AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Paroxysmal cold hemoglobinuria (PCH) has the distinction of being the first, albeit rarest, type of autoimmune hemolytic anemia (AIHA) to be identified. This condition was first described in 1854 as an abrupt onset of systemic symptoms including severe anemia and hemoglobinuria upon exposure to cold temperatures, occurring as a manifestation of massive intravascular hemolysis.  The pathophysiology became apparent when Julius Donath and Karl Landsteiner discovered a unique "biphasic hemolysin" in blood that could be demonstrated in the laboratory. This antibody attaches to the red blood cell (RBC) in the cold and induces hemolysis when the RBCs are warmed due to complement activity. Together they devised and published in 1904 what was to be the first immunohematologic test, referred to as the Donath-Landsteiner test^{1, 2}{{Ref3}⁴  (see Lab Studies).

In the latter half of the 19th century, the most common cause of paroxysmal cold hemoglobinuria was congenital or adult tertiary-stage syphilis. The ability to treat syphilis through antibiotic use resulted in the near elimination of this secondary cause to the chronic paroxysmal cold hemoglobinuria form. Currently, this condition commonly manifests as an abrupt onset and transitory process related to infections, usually representing a postviral episode. A recent study of children found that as many as 40% of immune hemolytic anemias were due to the Donath-Landsteiner (D-L) antibody.⁵{{Ref6}

Although most cases occur in children younger than 5 years as an acute event, recurrent episodes have been reported.{{Ref3}{{Ref6}^{7, 8, 9, 10} Furthermore, because the D-L antibody does not necessarily occur with a specified cold exposure event, nor is it recurrent in nature, an alternative classification of Donath-Landsteiner hemolytic anemia has been proposed.¹¹

In the adult population, infections and neoplasms have been associated with the development of D-L antibody.¹² Reported neoplasms include solid organ carcinomas as seen with pulmonary small cell carcinoma and hematopoietic disorders such as non-Hodgkin lymphoma, chronic lymphocytic lymphoma, primary myelofibrosis with myeloid metaplasia, and in the presence of a monoclonal protein with Bence Jones proteinuria.{{Ref6}^{11, 13, 14, 15, 16} With an underlying disease that is controllable or self-limited, the process may resolve spontaneously and quickly. Unfortunately, due to the transitory nature of the disease, lack of awareness may lead to a failure in recognizing and diagnosing this uncommon syndrome.  

Pathophysiology

Although paroxysmal cold hemoglobinuria shares similar antibody thermal activity range as cold hemagglutinin disease (CHD), the more common cold variant of autoimmune hemolytic anemia, the D-L antibody is not classified as a monophasic immunoglobulin (Ig) 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; and, yet, the glycosphingolipid P antigen is considered its primary target.{{Ref6}

This interaction sensitizes the erythrocytes to allow further interaction with the complement system. However, unlike cold hemagglutinin disease in which the IgM-complement interaction results in the cells removal, via extravascular phagocytosis, paroxysmal cold hemoglobinuria occurs upon completion of complement lysis within the vascular circulation. Intravascular hemolysis occurs preferentially at 37°C, at which temperature the antibody has dissociated yet maintains maximal complement activity, providing the biphasic nature of the disease.{{Ref3}

The exact etiology of the D-L antibody is unknown. There is a close relationship observed upon exposure to viral or bacterial agents and the development of paroxysmal cold hemoglobinuria within 2-3 weeks of upper respiratory or gastrointestinal symptoms. Young children are the most susceptible within the general population, developing a single, brief, postviral hemolytic episode.^{2, 17} The stimulus for production of this antibody is likely a form of molecular mimicry in which a microorganism's antigen shares structural similarity to the P antigen on human RBCs, resulting in immunogenic cross-reactivity.³ Interestingly, the P antigen has been found on lymphocytes and skin fibroblasts; the latter is thought to be the reason for the development of urticaria in persons with this syndrome.

