Content uploaded by Hasitha Gajaweera
Author content
All content in this area was uploaded by Hasitha Gajaweera on Aug 01, 2021
Content may be subject to copyright.
654
Bangladesh Journal of Medical Science Vol. 20 No. 03 July’21
Case report
Acute paroxysmal cold haemoglobinuria; a case report and literature review
Hasitha Gajaweera1, Kavinda Dayasiri2, Nayani Suraweera3, Chandrachapa Gamage4,
Kumudu Weerasekara5
Abstract
Paroxysmal cold hemoglobinuria (PCH) is a very rare subtype of autoimmune hemolytic
anemiacausedbythepresenceofcold-reactingautoantibodiesinthebloodandcharacterizedby
thesuddenpresenceofhemoglobinuria,typicallyafterexposuretocoldtemperatures.Theacute
onsetPCHoccursfollowingviralillnesseswhilstthechronicformissecondarytohematological
malignanciesandtertiarysyphilis.Itisacomplementmediatedintravascularhemolyticanemia
associatedwithabiphasicantibodyagainstthePantigenonredcells.Wedescribeathreeyear
childwhohadacuteonsetPCHfollowinglikelyviralinfection.Thediagnosiswasconrmed
by demonstration of strongly positive Donnath Landsteiner antibodies. She made a gradual
recovery with supportive treatment, ten days following the initial detection of haemolysis.
Parentswereeducatedabouttheneedtoavoidcoldexposuretopreventprecipitationoffurther
haemolysisandfolicacidwascommencedtoassisttherecoveryoferythropoiesis.
Correspondence to: Dr. Kavinda Dayasiri, Lady Ridgeway Children’s hospital, Colombo, Sri Lanka.
E-mail: kavindadayasiri@gmail.com
1. HasithaGajaweera,MBBSMDSeniorRegistrarinPaediatricRespiratoryMedicine
2. KavindaDayasiri,MBBSMDMPhilFRCPCH,SeniorRegistrarinPaediatrics
3. NayaniSuraweera,MBBSMD,SeniorRegistrarinPaediatrics
4. ChandrachapaGamage,MBBSMD,SeniorRegistrarinHematology
5. KumuduWeerasekara,MBBSMDMRCPCH,ConsultantPaediatrician
LadyRidgewayChildren’shospital,Colombo,SriLanka
Bangladesh Journal of Medical Science Vol. 20 No. 03 July’21. Page : 654-657
DOI: https://doi.org/10.3329/bjms.v20i3.52811
Introduction
Paroxysmal cold hemoglobinuria (PCH) is a
rare subtype of autoimmune hemolytic anemia
characterizedbypresenceof biphasic cold reactive
IgG type autoantibodies against p antigen on red
bloodcells.Theseantibodiesresultincomplement-
mediatedintravascularhemolysisfollowingexposure
tocoldtemperaturesandpatientpresentswithacute
onsetheamoglobinuria.WhilstacutePCHcanoccur
following viral infections and chronic PCH can
presentsecondarilytochronicmedicalillnessessuch
ashaematologicalmalignancies,andtertiarysyphilis.
The cold reactive IgG antibody is also known as
“Donnath Landsteiner” antibody which was rst
described by Julius Donath and Karl Landsteiner in
medical literature. Donnath Landsteiner antibodies
bind red blood cells at colder temperatures and
antibodyboundredbloodcellsundergocomplement
mediated haemolysis while circulating through
warmer temperatures. The characteristic features
of acute PCH include haemolytic anemia and
haemoglobinuria.
Paroxysmal cold heamoglobinuria accounts for less
than 1% of all autoimmune haemolytic anaemias,.
The estimated annual incidence of PCH was 0.4
casesper100,000 population inonestudy.Herein,
the authors describe a child who had paroxysmal
coldhaemaglobinuriafollowingaviralinfection.
