INTRODUCTION — Paroxysmal cold hemoglobinuria (PCH, also called Donath-Landsteiner hemolytic anemia or Donath-Landsteiner syndrome) is an uncommon type of autoimmune hemolytic anemia (AIHA) in which autoantibodies to red blood cells bind to the cells in cold temperatures and fix complement, which can cause intravascular hemolysis upon warming.
Diagnosis and management of PCH is challenging because it is a rare disorder and patients can become quite ill from intravascular hemolysis. There are also other cold-induced disorders such as cold agglutinin disease and cryoglobulinemia that may be confused with PCH (table 1).
The clinical manifestations, diagnosis, and management of PCH are discussed here. Separate topic reviews discuss warm AIHA and other conditions in which autoantibodies react in the cold to cause clinical disease:
●Warm AIHA in children – (See "Overview of hemolytic anemias in children".)
●Warm AIHA in adults – (See "Warm autoimmune hemolytic anemia (AIHA) in adults".)
●Cold agglutinin disease – (See "Cold agglutinin disease".)
●Cryoglobulinemia – (See "Overview of cryoglobulins and cryoglobulinemia".)
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired form of hemolytic anemia due to a stem cell defect that produces a clone of cells that lack a natural resistance to complement-mediated hemolysis. Both PCH and PNH are hemolytic anemias associated with hemoglobinuria, but otherwise they are unrelated. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)
PATHOPHYSIOLOGY — PCH is an acquired hemolytic anemia caused by an immunoglobulin (Ig) G autoantibody that fixes complement in the cold and causes intravascular hemolysis (and hemoglobinuria) upon rewarming.
Antibody formation and specificity — In most cases, PCH occurs in the setting of an infection or autoimmune disorder, suggesting that immune stimulation of an autoantibody has occurred. Underlying conditions that promote formation of the autoantibody include a number of infectious organisms and autoimmune disorders as outlined below. (See 'Associated conditions' below.)
The mechanisms by which these conditions promote formation of antibodies that react with red blood cells (RBCs) is unknown. One possible mechanism involves generation of a cross-reacting antibody (ie, an antibody against a virus or spirochete that cross reacts with the "P" antigen on RBCs), also referred to as molecular mimicry.
The autoantibody in PCH has several characteristic properties:
●Specificity – PCH antibodies bind to the RBC P antigen, a polysaccharide antigen on a ceramide base on the surface of the RBC [1]. The P antigen belongs to the GLOB blood group. It is present in nearly all individuals, with the exception of the rare pp or Tj(a) phenotype. The P antigen is also a binding site (receptor) for parvovirus. (See "Red blood cell antigens and antibodies", section on 'Lewis, P1P(K), GLOB, and I blood group systems'.)
Occasional antibodies in patients with PCH have anti-i or anti-Pr specificity such as that seen in cold agglutinin disease (CAD) [2]. (See "Cold agglutinin disease", section on 'Pathogenesis'.)
●Polyclonality – PCH antibodies are polyclonal (made from a number of different B cells rather than a single B cell clone). The significance is that polyclonal antibodies are not associated with lymphoid malignancies or lymphoproliferative disorders. This contrasts with CAD in that many CAD antibodies are monoclonal.
●Class – PCH antibodies are IgG. This contrasts with CAD in that cold agglutinins are IgM; the pentameric structure of IgM facilitates RBC agglutination. Rare exceptions of IgA and IgM have been described [3-5]. IgG antibodies in PCH do not agglutinate RBCs and thus do not cause acrocyanosis. (See 'Clinical manifestations' below.)
●Thermal properties – PCH antibodies react with RBCs at cold temperatures (colder than normal body temperature; typical thermal range for RBC binding <20°C) [6]. The maximum temperature at which these antibodies are able to interact (referred to as their thermal amplitude) varies greatly from patient to patient. The antibodies dissociate upon rewarming, but complement remains attached to the RBCs and lyses the cells at higher temperatures (eg, body temperature). The biphasic antibody that bound to RBCs in the cold and dissociated upon warming was named for its discoverers, who first described it in 1904, and is referred to as the Donath-Landsteiner antibody [7]. Testing for the Donath-Landsteiner antibody is an important component of diagnostic testing, as discussed below. (See 'Testing for the Donath-Landsteiner antibody' below.)
●Complement fixation – PCH antibodies fix complement in the cold; this is responsible for the intravascular hemolysis that occurs upon rewarming (after the autoantibody dissociates, complement remains).
Intravascular hemolysis — The mechanism of antibody binding to RBCs in PCH is similar to that in CAD. As the blood circulates to the periphery, it cools, and the antibody and the first two components of complement are fixed to the RBC surface. The complement cascade is completed only when the RBCs are subsequently warmed to 37°C.