Because complement-mediated injury to the RBC is an intravascular process, hemoglobinemia, hemoglobinuria, and, sometimes, renal failure may develop.^{10, 19, 20, 21, 22, 23} Even after the acute event remits, the D-L antibody may persist for 1-8 months to several years.²⁴

Frequency

United States

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

International

Sotol et al estimated the annual incidence of paroxysmal cold hemoglobinuria at 0.4 cases per 100,000 people. Unfortunately, due to the scarcity of subjects, European epidemiological results have varied widely from 1.6% to as high as 40% of autoimmune hemolytic anemia cases, with the latter value restricted to children.⁴{{Ref6}^{10, 24}

Mortality/Morbidity

• When promptly diagnosed and appropriately treated with supportive care, most patients recover spontaneously within days to a few weeks. Thus, the prognosis for this disorder is excellent.
• Fatality is a rare event, more commonly attributed to severe anemia. 

Race

No racial predisposition is recognized.

Sex

There is a mild male sex predilection, with a male-to-female ratio of approximately 2:1 to 5:1.^{10, 20}

Age

• Acute paroxysmal cold hemoglobinuria is a disease that affects mostly young children, commonly following an acute viral or upper respiratory illness.
• Chronic paroxysmal cold hemoglobinuria is commonly seen in the elderly. Contributing secondary causes are generally neoplastic in origin, followed by infections.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

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

Once strongly linked with syphilis, paroxysmal cold hemoglobinuria is now associated with numerous infectious agents. Identified pathogens have included the following: measles, mumps, influenza, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, parvovirus B19, coxsackie A9, Haemophilus influenzae, Mycoplasma pneumoniae, and Klebsiella pneumoniae.^{5, 7, 8, 25} The development of the D-L antibody has also been reported following measles immunization. Other associations include solid organ and hematopoietic neoplasms.²⁶

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. 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.²⁷ These generalized symptoms are likely attributed to the release of large quantities of hemoglobin from lysed RBCs, which then act as an irritant to various tissues.

Physical

Patients are in acute distress, with obvious pain and elevation of body temperature.

• Symptoms associated with respiratory infection is the most common initial presentation.
• Physical signs of massive RBC hemolysis include pallor, icterus, and urticarial dermal eruption. Severe hemoglobinuria is commonly detected during the acute event, resulting in a red-brown discoloration to the urine.
• Hepatosplenomegaly can be attributed to an underlying lymphoproliferative or other neoplastic process but has also been observed as a reactive process in 25% of paroxysmal cold hemoglobinuria cases.{{Ref3}
• Other constitutional symptoms are likely related to an underlying secondary pathological process.

Causes

• Known risk factors are attributed to underlying pathogenic states including infectious diseases and neoplasms (see History).
• In most cases, the P antigen must be present on the RBCs for this syndrome 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 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 one study.²⁰

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

• 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 anatomical 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 PCH 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 PCH direct agglutinin test (DAT) positivity that is restrictedtothe monoclonal anti-C3, the D-L test is negative.²⁸
• Paroxysmal nocturnal hemoglobinuria (PNH) may be confused with paroxysmal cold hemoglobinuria because of its 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 glycophosphatidylinositol (GPI) to the cellular membrane.  The absence or marked reduction of expression of GPI antigens such as CD59 and CD55, which have inhibitory complement function, can result in unimpeded destruction of various hematopoietic cells including erythrocytes.  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. DAT results are negative as are results from the Donath-Landsteiner antibody test.^{29, 30, 31, 32, 33}
• 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.
• Malaria caused by Plasmodium falciparum infection is a fulminating disease that may manifest with episodic, massive, intravascular hemolysis and hemoglobinuria, with systemic symptoms of fever and pain. Peripheral blood smears may identify the pathogens and serological 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.
• Myoglobinuria may be misinterpreted as hemoglobinuria at preliminary urine analysis. This condition is generally precipitated by exertion or trauma. RBC hemolysis is not a feature of this disease.