Case report
A three year old girl who was previously healthy
andborntonon-consanguineousparentsfromalow
655
Acuteparoxysmalcoldhaemoglobinuria;acasereportandliteraturereview
socialbackground, presented withacute onset cola
coloururineforonedayduration.Therehadbeena
precedinghistoryofupperrespiratorytractinfection
2weeksbeforetheonsetofillness.Colacolourwas
moreintenseduringearlymorning.Therehadbeenno
historyofexposuretocoldclimatesortemperatures.
Urineoutputwasnotreduced.Thechilddidnothave
symptomsof anemiaor heartfailure onadmission
totheward.Therewasnorecentmedicationhistory.
Further clinical evaluation did not reveal features of
malignancy, infections or connective tissue disorders.
Examination revealed a pale and icteric child
with adequate physical growth (weight –10 kg,
height – 94 cm). There was no lymphadenopathy,
rashes, arthritis, oral ulcers, exudative tonsillitis or
hepatosplenomegaly.Cardiovascularandrespiratory
systems were clinically normal. Table 1 shows
sequentialhematologicalindices and bilirubin over
the course of illness.
Table 1 - Variation of hematological indices and
bilirubin over the course of illness
1
week
prior
Day 1 Day 2 Day 3 Day 4 Day 5 Day 7
Hemoglobin
(g/dl) 12.5 9.2 5.1 5.2 5.4 5.6 6
Platelets (x 109)333 390 360 347 348 323 325
TotalBilirubin
(mg/dl) -129 127 172 131 53 34
Indirect
Bilirubin (mg/
dl)
-86 104 146 103 43 26
Full blood count revealed normochromic normocytic
anemia.Bloodpictureshowedpolychromaticcells,
red cell agglutinins and erythrophagocytosis with
evidence of cold autoimmune haemolytic anemia.
Reticulocytecountwas0.8%.Liverfunctions were
withinnormallimits(SGOT–43U/L,SGPT–35).
Serumcreatininewas28µmol/landbloodureawas
7.3mg/dl.DirectCoombstestwaspositivewithC3d
specicity.Epstein-Barrvirus,Cytomegalovirusand
Mycoplasmaserologywerenegative.Urineanalysis
revealed haemoglobinuria and haemosiderinuria
whilsthaematuriawasabsent.DonnathLandsteiner
antibodieswerestronglypositive.
Thechildwasmanagedwithintravenousuids,blood
transfusions and warming with regular monitoring
of hematological indices and serum bilirubin. She
madeagradualrecovery10daysfollowingtheinitial
detection of haemolysis. Parents were educated
about the need to avoid cold exposure to prevent
precipitationoffurtherhaemolysisandfolicacidwas
commencedtoassisttherecoveryoferythropoiesis.
Discussion
The rst report of PCH as a syndrome of passage
of red coloured urine upon exposure to cold was
coinedin1872.PCHweredescribedpredominantly
following secondary and tertiary syphyllis in the
past,.Presently,PCHisknowntofollowanumberof
viralillnesses,suchasparvovirusB19,Epstein-Barr
virus,coxsackievirusA9,mumps,inuenza,chicken
pox, measles, cytomegalovirus, and adenovirus,,.
However,aspecictriggerisnotidentiedinmany
children14,16.PCHhavealsobeenreportedinpatients
withchroniclymphocyticleukemia.
Although acute onset haemolysis and
haemoglobinurisin PCH occurfollowing exposure
tocoldtemperatures,occasionally ahistoryofcold
exposure may not be present. Children are more
susceptibleforacute PCH andcanpresent with an
isolated,shortlasting,hemolyticepisodefollowinga
viralinfection.However,recurrentepisodesofPCH
in children have been reported127. Haemolysis is
usuallyrapidlyprogressiveandcanbelifethreatening
leading to severe anaemia. Reticulocyte count is
oftenlow for the degree ofanaemia suggesting an
inadequate bone marrow response due to marrow
suppressionfromviralinfection.
