Paroxysmal Cold Hemoglobinuria

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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 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.

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]

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.

History

The initial inciting event to the predisposition of Donath-Landsteiner (D-L) antibody synthesis remains unknown. However, paroxysmal cold hemoglobinuria can occur soon after developing upper respiratory and gastrointestinal symptoms.[20]

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.[6, 8, 9, 21] The development of the D-L antibody has also been reported following measles immunization. Other associations include solid organ and hematopoietic neoplasms .[12]

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.[22] 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. A clinical examination (to rule out lymphadenopathy and/or splenomegaly) is obligatory.

Another feature can be sequelae of microthrombosis, but generally it is rare.[23]

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 the adult population, infections and neoplasms have been associated with the development of D-L antibody.[24]

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, myelodysplastic syndrome, and in the presence of a monoclonal protein with Bence Jones proteinuria.[7, 12, 25, 26, 27, 28, 29]

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.[15]

Laboratory Studies

The diagnosis of autoimmune hemolytic anemia (AIHA) is usually straightforward and made on the basis of the following laboratory findings:

Two pieces of information are of utmost importance for the clinician to make an appropriate treatment decision:

  1. What type of the antibody is involved? 
  2. Is the AIHA primary or secondary?

The type of antibody can be identified with the use of monospecific antibodies to immunoglobulin G (IgG) and C3d. When the red cells are coated with IgG or IgG plus C3d, the antibody is usually a warm antibody (warm antibody AIHA [WAIHA]). When the red cells are coated with C3d only, the antibody is often but not always a cold antibody. In some cases (direct antiglobulin test negativity, IgM warm antibodies, cold antibodies with low titers, or Donath-Landsteiner antibodies), diagnosis may be difficult, and the expertise of an immune-hematologic laboratory is required.

For the diagnosis of secondary AIHA, a careful history, including information on the onset (acute or insidious), history of infections, information on recent transfusions, exposure to drugs or vaccination, signs of immune disease (arthritis), and general clinical condition, is helpful. The exclusion of a drug-induced hemolytic anemia is particularly important, because stopping the drug is the most effective therapeutic measure in this situation. A clinical examination (to rule out lymphadenopathy and splenomegaly) is needed.[37]

Blood cell studies

Findings on complete blood cell (CBC) count, differential, reticulocyte count, absolute reticulocyte count, platelet count, and peripheral blood smear are as follows:

Urinalysis

In the early part of an acute attack, the urine is dark red-brown because of the presence of free hemoglobin or methemoglobin. Hematuria is generally absent in paroxysmal cold hemoglobinuria, although a minimal quantity of RBCs can be seen (reported as large blood but only few RBCs).

Hemosiderin associated with a chronic hemolytic process is detectable. Kidney tubular epithelial cells, containing a deposition of hemosiderin, are shed and collected in urine.

Serum chemistry and complement studies

Test results for acute hemolysis are usually positive and include the following:

Due to consumption during the acute phase of massive hemolysis, measured plasma complement levels, such as C2, C3, and C4, are decreased in paroxysmal cold hemoglobinuria.

Infectious disease testing

Evaluation for suspected underlying infectious diseases, if clinically warranted, may include the following:

Direct antiglobulin testing

The direct antiglobulin test (direct Coombs test, DAT) should be performed with monoclonal anti-IgG, polyclonal screening antisera and monoclonal C3 antisera. Polyclonal screening antisera are inadequate for this purpose because they have poor sensitivity to complement components.

Monoclonal C3 antisera generally show DAT positivity due to C3d fragments on the RBCs. This reaction occurs during or shortly after the acute paroxysmal cold hemoglobinuria hemolytic episode.[40]

Monoclonal anti-IgG DAT results are usually negative. This is thought to be due to the restrictive thermal range of the D-L antibody, which dissociates at the warmer temperatures at which the DAT is generally performed.[41, 42, 43, 44] Alternatively, if the blood is tested at cold temperatures, then the DAT result may also be positive.