For reasons that are unclear, perhaps because the antigen is located on the RBC membrane surface, these antibodies are quite efficient in bringing about direct lysis by complement. Thus, the hemolysis is intravascular (within the circulation) rather than extravascular (within the reticuloendothelial system, as seen in CAD). (See "Diagnosis of hemolytic anemia in adults", section on 'Intravascular hemolysis'.)
Intravascular hemolysis liberates free hemoglobin into the circulation, which produces dark or red to brown urine (hemoglobinuria) and can also cause symptoms of abdominal pain or cramping, back pain, and fever and chills. (See 'Clinical manifestations' below.)
The dramatic presentation of intravascular hemolysis led to the identification of PCH as a hematologic syndrome in the late 1800s.
Associated conditions — PCH is most commonly seen in children following a viral infection. In adults and in the early 20th century, the most common association was with congenital or tertiary syphilis; congenital syphilis has been eliminated in some populations but remains a concern in other parts of the world. These associations are summarized in the table (table 2).
Viral infections in children — A common presentation of PCH is following infection in children (most often viral). One report noted a strong association with measles and possibly with mumps viruses, as well as infectious mononucleosis [6].
The clinical scenario for PCH is quite similar to that seen in both warm autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) in children in that the antibody appears approximately 7 to 10 days after the onset of the febrile illness and persists for 6 to 12 weeks afterward [8-10]. The peak antibody titer is reached rapidly and may cause severe hemolytic anemia if not properly controlled (table 1).
PCH may also follow other infections, including Mycoplasma pneumoniae infection, Klebsiella, Escherichia coli, Haemophilus influenzae, and visceral leishmaniasis in one case [11]. It has also been seen following vaccination for measles.
In children, PCH most often follows a viral infection, often varicella. Other viral infections that have been implicated include measles, mumps, Epstein-Barr virus, cytomegalovirus, adenovirus, respiratory syncytial virus (RSV), and influenza A [12-14].
Syphilis — Early descriptions of PCH in the early 1900s often involved individuals with congenital or tertiary syphilis.
For children with congenital syphilis, presentation clustered around two to four years of age [6].
However, syphilis continues to infect millions of individuals worldwide, and epidemiologic trends continue to increase in certain populations. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Epidemiology' and "Syphilis in pregnancy".)
Autoimmune or lymphoproliferative disorders — In adults and occasionally in children, PCH may occur in the context of other immune abnormalities and rarely in lymphomas and chronic lymphocytic leukemia. The following examples illustrate the range of findings in case reports:
●A review from Canada described a man who presented with non-Hodgkin lymphoma at age 43 and later developed prostate cancer; he had waxing and waning hemolysis over several decades [15]. Donath-Landsteiner testing was intermittently positive. Two other case reports have described older individuals with PCH in the context of a high-grade B-cell lymphoma [16,17]. In one case, chemotherapy for lymphoma resulted in clinical remission and no recurrence of hemolytic anemia [17]. In the other, the patient died and the diagnosis of lymphoma was made after death [16]. A third case report described PCH in an older individual in which the Donath-Landsteiner antibody reacted with the "i" antigen rather than the P antigen [2].
●The Canadian review described a 55-year-old woman with inflammatory arthritis and connective tissue disease who developed AIHA with a marked drop in hemoglobin (from 14 to 6 g/dL), positive direct Coombs test for complement component 3d (C3d), and positive Donath-Landsteiner testing, all of which resolved spontaneously [15].
●Another case report described PCH in an adult with myelofibrosis and antiphospholipid syndrome [18]. A case of PCH was also described in an adult with chicken pox [19].
EPIDEMIOLOGY — PCH is rare; the exact incidence is unknown. It likely accounts for <1 percent of all autoimmune hemolytic anemias (AIHAs) [20].
PCH is primarily a disease of children.
●In a 1990 study that evaluated the cause of immune hemolytic anemia in 599 patients, PCH accounted for 22 of 68 children (32 percent) and was not observed in any of the 531 adults [13]. By comparison, cold agglutinin disease (CAD) accounted for 39 of the adults (7 percent) and none of the children.
●In a 2014 study that evaluated primary AIHA in 308 adults, only one case of PCH was observed [21].
●In a 2017 survey of reference laboratories that provided Donath-Landsteiner testing (a surrogate for suspected cases of PCH) to approximately 60 percent of the Canadian population, there were 52 tests requested over a one-year period [15]. Over a cumulative period of testing from 1983 to 2013, results were positive in 14 children and 3 adults.
Most studies have noted a higher prevalence of PCH in boys than in girls [13,22].
CLINICAL MANIFESTATIONS — The clinical presentation of PCH differs in children and adults due to the associated illnesses. In children, development of hemolytic anemia is temporally very close to (or concomitant with) a viral illness, whereas in adults there is not a clear temporal relationship.