The clinical features of PCH include passage of
red or brown coloured urine (heamoglobinuria),
abdominalpain,headache,fever,malaise,feverwith
chills,andvomiting.Accumulationofbilepigments
canrarelyleadtoacutekidneyinjury.IgMmediated
cold autoimmune haemolytic anaemia is the main
dierentialdiagnosis.
TheantibodyinPCHiscold-reactiveIgG.Although
IgG antibodies do not cause red cell agglutination as
seenwithIgM,IgGboundredcellsreadilyundergo
complement mediated haemolysis. This leads to
intravascularhemolysisin warm temperatures. The
rate of haemolysis at dierent temperatures is
variableindierentpatients.
656
HasithaGajaweera,KavindaDayasiri, et al.
The gold standard for diagnosis of PCH is
demonstration of Donnath-Landsteiner antibodies.
DonnathLandsteinerantibodieswererstdescribed
in1904.Theseantibodiesusuallyappear1weekafter
theonsetofhaemolysisandcanbedemonstratedup
to three months.
Treatmentismainlysupportive.Adequatehydration,
pain relief and avoidance of cold form a key part
of management. Red cell transfusions are indicated
forpatientswithsevereanaemiaandacutewarming
helps in mitigating severe haemolysis. It is also
important to monitor blood counts, reticulocyte
countandifindicated,renalfunctionsuntilcomplete
recovery. Immunosuppressive therapy may be
eectiveinseverecases.Inmostchildrenwithcute
PCH,haemolysisisself-limitingandsupportivecare
and monitoring are all that is required. However,
untreated children can develop acute kidney
injuryandcomplicationsfollowingsevereanemia.
Funding–Notapplicable
Conict of Interest – None declared
Acknowledgement – None
Written consent has been obtained from index
patient’sparents
Ethical clearance–Notapplicable
Authors’ contribution – HG, KD, NS, CG, KW
clinically managed the patient, HG, KD, NS
performed literature survey, HG, KD, NS, CG
preparedthemanuscript,KWsupervisedpreparation
of the manuscript, All authors approved the nal
versionofmanuscript.
657
Acuteparoxysmalcoldhaemoglobinuria;acasereportandliteraturereview
References:
1. Akpoguma AO, Carlisle TL, Lentz SR. Case
report: paroxysmal cold hemoglobinuria
presenting during pregnancy. BMC Hematology.
2015;15:3. doi:10.1186/s12878-015-0023-7.
https://doi.org/10.1186/s12878-015-0023-7
2. SanfordKW,RoseSD.Detectionand signicanceof
Donath-Landsteiner antibodies in a 5-year-old female
presenting with hemolytic anemia. Lab Medicine.
2010;41(4):209-12.doi:10.1309/LM1E9Z2QZEREPAI.
https://doi.org/10.1309/LM1E9Z2QZEREPAI
3. Sivakumaran M, Murphy PT, Booker DJ, Wood
JK, Stamps R, Sokol RJ. Paroxysmal cold
haemoglobinuria caused by non-Hodgkin’s
lymphoma. Brit J Haematol. 1999;105(1):278-9
https://doi.org/10.1046/j.1365-2141.1999.01315.x
4. Stefanizzi C, Breccia M, Santopietro M, Coluzzi S,
Cannella L, Girelli G, et al. Unusual association of
paroxysmal cold hemoglobinuria as the rst sign of
disease in myelodysplastic patient. Int J Hematol.
2009;89(5):720-1. doi: 10.1007/s12185-009-0342-1.
https://doi.org/10.1007/s12185-009-0342-1
5. SokolRJ,HewittS.Autoimmune hemolysis: a critical
review. Crit Rev OncolHematol. 1985;4(2):125-54.
https://doi.org/10.1016/S1040-8428(85)80013-5
6. BarcelliniW.ImmuneHemolysis:DiagnosisandTreatment
Recommendations. Semin Hematol 2015; 52:304.
https://doi.org/10.1053/j.seminhematol.2015.05.001
7. Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical
heterogeneity and predictors of outcome in primary
autoimmune hemolytic anemia: a GIMEMA
study of 308 patients. Blood 2014; 124:2930.
https://doi.org/10.1182/blood-2014-06-583021
8. Sokol RJ, Hewitt S, Stamps BK. Autoimmune
haemolysis associated with Donath-Landsteiner
antibodies. Acta Haematol 1982; 68: 268-277
https://doi.org/10.1159/000206992
9. Salido EJ, Cabañas V, Berenguer M, et al.
Serological Findings in a Child with Paroxysmal
Cold Haemoglobinuria. Case Reports in Medicine.
