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Paroxysmal cold hemoglobinuria

Paroxysmal cold hemoglobinuria
Literature review current through: Jan 2024.
This topic last updated: Apr 05, 2023.

INTRODUCTION — Paroxysmal cold hemoglobinuria (PCH, also called Donath-Landsteiner hemolytic anemia or Donath-Landsteiner syndrome) is an uncommon 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.

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).

This topic discusses 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 in which a clone of cells becomes susceptible to complement-mediated hemolysis. Both PCH and PNH are hemolytic anemias associated with hemoglobinuria but are otherwise 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 — PCH usually occurs with an infection or autoimmune disorder, suggesting immune stimulation of an autoantibody. (See 'Associated conditions' below.)

The mechanisms by which these conditions promote autoantibodies against red blood cells (RBCs) is unknown. One possibility involves generation of a cross-reacting antibody (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 RBC surface [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 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 (specificities seen in cold agglutinin disease) [2]. (See "Cold agglutinin disease", section on 'Pathogenesis'.)

Polyclonality – PCH antibodies are polyclonal (made from many different B cells rather than a single B cell clone). Polyclonal antibodies generally are not associated with lymphoid malignancies or lymphoproliferative disorders.

Class – PCH antibodies are IgG. In contrast, cold agglutinins are IgM; the pentameric structure of IgM facilitates RBC agglutination. Rare exceptions with IgA and IgM antibodies in PCH 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 colder than normal body temperature (typical thermal range for RBC binding <20°C) [6]. The maximum temperature at which they interact (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 body temperature. This biphasic antibody was first described it 1904 and is referred to as the Donath-Landsteiner antibody [7].

Testing for the Donath-Landsteiner antibody is important in diagnosis. (See 'Donath-Landsteiner antibody' below.)

Complement fixation – PCH antibodies fix complement in the cold; this is responsible for the intravascular hemolysis that occurs upon rewarming.

Intravascular hemolysis — The PCH antibody binds to RBCs as the blood circulates to the periphery and cools, along with the first two components of complement. The complement cascade is completed only when the RBCs are subsequently warmed to 37°C.

For unclear reasons, these antibodies are quite efficient in causing complement-mediated lysis by. The hemolysis is intravascular rather than in the reticuloendothelial system. (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 cause abdominal pain, cramping, back pain, fever, and chills. (See 'Clinical manifestations' below.)

Associated conditions — Associated conditions are summarized in the table (table 2).

Viral infections in children — A common presentation of PCH is following infection in children (most often viral).

In a 2023 review of 230 patients with PCH confirmed by a positive Donath Landsteiner (DL) test from 125 individual reports, several antecedent infectious processes were identified, most frequently upper respiratory tract infections, gastroenteritis, and Mycoplasma pneumoniae infections, while other viruses are mainly reported as single case reports [8].

Implicated organisms include [6,8-13]:

Viruses

Measles virus and measles virus vaccination

Epstein-Barr virus and infectious mononucleosis

Mumps viruses

Varicella virus

Cytomegalovirus

Adenovirus

Respiratory syncytial virus (RSV)

Influenza A

Parvovirus B19

Bacteria

Mycoplasma pneumoniae

Klebsiella

Escherichia coli

Haemophilus influenzae

Visceral leishmaniasis

The clinical scenario for PCH is similar to warm autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) in children. The antibody appears approximately 7 to 10 days after the onset of the febrile illness and persists for 6 to 12 weeks afterward [14-16]. The peak antibody titer is reached rapidly and may cause severe AIHA if not controlled (table 1).

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].

Congenital syphilis has been eliminated in some populations but remains a concern in other parts of the world, and syphilis continues to infect millions of individuals worldwide, with increasing epidemiologic trends in certain populations. In a 2023 report that included 230 patients with PCH from 125 individual articles, syphilis was mostly identified in patients diagnosed with PCH prior to 1963, and none were in children [8]. (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 with other immune abnormalities and rarely in lymphomas and chronic lymphocytic leukemia.

In a 2023 review of 230 PCH patients, 21 had antecedent hematologic malignancies, including five chronic lymphocytic leukemia, five monoclonal gammopathy of undetermined significance or multiple myeloma, five non-Hodgkin lymphoma, four myelodysplastic syndrome, and single cases of primary myelofibrosis and T cell acute lymphoblastic leukemia [8].