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Complete blood cell count, differential, platelet count, and review of the peripheral blood smear
• • A sudden onset of a marked normochromic, normocytic, or macrocytic anemia may be noted, particularly in a severe attack.
  • The reticulocyte count is usually low during an acute episode, representing an ineffective marrow response 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 briefly reveal the presence of poikilocytosis, spherocytes, polychromasia, and nucleated red blood cells.  Aggregation of the RBCs can occur but is considered mild compared to cold hemagglutinin disease.⁶
  • 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 make the observer suspicious for this entity.{{Ref35}^{36, 37}
• Urinalysis 
• • In the early part of an acute attack, the urine is dark red/brown because of the presence of free hemoglobin or methemoglobin. Hematuria is generally absent, although minimal quantity of RBCs can be seen.
  • Hemosiderin associated with a chronic hemolytic process is detectable.  Kidney tubular epithelial cells, containing a deposition of hemosiderin, are shed and collected in urine.
• Biochemical testing: Test results for acute hemolysis are usually positive and include an elevated lactate dehydrogenase level, increased indirect or unconjugated bilirubin levels (particularly prominent if concomitant liver dysfunction is present), low haptoglobin values, and the presence of free plasma hemoglobin.
• Complement levels: Due to consumption during the acute phase of massive hemolysis, measured plasma complement levels, such as C2, C3, and C4, are decreased.
• Evaluation of suspected underlying infectious diseases, if clinically warranted:
• • Test plasma for Treponema palidium antibody.
  • Serological evaluation for the following viruses: measles, mumps, influenza, VZV, CMV, EBV, adenovirus, parvovirus B19, coxsackie A9.
  • Gram smear and culture for bacteria such as Haemophilus influenzae, Mycoplasma pneumoniae, and Klebsiella pneumoniae.
  • Review thick and thin smears for malaria.
• Direct antiglobulin test (ie, direct Coombs test, DAT)
• • Monoclonal C3 antisera generally shows DAT positivity due to C3d fragments on the RBCs. This reaction occurs during or shortly after the acute paroxysmal cold hemoglobinuria hemolytic episode.^{37, 38}
  • Polyclonal screening antisera are inadequate for this purpose because they have poor sensitivity to complement components.
  • 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.^{39, 40, 41, 42}  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 3 specimens: (1) the patient's serum, (2) a mix of patient 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 1). If the D-L antibody is present, samples 1 and 2 should be positive.  As negative controls, the set of 3 samples are replicated at testing conditions in which temperature is maintained at 4°C and 37°C throughout.{{Ref3} 
  • Because complement may be readily consumed during sample processing, giving a false-negative result, normal ABO-compatible serum is provided as an additional complement source.
  • The serum reacts equally well with normal adult RBCs and fetal RBCs. Only the rare pp RBCs (homozygous for the absence of P antigen) do not react.⁸
  • Modification of the Donath-Landsteiner test is done to enhance the antigenicity of the red blood cells. This is performed by exposing the erythrocytes to an enzyme, papain, treatment which then further unveils group P antigens.²⁴
  • 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.³⁰
• Indirect antiglobulin test
• • Another interesting maneuver is to demonstrate the D-L antibody with a modified indirect Coombs test. Control (normal) RBCs are incubated with patient's serum containing 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 Immunoglobulin M. 
• Conclusions
• • The D-L antibody test, DAT, and the indirect antiglobulin test are all useful in confirming the clinical diagnosis of paroxysmal cold hemoglobinuria.
  • If the Donath-Landsteiner test results are negative or equivocal and a cold reacting antibody is still suspected, perform a cold agglutinin titer.  Titers greater than 64 are likely due to a CHD antibody, although hemolysis rarely occurs at titers less than 1000.{{Ref35}
  • Test for the presence of CD55 or CD59 on the RBC membrane if paroxysmal nocturnal hemoglobinuria is suspected (see Differentials). Flow cytometry is a more sensitive tool to help exclude the presence of paroxysmal nocturnal hemoglobinuria when compared to the classic standard Ham test or sugar water test.

Imaging Studies

Although results from imaging studies do not define the diagnosis of paroxysmal cold hemoglobinuria, the findings can assist in identifying an underlying contributory condition. 

Because hemosiderin is a known nephrotoxic agent, patients undergoing severe hemolysis should avoid further exposure to renal irritants such as intravenous pyelogram dye.⁴³

Other Tests

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.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

• The mainstay of treatment is supportive care and the avoidance of cold exposure.  
• Administer warmed, packed RBC transfusions for life-threatening hemolysis and symptomatic anemia. Utilizing washed RBC units has not been proven to improve transfusion safety but can be performed if patient remains refractory to standard warmed products.{{Ref3} 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.³³ Normal use of plasmapheresis for removal of IgG induced processes is not as effective due to rebound of immunoglobulin as it shifts from extra- to the intravascular compartment. However, due to the low titer and limited production period of the D-L antibody, the process can be effectively controlled. Another theory is that the antibody preferentially binds to the RBC, shifting the antibody equilibrium to the intravascular component, allowing for ease in its removal.⁴⁵
• Steroids are commonly employed but have not been shown to shorten the clinical course.
• Treat underlying secondary conditions with appropriate medical therapy.
• Hydration, alkalinization of the urine, and other measures may become necessary to prevent renal failure. Symptoms of cold urticaria may be ameliorated by antihistamines.

