w w w . h t c t . c o m . b r
Hematology, Transfusion and Cell Therapy
Original article
Chronic transfusion therapy effectiveness as primary stroke prophylaxis in sickle cell disease patients
Juliana Moreira Franco
∗, Carla Caroline Lopes Borges, Marília Alves Ansaloni, Renata Dudnick de Lima Mauro, Ylle Carolinne da Cruz Souza,
Josefina Aparecida Pellegrini Braga
UniversidadeFederaldeSãoPaulo(Unifesp),SãoPaulo,SP,Brazil
a r t i c l e i n f o
Articlehistory:
Received8March2018 Accepted28May2018
Availableonline31October2019
Keywords:
Sicklecellanemia Stroke
Transcranialdopplererythrocyte transfusionchildren
a bs t r a c t
Introduction:About10%ofsicklecellanemia patientswillhaveischemicstroke.Adams showedstrokeincidencereductioninchildrenreceivingmonthlyerythrocytetransfusions byreducingtranscranialDoppler(TCD)velocities.Sincethen,chronictransfusionisrec- ommendedasprimarystrokeprophylaxis.Thisstudyaimstoassesstheeffectivenessof chronictransfusionsasstrokeprophylaxis.
Method:Retrospectivestudy,reviewingmedicalrecordsfrom15sicklecellanemiapatients undergoingchronictransfusion.Datacollectedwereage,sex,adversereactions,stroke, hemoglobin,reticulocytes,ferritin,HbSandTCDvalues(baseline,after12and24monthsof treatment).
Results:Themeanagewas118.67±41.40months;sixpatientsexperiencedallergicreac- tions.Nostrokewasrecorded.Onepatienthadalloimmunization.Therewasadecrease in the HbS rateand an increase in hemoglobinvalues in the first 12months. Values weremaintainedafter24months,butwith noimprovementofdata.Before treatment, themeanHbSratewas75.18%±11.69;after12months,41.63±14.99andafter24months, 43.78±10.6.Thirteenpatientsinitiatedchelation after12monthsfromthebeginningof chronictransfusionsandferritindeclineafter24months.Pre-transfusionalTCDvelocities were204.28±9.41cm/s(right)and198.85±33.37cm/s(left).Aftera12-monthtreatment, thesevalueswere158.5±28.89cm/sand157.62±34.43cm/s,respectively,andthisreduction wasstatisticallysignificant(p=0.002rightandp=0.02left).After24months,thesevalues were149.63±26.95cm/s(right)and143.7±32.27cm/s(left).
Conclusion:Significantreductionof TCDvelocity occurred aftertreatment with chronic transfusioninsickle cellanemia patients, leading toa normalor conditional testand reducingstrokeriskinallbutonepatient.
©2019Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published byElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).
∗ Correspondingauthorat:DepartmentofPediatrics,UniversidadeFederaldeSãoPaulo(Unifesp),RuaBotucatu,598,SãoPaulo,SP,Brazil.
E-mailaddress:[email protected](J.M.Franco).
https://doi.org/10.1016/j.htct.2018.05.015
2531-1379/©2019Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Sicklecelldisease(SCD)isthemostcommonseveremono- genetic disorder in the world. It is estimated that 25–30 thousandpeopleinBrazillivewiththisdiagnosis.Thenew caseincidenceisapproximately3500casesayear.1Thepres- enceofhemoglobinS,insituationsofhypoxiaordehydration canleadtoitspolymerization,causingerythrocyterigidityand vascularocclusion,whichisthecentralpathophysiologyofthe disease.Chronichemolysisisahallmarkofthediseaseandis bothintra-andextravascular.2
Strokephysiopathology inSCD implicatesinsickledred bloodcell,causingacutevascularocclusion,associatedwith previousvasculopathy,mainlyindistalintracranialinternal carotidartery segmentsand proximalportions ofthemid- dleandanteriorcerebralarteries.Vasculopathyresultsfrom fibroblastproliferationinthevascularintima.Thisnarrowing appearsinMRIasmuchasintranscranialDopplerultrasonog- raphy(TCD)duetorisingbloodflowvelocitiesinthestudied vessels.3 Thus,sinceitisless expensive,offerslessrisk to patientsand ishighly accurate,the TCD iswidelyused as strokeriskassessment.3,4
Onein10sicklecelldiseasepatientswillsufferastroke,5 this being one major cause of death in this population.6 Theisquemicformispredominantinchildren,whereasthe hemorrhagic form is more common in adulthood. There’s a bimodal peak incidence between 2–5 years and after 29 years, with decreased incidence from 10 to 19 years.7,8 Most pediatric patients recover without physical sequelae afterpropertreatment,neverthelesscognitivesequelaemay persist.8Therefore,focusonprimarypreventionisimportant.