Typical age — PCH can occur at any age, but with the exception of adults with tertiary syphilis, nearly all cases affect young children. In a series of 22 cases of PCH at a single institution, all children were between one and five years old and had recently recovered from a viral infection (within the preceding three weeks) [13]. (See 'Viral infections in children' above.)
PCH is unusual in adults and if present should prompt consideration of tertiary syphilis, other infections, lymphoproliferative disorders, or myeloproliferative disorders. (See 'Syphilis' above and 'Autoimmune or lymphoproliferative disorders' above.)
A case report described an 18-year-old woman who presented with PCH during the first trimester of pregnancy that resolved spontaneously; she delivered a healthy-term infant [23].
Intravascular hemolysis — Signs and symptoms related to intravascular hemolysis are the hallmark of PCH. These include [6]:
●Dark (red to brown) urine, beginning a few minutes to several hours after exposure to cold
●Back or leg pain and abdominal cramping
●Weakness and malaise
●Nausea and vomiting
●Fever or chills
●In severe cases, subsequent pallor and/or jaundice
The onset of hemolysis is soon after cold exposure, and the hemolysis generally does not persist if cold exposure ceases. In one study, findings associated with intravascular hemolysis were described as lasting a few minutes to a few hours; in some cases, immersion of one hand in ice water for a few seconds or drinking a beverage with ice could bring on an attack of hemolysis [6]. In the series of 22 children described above, all recovered within two weeks [13]. (See 'Typical age' above.)
Although the association with cold exposure is useful if described, it should not be elicited merely as a means to test for its presence, as this may precipitate potentially life-threatening intravascular hemolysis. (See 'Avoidance of cold' below.)
Some patients may also have symptoms associated with peripheral vasoconstriction such as Raynaud phenomenon or urticaria, although acrocyanosis is not common.
Acute kidney injury (due to heme pigment nephropathy and/or sepsis) is a rare complication of PCH [24,25]. Hydration to reduce this risk is appropriate in those with significant intravascular hemolysis (eg, pink serum or urine, indicative of free hemoglobin). (See 'Hydration to prevent acute kidney injury' below.)
Anemia — Hemolysis due to PCH can cause anemia; in children, this is often severe or even fatal. The degree of anemia is variable and depends on the titer of the antibody, its thermal amplitude, and the duration of cold exposure.
●Acute PCH in children – In the series from 1990 that included 22 children admitted to the hospital with PCH, the mean hemoglobin level at admission was 6.1 g/dL (range, 4.4 to 8.8 g/dL); of these 22 children, 17 (77 percent) had anemia severe enough to warrant blood transfusions [13]. (See 'Transfusions for severe anemia' below.)
●Chronic PCH in adults – In populations in which late syphilis was endemic, chronic anemia from PCH was a recognized disorder in adults. However, eradication or marked reduction in cases of late syphilis in many high-resource countries have rendered this diagnosis obsolete in some populations [15]. (See 'Syphilis' above.)
Time-course of recovery — As noted above, recovery is rapid in children with acute PCH associated with a viral syndrome (within two weeks in one series) [13]. (See 'Viral infections in children' above.)
Recurrent episodes are generally confined to adults, although one child had two episodes of PCH two years apart [26].
Some adults with PCH tend to have a chronic hemolytic anemia that can last for several years, while others have self-limited disease, as illustrated in the case reports described above. (See 'Autoimmune or lymphoproliferative disorders' above.)
EVALUATION AND DIAGNOSIS
Indications for testing — PCH should be suspected in any individual who presents with signs or symptoms of autoimmune hemolytic anemia (AIHA), especially children and individuals who develop symptoms after exposure to cold temperatures [22]. PCH testing should be pursued in those who have signs of intravascular hemolysis with a positive Coombs test for complement (negative for IgG) and no red cell agglutination on the peripheral blood smear.
Initial laboratory testing — Typical laboratory testing that will lead to the consideration of PCH as a diagnosis will generally include positive tests for hemolysis, followed by Coombs testing that identifies an immune, intravascular mechanism. However, the Coombs test is only positive for complement, not IgG. Further, the Coombs test may be negative in some individuals (or may rapidly become negative following an acute episode), and a negative Coombs test cannot be used in isolation to exclude the diagnosis of PCH.
●Hemolysis – Testing consistent with hemolysis will include many of the following:
•CBC - The complete blood count (CBC) will show anemia, often severe. (See 'Anemia' above.)
•Reticulocyte count – The absolute reticulocyte count will be increased, with the exception of those who have residual erythropoietic suppression due to the recent infection. The reticulocyte index (reticulocyte values as a function of hemoglobin or hematocrit) may also be useful.
•Blood smear – The peripheral blood smear may show polychromasia (due to reticulocytosis) and spherocytosis. Other findings on the blood smear can include rosetting of RBCs around neutrophils, RBC couplets, and erythrophagocytosis (picture 1); these findings are highly specific for PCH but not particularly sensitive [27]. Erythrophagocytosis has been described in other reports as well [28-30].
