Practice Essentials
Paroxysmal cold hemoglobinuria (PCH) is a form of autoimmune hemolytic anemia (AIHA) that, while rare, is nevertheless one of the most common causes of acute AIHA in young children. In PCH, the red blood cells are targeted by an autoantibody, the Donath-Landsteiner antibody, whose formation is most often triggered by infectious disease or neoplasms. [1]
Episodes of PCH typically develop within minutes to a few hours after exposure to cold temperatures. Patients present with a combination of the following: sudden onset of back and abdominal pain, headache, leg cramps, fever, rigors, chills, nausea, vomiting, diarrhea, and esophageal spasms. Severe hemoglobinuria is commonly detected during the acute event, resulting in a red-brown discoloration to the urine. See Presentation.
The mainstay of treatment for PCH is supportive care and the avoidance of cold exposure. Warmed, packed RBC transfusions are used for life-threatening hemolysis and symptomatic anemia. See Treatment. Acute episodes of PCH are generally transitory and recurrence is rare.
Background
Paroxysmal cold hemoglobinuria (PCH) has the distinction of being the first, albeit rarest, type of autoimmune hemolytic anemia (AIHA) to be identified. This condition was first described in 1854 as an abrupt onset of systemic manifestations, including severe anemia and hemoglobinuria, occurring upon exposure to cold temperatures and resulting from massive intravascular hemolysis.
At the beginning of the 20th century, Julius Donath and Karl Landsteiner advanced the understanding of the pathophysiology of this disorder when they discovered a unique "biphasic hemolysin" in blood that could be demonstrated in the laboratory. This antibody attached to red blood cells (RBCs) in the cold and induced hemolysis when the RBCs are warmed due to complement activity. Together these investigators devised and published in 1904 what was to be the first immunohematologic test, referred to as the Donath-Landsteiner test. [2, 3, 4, 5] (See Workup/Laboratory Studies.)
In the latter half of the 19th century, the most common cause of paroxysmal cold hemoglobinuria was congenital or adult tertiary-stage syphilis. The ability to cure syphilis with antibiotics resulted in the near elimination of this secondary cause of the chronic form of the disorder. Currently, episodes of paroxysmal cold hemoglobinuria usually occur after a viral infection and are abrupt in onset and transitory. A study of children found that as many as 40% of immune hemolytic anemias were due to the Donath-Landsteiner (D-L) antibody. [6, 7]
Although most cases of paroxysmal cold hemoglobinuria occur as an acute event in children younger than 5 years, recurrent episodes have been reported. [7, 8, 9, 10, 11] . Most cases occur in young boys with a reported boy:girl ratio of 2:1. The incidence rate does not appear to vary by ethnicity. [12] Furthermore, because the D-L antibody does not necessarily occur with a specific cold exposure event, nor is it recurrent in nature, renaming paroxysmal cold hemoglobinuria as Donath-Landsteiner hemolytic anemia has been proposed. [13]
With an underlying disease that is controllable or self-limited, the process may resolve spontaneously and quickly. Unfortunately, due to the transitory nature of paroxysmal cold hemoglobinuria, lack of awareness may lead to a failure in recognizing and diagnosing this uncommon syndrome.
Pathophysiology
The antibody thermal activity range of paroxysmal cold hemoglobinuria is simlar to that of cold hemagglutinin disease (CHD), the more common cold variant of autoimmune hemolytic anemia. However, the D-L antibody is not a monophasic immunoglobulin M (IgM), but rather a biphasic, usually polyclonal, IgG. The D-L antibody is known to bind to various antigens such as I-, i-, p-, Pr-, on the RBC surface, but the glycosphingolipid P antigen is considered its primary target. [7]
This interaction sensitizes the erythrocytes to allow further interaction with the complement system. However, unlike cold hemagglutinin disease, in which the IgM-complement interaction results in the cells' removal (via extravascular phagocytosis), paroxysmal cold hemoglobinuria occurs upon completion of complement lysis within the vascular circulation. Intravascular hemolysis occurs preferentially at 37°C, at which temperature the antibody activates the classical complement cascade, providing the biphasic nature of the disease of D-L antibody binding at cold temperatures and hemolysis at wamer temperatures.
