eMedicine Specialties > Hematology > Immune System and Disorders

Hemoglobinuria, Paroxysmal Cold

Author: Corinne Goldberg, MD, Fellow in Transfusion Medicine/Blood Banking, Transfusion Medicine Department, Hoxworth Blood Center, University of Cincinnati
Coauthor(s): Ronald A Sacher, MB, BCh, MD, FRCPC, Director of the Hoxworth Blood Center, Professor, Departments of Internal Medicine and Pathology, University of Cincinnati Medical Center
Contributor Information and Disclosures

Updated: Nov 21, 2008

Introduction

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 symptoms including severe anemia and hemoglobinuria upon exposure to cold temperatures, occurring as a manifestation of massive intravascular hemolysis.

The pathophysiology of paroxysmal cold hemoglobinuria became apparent when Julius Donath and Karl Landsteiner discovered a unique "biphasic hemolysin" in blood that could be demonstrated in the laboratory. This antibody attaches to red blood cells (RBCs) in the cold and induces 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.^1,2,3,4 (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 to the chronic paroxysmal cold hemoglobinuria form. Currently, this condition commonly manifests as an abrupt onset and transitory process related to infections, usually representing a postviral episode. A study of children found that as many as 40% of immune hemolytic anemias were due to the Donath-Landsteiner (D-L) antibody.^5,6

Although most cases of paroxysmal cold hemoglobinuria occur as an acute event in children younger than 5 years, recurrent episodes have been reported.^6,7,8,9,10 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.¹¹

In the adult population, infections and neoplasms have been associated with the development of D-L antibody.12  Reported neoplasms include solid organ carcinomas as seen with pulmonary small cell carcinoma and hematopoietic disorders such as non-Hodgkin lymphoma (NHL), chronic lymphocytic lymphoma (CLL), primary myelofibrosis with myeloid metaplasia, and in the presence of a monoclonal protein with Bence Jones proteinuria.^{6,11,13,14,15,16}  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 excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

Related eMedicine topics:
Cold Agglutinin Disease
Cold Agglutinin Disease [in the Pediatrics: General Medicine section]
Paroxysmal Cold Hemoglobinuria [in the Pediatrics: General Medicine section]

Related Medscape topics:
Resource Center Non-Hodgkin's Lymphoma
Specialty Site Hematology-Oncology
Specialty Site Pathology & Lab Medicine
CME Improving the Quality of Life for Patients With PNH (Slides With Audio)
CME Introduction to the Pathophysiology of Paroxysmal Nocturnal Hemoglobinuria: Intravascular Hemolysis and Failed Hematopoiesis (Slides With Transcript)
CME PNH Diagnosis: A Rapidly Changing World (Slides With Transcript)

Pathophysiology

Although paroxysmal cold hemoglobinuria shares similar antibody thermal activity range as cold hemagglutinin disease (CHD), the more common cold variant of autoimmune hemolytic anemia, 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.⁶

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 relationship observed upon exposure to 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.^2,17

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.³ 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.^{10,18,19,20,21,22}  Even after the acute event remits, the D-L antibody may persist for 1-8 months to several years.²³

Related Medscape topics:
Specialty Site Allergy & Clinical Immunology
Specialty Site Infectious Diseases
Specialty Site Nephrology
Specialty Site Pulmonary Medicine

Frequency

United States

Paroxysmal cold hemoglobinuria is a rare disorder, with a prevalence rate that remains largely unknown within the United States population.

International

Sokol et al estimated the annual incidence of paroxysmal cold hemoglobinuria at 0.4 cases per 100,000 people.^7,8  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.^6,10,23

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

No racial predisposition is recognized for paroxysmal cold hemoglobinuria.

Sex

There is a mild male sex predilection with paroxysmal cold hemoglobinuria; the male-to-female ratio is approximately 2:1 to 5:1.^10,19

Age

• 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.

Clinical

History

The initial inciting event to the predisposition of D-L antibody synthesis remains unknown. However, there does appear to be an indirect correlation to an infectious source, as paroxysmal cold hemoglobinuria can occur soon after developing upper respiratory and gastrointestinal symptoms.

Once strongly linked with syphilis, paroxysmal cold hemoglobinuria is now associated with numerous infectious agents. Identified pathogens have included the following: measles, mumps, influenza, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, parvovirus B19, Coxsackie A9, Haemophilus influenzae, Mycoplasma pneumoniae, and Klebsiella pneumoniae.^5,7,8,24  The development of the D-L antibody has also been reported following measles immunization. Other associations include solid organ and hematopoietic neoplasms.¹¹

Within minutes to a few hours of exposure to cold temperatures, the patient develops a combination of the following: sudden onset of back and abdominal pain, headache, leg cramps, fever, rigors, chills, nausea, vomiting, diarrhea, and esophageal spasms. The hemoglobinuria can be severe enough to alter the urine to a dark red-brown color, although hematuria is generally minimal or absent. Oliguria or anuria can develop upon renal dysfunction. Cold urticaria and jaundice may also occur.25  These generalized symptoms are likely attributed to the release of large quantities of hemoglobin from lysed RBCs, which then act as an irritant to various tissues.

Physical

Patients who present with paroxysmal cold hemoglobinuria are in acute distress, with obvious pain and elevation of body temperature.

• Symptoms associated with respiratory infection are the most common initial presentation.
• Physical signs of massive RBC hemolysis include pallor, icterus, and urticarial dermal eruption. Severe hemoglobinuria is commonly detected during the acute event, resulting in a red-brown discoloration to the urine.
• Hepatosplenomegaly can be attributed to an underlying lymphoproliferative or other neoplastic process, but it has also been observed as a reactive process in 25% of paroxysmal cold hemoglobinuria cases.
• Other constitutional symptoms are likely related to an underlying secondary pathologic process.

Causes

• Known risk factors for paroxysmal cold hemoglobinuria are attributed to underlying pathogenic states, including infectious diseases and neoplasms (see History).
• 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.¹⁹

• Search for CME/CE on This Topic »

• Paroxysmal Nocturnal Hemoglobinuria (Hematology)
• Anemia (Hematology)
• Donath-Landsteiner Hemolytic Anemia (Pediatrics: General Medicine)
• Hyperbilirubinemia, Unconjugated (Gastroenterology)

• Clinical Outcomes of ABO-Incompatible RBC Transfusions
• Immunological Complications of Blood Transfusion
• Renal Hemosiderosis