Case reports describe PCH with the following conditions:

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 [17]. Donath-Landsteiner testing was intermittently positive.

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 [17].

Older individuals with PCH and high-grade B-cell lymphoma [18,19]. In one, chemotherapy resulted in clinical remission and no recurrence of hemolytic anemia [19]. The other patient died and the diagnosis of lymphoma was made after death [18].

An adult with myelofibrosis and antiphospholipid syndrome [20].

An adult with chicken pox [21].

An individual who presented with PCH during the first trimester of pregnancy that resolved spontaneously; she delivered a healthy-term infant [22].

An individual who received a COVID-19 vaccine [23].

An individual with paroxysmal nocturnal hemoglobinuria [24].

EPIDEMIOLOGY — PCH is rare; the exact incidence is unknown. It likely accounts for <1 percent of all autoimmune hemolytic anemias (AIHAs) [25-28].

PCH is primarily a disease of children.

In a 1990 study that evaluated AIHAs in 599 patients, PCH accounted for 22 of 68 children (32 percent) and none of the 531 adults [11]. 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 [29].

In a 2017 survey of reference laboratories that provided Donath-Landsteiner testing (a surrogate for suspected PCH) to approximately 60 percent of the Canadian population, there were 52 tests requested over a one-year period [17]. 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 [11,30].

CLINICAL MANIFESTATIONS — The presentation of PCH differs in children and adults due to the associated illnesses. In children, hemolytic anemia is temporally 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. However, with the exception of adults with tertiary syphilis, nearly all affected individuals are young children. In one series of 22 children, all were between one and five years old and had recovered from a viral infection within the preceding three weeks [11]. (See 'Viral infections in children' above.)

PCH is unusual in adults and if identified should prompt consideration of tertiary syphilis, other infections, lymphoproliferative disorders, or myeloproliferative disorders. (See 'Syphilis' above and 'Autoimmune or lymphoproliferative disorders' above.)

Intravascular hemolysis — Signs and symptoms of intravascular hemolysis are the hallmark of PCH [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

In a 2023 review of 230 PCH cases, hemoglobinuria or dark urine was reported in 69 percent of patients, with jaundice and fever in approximately one-fourth; other symptoms were less frequent [8].

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 lasted 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 [11]. (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 'Cold avoidance' below.)

Some patients may have symptoms of peripheral vasoconstriction such as Raynaud phenomenon or urticaria, although acrocyanosis is rare.

Acute kidney injury (due to heme pigment nephropathy and/or sepsis) is a rare complication of PCH [31,32]. Hydration is appropriate in those with significant intravascular hemolysis [33]. (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 severity is variable and depends on the antibody titer and thermal amplitude, and the duration of cold exposure.

In a 2023 review of 230 PCH cases, mean hemoglobin value at presentation was 6.5 g/dL (range, 2.3 to 14.7 g/dL), with a median nadir of 5.5 g/dL (range, 2.0 to 16.1 g/dL) [8].

Children – In a 1990 series of 22 children hospitalized with PCH, the mean hemoglobin at admission was 6.1 g/dL (range, 4.4 to 8.8 g/dL); 17 children (77 percent) received blood transfusions [11]. In a 2023 review that included mostly children, the lowest median hemoglobin nadir was in the 10 to 19 year age group (4.8 g/dL; range 2.3-10.6 g/dL), followed by younger children (median hemoglobin 5.3 g/dL, range 2.0 to 12.9 g/dL) [8]. (See 'Transfusions for severe anemia' below.)

Adults – Chronic anemia from PCH associated with syphilis was recognized in adults (see 'Syphilis' above), but this diagnosis has become obsolete in many populations [8,17]. In the 2023 series of 230 patients with PCH, adults ages 20-29 years had median hemoglobin of 5.4 g/dL (range 2.7 to 16.1 g/dL).

Time-course of recovery — Recovery is rapid in children with acute PCH associated with a viral syndrome (within two weeks in one series) [11]. (See 'Viral infections in children' above.)

