hemolytic episodes.
- Smear exhibits spherocytosis, polychromatophilia, nucleated RBCs, and sometimes erythrophagocytosis by neutrophils (see Images 1-2). Schistocytes are usually not present.
- Blood bank
- Perform blood typing in the event that a blood transfusion is needed.
- The presence of autoantibodies may interfere with blood typing.
- The autoantibody may react with the RBCs of all potential donors, making detection of alloantibodies difficult. Compatibility testing can be improved by performing the test at 37°C.
- Direct antiglobulin test (DAT) with anti-IgG produces negative results because of dissociation of IgG from the RBC surface at warm temperatures.
- DAT may occasionally produce positive results if run at a cold temperature.
- DAT results are positive with anticomplement.
- The Donath-Landsteiner IgG autoantibody may be detected with the indirect antiglobulin test if it is performed at a cold temperature using anti-IgG.
- Assays using labeled monoclonal anti-IgG are preferable.
- The autoantibody is IgG with anti-P specificity, although the specificity may be for other antigens.
- The titer is usually less than 1:100.
- Perform the Donath-Landsteiner bithermic hemolytic test by incubating normal RBCs with the patient's serum and a source of complement at 4°C for 30 minutes, then at 37°C for 30 minutes.
- The presence of hemolysis constitutes a positive test result.
- The Donath-Landsteiner test has a low sensitivity.
- Sensitivity can be increased by using RBCs from patients with paroxysmal nocturnal hemoglobinuria instead of normal RBCs.
- Blood chemistry
- Indirect bilirubin, lactate dehydrogenase, and plasma hemoglobin are elevated.
- BUN and creatinine levels may be elevated if renal insufficiency is present.
- Complement levels are decreased.
- Urinalysis
- Hemoglobinuria, methemoglobinuria, and hemosiderinuria are demonstrated.
- Proteinuria may be present.
- Serology: Tests results for syphilis, mycoplasmal infection, and viruses (eg, influenza A, measles, mumps, adenovirus, cytomegalovirus, varicella, Epstein-Barr virus) may be positive depending on the underlying cause.
Medical Care
Treatment of PCH depends on the severity of the disease and the presence of an underlying cause. In children, PCH is usually transient.
- Supportive care includes avoidance of cold exposure and judicious use of RBC transfusions.
- RBC transfusion is indicated when anemia is severe or symptomatic.
- Perform compatibility testing using the techniques described above to minimize the interference caused by the autoantibody (see Workup).
- Although most banked blood units are P antigen positive, blood transfusion may be safely accomplished in most patients and result in the expected hemoglobin increases based on the amount administered.
- Use blood warmers to perform the RBC transfusion at 37°C.
- Viral infections are self-limited. Treat syphilis and mycoplasma infections with appropriate antibiotics.
- Prednisone may be indicated in patients with PCH and severe anemia.
Surgical Care
- Splenectomy
- Splenectomy usually has no role in the treatment of PCH.
- However, splenectomy may be indicated in severe chronic PCH that is refractory to medical therapy and caused by an autoantibody with a high thermal maximum.
Consultations
Consult a hematologist and/or blood bank specialist to aid in the diagnosis and treatment of PCH.
Activity
- Advise patients with anemia to avoid strenuous exercise.
- Advise patients with PCH to avoid exposure to cold and hypothermia.
Prednisone may be effective in controlling hemolysis. However, evidence for effectiveness in PCH is anecdotal.
Drug Category: Glucocorticoids
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.
| Drug Name | Prednisone (Deltasone, Meticorten, Orasone, Sterapred) |
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| Description | Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. |
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| Adult Dose | 60 mg/d PO qd or divided bid/tid; taper over 2 wk as symptoms resolve |
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| Pediatric Dose | 2 mg/kg/d PO divided bid/tid; taper over 2 wk as symptoms resolve |
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| Contraindications | Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease |
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| Interactions | Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use |
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Further Inpatient Care
- Indications for hospitalization
- Severe anemia
- Respiratory or circulatory compromise
- Renal failure
- Severe infection
- Other complications
Further Outpatient Care
- Perform the following evaluations weekly until the patient is stable, then monthly until PCH resolves:
- Clinical examination
- Complete blood count
- Reticulocyte count
- Urinalysis
- Perform direct antiglobulin test monthly until PCH resolves.
Transfer
- Transfer patients with severe anemia or complications to a facility where pediatric hematology/oncology, blood bank, and pediatric intensive care services are available.
Deterrence/Prevention
- Currently, prevention of PCH is not possible. For chronic idiopathic PCH, avoidance of cold exposure is important to prevent symptoms from occurring.
Complications
- Complications in individuals with PCH are rare.
- Severe anemia
- Respiratory or circulatory compromise due to severe anemia, including congestive heart failure and shock
- Renal failure due to hemolysis
Prognosis
- Acute PCH is usually transient and self-limiting.
- Chronic idiopathic PCH is usually mild and responds to general measures, such as avoidance of cold exposure.
- Chronic syphilis-associated PCH resolves with treatment of syphilis with appropriate antibiotics.
Patient Education
- Teach patients to observe for symptoms of anemia (eg, dyspnea, palpitations, pallor) and to observe for symptoms of hemolysis (eg, jaundice, dark urine).
- Instruct patients to avoid exposure to cold and strenuous exercise.
Medical/Legal Pitfalls
- The diagnosis of PCH depends on the performance of the specific test to detect the autoantibody, the Donath-Landsteiner autoantibody. The clinician must have a high index of suspicion. PCH can be confused with cold agglutinin disease and with warm-antibody autoimmune hemolytic anemia.
- Limit the use of prednisone to individuals with severe disease. Overuse of prednisone may lead to unnecessary risk.
- Blood transfusion is indicated only in selected individuals with PCH. Avoid unnecessary transfusions because of the transient nature of the disease. Risks of blood transfusion include transfusion reactions and transmission of infection.
| Media file 1:
Blood smear showing spherocytosis, polychromatophilia, and erythrophagocytosis by neutrophils. |
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Media type: Photo
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| Media file 2:
Blood smear showing spherocytosis, polychromatophilia, and erythrophagocytosis by neutrophils. |
 | View Full Size Image | |
Media type: Photo
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Paroxysmal Cold Hemoglobinuria excerpt Article Last Updated: Aug 10, 2006
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