revbrashematolhemoter.2015;37(4):266–268
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Case
Report
Hyperhemolysis
syndrome
in
a
patient
with
sickle
cell
anemia:
case
report
Maria
Emmerick
Gouveia
∗,
Natalia
Bertges
Soares,
Mario
Sant’Anna
Santoro,
Flávia
Carolina
Marques
de
Azevedo
InstitutoEstadualdeHematologiaArthurdeSiqueiraCavalcanti(HEMORIO),RiodeJaneiro,RJ,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received10August2014 Accepted27November2014 Availableonline11April2015
Introduction
Sicklecell anemia(SCA) isageneticdisorder characterized byhomozygoushemoglobinS(HbS),chronichemolytic ane-miaandpainfulepisodes.1PatientswithSCAusuallyrequire
red blood cell (RBC) transfusions to manage complications and to reduce morbidity during surgical procedures.1 One
possiblecomplicationofmultipletransfusionsis alloimmu-nization, which occurs due to the recognition of foreign surfaceantigensontransfusedRBC byantibodiesproduced bytherecipient(alloantibodies).2,3Thisphenomenoncanlead
toadelayedhemolytictransfusionreaction/hyperhemolysis syndrome (DHTR/HS).1 However,patients who present this
syndromegenerallydonotshowanynewalloantibodies,and adirectantiglobulin test(DAT)isusuallynegative.4,5 Asno
newantibodiesaredetectedandthesymptomscanbe con-fusedwithotherSCAcomplications,thissyndromerepresents an importantdiagnostic challenge. Therecognition ofthis syndrome is importantfor the management of the symp-tomsandtopreventfutureonsets.Asitistriggeredbyblood
∗ Correspondingauthorat:RuaFreiCaneca,8,Centro,RiodeJaneiro,RJ,Brazil.
E-mailaddress:[email protected](M.E.Gouveia).
transfusions,itisimportanttorecognizeitandavoidfurther transfusions.
Thispaperaimstohighlighttheimportanceof recogniz-ingHS,becausewrongmanagementofacrisiswithanextra RBC transfusioncanincreasethehemolysisandcause life-threateninganemia.WereportacaseofayounggirlwithSCA thatdevelopedanepisodeofhyperhemolysissevendaysafter abloodtransfusion.
Case
report
An18-year-oldgirlwithSCAwasadmittedwithacutechest syndrome and was treated withintravenous fluid, analge-siaand antibiotics. Herblood testsshowed anhemoglobin (Hb)levelof6.10g/dL,hematocrit(Ht)of19.2%,lactate dehy-drogenase(LDH)of743U/L,andbilirubinlevelof5.95mg/dL (unconjugated:3.69mg/dL).Shereceivedoneunitof pheno-typicallymatchedpackedRBCs,withnocomplicationsduring the procedure. Laboratorialexams atdischarge showed Hb levelof9.32g/dL,Htof30.8%,LDHof643U/Landbilirubinlevel of4.29mg/dL.
http://dx.doi.org/10.1016/j.bjhh.2015.03.005
revbrashematolhemoter.2015;37(4):266–268
267
Twodaysafterdischarge(sevendaysaftertheRBC trans-fusion)shewasre-admittedwithjaundice,hemoglobinuria, pain crisis, paresthesia offeet, lethargy, dyspnea and pul-monary rales in lower third of both lungs. Her Hb level was 4.71g/dL, Ht 14.7%, white blood cell count (WBC) 37.8×109cells/L, LDH 3910U/L and bilirubin 13.65mg/dL
(unconjugated9.55mg/dL).NoRBCantibodiesweredetected usingthegelmethod(SerascanDiana2/SerascanDiana2P– Grifols,S.A.)andconfirmedwiththeID-System(BIORAD®). HLAantibodieswerealsonotdetectedbyaLABScreen®MULTI (One LambdaInc.) assay. HerHb Alevel was 4%andHb S was86%.Excludinginfectionand otherSCDcomplications, weconsideredthehypothesisofDHTR/HSandstarted high-dose intravenous methylprednisolone (1.5g/day). One day after,herHblevelsdroppedevenfurther,reaching3.0mg/dL andherLDHlevelsincreasedto6680U/L,accompaniedbya decreasedlevel ofconsciousness.Giventhe severityofthe casewedecidedtogiveheroneunitofpackedRBCs.Wealso startedtheadministrationof1g/kgintravenous immunoglob-ulin(IVIG),erythropoietin(4000U)andfolicacid.Sheimproved andwasdischargedaftertwoweekswithHbof7.96mg/dL, Htof24.5%,LDHof1694U/Landbilirubinlevelof5.69mg/dL. Serialimmunohematologicalstudiesperformedafterthis cri-sisalsoshowednegativeDATandHLAantibodies.