•Serum tests for hemolysis – Haptoglobin will be low; lactate dehydrogenase (LDH) and indirect bilirubin will be increased. Notably, LDH is particularly elevated in intravascular hemolysis (versus only mild elevations in extravascular hemolysis) [31].Possible confounders for increased LDH include concomitant necrosis of various tissues. Possible confounders for hyperbilirubinemia are concomitant Gilbert syndrome. Possible confounders for reduced haptoglobin are congenital deficiency or liver disease. On the contrary, inflammation may increase haptoglobin levels, possibly masking underlying hemolysis.
This testing is discussed in more detail separately. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis" and "Diagnosis of hemolytic anemia in adults".)
●Intravascular – Testing that specifies intravascular hemolysis includes free hemoglobin in the serum (also detected as pink serum) and/or urine (also detected as a positive urine dipstick for heme).
●Immune – Testing that specifies with an immune mechanism (complement-mediated hemolysis) is a direct antiglobulin test (DAT; Coombs test) that is positive for complement but negative for immunoglobulins (negative for IgG or IgM).
•The principles of Coombs testing are illustrated in the figure (figure 1).
•The results of the DAT in different types of AIHA are summarized in the table (table 3).
As noted above, Coombs testing may become negative in children with an acute episode of PCH [6]. In one series of six children diagnosed with PCH, five had a negative Coombs test [32]. The Coombs test is more likely to remain positive in an adult with chronic PCH.
Other findings that have been reported include neutropenia (mechanism unknown) and increased creatinine (likely due to acute kidney injury from hemoglobinemia).
Complement levels may be low, but this testing is nonspecific and generally not indicated or helpful.
Testing for the Donath-Landsteiner antibody — The Donath-Landsteiner test was developed over 100 years ago. The test assays the presence of an antibody that binds to red blood cells (RBCs) in the cold, fixes complement, and dissociates upon warming; this is sometimes referred to as a "biphasic hemolysin."
Donath-Landsteiner testing can be obtained from a reference laboratory, with a typical turnaround time of one to three days. In some cases, the hospital blood bank will perform the test, but the number of tests performed is limited [15]. It is critically important to maintain the blood sample at 37°C until the clot is formed and the serum can be isolated to avoid loss of the antibody.
The results of the test are expressed as positive (antibody present) or negative (antibody absent), and a titer and thermal amplitude may be described. The majority of laboratories provide only a positive/negative report for the Donath-Landsteiner antibody test and do not provide an antibody titer.
The original assay used patient serum, which would contain the Donath-Landsteiner antibody if present, along with test RBCs and pooled human serum. The serum provides a source of complement, which may have been depleted from the patient's serum. These are incubated at 4°C to allow the antibody (if present) to bind and fix the early components of complement and then transferred to 37°C to allow the later components of complement to be activated and cause hemolysis. As a control, hemolysis does not occur if the reaction mixture is maintained continuously at 37°C because the PCH antibody requires cold temperatures to bind to RBCs. To demonstrate the P antigen specificity of the Donath-Landsteiner antibody, ABO-compatible, P antigen-negative RBCs can be used as an additional negative control.
Variations of the original assay continue to be used in the diagnosis of PCH [15]. Modifications have been developed to increase sensitivity. As an example, the enzyme papain can be used to pretreat the RBCs, allowing greater access of the PCH antibody to the P antigen on the RBCs. Thermal amplitude and titer can be determined, but information on their clinical utility is limited. A typical titer is <1:160 (significantly lower than the titer of cold agglutinins in cold agglutinin disease [CAD]).
Donath-Landsteiner testing can be time-consuming, resource-intensive, and prone to inaccuracy due to low sensitivity [15]. Results may only be positive for high titer antibodies and for a relatively short period of time surrounding the period of hemolysis. Thus, a negative result in a patient with a compelling clinical presentation cannot be used as evidence against the diagnosis of PCH. Technical skill is required for the mechanics of performing the test and for its interpretation.
Interpretation of the assay must include the entire clinical picture. Ideally, the assay is only performed in individuals who have clinical features of PCH and a positive Coombs test for complement component 3 (C3) [15]. If the clinical picture is compelling, a negative Donath-Landsteiner test result cannot be used in isolation to exclude the diagnosis of PCH.
Diagnosis — The diagnosis of PCH is a clinical and laboratory diagnosis that is made in a patient with intravascular hemolysis in whom the Coombs (direct antiglobulin) test is positive for complement but negative for IgG and testing is positive for a Donath-Landsteiner antibody (an IgG antibody in patient serum that binds RBCs at cold temperatures, fixes complement, and dissociates upon warming). (See 'Testing for the Donath-Landsteiner antibody' above.)