Recurrent episodes are generally confined to adults, although one child had two episodes of PCH two years apart [34].

Some adults with PCH have chronic hemolytic anemia for several years, while others have self-limited disease, as described above. (See 'Autoimmune or lymphoproliferative disorders' above.)

EVALUATION AND DIAGNOSIS

Indications for testing — PCH should be suspected in:

Any individual with signs or symptoms of autoimmune hemolytic anemia (AIHA), especially children and individuals who develop symptoms after cold exposure [30].

Individuals with 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 — Typically, laboratory testing includes evidence of hemolysis (table 3), followed by Coombs testing that identifies an immune, intravascular mechanism. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis" and "Diagnosis of hemolytic anemia in adults".)

Hemolysis

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 be useful.

Blood smear – The peripheral blood smear may show polychromasia (due to reticulocytosis) and spherocytosis.

Other findings may include rosetting of RBCs around neutrophils, RBC couplets, and erythrophagocytosis (picture 1); these findings are highly specific for PCH but not particularly sensitive [35-41].

Hemolysis – Haptoglobin will be low; lactate dehydrogenase (LDH) and indirect bilirubin will be increased (table 3).

LDH is particularly elevated in intravascular hemolysis (versus only mild elevations in extravascular hemolysis) [42]. 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. Inflammation may increase haptoglobin levels, possibly masking underlying hemolysis.

Free hemoglobin – Intravascular hemolysis causes free hemoglobin in the serum (also detected as pink serum) and/or urine (detected as a positive urine dipstick for heme).

Coombs test – Complement-mediated hemolysis is associated with a positive direct antiglobulin test (DAT; Coombs test) 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 4).

The Coombs test may be negative in some individuals (or may rapidly become negative following an acute episode, especially in children), and a negative Coombs test cannot be used in isolation to exclude the diagnosis of PCH [6]. In one series of six children diagnosed with PCH, five had a negative Coombs test [43]. The Coombs test is more likely to remain positive in an adult with chronic PCH.

In a 2023 review of 230 PCH cases, 3 patients had a positive DAT for IgG but not C3, 14 had negative results using only a polyspecific reagent, and 10 had negative results with both polyspecific and monospecific reagents [8]. The specificity of the IgG was against the P antigen in 83 percent, while other specificities were rare (IgG anti-I, IgM anti-I, anti-PP1Pk (Tja), IgG anti-i, IgM anti-P, IgA anti-P, and anti-Pr-like).

Other findings – Neutropenia (mechanism unknown) and increased creatinine (likely due to acute kidney injury from hemoglobinemia) have been reported.

Complement levels may be low, but this testing is nonspecific and generally not indicated or helpful.

Donath-Landsteiner antibody — Ideally, Donath-Landsteiner testing is only performed in individuals who have clinical features of PCH and a positive Coombs test for complement component 3 (C3) [17].

The assay detects an antibody that binds to red blood cells (RBCs) in the cold, fixes complement, and dissociates upon warming, referred to as a "biphasic hemolysin."

Testing is generally obtained from a reference laboratory, with a typical turnaround time of one to three days. A hospital blood bank may perform the test, but the number of tests performed is limited [17]. 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); the titer and thermal amplitude may be described. Most laboratories provide only a positive/negative report without a titer. The titer provides limited clinical utility. A typical titer is <1:160.

The original assay, developed over 100 years ago, used patient serum containing the Donath-Landsteiner antibody if present, test RBCs, and pooled human serum. The pooled serum provides 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 early complement components, and then it is transferred to 37°C to allow activation of later complement components and RBC lysis. As a control, hemolysis does not occur if the reaction is maintained continuously at 37°C. To demonstrate the P antigen specificity, ABO-compatible P antigen-negative RBCs can be used as an additional negative control.

Variations of the original assay with increased sensitivity can be used [17]. Pretreating the RBCs with papain provides greater exposure of the P antigen. Technical skill is required for the mechanics of performing the test and for its interpretation.

Donath-Landsteiner testing can be time-consuming, resource-intensive, and prone to inaccuracy due to low sensitivity [17]. Results may only be positive for high titer antibodies during 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.

