Paroxysmal Cold Hemoglobinuria

Updated: Mar 13, 2018
  • Author: Neetu Radhakrishnan, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

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.

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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 Lab 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 treat syphilis through antibiotic use 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] Furthermore, because the D-L antibody does not necessarily occur with a specified cold exposure event, nor is it recurrent in nature, an alternative classification of Donath-Landsteiner hemolytic anemia was proposed. [12]

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.

For patient education resources, see Anemia.

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Pathophysiology

Paroxysmal cold hemoglobinuria shares similar antibody thermal activity range as cold hemagglutinin disease (CHD), the more common cold variant of autoimmune hemolytic anemia. However, the D-L antibody is not classified as 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; yet, 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 has dissociated yet maintains maximal complement activity, providing the biphasic nature of the disease.

The exact etiology of the D-L antibody is unknown. There is a close temporal relationship observed between viral or bacterial agents and the development of paroxysmal cold hemoglobinuria within 2-3 weeks of upper respiratory or gastrointestinal symptoms. Young children are the most susceptible within the general population, developing a single, brief, postviral hemolytic episode. [3, 13]

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 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.

Because complement-mediated injury to the RBC is an intravascular process, hemoglobinemia, hemoglobinuria, and, sometimes, renal failure may develop. [11, 14, 15, 16, 17, 18] Even after the acute event remits, the D-L antibody may persist for 1-8 months to several years. [19]

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Epidemiology

Frequency

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). [20]

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, 19]

Mortality/Morbidity

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 this disorder is excellent. Fatality is a rare event, more commonly attributed to severe anemia.

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, 15]

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 in origin, followed by infections.

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