As noted above, Donath-Landsteiner testing is relatively insensitive and may rapidly become negative. Thus, it may be advisable to treat for a presumptive diagnosis of PCH even if definitive laboratory evidence of PCH is not obtained, especially in groups in which PCH is most likely (young children with a recent viral infection; individuals with congenital or late syphilis; and/or those who experience bouts of hemolysis following exposure to cold environments, contact with cold substances, or ingestion or infusion of cold liquids).
As noted above, the association of hemolysis with cold exposure is helpful if present but should not be elicited merely as a means of testing or confirming the diagnosis. (See 'Intravascular hemolysis' above.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PCH includes other causes of intravascular hemolysis, other immune hemolytic anemias, and other cold-induced syndromes. The most similar to PCH is cold agglutinin disease (CAD), which, like PCH, involves a red blood cell (RBC) autoantibody with low thermal amplitude that binds complement and causes intravascular hemolysis; differences are summarized below and in the table (table 1).
●Intravascular hemolysis – Intravascular hemolysis can be caused by complement-mediated lysis or mechanical lysis of RBCs. Causes are listed in the table (table 4). Like PCH, these conditions can cause signs and symptoms of intravascular hemolysis as described above (see 'Intravascular hemolysis' above). Unlike PCH, these conditions are not caused by a Donath-Landsteiner antibody.
●Immune hemolytic anemias – Other immune hemolytic anemias include CAD, warm autoimmune hemolytic anemia (AIHA), drug-induced AIHA, and hemolytic transfusion reactions:
•CAD – CAD is another rare type of immune hemolytic anemia in which a cold-induced antibody may cause an acute crisis with intravascular hemolysis, usually upon exposure to cold. CAD is typically seen in adults and is frequently associated with a lymphoproliferative syndrome, autoimmune disorder, or lymphoid malignancy. However unlike PCH, CAD is usually a chronic disease with extravascular hemolysis.
Unlike PCH, in CAD the autoantibody is an IgM that also causes RBC agglutination, which in turn can lead to acrocyanosis and Raynaud phenomenon. These and other differences are summarized in the table (table 1). (See "Cold agglutinin disease".)
•Warm AIHA – Warm AIHA is the most common form of immune hemolytic anemia. Like PCH, warm AIHA can cause bouts of hemolysis that may be exacerbated by acute infections. Unlike PCH, warm AIHA is not exacerbated by cold, and the hemolysis is typically extravascular. (See "Warm autoimmune hemolytic anemia (AIHA) in adults".)
•Mixed AIHA – Mixed AIHA is a very rare condition in which warm AIHA and high titer of cold agglutinins coexist. Like PCH, there is evidence of hemolysis, but unlike PCH there is evidence of extravascular hemolysis, and findings associated with RBC agglutination (acrocyanosis and Raynaud phenomenon) may be present. (See "Cold agglutinin disease", section on 'Mechanism of hemolysis'.)
•Drug-induced AIHA – A number of drugs can cause AIHA by various mechanisms. Like PCH, there may be an acute episode that appears to be precipitated by an acute infection (but may actually be precipitated by a drug taken to treat the infection). Unlike PCH, drug-induced AIHA is temporally related to the drug, it is not exacerbated by cold, and the hemolysis is typically extravascular. (See "Drug-induced hemolytic anemia".)
•Hemolytic transfusion reactions – Hemolytic transfusion reactions (HTRs) occur when an alloantibody reacts with an antigen on transfused blood. The most serious HTR is an acute reaction due to ABO mismatch, typically caused by a clerical error (wrong blood-wrong patient). Like PCH, patients with an acute HTR due to ABO mismatch will have intravascular hemolysis with signs and symptoms of intravascular hemolysis, as described above (see 'Intravascular hemolysis' above). Unlike PCH, HTRs are temporally related to a transfusion, and the transfusion reaction evaluation will reveal evidence of alloantibody-mediated hemolysis. (See "Approach to the patient with a suspected acute transfusion reaction" and "Hemolytic transfusion reactions", section on 'Acute hemolytic transfusion reactions'.)
Additional general features of hemolytic anemia and an approach to distinguishing among the various types are presented separately. (See "Diagnosis of hemolytic anemia in adults".)
●Cold-induced syndromes – Cold-induced syndromes include CAD, mentioned above, as well as cryoglobulinemia, the Raynaud phenomenon, and cold-induced anaphylaxis. Like PCH, these conditions may be precipitated by cold exposure, and the patient may be clinically ill. Unlike PCH and CAD, these other syndromes are not associated with intravascular, immune hemolysis. (See "Overview of cryoglobulins and cryoglobulinemia" and "Clinical manifestations and diagnosis of Raynaud phenomenon" and "Cold urticaria".)
