Information on the following diseases can be found in the Related Disorders section of this report:

• Paroxysmal Nocturnal Hemoglobinuria
• Cold Antibody Hemolytic Anemia

Attacks of paroxysmal cold hemoglobinuria (PCH) can occur within minutes of, or up to eight hours after, exposure to cold. Symptoms may include fever, malaise, anorexia, flank pain, pain in the back and legs, headache, vomiting, diarrhea, mild anemia, and the passage of dark brown urine (hemoglobinuria). This urine contains the iron-bearing, oxygen transporting, protein pigment of blood called hemoglobin. The presence of hemoglobin causes the dark brown color of the urine. Attacks of paroxysmal cold hemoglobinuria may be followed by yellowing of the skin (jaundice). There may also be enlargement of the liver and spleen (hepatosplenomegaly).
.

Most cases of paroxysmal cold hemoglobinuria occur after a viral infection such as chickenpox or mumps, or in conjunction with congenital or acquired syphilis. Cases that involve children tend to be acute and self-limited. Cases involving adults run a more chronic, relapsing course. With the dramatic decline in the prevalence of syphilis, PCH in adults has declined, and the current understanding of the adult form of the disease is less clear.

Paroxysmal cold hemoglobinuria may also affect individuals with no history of another disorder. In these cases, the cause is unknown.

When the disorder follows a viral infection, it appears that the virus generates a specific biochemical response (antigen) that cross-reacts with another antigen found in red blood cells. The product of this reaction is an agent with considerable powers to cause the red blood cell walls to disintegrate.

Autoimmune disorders are caused when the body’s natural defenses against "foreign" or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. In individuals affected with paroxysmal cold hemoglobinuria, this occurs when red blood cells are attacked as if they were a virus or bacteria. Localized exposure to cold such as washing one's hand in cold water or drinking cold water may also trigger an attack in some severe cases.
.

Anyone may acquire paroxysmal cold hemoglobinuria, but it is more common among children than among adults. An individual with a viral infection such as chickenpox or mumps, or anyone affected with syphilis, is at higher risk of contracting the disorder. No known genetic, sex, or racial risk factors exist, although the disease has been reported in families. Incidence is approximately equal in men and women.
.

Symptoms of the following disorders can be similar to those of Paroxysmal Cold Hemoglobinuria. Comparisons may be useful for a differential diagnosis:

Paroxysmal Nocturnal Hemoglobinuria is a form of anemia resulting from defects in the membranes of red blood cells. It is characterized by the presence of hemoglobin in the urine (hemoglobinuria) chiefly occurring at night. Symptoms of Paroxysmal Nocturnal Hemoglobinuria include severe abdominal or back pain occurring during the phase where the oxygen carrying portion of the red blood cell (hemoglobin) is released from the red blood cells (hemolysis). Other symptoms may include blood in the urine, yellowing of the skin (jaundice) and enlargement of the liver and spleen. (For more information on this disorder, choose "Paroxysmal Nocturnal Hemoglobinuria" as your search term in the Rare Disease Database.)

Cold Antibody Hemolytic Anemia is a rare autoimmune disorder in which red blood cells are attacked and destroyed by the body's natural defenses in temperatures of 15 degrees Centigrade or below. Symptoms of Cold Antibody Hemolytic Anemia may include weakness, dizziness, headache, ringing in the ears (tinnitus), spots before the eyes, fatigue, drowsiness, irritability or bizarre behavior. Absent menstruation, gastrointestinal complaints, yellowing of the skin, and enlargement of the spleen may also occur. Heart failure or shock may result. More rarely, there may be a passing of dark urine (hemoglobinuria). (For more information on this disorder, choose "Cold Antibody Hemolytic Anemia" as your search term in the Rare Disease Database.)

Most cases terminate spontaneously and only require supportive therapy for a few days to weeks after onset. Strict avoidance of cold temperatures is the most important preventive measure to protect against the breaking down of red blood cells and liberation of hemoglobin (hemolysis).

When transfusion is necessary due to severe anemia, it should not be delayed. Use of a blood warmer during transfusion is particularly important.

Due to the transient nature of the disease in children, most are in the recovery phase of the illness at the time symptoms become apparent. Most cases that involve children and are linked to a viral infection require only supportive therapy, bed rest, and protection of the affected individual from cold temperatures.
.

TEXTBOOKS
Depcik-Smith N, Brecher ME. Paroxysmal Cold Hemoglobinuria. In: NORD Guide to Rare Diseases. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:388-89.

Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:874.

Schreiber AD. Autoimmune hemolytic anemias. In: Bennett JC, Plum F. Eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996:859-68 [863].

Packman CH, Leddy JP. Cryopathic hemolytic syndromes. In: Beutler E, Lichtmen MA, Collier BS, et al. eds. William’s hematology, 6th ed. New York: McGraw-Hill, 2001:649-53.

REVIEW ARTICLES
Gehrs BC, Friendberg RC. Autoimmune hemolytic anemia. Am J Hematol. 2002;69:258-71.

Petz LD. Treatment of autoimmune hemolytic anemia. Curr Opin Hematol. 2002;8:411-16.

JOURNAL ARTICLES
Roy-Burman A, Glader EE. Resolution of severe Donath-Landsteiner autoimmune hemolytic anemia temporarily associated with institution of plasmapheresis. Crit Care Med. 2002;30:931-34.

Depcik-Smith ND, Escobar MA, Ma AD, et al. Transfusion Medicine Illustrated: RBC rosetting and erythrophagocytosis in adult paroxysmal cold hemoglobinuria. Transfusion. 2001;41:163.

Gottshe B, Salama A, Mueller-Eckhardt C. Donath-Landsteiner autoimmune hemolytic anemia in children: a study of 22 cases. Vox Sang. 1990;58:281-86.

Heddle NM. Acute paroxysmal cold hemoglobinuria. Trans Med Rev. 1989;3:219-29.

JefferiesLC. Transfusion therapy in autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 1994;8:1087-104.

FROM THE INTERNET
Elstrom R. MEDLINEplus. Medical Encyclopedia. Paroxysmal cold hemoglobinuria. 2pp.
www.nlm.nih.gov/medlineplus/ency/article/000557.htm

Moses. S. Paroxysmal Cold Hemoglobinuria. In: Family Practice Notebook. Last revised; 9/29/2002:2pp.
www.fpnotebook.com/HEM54.htm

Camilo NA. Paroxysmal Cold Hemoglobinuria. eMedicine. Last Updated; October 1, 2002:9pp.
www.emedicine.com/ped/topic512.htm