The Donath-Landsteiner test

The procedure involves incubating three specimens: (1) the patient's serum, (2) a mix of patient's and normal serum, and (3) normal serum with P-positive RBCs at 4° C. The sample is heated to 37° C, followed by visual analysis of the serum for hemolysis, which is indicative of a positive reaction (see image below). If the D-L antibody is present, samples 1 and 2 should be positive. As negative controls, the three samples are replicated at testing conditions in which temperature is maintained at 4°C and 37°C throughout.



View Image

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 co....

Because complement may be readily consumed during sample processing, leading to a false-negative result, normal ABO-compatible serum is provided as an additional complement source.

Test considerations are as follows:

Indirect antiglobulin test

Another interesting technique is to demonstrate the D-L antibody with a modified indirect Coombs test. Control (normal) RBCs are incubated with the patient's serum that contains the D-L antibody. These RBCs are washed with ice-cold saline solution to avoid dissociating the D-L antibody from the RBCs. Monoclonal IgG antiserum is then added.

This test is a sensitive indicator of the presence of the D-L antibody in the patient's serum. Note that the antibody in cold agglutinin disease is usually an IgM.

Conclusions

The D-L antibody test, DAT, and the indirect antiglobulin test are all useful in confirming the clinical diagnosis of paroxysmal cold hemoglobinuria.



View Image

Workup for hemolytic anemia. Abbreviations: LDH, lactate dehydrogenase; DAT, direct antiglobulin; AIHA, autoimmune hemolytic anemia; WAIHA, warm autoi....

If the Donath-Landsteiner test results are negative or equivocal and a cold reacting antibody is still suspected, perform a cold agglutinin titer. For definite diagnosis of a cold antibody AIHA (CAIHA), the cold agglutinin titer should be markedly elevated (> 1:512). Titers greater than 64 are likely due to a CHD antibody, although hemolysis rarely occurs at titers less than 1000.[38]

Test for the presence of CD55 or CD59 on the RBC membrane if paroxysmal nocturnal hemoglobinuria is suspected (see Differentials). Flow cytometry is a more sensitive tool to help exclude the presence of paroxysmal nocturnal hemoglobinuria when compared with the classic standard Ham test or sugar water test.

Imaging Studies

Although results from imaging studies do not define the diagnosis of paroxysmal cold hemoglobinuria, the findings can assist in identifying an underlying contributory condition. Appropriate imaging studies include a chest radiograph to look for pneumonia or CT scans to look for lymphoproliferative disease in suspected appropriate cases.

Because hemosiderin is a known nephrotoxic agent, patients undergoing severe hemolysis should avoid further exposure to renal irritants such as intravenous pyelogram dye.[47]

Other Tests

The presence of lymphadenopathy is suggestive of infection, lymphoma, or other underlying disease. Excisional biopsy of enlarged lymph nodes, with flow cytometry and gene rearrangement studies, may prove useful in such cases.

The need for additional investigations must be determined by history, clinical findings, and the type of antibody. Routine workup relevant for treatment decisions may include abdominal examination by CT scan (eg, to search for splenomegaly, abdominal lymphomas) or a bone marrow examination and a search for clonal immunoglobulins (immune fixation), serum protein electrophoresis, and quantitative determination of immunoglobulins in case of cold antibodies.

Medical Care

The mainstay of treatment for paroxysmal cold hemoglobinuria is supportive care and the avoidance of cold exposure.

Once hemolysis is suspected, folic acid 1 mg/d orally should be instituted to help with erythropoiesis. Folic acid is lost via the hemolytic process and hence needs to be replenished.

Administer warmed, packed RBC transfusions for life-threatening hemolysis and symptomatic anemia. Utilizing washed RBC units has not been proven to improve transfusion safety, but this can be performed if patient's condition remains refractory to standard warmed products.

