Hematology & immune disorders

Hemolytic anemia

Paroxysmal cold hemoglobinuria (PCH)


Resident / Fellow Advisory Board: Frido Bruehl, M.D.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Louise Helander, M.B.B.S.
Kyle Annen, D.O.

Last author update: 19 October 2023
Last staff update: 19 October 2023

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PubMed Search: Paroxysmal cold hemoglobinuria

Louise Helander, M.B.B.S.
Kyle Annen, D.O.
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Cite this page: Helander L, Annen K. Paroxysmal cold hemoglobinuria (PCH). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/hematologyPCH.html. Accessed May 19th, 2024.
Definition / general
  • Acquired complement mediated intravascular hemolytic anemia due to biphasic autoantibody, usually against the P red blood cell (RBC) antigen
Essential features
  • Paroxysmal cold hemoglobinuria (PCH) is an acquired complement mediated hemolytic process associated with polyclonal biphasic IgG autoantibodies against the P antigen, which bind at cold temperatures, resulting in activation of the complement cascade and intravascular hemolysis on warming to 37 °C (Hematol Oncol Clin North Am 2015;29:473)
  • Most commonly seen in children < 5 years old with acute hemolysis 1 - 3 weeks after a viral or bacterial infection (Transfusion 2017;57:1332)
  • Rarely seen in adults (because of the common use of antibiotics) but historically seen in association with congenital or tertiary syphilis, which causes chronic relapsing PCH (Hematol Oncol Clin North Am 2015;29:473)
  • Generally transient and self limiting
Terminology
  • Paroxysmal cold hemoglobinuria (PCH)
  • Donath-Lansteiner hemolytic anemia
  • Donath-Landsteiner test
ICD coding
  • ICD-10: D59.6 - hemoglobinuria due to hemolysis from other external causes
  • ICD-11: 3A20.3 - paroxysmal cold hemoglobinuria
Epidemiology
Sites
Pathophysiology
  • Caused by a weak affinity biphasic autoantibody, usually IgG
    • Also referred to as the Donath-Landsteiner antibody
    • Reports of biphasic IgA and IgM autoantibodies (Pediatr Blood Cancer 2015;62:2044, Pediatr Int 2013;55:664)
    • Autoantibodies are most commonly directed against the P red cell antigen but there have been reports of other carbohydrate antigen targets (i, I, HI, Pr) (Transfusion 2017;57:1332)
    • Autoantibody most commonly forms ~1 - 3 weeks post-viral or bacterial infection (Transfusion 2017;57:1332)
      • Other causes include vaccination, autoimmune disorders, hematopoietic malignancy, tertiary or congenital syphilis (historically)
      • Mechanism of autoantibody sensitization is unknown; hypotheses include viral modification of RBC membrane, production of crossreactive antibodies or altered immune regulation (Transfusion 2017;57:1332)
  • 2 phase process
    • Autoantibody binds to the RBC membrane at temperatures < 37 °C
    • On recirculation and rewarming to 37 °C, the autoantibody dissociates but the complement components remain bound, thus activating the terminal complement pathway with formation of the membrane attack complex on the RBC surface and resulting in intravascular RBC lysis (Hematol Oncol Clin North Am 2015;29:473)
      • Free hemoglobin released during hemolytic episodes can result in acute kidney injury (Blood 2018;131:2506)
Etiology
  • More prevalent in the pediatric population
    • Pediatrics: > 70% of cases post-upper respiratory tract infection (URI), viral or bacterial
      • Most commonly enveloped viral infections (Transfusion 2017;57:1332)
      • Also associated with gastrointestinal illness, vaccination (most common association: pneumococcal vaccination), autoimmune disorder, hematopoietic malignancy, very rarely parvovirus B19 infection (Transfusion 2017;57:1332)
    • Adults: rare
Clinical features
  • Presentation is variable but includes some degree of intravascular hemolysis (J Clin Med 2021;10:216)
    • Intravascular hemolysis at presentation can be severe, necessitating immediate intervention
    • Possible symptoms include anemia, jaundice, fatigue, pallor, fever, chills, back or abdominal pain
  • Symptoms appear 1 - 3 weeks postinfection; strong relationship to viral infections in children (Transfusion 2017;57:1332)
    • Symptom onset can be associated with cold exposure (e.g., outside in cold weather, air conditioning, drinking cold beverage) (J Clin Med 2021;10:216)
  • Prognosis is favorable (Lab Med 2014;45:253)
    • Transient, self limiting and generally does not recur
Diagnosis
  • Classic presentation warrants immediate Donath-Landsteiner testing
    • Hemolytic anemia in anyone under 18 years old with recent infection (viral or bacterial) (Immun Ageing 2020;17:38)
      • Hemolysis may be sudden and severe
    • New onset Coca-Cola colored urine reported
    • Direct antiglobulin test (DAT) negative for IgG, positive for complement (most commonly)
  • Presence of Donath-Landsteiner antibody is pathognomonic
Laboratory
  • Labs indicating hemolysis (Immun Ageing 2020;17:38)
    • Increased indirect (unconjugated) bilirubin
    • Low / absent haptoglobin
    • Elevated lactate dehydrogenase
    • Increased urinary urobilogen
    • Hemosiderin in urine ~1 week after start of hemolysis
  • Organ damage resulting from acute hemolysis (Hematol Oncol Clin North Am 2015;29:473)
  • Relative reticulocytopenia is possible despite significant anemia; more common in children (Transfusion 2017;57:1332)
    • May reflect sudden severity of hemolysis and cause depletion of reticulocytes in marrow pool
      • Reticulocytes may be a target of the autoantibody
    • Reticulocytopenia is not considered a poor prognostic sign in children with PCH as in adult populations with AIHA; children normally recover in 1 - 4 weeks
  • Direct Coombs / DAT test is negative for IgG and positive for C3 (Clin Exp Rheumatol 2015;33:588)
  • Absence of warm autoantibodies (Transfusion 2017;57:1332)
  • Positive Donath-Landsteiner test: in vitro test to measure biphasic hemolysins with anti-P specificity (Hematol Oncol Clin North Am 2015;29:473)
    • Sample is required to be collected and maintained at 37 °C during transport
    • Sample must be collected in tubes with no anticoagulant (red top Vacutainer)
    • Can result in false negative results due to incorrect specimen handling or transient nature of the autoantibody
      • Antibody titers are highest during periods of clinical hemolysis
Case reports
  • 15 month old boy presented with an upper respiratory infection and sudden onset of pallor with dark urine (J Pediatr Hematol Oncol 2022;44:60)
  • 23 month old girl and 4 year old girl both admitted to the hospital with acute hemolytic anemia following upper respiratory infections and otitis media in the weeks prior (Lab Med 2014;45:253)
  • 4 year old boy presented with presumed viral infection and sudden onset severe hemolysis successfully treated with eculizumab therapy (Blood Adv 2019;3:3575)
  • 18 year old woman in early pregnancy with acute hemolytic anemia was found to be D - L antibody positive (BMC Hematol 2015:15:3)
  • 27 year old woman presented with cough and acute hemolytic anemia leading to acute kidney injury and oliguric renal failure requiring hemodialysis (Blood 2018;131:2506)
Treatment
Clinical images