2014;2014:316010. doi:10.1155/2014/316010.
https://doi.org/10.1155/2014/316010
10. EderAF.Review: acute Donath-Landsteiner hemolytic
anemia. Immunohaematology. 2005;21(2):56-62.
11. Petz LD. Cold antibody autoimmune hemolytic anemias.
Blood Rev. 2008 Jan;22(1):1-15. Epub 2007 Sep 27.
https://doi.org/10.1016/j.blre.2007.08.002
12. Sokol RJ, Booker DJ, Stamps R.Erythropoiesis:
Paroxysmal Cold Haemoglobinuria: A Clinico-
PathologicalStudyof Patients withaPositiveDonath-
Landsteiner Test. Hematology. 1999;4(2):137-164.
https://doi.org/10.1080/10245332.1999.11746439
13. Bunch C, Schwartz FC, Bird GW. Paroxysmal cold
haemoglobinuria following measles immunization.
Arch Dis Child. 1972;47(252):299-300.
https://doi.org/10.1136/adc.47.252.299
14. Göttsche B, Salama A, Mueller-EckhardtC.Donath-
Landsteiner autoimmune hemolytic anemia in children.
A study of 22 cases. Vox Sang. 1990;58(4):281-6.
https://doi.org/10.1111/j.1423-0410.1990.tb05000.x
15. ShararaAI,HillsleyRE,WaxTD,RosseWF.Paroxysmal
cold hemoglobinuria associated with non-Hodgkin’s
lymphoma. South Med J. 1994 Mar;87(3):397-9.
https://doi.org/10.1097/00007611-199403000-00019
16. Sood R, Suman N, Rani S, Kumar V. Paroxysmal
Cold Hemoglobinuria: Role of Hospital Transfusion
Medicine and Immunohematology Department in the
Diagnosis. J Thrombo Cir 2016;2:105. doi:10.4172/
jtcoa.1000105.
17. Göttsche B, Salama A, Mueller-Eckhardt C. Donath-
Landsteiner autoimmune hemolytic anemia in children.
A study of 22 cases. Vox Sang 1190;58: 281-286.
https://doi.org/10.1111/j.1423-0410.1990.tb05000.x
18. Taylor CJ, Neilson JR, Chandra D, Ibrahim Z (2003)
Recurrentparoxysmalcoldhaemoglobinuriaina3-year-
oldchild:acasereport.Transfus Med 2003; 13:319-321.
https://doi.org/10.1046/j.1365-3148.2003.00460.x
19. Gunawardena D, Velu M, Senaviratne SN.
Case report on a child with paroxysmal cold
haemoglobinuria. Indian J Hematol Blood Transfus.
2012;28(2):112-3. doi: 10.1007/s12288-011-0094-y.
https://doi.org/10.1007/s12288-011-0094-y
20. Storrar N, Miller-Hodges E, Neary J, et al.
Microangiopathy and acute kidney injury in
paroxysmal cold hemoglobinuria: A challenge
for management. Am J Hematol 2018; 93:718.
https://doi.org/10.1002/ajh.25038
21. Donath J, Landsteiner K. About
paroxysmal hemoglobinuria. München Med
Wochenschr.1904;51:1590-1593.
22. Petz LD. Cold antibody autoimmune
hemolytic anemias. Blood Rev. 2008;22(1):1-
15. doi: 10.1016/j.blre.2007.08.002.
https://doi.org/10.1016/j.blre.2007.08.002