TREATMENT
Acute episode — The treatment of an acute attack of PCH is generally supportive with rest, pain medication if needed, and cold avoidance [22]. Some individuals with severe hemolysis may require other interventions such as transfusions, hydration, or glucocorticoids.
The decision to admit the patient versus providing care as an outpatient depends on the severity of the developing anemia and hemolysis in conjunction with the need to avoid exposure to cold and maintain the patient at a warm temperature. If hemolysis is improving and the hemoglobin level is stable with appropriate reticulocytosis, outpatient treatment is likely to be appropriate.
For a child with an acute viral illness, further testing to determine an underlying cause that precipitated the development of PCH is usually not indicated.
For an adult, it may be appropriate to evaluate for underlying conditions that might have led to the development of PCH. We start with a thorough history and physical examination to assess for underlying infections, autoimmune disorders, or lymphoproliferative disorders. If the history and examination are unrevealing and the complete blood count does not show unexpected findings (eg, if there is no evidence of pancytopenia, leukocytoses, immature white blood cells), we generally follow the patient clinically.
Testing for syphilis is appropriate in an individual with PCH (including a child, who may have acquired a congenital infection).
Avoidance of cold — Strict avoidance of exposure to cold is important in order to avoid precipitating hemolysis, which can be severe even after a single brief exposure [6].
●Ambient cold – The individual should be kept in a warm environment. The ambient temperature should be well above the thermal amplitude of the autoantibody (the highest temperature at which it fixes complement), which may be obtained from the laboratory or inferred from the history. In some cases, it may be necessary to keep the temperature uncomfortably warm or to clothe the patient in warm garments [33]. One case report described a young boy with PCH who had recovered from hemolysis but developed croup in the hospital; hemolysis recurred after he was given a sponge bath to reduce his fever [34].
●Cold surfaces – The individual should be advised to refrain from touching cold surfaces (cold or frozen foods or beverages, other cold objects) until the episode has completely subsided.
●Cold beverages – The individual should be advised not to drink cold or iced beverages until the episode has completely subsided.
●Cold infusions – Care should be taken to ensure that any intravenous solutions be warmer than the thermal amplitude of the autoantibody.
The appropriate duration of cold avoidance is not known. Presumably, the antibody will persist for some days to weeks after hemolysis has resolved, but the timing has not been clearly established. Patients should use care when encountering cold temperatures after recovery until it is clear that hemolysis has not recurred.
Transfusions for severe anemia — Individuals with severe anemia may require transfusions. The decision to transfuse is individualized based on the hemoglobin level, rate of decline, age of the patient, comorbidities, and clinical symptoms. Patients are more likely to be symptomatic if they are older, have comorbidities, and/or have a rapid decline in hemoglobin level. To assist with decision making, we monitor the hemoglobin level at least daily if it is decreasing (more frequent testing may be necessary if the hemoglobin is decreasing rapidly or if the individual has received a transfusion). The monitoring interval can be extended once the hemoglobin level becomes stable or starts to increase.
●Children generally are given transfusions if the hemoglobin level is <5 to 6 g/dL regardless of symptoms. For those with hemoglobin levels between 6 and 10 g/dL, the need for transfusions is individualized depending on clinical status, and transfusions are generally not appropriate if the hemoglobin level is stable or increasing at 10 g/dL or greater. This subject is discussed in more detail separately. (See "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome", section on 'Severe or life-threatening anemia'.)
●Adults are generally given transfusions for a hemoglobin <7 to 8 g/dL; transfusions may be indicated at a higher hemoglobin value if the hemoglobin is rapidly decreasing or if the patient has severe symptoms or comorbidities. Specific patient groups are discussed in more detail separately. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult".)
All transfusions should be administered using a blood warmer to prevent binding of the autoantibody to transfused cells.
Importantly, transfusions should not be withheld if indicated due to difficulties in finding compatible units of blood. The transfusion service should be made aware of the diagnosis (or suspected diagnosis) of PCH so that they can pay attention to temperature considerations during compatibility testing. Compatibility testing of donated blood may show a panagglutinin if testing is done at a low temperature (close to the thermal amplitude of the antibody). The P antigen is ubiquitous, and it is generally not possible or necessary to find P-negative units, especially if the blood and patient are kept warm.
It may be possible to avoid transfusions if the hemolysis has ceased and there is a brisk reticulocytosis, depending on the patient's clinical status. Close discussion between the treating clinician, the consulting hematologist, and the transfusion service is advised. (See 'Monitoring for recovery' below.)
Hydration to prevent acute kidney injury — Intravascular hemolysis has the potential to cause acute kidney injury (AKI) due to heme pigment toxicity, especially if there is concomitant volume depletion or metabolic acidosis. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury", section on 'Pathogenesis'.)