Surgical Care

Surgery is not indicated, other than to diagnose underlying infections or neoplasms.

Consultations

• A hematologist-oncologist and an infectious diseases expert may be helpful for proper diagnosis and treatment.
• The family physician, pediatrician, or internist may also consult a nephrologist as needed to assist in care.
• The support of an experienced laboratory/blood bank is essential for all the serologic testing.

Diet

Folic acid supplements may be useful in the chronic form of the disease. Encourage eating of fresh fruits and vegetables rich in folate.

Activity

Patients 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 extremities from becoming chilled.

MEDICATION

Section 7 of 12  

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Currently there are no pharmaceutical agents available for the treatment of paroxysmal cold hemoglobinuria. 

FOLLOW-UP

Section 8 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Hospitalization is required to monitor and treat complications associated with severe anemia secondary to massive hemolysis.
• Maintain cardiorespiratory function and hydration status.
• Daily laboratory evaluation of anemia should include complete blood counts, lactate dehydrogenase levels, reticulocyte count.
• Monitor hemoglobinuria with routine urine analysis.
• Evaluate for secondary cause (ie, viral and bacterial serologic and culture assays, imaging studies).

Further Outpatient Care

When the acute phase is over, several follow-up visits for assessment of blood counts to ensure recovery may be all that is necessary, with instructions to avoid cold exposure. Confirming that the D-L 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 they are deemed cured or in remission.

Deterrence/Prevention

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

Complications

• 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.
• Renal failure is possible if patients are inadequately hydrated or have a predisposition to renal disease.
• Mortality is rare and is most commonly due to multiorgan failure from severe anemia secondary to massive acute hemolysis.

Prognosis

• Acute episodes are generally transitory in nature and rarely recur.  Prognosis is excellent with supportive therapy. 
• The chronic idiopathic forms may persist for years with variable morbidity.
• Paroxysmal cold hemoglobinuria usually ameliorates if the underlying disease responds to specific therapy.

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. Patients should also understand the need to take folate supplements to assist erythrocyte production.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to recognize the acute hemolytic event and/or correlate the event with paroxysmal cold hemoglobinuria. 
• Failure to institute hydration and other measures needed to prevent renal failure or cardiopulmonary dysfunction in a patient with massive intravascular hemolysis
• Failure to diagnose underlying or associated disease states

Special Concerns

• Avoid biphasic D-L antibody activity by providing warmed RBC units.
• Exacerbation of hemolysis can be avoided by monitoring patient while slowly transfusing blood components.
• Monitor hydration status, particularly in those with cardiac complications.

ACKNOWLEDGMENTS

Section 10 of 12  

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• Acknowledgments
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• References

The authors and editors gratefully acknowledge the contributions of previous authors, Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems and Harry L Messmore, Jr, MD, Professor, Department of Medicine, Division of Hematology/Oncology, Loyola University Stritch School of Medicine, to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

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• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Paroxysmal cold hemoglobinuria. Seen here is a Donath-Landsteiner test result 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).
	View Full Size Image
Media type:  Photo

REFERENCES

Section 12 of 12

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• Introduction
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• Differentials
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• Follow-up
• Miscellaneous
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• References

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18. Rausen AR, LeVine R, Hsu TC, Rosenfield RE. Compatible transfusion therapy for paroxysmal cold hemoglobinuria. Pediatrics. Feb 1975;55(2):275-8. [Medline].
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20. Petz LD, Garratty G. Acquired Immune Hemolytic Anemias. New York, NY: Churchill Livingstone; 1980:37-50.
21. Dacie J. The Haemolytic Anaemias. 3^rd ed. New York, NY: Churchill Livingstone; 1992:210-362.
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24. Breccia M, D'Elia GM, Girelli G, Vaglio S, Gentilini F, Chiara S, et al. Paroxysmal cold haemoglobinuria as a tardive complication of idiopathic myelofibrosis. Eur J Haematol. Oct 2004;73(4):304-6. [Medline].
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Article Last Updated: Dec 7, 2007