In reviews of Donath-Landsteiner testing from 2020 and 2022, the most common cause of false-negative tests were low or undetectable antibody levels and rapid disappearance of the antibodies from the circulation [44,45]. This false negativity may be reduced by using fresh donor serum as the source of complement and maintaining the patient's serum sample at 37°C. The blood sample should be kept at 37°C until the serum is separated from the cellular component to prevent adsorption of anti-P antibodies onto autologous RBCs at low temperatures.

Diagnosis — PCH is a clinical and laboratory diagnosis made in a patient with intravascular hemolysis in whom the Coombs (direct antiglobulin) test is positive for complement but negative for IgG and Donath-Landsteiner testing is positive. (See 'Donath-Landsteiner antibody' 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 is lacking, especially in 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.

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 5). (See 'Intravascular hemolysis' above.)

Like PCH, these conditions can cause signs and symptoms of intravascular hemolysis. 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 a rare AIHA in which an autoantibody may cause an acute 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.

Unlike PCH, CAD is usually a chronic disease with extravascular hemolysis. 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 AIHA. Like PCH, warm AIHA can cause bouts of hemolysis 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 with both warm AIHA and high titer cold agglutinins. Like PCH, there is hemolysis, but unlike PCH, 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 – Many drugs can cause AIHA. 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, 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 (see 'Intravascular hemolysis' above). Unlike PCH, HTRs are temporally related to a transfusion, and the evaluation reveals 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 features of hemolytic anemias and an approach to distinguishing among them are presented separately. (See "Diagnosis of hemolytic anemia in adults".)

Cold-induced syndromes – Cold-induced syndromes include CAD, cryoglobulinemia, 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 — Acute attacks are treated with rest, pain medication if needed, and cold avoidance [30]. 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 maintain the patient at a warm temperature. If hemolysis is improving and the hemoglobin is stable with reticulocytosis, outpatient treatment is generally appropriate.

Children with an acute viral illness generally do not require further testing.

Adults are generally evaluated for underlying conditions associated with PCH. We start with a thorough history and physical examination to assess for underlying infections, autoimmune disorders, or lymphoproliferative disorders. (See 'Associated conditions' above.)

Testing for syphilis is appropriate in an individual with PCH (including a child, who may have acquired a congenital infection).

If the history and examination are unrevealing and the complete blood count (CBC) does not show pancytopenia, leukocytoses, or immature white blood cells, we generally follow the patient clinically.

Cold avoidance — Strict cold avoidance is important to avoid precipitating hemolysis, which can be severe even after a single brief exposure [6].

Ambient temperature – The individual should be kept in a warm environment with ambient temperature well above the thermal amplitude of the autoantibody, which may be obtained from the laboratory or inferred from the history. It may be necessary to keep the temperature uncomfortably warm or to clothe the patient in warm garments [46]. 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 [47].

Surfaces – The individual should refrain from touching cold surfaces such as cold or frozen foods or beverages until the episode has completely subsided.

Ingestions/infusions – The individual should be advised not to drink cold or iced beverages until the episode has completely subsided. Any intravenous solutions or transfusions must be warmer than the thermal amplitude of the antibody.

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 hemolysis ceases.

Transfusions for severe anemia — Individuals with severe anemia may require transfusions. The decision to transfuse is individualized based on patient age, comorbidities, symptoms, hemoglobin, and rate of decline.

In a 2023 review of 230 PCH cases, 73 percent of patients received at least one transfusion, with a median number of two units (range 1 to 34 units) over the hospitalization [8]. Most recommended transfused blood was warm [8,48].

Symptoms are more likely in older individuals, those with comorbidities, and/or those with a rapid decline in hemoglobin. We monitor the hemoglobin at least daily if it is decreasing (more frequently if the decline is rapid or if transfusion has been administered). The monitoring interval is extended once the hemoglobin stabilizes or starts to increase.

Children generally are transfused if the hemoglobin is <5 to 6 g/dL regardless of symptoms. Transfusions are individualized for hemoglobins of 6 and 10 g/dL and generally not used for hemoglobin ≥10 g/dL. (See "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome", section on 'Severe or life-threatening anemia'.)