As most of the blood supply is P-antigen positive, finding phenotypic p, also called Tj(a-), blood may not be feasible. However, the antibody should not interfere with donor cell survival, nor should it be problematic with pretransfusion and compatibility testing, as the pathogenic immunoresponse does not occur at normal body temperatures. Treat the uncommon chronic form with RBC transfusions only when severe exacerbation occurs.

Plasma exchange therapy with 5% albumin fluid replacement has been successfully employed.[38] Normal use of plasmapheresis for removal of IgG-induced processes is not as effective due to rebound of immunoglobulin as it shifts from the extravascular to the intravascular compartment. However, due to the low titer and limited production period of the D-L antibody, the process can be effectively controlled. Another theory is that the antibody preferentially binds to the RBC, shifting the antibody equilibrium to the intravascular component, allowing for ease in its removal.[45]

Steroids are commonly employed, but these agents have not been shown to shorten the clinical course of paroxysmal cold hemoglobinuria.

Treat underlying secondary conditions with appropriate medical therapy.

Hydration, alkalinization of the urine, and other measures may become necessary to prevent renal failure. Symptoms of cold urticaria may be ameliorated by antihistamines.

Surgical Care

Surgery is not indicated in cases of paroxysmal cold hemoglobinuria, other than to aid in the diagnosis of underlying infections or neoplasms.

Consultations

See the list below:

Diet

Folic acid supplements may be useful in the chronic form of paroxysmal cold hemoglobinuria. Encourage patients to eat fresh fruits and vegetables rich in folate.

Activity

Patients with paroxysmal cold hemoglobinuria should limit activities while severely anemic or if complications such as renal insufficiency are present. Avoid activities in the outdoors that are likely to result in cold exposure. Patients with the chronic form of the disease must wear proper clothes and garments to protect the extremities from becoming chilled.

Medication Summary

Until recently, no pharmaceutical agents were available for the treatment of paroxysmal cold hemoglobinuria. However, rituximab was reported to show efficacy in a case report.[48] A review of the literature did not show any benefit with eculizumab in this condition (unlike in paroxysmal nocturnal hemoglobinuria).[49]

Further Outpatient Care

When the acute phase of paroxysmal cold hemoglobinuria is over, several follow-up visits for assessment of blood counts to ensure recovery may be all that is necessary, with instructions to patients to avoid cold exposure. Confirming that the D-L antibody test result is no longer positive may be valuable on subsequent regular checkups; however, note that low titers of the antibody may persist for several years after an acute episode. Appropriate treatment and follow-up care for syphilis or other infections are needed until the conditions are deemed cured or in remission.

Further Inpatient Care

See the list below:

Deterrence/Prevention

In patients with the chronic form of paroxysmal cold hemoglobinuria, avoiding exposure to cold is essential to prevent recurrent episodes of hemolysis. These patients should avoid activities that would increase their likelihood of being chilled, such as jogging outside in cold weather and handling of cold objects that can alter the body's peripheral thermal property.

Complications

See the list below:

Prognosis

See the list below:

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.

Author

Neetu Radhakrishnan, MD, Associate Professor (Adjunct) of Medicine, Division of Hematology/Oncology, University of Cincinnati Medical Center; Hematology/Oncology Medical Director, West Chester Outpatient Clinics

Disclosure: Nothing to disclose.

Coauthor(s)

Ronald A Sacher, MBBCh, FRCPC, DTM&H, Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MBBCh, FRCPC, DTM&H, Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Additional Contributors

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Corinne Goldberg, MD Fellow in Transfusion Medicine/Blood Banking, Transfusion Medicine Department, Hoxworth Blood Center, University of Cincinnati

Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Harry L Messmore, Jr, MD Professor, Department of Medicine, Division of Hematology/Oncology, Loyola University Stritch School of Medicine

Harry L Messmore, Jr, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Angiology, American College of Physicians, American Heart Assocation, American Society of Hematology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

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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).

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.

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).

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.