Paroxysmal Cold Hemoglobinuria

Updated: Jan 20, 2022
Author: Hira Latif, MD; Chief Editor: Emmanuel C Besa, MD 


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.


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.



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]


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]


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]


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.


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.




The initial inciting event to Donath-Landsteiner (D-L) antibody synthesis remains unknown. However, paroxysmal cold hemoglobinuria frequently occurs shortly after upper respiratory or gastrointestinal infections.[27]

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, 28] The development of the D-L antibody has also been reported following measles immunization. Other associations include solid organ and hematopoietic neoplasms .[13]

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.[29] 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 Examination

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 red blood cell 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.[30]

Other constitutional symptoms are likely related to an underlying secondary pathologic process.



Diagnostic Considerations

Cold hemagglutinin disease

Cold hemagglutinin disease manifests as an immune hemolytic anemia with acrocyanosis and, rarely, hemoglobinuria following cold exposure. In the same manner as paroxysmal cold hemoglobinuria, the cold hemagglutinin disease antibody, usually IgM, binds in colder areas of the body, allowing interaction with complement (ie, C3), followed by dissociation of the antibody upon circulating through warmer anatomic regions.

The complement remains attached to the erythrocyte and is degraded into its intermediate by-products (ie, C3b, iC3b). This is a decisive point that deviates from the paroxysmal cold hemoglobinuria pathway, as the cold hemagglutinin disease route results in the recognition and clearance of the complement-coated RBC by the reticuloendothelial system. Completion of the complement cascade, resulting in intravascular hemolysis, does not occur. Although laboratory analysis reveals a similar paroxysmal cold hemoglobinuria direct agglutinin test (DAT) positivity that is restricted to the monoclonal anti-C3, the D-L test is negative.[31]

Paroxysmal nocturnal hemoglobinuria (PNH)

PNH has similar presentation of hemoglobinuria, hemoglobinemia, and anemia secondary to intravascular hemolysis. However, paroxysmal nocturnal hemoglobinuria pathogenesis is dependent on a mutated cellular enzyme called phosphatidylinositol glycan A (PIG-A) that is required to anchor proteins known as glycophosphatidylinositols (GPIs) to the cellular membrane.

In addition, paroxysmal nocturnal hemoglobinuria characteristically manifests with persistent cytopenias and absent bone marrow iron. DAT results are negative, as are results from the D-L antibody test. Testing for paroxysmal nocturnal hemoglobinuria depends on the absence of the GPI antigens determined via various tests, including the highly sensitive flow cytometry and the bacterial toxin aerolysin assay.[32, 33, 34, 35, 36, 37]

Hemolytic transfusion reactions

Hemolytic transfusion reactions can result in life-threatening intravascular hemolysis and hemoglobinuria upon transmission of incompatible blood products. The recipient's preformed alloantibodies interact with the donor's RBCs, activating the complement sequence. Generally, these antibodies are IgG in origin, resulting in both polyclonal and monoclonal anti-IgG DAT positivity. Clinical history is important for identifying this condition and providing immediate therapeutic intervention.

Other conditions

Malaria caused by Plasmodium falciparum infection is a fulminating disease that may manifest with episodic, massive, intravascular hemolysis and hemoglobinuria, hepatosplenomegaly, icterus, fever and pain. Peripheral blood smears may identify the pathogens and serologic studies can confirm their presence.

Warm autoimmune hemolytic anemia (ie, direct Coombs-positive or warm antibody–induced hemolytic anemia) is caused by an antibody that binds to RBCs at 37°C, in contrast to the D-L antibody, which binds to RBCs in the cold. The antibody specificity in autoimmune hemolytic anemia is to the Rh system, and hemoglobinuria is uncommon. DAT results are positive, but the D-L antibody test is negative.

Myoglobinuria may be misinterpreted as hemoglobinuria at preliminary urine analysis. This condition is generally precipitated by exertion or trauma. Fever may be present, but icterus is rate. RBC hemolysis is not a feature of this disease.

Differential Diagnoses



Approach Considerations

The workup for hemolytic anemia, which will differentiate paroxysmal cold hemoglobinuria from other hemolytic disorders (see DDx), is illustrated in the image below. The Donath-Landsteiner antibody test, direct antiglobulin test (DAT), and indirect antiglobulin test are all useful in confirming the clinical diagnosis of paroxysmal cold hemoglobinuria.

Workup for hemolytic anemia. Abbreviations: LDH, l 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.

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 autoimmune hemolytic anemia, the cold agglutinin titer should be markedly elevated (> 1:512). Titers greater than 1:64 are likely due to a cold hemagglutinin disease (CHD) antibody, although hemolysis rarely occurs at titers less than 1000.[38]

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

Laboratory Studies

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

  • Normocytic or macrocytic anemia
  • Normal platelet count
  • Reticulocytosis
  • Low serum haptoglobin levels
  • Elevated lactate dehydrogenase (LDH) level
  • Increased indirect bilirubin level
  • A positive direct antiglobulin test with a broad-spectrum antibody against immunoglobulin and complement

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 complement 3d (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 [D-L] antibodies), diagnosis may be difficult, and the expertise of an immune-hematologic laboratory is required.