Discussion
AyoungSCApatientwasdiagnosedwithDHTR/HSsevendays afteraRBCtransfusion.Shepresentedwithsevereanemia,Hb levelslowerthanbeforethetransfusion,signsofhemolysis andpaincrisis.Facedwiththissituationandexcludingother causes,thehypothesisofDHTR/HSwasestablished.DHTR/HS isanuncommonbutsevere complicationof alloimmuniza-tionthat occursinpatientssubmittedtoRBC transfusions, especially those with SCD, who are submitted to multiple transfusions duringtheir lives.4 Therate of
alloimmuniza-tioninSCDpatientsisaround5–36%,1,6andtheincidenceof
DHTR/HSinSCDpatientsisaround1–19%.1,7
Whenweevaluatedhermedicalchart,weobservedthat she had a similar condition three years previously. Two daysbeforeahipsurgerysheunderwentapartialexchange transfusion and received phenotypically matched RBCs. BeforetransfusionherHblevelwas7.2mg/dL,Htwas21.9% andWBCwas17.3×109cells/L.Thesurgerywentwell,and
shedidnotneedanyother transfusionsduringorafterthe procedure.However,fivedaysafterthesurgery(sevendays after the transfusion) she was admitted as an emergency presentingwithfatigue,jaundice,pallorandtachycardia.She didnotexhibitfeverorpain.HerlaboratorytestsshowedHb of4.08mg/dL,Htof12.7%,WBCof41.5×109cells/L,LDHof
3346U/Landbilirubinlevelat12.09mg/dL.Concernedabout the risk of infection, intravenous fluid and oxacillin were administered. Blood cultures were negative. She was also managedwiththetransfusionofoneunitofpackedRBCs.Her symptomsimprovedandtwodaysaftershewasdischarged on oral antibiotics. On that occasion she was diagnosed with infection, despite the fact that she did not present withfeverorsigns ofbacterialinfection.Thesymptomsof DHTR/HScaneasilybemistakenforothersicklecelldisease
complications, including infections and vaso-occlusive crises.7 Themost importantissueistorecognize the
tem-poralappearanceofthesymptomsand itscorrelationwith transfusions of RBCs. DHRT/HS usually begins seven days afteraRBCtransfusion(range:4–11days).1Itisalsoimportant
tomeasuretheHblevels.Thus,thediagnosisofDHRT/HSis madebyclinicalfeatures,timebetweenRBCtransfusionand clinical onset,laboratorytestsand exclusion ofdifferential diagnoses.6
Beforethefirstsupposedepisode,whenshewas15years old, our patient had received over 16 RBC transfusions. Thus,shehadahighriskofdevelopingalloantibodies,even receiving phenotypically matched RBCs. Over time, some alloantibodiesdecreasetolevelsnotdetectedbyserological tests.1Oncethoseantibodiesarenotdetected,cellsseemto
bephenotypically compatible and are releasedfor transfu-sion.However,subsequentre-exposuretotheantigensthat triggeredtheantibodyproductionstimulatesananamnestic responseleadingtohemolysis.1,6
HS is mainly caused by destruction ofboth donor and recipient RBCs, but the exact mechanism is still not well understood.4,5 OnepossibleexplanationforautologousRBC
destruction is“bystanderhemolysis” wherebysickledRBCs are destroyedbyantibodieswithout expressingthespecific antigen against which this antibody is directed.5 Another
explanation for the patient’s RBC reduction is the activa-tionofmacrophagesleadingtoperipheraldestruction.Sickled RBCsexposesomeantigens(e.g.phosphatidylserine)andhigh levelsofIgGontheiroutersurface,allowingrecognitionby hyperactivatedmacrophages.6Ourpatientdidnotexhibitany
alloantibodiesor HLAantibodiesafterthe hemolysiscrisis, so it is believed that the patient’s and donor’s RBCs were destroyedbythehyperactivatedmacrophages.