In1998,theSTOPstudyfounda92%reductioninstroke incidenceinchildrenundergoingchronictransfusion.Higher risk patients were found by TCD values; they must not havehadapreviouscerebrovascularevent.Sinceitspublica- tion,chronictransfusionisrecommendedasprimarystroke prophylaxis.9Thesepatientsalsohadfewervaoscularocclu- sivecrises(VOC)andacutechestsyndrome(ACS)episodes.5 AnotherretrospectivestudyshowedthatTCDscreeningand useofregulartransfusionsinhigh-riskpatientsdecreasedthe annualstrokeratefrom0.44to0.19per100person-years.10 Still,risksassociatedwiththistherapy,suchasalloimmuniza- tion,ironoverloadanddiseasetransmission,arerelevant.
Thisstudyaimstoassesschronictransfusioneffectiveness asprimarystrokeprophylaxisinsicklecelldiseasepatients.
Method
Thisisa retrospective study,approvedbythe Ethics Com- mitteeoftheUniversidade FederaldeSãoPaulo–UNIFESP (CAAE:68549617.3.0000.5505).Medicalrecordsfrom23sickle cell disease patients undergoing chronic transfusion, from January2008untilJune2016werereviewed.Laboratorialtests datawerefoundinelectroniccharts.Patientswithlessthan 12monthsoftreatment,incompletedataorpreviousstroke wereexcluded.
Sicklecelldiseasepatients(HbSSandHbS0)between2–16 yearsarescreenedannuallyforstrokeriskwithTCD,asper
global consensus, by the Neurovascular Unit of the hospi- tal. Patients with 2abnormal tests are referred to chronic transfusion therapy; the Pediatric Hematology unit offers comprehensive SCD care, including chronic blood transfu- sion.Inourhospital,weusesimpleredbloodcelltransfusion, aiming toreducethe HbS rate below50% and tokeep the pre-transfusionalmeanbaselinehemoglobinbelow10g/dLto avoidhyperviscosity.Patientswithovertstrokewerereferred to chronic transfusion as well for secondary stroke pro- phylaxis. The TCD was performed in accordance with the StrokePreventionTrialinSickleCellAnemia(STOP)Protocol.9 Chelationwasinitiatedafter3ferritinlevelmeasuredabove 1000ng/mL.
Thedata collected were age, sex,date ofthe beginning oftreatmentanditsclinicalindication,presenceorabsence oftransfusion-related reactions(such asalloimmunization, allergic reaction, hemolytic reaction), presence or absence of stroke, HbS, hemoglobin and serum ferritin values at the beginning of treatment and after 12 and 24month of chronictransfusionsandTCDvaluesbeforeandafter12and 24monthsoftreatment.
Anewneurologiceventwasconsideredcompatibleafter evaluation byapediatric neurologist and suggestive radio- logicalimaging.8 Acutechest syndromewasdefinedasthe presenceofrespiratorysymptomsassociatedwithnewradio- logicalimaging.11
Statistical analysiswasmadewith descriptivevariables, including means and standard deviations (SD) to describe thepatients’characteristics.TheStudent’sttestwasusedto comparemeansbetweentheTCDvelocities,andhemoglobin andsicklehemoglobinbeforeandafterchronictransfusion.
Theserumferritinleveldidnotpresentnormaldistribution.
Therefore,statisticalevaluationwasmadewiththeWilcoxon RankedTest.Thelevelofsignificancewassetatp<0.05.The STATA/SEversion11.2wasusedforanalysis.
Results
From the 23 selectedpatients, 8were excluded becauseof previousstroke.Fifteenpatientswereincluded(HbSS).Their meanagewas118.67±41.40months;40%weremaleand60%
were female. Themean transfusion treatment period was 45.60±11.28months.Sixpatientsexperiencedadversereac- tions(40%);allofthemwereallergicreactions.Nostrokewas recorded.Alloimmunizationwasobservedinonlyonepatient (6.67%).