For the diagnosis of secondary AIHA, a careful history that includes information on the following is helpful:

  • Onset (acute or insidious)
  • Recent infections
  • Recent transfusions
  • Exposure to drugs or vaccination
  • Signs and symptoms of immune disease (eg, arthritis)
  • General clinical condition

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.[39]

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:

  • A sudden onset of a marked normochromic, normocytic, or macrocytic anemia may be noted in paroxysmal cold hemoglobinuria, particularly in a severe attack.

  • The reticulocyte count is usually low during an acute episode, representing an ineffective marrow response due either to viral hematopoietic suppression or preferential destruction of RBCs by the D-L antibody. Reticulocytosis occurs with resolution of the antibody.

  • Examination of the peripheral blood smear may reveal poikilocytosis, spherocytes, polychromasia, and nucleated RBCs. Aggregation of the RBCs can occur, but this is considered mild compared with cold hemagglutinin disease.[7]

  • Monocytes and granulocytes may show erythrophagocytosis. Although more commonly seen in other types of autoimmune hemolytic anemia, the specific presence of RBC engulfment by neutrophils within the peripheral blood has a stronger association with paroxysmal cold hemoglobinuria and should raise suspicion for this entity.[37, 38, 40]

  • A constellation of peripheral smear findings with high specificity but low sensitivity for paroxysmal cold hemoglobinuria is neutrophil erythrocyte rosettes, erythrocyte couplets without overt agglutination, and active neutrophil erythrophagocytosis.[41]


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 marked heme positivity 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:

  • Elevated LDH level
  • Increased indirect or unconjugated bilirubin levels (particularly prominent if concomitant liver dysfunction is present)
  • Low haptoglobin values
  • The presence of free plasma hemoglobin

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:

  • Test plasma for Treponema pallidum antibody
  • Obtain serologic evaluation for the following viruses: measles, mumps, influenza, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, parvovirus B19, Coxsackie A9
  • Perform Gram smear and culture for bacteria such as Haemophilus influenzae, Mycoplasma pneumoniae, and Klebsiella
  • Review thick and thin smears for malaria

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.[42]

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.[43, 44, 45, 46] 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.

A Donath-Landsteiner test result is seen here, sho 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).

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:

  • The serum reacts equally well with normal adult RBCs and fetal RBCs; only in the rare case of patients homozygous for group P system phenotype p (pp RBCs, which lack P antigen) will the RBCs not react.[9]

  • Modification of the Donath-Landsteiner test is done to enhance the antigenicity of the RBCs; this is performed by exposing the erythrocytes to an enzyme (papain) treatment, which then further unveils group P antigens.[47]

  • The specificity of the antibody-mediated hemagglutination and antibody-complement–mediated hemolysis can be confirmed further by inhibition of these processes by globoside and Forssman glycosphingolipid.[34]

  • A review of Donath-Landsteiner testing practices in Canada concluded that in the rare cases of possible paroxysmal cold hemoglobinuria in adults, establishing the diagnosis can be challenging. The review found poor agreement among experts on the interpretation of a positive Donath-Landsteiner test in adults.[48]

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.

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.[49]

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. Patients require hospitalization to monitor and treat complications associated with severe anemia secondary to massive hemolysis.

During inpatient treatment maintain the patient's cardiorespiratory function and hydration status. Daily laboratory evaluation of anemia should include complete blood cell counts, lactate dehydrogenase (LDH) levels, and reticulocyte counts. Hemoglobinuria is monitored with routine urinalysis. 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.

Transfuse warmed, packed red blood cells (RBCs) for life-threatening hemolysis and symptomatic anemia. Utilizing washed RBC units has not been proven to improve transfusion safety, but this can be done if the 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 Donath-Landsteiner (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.[47]

Secondary causes of paroxysmal cold hemoglobinuria should be evaluated (eg, with viral and bacterial serologic and culture assays, imaging studies). Treat underlying secondary conditions with appropriate medical therapy.

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

No pharmaceutical agents have consistently shown benefit for reversal of paroxysmal cold hemoglobinuria. Case reports describe use of corticosteroids, rituximab, intravenous IgG, and eculizumab.[50, 51]  Steroids are commonly employed, but these agents have not been shown to shorten the clinical course of paroxysmal cold hemoglobinuria. Eculizumab led to rapid and complete resolution of acute  paroxysmal cold hemoglobinuria in a 4-year-old boy, which should encourage further investigation into complement-directed therapies in this setting.[51]  However, in an adult patient with chronic paroxysmal cold hemoglobinuria, eculizumab substantially improved intravascular hemolysis improved substantially but anemia persisted, presumably due to extravascular hemolysis.[52]


A hematologist-oncologist and an infectious diseases expert may be helpful for the proper diagnosis and treatment of paroxysmal cold hemoglobinuria. A nephrologist may also be consulted as needed to assist in the care of affected patients.

The support of an experienced laboratory/blood bank is essential for all the serologic testing.


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.


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.


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.

Long-Term Monitoring

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.