Adults are generally transfused for hemoglobin <7 to 8 g/dL; transfusions may be indicated at a higher hemoglobin if symptoms are severe, comorbidities are present, or the decline in hemoglobin is rapid. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

All transfusions should be administered using a blood warmer. (See 'Cold avoidance' above.)

Transfusions should not be withheld if indicated due to difficulties in finding compatible blood.

The transfusion service should be made aware of the diagnosis (or suspected diagnosis) of PCH so 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 can cause acute kidney injury (AKI) due to heme pigment toxicity, especially if volume depletion or metabolic acidosis is present. (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 kidney perfusion, although it is important not to cause volume overload.

If transfusion is also indicated, it should be administered before fluids. 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 suppression of clonal antibody production is not required. In a 2023 review of 230 PCH cases, 94 patients (41 percent) received at least one dose of a glucocorticoid, with variable doses, frequency, and route of administration [8]. Glucocorticoids were more frequently administered to individuals with acute PCH. There was no difference among age groups, and with the length of hospital admission (median hospitalization 13 days, range 1 to 72 days).

There are no randomized trials or large studies that address the role of adding glucocorticoids to routine supportive care described above. (See 'Acute episode' above.)

Case reports have described resolution of hemolysis with glucocorticoids, but cause and effect were not established. Thus, we take into account the trajectory of hemolysis and the potential adverse effects of glucocorticoids and individualize decisions regarding use.

A course of glucocorticoids is reasonable in individuals with ongoing hemolysis. Consultation with a hematologist with expertise in treating hemolytic anemias may be helpful. If hemolytic parameters do not improve within one to two weeks, glucocorticoids are discontinued and other treatments may be given. (See 'Recurrent episode(s) or chronic hemolysis' below.)

If glucocorticoids are used, a dose similar to warm autoimmune hemolytic anemia (AIHA) is reasonable (eg, prednisone 1 mg/kg daily). (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 the hemoglobin is stable or increasing, followed by tapering and discontinuation. The taper may be more rapid in children and more gradual in adults.

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. Absence of brisk reticulocytosis suggests another cause of anemia in addition to (or instead of) PCH.

Once the patient has recovered, monthly CBC, reticulocyte count, LDH, and bilirubin is reasonable. After two consecutive normal studies, monitoring can be discontinued and the patient instructed regarding symptoms for which they should seek medical attention.

Increasing reticulocyte count after recovery is an early and specific sign of recurrent hemolysis and should prompt more intensive monitoring and/or evaluation for a cause of recurrence.

Recurrent episode(s) or chronic hemolysis — Chronic hemolytic anemia due to PCH is challenging. This concern mostly applies to adults, although some children also have recurrent or chronic hemolysis [49].

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 [30]:

Cold avoidance – (See 'Cold avoidance' above.)

Transfusions and/or hydration if needed – (See 'Transfusions for severe anemia' above and 'Hydration to prevent acute kidney injury' above.)

Additional evaluations – Any underlying condition that may be contributing should be evaluated and treated (table 2). (See 'Syphilis' above and 'Autoimmune or lymphoproliferative disorders' above.)

Glucocorticoids – This may be reasonable, although supporting evidence is weak. We have a slight preference for a glucocorticoid trial in the short term. However, some individuals may reasonably choose another approach, especially if they do not tolerate glucocorticoids. (See "Major adverse effects of systemic glucocorticoids".)

A reasonable regiment is prednisone 1 mg/kg daily followed by a taper when the hemoglobin has increased and the reticulocyte count has begun to decrease, similar to warm AIHA. (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'.)

Options for continued hemolysis despite these measures include more potent immunosuppressive therapies and/or anti-complement therapies:

Immunosuppression – Resolution has been reported in individuals treated with rituximab, cyclophosphamide (example adult dose, 100 mg/day orally), or azathioprine (example adult dose, 100 mg/day orally) [50-54]. In a patient with multiple myeloma, cyclophosphamide 4 g/m2 was effective, whereas oral prednisone and cyclophosphamide 1 g/m2 were not [51]. In a 2023 review of 230 PCH cases, 10 patients received intravenous immunoglobulin (IVIG) and 10 received rituximab [8]. Patients who received additional medications tended to be older (median age 58.5 years) and to have underlying hematologic neoplasms.