Thesicklehemoglobinpercentageandhemoglobinbase- line,beforeandafter12and24monthsofchronictransfusion, areshowninTable1.Therewasasignificantdecreaseinthe HbSrateandasignificantincreaseinhemoglobininthefirst 12months.Thevaluesweremaintainedafter24months,but withnoimprovementofdata.
Only 2 patients have not experienced iron overload.
Thirteenleftinitiatechelationwithdeferasiroxafterapproxi- mately12monthsfromthebeginningofchronictransfusions (range 6–40 months). Chelation did notshow a significant effectonferritinratesinthefirst12monthsaftertreatment.
However,ithasastatisticallysignificanteffectontheferritin
Table1–Hemoglobinandsicklehemoglobinbeforeandafterchronictransfusion.
Mean±SDBefore Mean±SDAfter12m Mean±SDAfter24m P1 P2 P3
Hb(g/dL) 8.09±0.80 8.85±0.81 9.02±0.95 <0.001 <0.001 0.19
HbS(%) 75.18±11.69 41.63±14.99 43.78±10.65 <0.001 0,002 0.32
Student’sttest.
P1:beforexafter12monthsoftransfusions.
P2:beforexafter24monthsoftransfusions.
P1:after12monthsoftransfusionsxafter24monthsoftransfusions.
Table2–Serumferritinvaluesbeforetransfusion,beforechelationandafter12and24monthsofchelation.
BeforeTransfusion BeforeChelation After12mofchelation After24mofchelation P1 P2 P3 P4
Median 222 1579 1101 542
0.003 0.33 0.03 0.12
Minimum 40 310 191 293
Maximum 2464 3318 3718 3169
WilcoxonRankedTest.
P1=beforetransfusionxbeforechelation.
P2=beforechelationxafter12monthsofchelation.
P3=beforechelationxafter24monthsofchelation.
P4=beforetransfusionxafter24monthsofchelation.
Serum Ferritin Values Variation
Serum ferritin before transfusions Serum ferritin before chelation Serum ferritin after 12 months of chelation Serum ferritin after 24 months of chelation
1,0002,0003,0004,0000
Fig.1–Serumferritindistributionbeforetransfusions,beforeironchelationandafterironchelation.
declineafteratleast24monthsand it canbecomparedto levelsbeforetransfusion.DataisshownonTable2andinFig.1.
TCDflowvelocitiesratesbeforeandaftertreatmentarein Table3.After12monthsoftreatment,therewasasignificant reductioninvelocities.After24monthsoftransfusions,these valueswere stilldropping.However,whendatabetween12 and24monthswerecompared,therewasnosignificantveloc- ityreduction.Afteratleast24monthsofchronictransfusions, threepatients persisted with conditionalTCD, onepatient maintainedabnormalvelocitiesandallotherschangedtonor- mal.
Discussion
Adamsetal.sawa92%reductioninstroke riskforchronic transfused patients in their STOP study.9 In 2016, the TWiTCHstudywaspublished.Ittestedthehydroxycarbamide (hydroxyurea)non-inferiorityafterchronictransfusionther- apywithdrawalinmaintenanceofnormalTCDvelocitiesin primarysicklecelldiseaseprophylaxis.Patientswerefollowed
for24monthsafterrandomization,withperiodicTCDtests.
Inbotharms,TCDvelocitieswerekeptnormal.Thealterna- tivearmachievedironoverloadreduction,whileitremained the same in the standard group. No stroke was reported.
Therefore,theauthorsconcludedthathydroxyureaisanalter- native for primarystroke insickle cell disease prophylaxis forpatientswithatleast1yearofchronictransfusionandno vasculopathy.12
Inthisstudy,therewasimportantdecreaseinTCDveloci- tiesafterchronictransfusiontreatmentinsicklecelldisease patients.Itturnedanabnormalintoanormalorconditional testinallbutonepatient,suggestinglowerstrokerisk.How- ever,TDCrateshavenotcontinueddropping,butratherhave onlybeenmaintained.
Theadvantagesofmaintainingchronictransfusionther- apy are undeniable and very well established in the current literature. However, the viability of maintain- ing this practice in most Brazilian health centers is questionable, since a minimum technological arsenal is needed, and this is not yet available throughout the country.
Table3–TranscranialDopplerultrasonography(TCD)velocitiesbeforeandafterchronictransfusion.