Prevention and treatment involve fluid repletion (if hypovolemic) and/or maintenance of renal perfusion, although it is important not to cause volume overload. If transfusion is also indicated, it should be administered first. Metabolic abnormalities should also be corrected. This subject is discussed in more detail separately. (See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)
Role of glucocorticoids — Most individuals with PCH are not treated with glucocorticoids, as the hemolysis is usually transient and there is no clonal production of the autoantibody that needs to be suppressed.
The efficacy of glucocorticoids is unknown, as there are no randomized trials or large studies that address the role of adding glucocorticoids to routine supportive care described above. Case reports, which describe administration of glucocorticoids, have reported resolution of hemolysis, but it is not possible to determine from these reports whether resolution was hastened by the glucocorticoids. Thus, we take into account the trajectory of hemolysis and the potential adverse effects of glucocorticoids and individualize decisions regarding use. It is reasonable in individuals with ongoing hemolysis to use a course of glucocorticoids. If the patient does not experience improvement in hemolytic parameters within one to two weeks, glucocorticoids are discontinued and other treatments may be given (see 'Recurrent episode(s) or chronic hemolysis' below). Consultation with a hematologist with expertise in treating hemolytic anemias may be helpful.
If glucocorticoids are used, a dose similar to that used for warm autoimmune hemolytic anemia (AIHA) (eg, prednisone 1 mg/kg daily) is reasonable. (See "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome", section on 'First-line therapy (glucocorticoids)' and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Glucocorticoids with or without rituximab as first-line agents'.)
The duration of therapy is also unknown and can be individualized. We often follow a similar approach as with warm AIHA, continuing prednisone until hemolysis slows (as evidenced by a stable or increasing hemoglobin level) followed by a taper and discontinuation. The taper may be more rapid in children and more gradual in adults. Details are presented separately.
Monitoring for recovery — Monitoring for recovery is individualized according to the clinical circumstances. The complete blood count (CBC) and reticulocyte count are the most useful laboratory tests. Lactate dehydrogenase (LDH) and bilirubin are also appropriate. We check the reticulocyte count more frequently if the hemoglobin does not begin to increase within a few days, as brisk reticulocytosis is expected, and its absence may suggest another cause of anemia in addition to (or instead of) PCH.
Once the patient has recovered from the initial episode, it would be reasonable to check a CBC, reticulocyte count, LDH, and bilirubin monthly. After two consecutive normal studies, monitoring can be discontinued and the patient instructed regarding symptoms for which they should seek medical attention.
An increase in reticulocyte count after the individual has recovered is an early and specific sign of recurrent hemolysis and should prompt more intensive monitoring and/or evaluation for a cause of disease recurrence.
Recurrent episode(s) or chronic hemolysis — The therapy of chronic hemolytic anemia due to PCH is challenging. For the most part, this concern applies to adults. However, there have been reports of recurrent PCH in the pediatric population, possibly associated with viral illnesses [35].
Most therapies have only been described in case reports or small series; there are no high-quality studies or trials to guide management. The following is reasonable [22]:
●Cold avoidance is appropriate for all patients, as discussed above for an acute episode. (See 'Avoidance of cold' above.)
●Transfusions and/or hydration may be used if needed. (See 'Transfusions for severe anemia' above and 'Hydration to prevent acute kidney injury' above.)
●Any underlying condition that may be contributing to ongoing production of the Donath-Landsteiner antibody (table 2) should be evaluated and treated. (See 'Syphilis' above and 'Autoimmune or lymphoproliferative disorders' above.)
●Glucocorticoids may be helpful in some cases, although the evidence for their efficacy is weak. We have a slight preference for giving a trial of glucocorticoids because they are relatively well-tolerated in the short term. However, some individuals may reasonably choose another approach, especially if they have intolerance or expect to have intolerance or serious adverse effects from glucocorticoids. (See "Major side effects of systemic glucocorticoids".)
If glucocorticoids are administered, we would use a regimen similar to that used for warm AIHA (eg, prednisone 1 mg/kg daily) followed by a taper when the hemoglobin has increased and the reticulocyte count has begun to decrease (indicative of resolving hemolysis). Details are similar to warm AIHA and are discussed separately. (See "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome", section on 'First-line therapy (glucocorticoids)' and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Glucocorticoids with or without rituximab as first-line agents'.)
For those who continue to have hemolysis despite these measures, other options include more potent immunosuppressive therapies and/or anti-complement therapies. Examples include:
●Resolution has been reported in individuals treated with rituximab, cyclophosphamide (eg, 100 mg/day orally for an adult), or azathioprine (eg, 100 mg/day orally for an adult) [36-40]. In one case, plasmapheresis was also used to attempt to lower the antibody titer [40]. In a patient with multiple myeloma, a dose of cyclophosphamide 4 g/m2 was effective, whereas oral prednisone and cyclophosphamide 1 g/m2 (and eculizumab) did not stop the hemolysis [37].