Plasmapheresis – Some case reports have reported the use of plasmapheresis in attempts to lower the antibody titer [33,54,55].

Anti-complement therapy – One case report stated that eculizumab resulted in only a partial reduction in hemolysis [51]. Another case report stated that a child was successfully treated with a single intravenous infusion of eculizumab 600 mg [56]. The response was prompt and persistent and related to successful complement blockade. Given the increased susceptibility to encapsulated bacteria, prophylaxis with penicillin was performed until complement activity reached 50 percent normalization (42 days after eculizumab administration). Another child with severe PCH and acute kidney failure was successfully treated with eculizumab and plasmapheresis [33].

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; splenectomy is not indicated.

PROGNOSIS — In a 2023 review involving 230 patients with PCH, 213 (93 percent) were alive at the time of report, 14 were unknown, and 3 were deceased [8]. The latter were a 3-year-old female with no medical comorbidities, a 60-year-old male with recent resolution of bacteremia, and a 77-year-old female with non-Hodgkin lymphoma.

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 an autoimmune hemolytic anemia (AIHA) caused by a polyclonal autoantibody against the red blood cell (RBC) P antigen that binds in the cold and fixes complement. Upon warming, the antibody dissociates and complement lyses the RBCs intravascularly. Common associated conditions include acute infections (often viral), chronic syphilis, or immune dysregulation (table 2). (See 'Pathophysiology' above.)

Epidemiology – PCH is extremely rare and mostly affects children ages one to five years. (See 'Epidemiology' above and 'Typical age' above.)

Clinical findings – Signs and symptoms include back or abdominal pain, weakness, nausea or vomiting, fever or chills, and dark or red urine). These typically are self-limited and correlate with cold exposure. Anemia can be severe. Acrocyanosis is not typically seen. (See 'Clinical manifestations' above.)

Evaluation

When to suspect – PCH should be considered in patients with intravascular hemolysis and a positive direct Coombs test (direct antiglobulin test [DAT]) for complement. (See 'Indications for testing' above.)

Laboratory – Initial testing shows anemia, low haptoglobin, high lactate dehydrogenase (LDH) and bilirubin, and free hemoglobin in serum and urine. The blood smear may show RBC rosetting and/or erythrophagocytosis (picture 1). Patients with these findings are tested for the Donath-Landsteiner antibody. (See 'Initial laboratory testing' above and 'Donath-Landsteiner antibody' above.)

Diagnosis – PCH is a clinical and laboratory diagnosis. A history of cold-induced symptoms is helpful if present but should not be provoked for confirmation. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis includes cold agglutinin disease (CAD) and other hemolytic anemias (warm AIHA, drug-induced hemolysis). The tables summarize differences between PCH, CAD, and cryoglobulinemia (table 1) and laboratory differences between PCH and other AIHAs (table 4). (See 'Differential diagnosis' above.)

Management

Acute – Avoid all cold exposures (ambient temperature, surfaces, foods or beverages, intravenous fluids, transfusions). Transfusions may be indicated for severe anemia; hydration may be used to prevent acute kidney injury, and plasmapheresis in very severe cases to lower the antibody titer. (See 'Acute episode' above.)

Except for children with an acute viral illness, evaluation for associated conditions and testing for syphilis is appropriate (table 2).

Recurrence/chronic hemolysis – Consulting an expert in hemolytic anemias may be helpful.

Avoid cold and provide transfusions and/or hydration if needed. Evaluate and treat for underlying conditions. (See 'Recurrent episode(s) or chronic hemolysis' above.)

For individuals who do not recover within one to two weeks, we suggest adding a glucocorticoid (Grade 2C). However, the benefit of glucocorticoids is unknown, and some individuals may reasonably avoid glucocorticoids. Glucocorticoid dosing and tapering is similar to warm AIHA. (See 'Role of glucocorticoids' above and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Glucocorticoids with or without rituximab as first-line agents'.)

Options for persistent hemolysis include cyclophosphamide, rituximab, azathioprine, or eculizumab. Splenectomy has no role.

ACKNOWLEDGMENTS

UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.

The editorial staff at UpToDate would also like to acknowledge Wendell F Rosse, MD, who contributed to earlier versions of this topic review.

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