Contributed by Samantha Mack, M.D.
Donath-Landsteiner assay interpretation worksheet

Donath-Landsteiner
assay interpretation
worksheet

Donath-Landsteiner tube assay example

Donath-Landsteiner tube assay example

Peripheral smear description
Sample assessment & plan
  • Assessment: Johnny is a 5 year old boy who presented with 1 week of symptoms consistent with an upper respiratory infection (cough, fever, congestion), anemia and new onset hemoglobinuria. Send out testing identified the presence of a biphasic antibody (Donath-Landsteiner antibody).
  • Plan: The patient presentation and laboratory workup are consistent with a diagnosis of paroxysmal cold hemoglobinuria.
    • Transfuse pRBCs as clinically indicated. A blood warmer is recommended.
    • Recommend patient avoid cold climates while antibody is present.
    • No special transfusion requirements or precautions.
Differential diagnosis
  • Autoimmune hemolytic anemia (AIHA) (Immun Ageing 2020;17:38):
    • Positive DAT (can be IgG, complement or both)
    • IgG autoantibody is panreactive
    • Maximum reactivity at 37 °C rather than below body temperature as seen in PCH
    • Evidence of extravascular hemolysis rather than intravascular hemolysis
  • Mixed autoimmune hemolytic anemia (J Clin Med 2021;10:216):
    • Cold reacting IgM and warm reacting IgG antibodies
    • DAT positive for IgG and C3
  • Cold agglutinin syndrome (CAS) (Immun Ageing 2020;17:38):
    • Presents similarly to PCH with intravascular hemolysis precipitated by recent infection (Mycoplasma pneumoniae or Epstein-Barr virus most frequently)
    • DAT positive for C3 but high titer IgM autoantibody with anti-Ia specificity
    • Cold agglutinin titer positive
    • Symptoms of both intravascular and extravascular hemolysis
Board review style question #1

Which of the following is considered the definitive test for diagnosis of paroxysmal cold hemoglobinuria (PCH)?

  1. Bone marrow biopsy
  2. Coombs test
  3. Donath-Landsteiner test
  4. Flow cytometry
Board review style answer #1
C. Donath-Landsteiner test. The Donath-Landsteiner test, an in vitro test to measure biphasic hemolysins with anti-P specificity, is positive in cases of PCH. Answer A is incorrect because bone marrow biopsy could range from normal to evidence of bone marrow compensation (e.g., erythroid hyperplasia) due to hemolysis in a patient with PCH. Erythroid hyperplasia is a nonspecific sign that can be seen in many disease states where hemolysis or anemia are present. Answer B is incorrect because the direct antiglobulin (Coombs) test is a nonspecific test. Both positive and negative results can be seen in a wide variety of disease states and it does not definitively define PCH. Answer D is incorrect because unlike paroxysmal nocturnal hemoglobinuria, there are no specific flow cytometry markers associated with PCH.

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Reference: Paroxysmal cold hemoglobinuria (PCH)
Board review style question #2
Which red cell antigen is the biphasic Donath-Landsteiner autoantibody usually reactive against?

  1. A antigen
  2. I antigen
  3. O antigen
  4. P antigen
Board review style answer #2
D. P antigen. The P antigen is a part of the globoside blood group system. It is a receptor for parvovirus B19 and some forms of E. coli. Antibodies to the P antigen have a known association with paroxysmal cold hemoglobinuria (PCH). Answers A and C are incorrect because blood group antigens A and O (the absence of blood group antigens A and B) have no known association with PCH. Answer B is incorrect because I antigens occur at the branching points of type II oligosaccharide chains. Decreased I antigen expression is associated with some leukemias. There is no known association with PCH.

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Reference: Paroxysmal cold hemoglobinuria (PCH)
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