●The anti-complement antibody eculizumab might be expected to reduce hemolysis. One case report stated that eculizumab resulted in only a partial reduction in hemolysis [37]. However, another case of PCH in a child was successfully treated with a single intravenous infusion of eculizumab 600 mg [41]. The response was prompt and persistent and related to successful complement blockade. Given the concern for an eculizumab-related increased susceptibility to encapsulated bacteria, prophylaxis with penicillin was performed until complement activity reached 50 percent normalization (42 days after eculizumab administration).
Eculizumab has also been used as a bridge to immunosuppressive therapy in a severe case of cold agglutinin disease with anti-Pr autoantibody [42]. (See "Cold agglutinin disease", section on 'Anti-complement therapies'.)
Consultation with an expert in hemolytic anemias may be helpful to identify ongoing clinical trials.
The spleen plays no role in the pathogenesis of the intravascular hemolysis in PCH. As a result, splenectomy is not indicated.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)
SUMMARY AND RECOMMENDATIONS
●Definition and pathophysiology – Paroxysmal cold hemoglobinuria (PCH) is a type of autoimmune hemolytic anemia (AIHA) in which an antibody binds to the red blood cell (RBC) P antigen in the cold and fixes complement. Upon warming, the antibody dissociates and complement lyses the RBCs, leading to intravascular hemolysis. Autoantibodies in PCH are polyclonal and are typically induced by acute infections (often viral), chronic syphilis, or states of immune dysregulation (table 2). (See 'Pathophysiology' above.)
●Epidemiology – PCH is extremely rare and mostly affects children between the ages of one and five years. (See 'Epidemiology' above and 'Typical age' above.)
●Clinical findings – Signs and symptoms related to intravascular hemolysis (back or abdominal pain, weakness, nausea or vomiting, fever or chills, and/or dark or red urine) are the hallmark of PCH. These typically are self-limited and correlate with cold exposure. Anemia can be severe. There may be peripheral vasoconstriction by acrocyanosis, but it is not typically seen. (See 'Clinical manifestations' above.)
●Evaluation – PCH should be considered in the evaluation of a patient with findings of intravascular immune hemolysis and a positive direct Coombs test (direct antiglobulin test [DAT]) for complement. Initial testing will show anemia, low haptoglobin, high lactate dehydrogenase (LDH) and bilirubin, and free hemoglobin in serum and urine. Patients with these findings can be tested for the Donath-Landsteiner antibody (an autoantibody that binds to RBCs and fixes complement in the cold and dissociates upon warming). The blood smear may show RBC rosetting and/or erythrophagocytosis (picture 1). (See 'Evaluation and diagnosis' above.)
●Differential diagnosis – The differential diagnosis of PCH includes cold agglutinin disease (CAD) and other forms of hemolytic anemia (warm AIHA, drug-induced hemolysis). The tables summarize differences between PCH, CAD, and cryoglobulinemia (table 1) and differences in DAT results in PCH and other autoimmune hemolytic anemias (table 3). (See 'Differential diagnosis' above.)
●Acute management – Management of the acute episode is supportive. It is important to avoid all cold exposures including cold ambient temperature, cold surfaces, ingestion of cold foods or beverages, and infusion of cold substances (fluids, blood transfusions). Some individuals may require transfusions for severe anemia and/or hydration to prevent acute kidney injury. With the exception of a child with an acute viral illness, clinical evaluation for associated conditions and testing for syphilis is appropriate (table 2). (See 'Acute episode' above.)
●Long-term management – For individuals with recurrent episodes or chronic hemolysis, we use the treatments for the acute episode (cold avoidance, transfusions, and/or hydration if needed), and we evaluate and treat for any underlying condition that may be contributing to the production of the Donath-Landsteiner antibody (eg, syphilis, autoimmune or lymphoproliferative disorder). For individuals who do not have rapid recovery from hemolysis (eg, within one to two weeks), we suggest the addition of a glucocorticoid (Grade 2C). However, it is noted that the benefit of glucocorticoids in PCH has not been established. Some individuals may reasonably choose not to use a glucocorticoid. If a glucocorticoid is given, we would use dosing similarly to that used for warm AIHA, followed by a taper, as discussed above and in more detail separately. Consultation with a specialist with expertise in hemolytic anemias may be helpful. (See 'Role of glucocorticoids' above and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Glucocorticoids with or without rituximab as first-line agents'.)
●Recurrence/chronic hemolysis – For the rare patient who has persistent hemolysis, other options include cyclophosphamide, rituximab, or azathioprine. Consultation with an expert in hemolytic anemias may be helpful in deciding which therapy to use first. (See 'Recurrent episode(s) or chronic hemolysis' above.)
ACKNOWLEDGMENTS
We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
The editorial staff at UpToDate would also like to acknowledge Wendell F Rosse, MD, who contributed to earlier versions of this topic review.