The exact etiology of the D-L antibody is unknown. There is a close temporal relationship observed between the development of paroxysmal cold hemoglobinuria within 2-3 weeks of viral or bacterial upper respiratory or gastrointestinal infections. Young children are the most susceptible, developing a single, brief, postviral hemolytic episode. [3, 14]
The stimulus for production of this antibody is likely a form of molecular mimicry in which a microorganism's antigen shares structural similarity to the P antigen on human RBCs, resulting in immunogenic cross-reactivity. [4] Interestingly, the P antigen has also been found on lymphocytes and skin fibroblasts; the latter is thought to be the reason for the development of urticaria in persons with paroxysmal cold hemoglobinuria. It has even been suggested that viral alteration of the P antigen on RBCs can cause the immune system to create autoantibodies to this slightly altered P antigen. Finally, there is the possibility of post-viral decreased T suppressor cell activity contributing to autoreactive antibody formation. [12]
Because complement-mediated injury to the RBC is an intravascular process, hemoglobinemia, hemoglobinuria, and, sometimes, kidney failure may develop. [11, 15, 16, 17, 18, 19] Even after the acute event remits, the D-L antibody may persist for 1-8 months to several years. [20]
Etiology
Known risk factors for paroxysmal cold hemoglobinuria are attributed to underlying pathogenic states, including infectious diseases and neoplasms (see Presentation/History). In the adult population, infections and neoplasms have been associated with the development of D-L antibody. [21]
Reported neoplasms include solid organ carcinomas, such as small cell lung cancer, and hematopoietic disorders, such as non-Hodgkin lymphoma (NHL), chronic lymphocytic lymphoma (CLL), primary myelofibrosis with myeloid metaplasia, and myelodysplastic syndrome. Paroxysmal cold hemoglobinuria has also been reported in the presence of a monoclonal protein with Bence Jones proteinuria. [7, 13, 22, 23, 24, 25, 26]
In most cases, the P antigen must be present on the RBCs for paroxysmal cold hemoglobinuria to develop. As most people express P antigen on their erythrocytes, nearly the entire population is susceptible to reactivity by the D-L antibody.
The degree and duration of hypothermia that is required to precipitate hemolysis depends on the temperature requirement of the antibody-RBC reaction and on the concentration availability of complement.
Male sex appears to be a risk factor in at least 1 study. [16]
Epidemiology
United States
Paroxysmal cold hemoglobinuria (PCH) is a rare disorder, with a prevalence rate that is largely unknown within the US population or worldwide. PCH occurs almost exclusively in children and accounts for 1-5% of childhood autoimmune hemolytic anemia (AIHA). [27]
International
Sokol et al estimated the annual incidence of paroxysmal cold hemoglobinuria at 0.4 cases per 100,000 population. [8, 9] Unfortunately, due to the scarcity of subjects, European epidemiologic results have varied widely from as low as 1.6% to as high as 40% of autoimmune hemolytic anemia cases, with the latter value restricted to children. [7, 11, 20]
Race- Sex-, and Age-related Demographics
No racial predisposition is recognized for paroxysmal cold hemoglobinuria.
There is a mild male sex predilection with paroxysmal cold hemoglobinuria; the male-to-female ratio is approximately 2:1 to 5:1. [11, 16] [12] .
Acute paroxysmal cold hemoglobinuria is a disease that affects mostly young children, commonly following an acute viral or upper respiratory illness. Chronic paroxysmal cold hemoglobinuria is commonly seen in the elderly. Contributory secondary causes are generally neoplastic, followed by infectious etiologies.
Prognosis
When paroxysmal cold hemoglobinuria is promptly diagnosed and appropriately treated with supportive care, most patients recover spontaneously within days to a few weeks. Thus, the prognosis for patients with this disorder is excellent. Mortality is rare and is most commonly due to multiorgan failure from severe anemia secondary to massive acute hemolysis.
Acute episodes are generally transitory and rarely recur. Paroxysmal cold hemoglobinuria usually ameliorates if the underlying disease responds to specific therapy. The chronic idiopathic forms may persist for years with variable morbidity.
Urticarial eruptions generally resolve spontaneously or with antihistamine therapy. Severe anemia, particularly in older patients with atherosclerotic disease, could result in exacerbation or precipitation of ischemic symptoms. Kidney failure is possible if patients with paroxysmal cold hemoglobinuria are inadequately hydrated or have a predisposition to kidney disease.
Patient Education
Educating patients about the need to avoid cold exposure is essential. Explain the role that chilling the body plays in the development of the acute hemolytic event in paroxysmal cold hemoglobinuria. Patients should also understand the need to take folate supplements to assist erythrocyte production.
For patient education resources, see Anemia.
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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.