Mean±SDBefore Mean±SDAfter12m Mean±SDAfter24m P1 P2 P3
TCDcm/sRight 204.28±9.41 158.50±28.89 149.63±26.95 0.002 <0.001 0.32
TCDcm/sLeft 198.85±33.37 157.63±34.43 143.7±32.27 0.02 0.005 0.084
Student’sttest.
P1:beforexafter12monthsoftransfusions.
P2:beforexafter24monthsoftransfusions.
P1:after12monthsoftransfusionsxafter24monthsoftransfusions.
Aygun et al. made an important observation regarding chronictransfusiontherapy:theyclaimedthatinarealworld situationitisdifficulttomaintainHbS<30%andthatmaybe thiswouldnotnecessarilydoharmtopatients,sincevalues above30%wereverifiedwhileconductingtheTWiTCHstudy andevenintheSTOPstudy.Itwasfoundthatthemeanpre- transfusionHbSofchronictransfusionpatientsinthemost importantacademichealthcentersintheUnitedStateswas 34%,whilethe75thand90thpercentileswere41%and50%, respectively.Itwasalsofoundthatthemostimportantvari- ablestoachieveHbS<30%werelowage,lesstimeonchronic transfusionandwhetherthetransfusionshadoccurredonthe correctdates(4weeksafterthelasttransfusion).Thestudy highlightedtechnicaldifficultiesinfollowingtheguidelines givenbylargestudies,takingintoaccountobstaclessuchas adherenceofthepatientandhisorherfamilyinattending tothecorrecttransfusiondate,hypersplenism,development of auto- and alloantibodies, and obtainment of peripheral venousaccess.13
Inthisstudy,patientshaven’tachievedHbSbelow30%after chronictransfusions.Apheresismachineswerenotavailable inourhospitalandwedonothaveenoughstaff members toperform exchange transfusion.Due to this,only simple transfusionisofferedtoallpatients.Onlyonepatienthadan alloantibodyandthehypersplenismwasnotdocumented.Itis presumedthatanHbSrateover30%maybeduetoanincom- pletemarrowsuppression,maintainingtheHbSproduction.
Anotherimportantcriticismofchronictransfusion ther- apyisitsadverseeffects,mainlysuchasironoverloadand alloimmunization.Ethnicdisparitiesbetweenbloodrecipients anddonorsincreasetheriskofdevelopingalloantibodies.It isknownthattheantibodiesproducedaregenerallyagainst antigens prevalent in the white population, the predomi- nantdonorethnicity,whereasthereceptorsaremostlyblack.
InBrazil,the profileofblood donorsin 2014wasfound to be49.45%white,37.48%brown,andonly11.87%black.14In UgandaandJamaica,wherethepopulationismoreuniform, alloimmunizationratesarelower:6.1%and2.6%,respectively.
IntheUSA,sickle-cellalloimmunizationratesrangefrom20 to50%,but amongthalassemicpatients(who havegreater ethniccompatibilitywithblooddonors)thisrateis10%.The earlierinitiationoftransfusions,asinthecaseofthalassemia, maypossiblyinducegreaterantigenictoleranceintheblood receptors.15
Astudyperformed inthestateofAlagoas, publishedin 2011, showed that the prevalence of alloimmunization in patientswiththeSSgenotypewas12.7%.Seventypercentof theantibodiesbelongedtotheRhandKellbloodgroups.The medianagewas11.5years.16InMinasGerais,in2005,agroup
saw9.9%alloimmunizationinpatientswithsicklecelldisease with23.3yearsasmedianage,79%ofwhichbelongedtothe RhesusandKellsystems.17 AnotherstudyconductedinSão Paulo,but withamedianageof25years,foundanalloim- munizationrateamongsicklecelldiseasepatientsof22.6%.
Theanti-Kellantibodywasthemostfrequent(7.5%),followed bytheanti-C(5.7%).18 Thesedatareinforcethe needtouse phenotypedcomponentsinordertoreducealloimmunization rates.Vichinskyetal.foundareductioninthealloimmuniza- tionratiousingextendedcompatibilityfortheantigensofthe Rh(D,C,E)andKellgroups.19
Chouetal.,inastudy publishedin2013,foundthatred bloodcelltransfusionsfromAfrican-descentdonorsfailedto reducethealloimmunizationrate.Inthisstudy,ahighrate ofunexplained Rh antibodies wasverified, forexample,in patientspositiveforanantibody-specificantigenorantibody formationinpatientsnegativeforagivenantigenandwho hadreceivednegativebloodtransfusionforthesameantigen.