HS is characterized by severe anemia, with Hb lower than pre-transfusional levels, pain, fever and signs of hemolysis(jaundice,increasedLDH,hyperbilirubinemiaand hemoglobinuria).1,5 Reticulocytopenia may be present5; HS
can be classified into acute or delayed.4 In the first
situa-tion,symptomsappearwithinsevendaysofreceivingRBCs, and a DATis generallynegative.Thedelayed formusually appearssevendaysafteratransfusion.4DATresultsare
usu-allypositiveand newalloantibodiescan bedetectedinthe patient’s serum.5 DHTR/HScan alsobeassociatedtosome
complicationssuchasacutechestsyndrome,congestiveheart failure,pancreatitis,acuterenalfailure,subarachnoid hemor-rhage,acuterespiratorydistresssyndrome,pneumonia,and splenicsequestration.1,3Thereisnospecifictesttodiagnose
DHTR/HS,andinmanycasesnoalloantibodiesaredetected. Win5proposesthatlaboratoryinvestigationswhenDHTR/HS
issuspected shouldcontemplate reticulocytecount, serum bilirubinlevel,LDH,DAT,screeningforantibodies,serial mea-surementofRBCs,Hbelectrophoresis,andhigh-performance liquidchromatography(HPLC)analysisoftheurine.
The treatment of DHRT/HS is based on the exclu-sion of other causes and management of steroids and immunoglobulins.4,5,8 Mild cases can receive prednisolone
(1–2mg/kg/day)withclosemonitoringofHblevels.5Avoiding
268
revbrashematolhemoter.2015;37(4):266–268reachedaverylow Hblevel withadecreasedlevel of con-sciousness.Wecomparedrisksandbenefitsanddecidedto giveheroneunitofRBCs,awarethatsubsequenttransfusions couldexacerbatehemolysisandbecomelifethreatening.4We
initiatedIGIVatthesametimetoavoidexacerbationofthe hemolysis.5 We also treated her with methylprednisolone,
erythropoietinandfolicacid.Steroidsand IVIGmayhavea synergisticeffectinsuppressingmacrophages,4,5andnew
evi-dencesuggeststhattheycanshortenthecourseofhemolysis.5
Theroleoferythropoietinisnotwellestablished,butitsserum levels are lowfor this levelof anemia.5 Win suggests that
erythropoietinmay correctanemia inDHTR/HS bydirectly stimulatingerythroidprecursorsandpreventingthe destruc-tionofyoungRBC.5
Otherstudies havereporteda similarscenario, success-fully treating patients with life-threatening HS with RBC transfusions,steroids and immunoglobulin.4,6,9 Onestudy5
recommendstheuseoflow-doseIVIG(0.4g/kg/day)forfive daysandintravenousmethylprednisolone(0.5g/dayforadults and4.0mg/kg/dayforchildren)fortwodays.Somestudiesalso suggesttheuseofRituximabandcyclophosphamideinsevere cases.10
HSisaseverediseaseandfewrecurrentcaseshavebeen describedintheliterature.Insomecasesitcanbelife threat-ening.Thisconditioncan bemisdiagnosedwithother SCD complications,soitisveryimportanttothinkaboutDHTR/HS whenfacedwithahemolysiscrisisinaSCDpatient, espe-cially aftera RBC transfusion.Thecorrect management of HSbyavoidingfurthertransfusionsandgivingsteroidsand immunoglobulincanchangethecourseofthedisease.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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