Thirty-fivepercentoftheseunexplainedantibodieshadaclin- icalrepercussion,withadelayedtransfusionreaction.These clinicallysignificant antibodies occurred notonlyinmulti- transfusedpatients,butalsoinpatientstransfusedonlyone time,suggestingthatchronictransfusionpatientsremainat riskofdevelopingsignificantalloantibodies,contrarytopre- viousreportsthatfoundsuchantibodiesonlyupto6months after the chronic transfusion had started. High-resolution genotypingofthesepatientsrevealedthat87% inheritedat least oneRhvariantallele,whichcould potentially encode alteredorpartialantigensthatmaynotbedistinguishedfrom traditionalantigensbysimpleserologicaltests.20,21
Thus,itissuggestedthatthebestpracticeispriorpatient genotyping and transfusion of compatible blood compo- nents. However, due to the high cost, this practice is not yet widely available in Brazilian public health services. In this study,extendedphenotypingwasdone forall patients beforethefirsttransfusionand alloimmunizationwasseen inonlyonepatient(6.67%).Nevertheless,notusinggenotyp- ing foracompletelycompatibletransfusiondidnotelevate thealloimmunization ratiointhis study.Otherfactors may havecontributedtolowerthealloimmunizationrate,asthe transfusions were always performed at the same institu- tion, avoiding the risk oftransfusions done atinstitutions not providing extended matching. Furthermore, children with SCD who are chronically transfused might have less chronicinflammationandmayhaveadecreasedimmunologic responsetoalloantigens.17
Anothermajordisadvantageofchronictransfusionisthe imminentironoverload.However,withtheuseoforaliron chelators and the possibility of transition to therapy with
hydroxyureaafter1yearofbloodtransfusion,thisadversity canbeovercome.
Hepaticironoverloadcanleadtofibrosisandinflamma- tion, leading toelevated risk of cirrhosis and hepatocarci- noma. Therefore, iron chelationin polytransfusedpatients is mandatory. Patients should be screened for serum fer- ritinlevelsandmustinitiatechelationwhenlevelsareabove 1000g/L.Ferritin,however,isnotagoodmarkerforchelation response;aprospectivestudyfoundasignificantdecreasein liverironconcentration(LIC)after1yearofchelation,whereas adecreaseinferritinvalueswasonlyachievedafter5years.
Inspiteofthis,intheBrazilianpublichealthsystemwedonot haveanotherwaytomanageironoverloadotherthanferritin levels. Theuseoforaliron chelation(deferasirox)provides goodpatientcompliance.15,22
Eventoday,chronic transfusionisthe onlyproventher- apycapableofpreventingstrokeinsicklecellchildren.Recent studies have demonstrated the efficacy of hydroxyurea in maintainingTCDvelocitiesstable,butpatientsathigherrisk (withabnormalTCDvelocity)shouldhaveatleast1yearof chronicbloodtransfusion.Thesestudies,althoughpromising, were short-termstudies (24months),and,therefore,longer onesareneededtoconfirmthesebenefits.Sincewearedeal- ingwithadverseeffectsasdeleteriousasthoseresultingfrom chronictransfusion,weareforcedtoseeknewalternativesto thistherapy.
Themajorlimitationsofthisstudywereitssmallsample sizeandretrospectivenature.
Conclusion
Regardlessofits smallsamplesizeand retrospectivelycol- lecteddata,thisstudyshowedthatchronictransfusionwas aseffectiveasprimarystroke preventioninhigh-risksickle celldiseasepatients.SignificantreductionoftheTCDveloc- ityoccurredaftertreatmentwithchronictransfusioninsickle celldiseasepatients,leadingtoanormalorconditionaltest andreducingthestrokeriskforthemajorityofpatients.
Conflicts of interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
Theauthors wouldlike tothanktheNeurovascularUnit in theDepartmentofNeurologyandNeurosurgery,Universidade FederaldeSãoPaulo,SãoPaulo,Brazil,forperformingtran- scranial Dopplerultrasonography onour patients. We also wouldliketothankDoctorIberêPereiraDattiwhowasincred- iblyhelpfulwithdataanalysis.
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