Transfusion‐induced platelet antibodies and regulatory T cells in multiply transfused patients 2021 Tiejun Song.pdf

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DOI:
RESEARCHARTICLE
Transfusion-­inducedplateletantibodiesandregulatoryTcells
inmultiplytransfusedpatients
Tiejun Song |Ying Zhang |Jun Huang |Zhiwei Liu
SirRunRunShawHospital,Schoolof
Medicine,ZhejiangUniversity,Hangzhou,Abstract
ChinaBackground:Platelettransfusionrefractoriness(PTR)remainsadifficultproblemin
Correspondencepatientsrequiringlong-­,therearelittledataon
ZhiweiLiuandJunHuang,,
Shawhospital,Schoolofmedicine,
ZhejiangUniversity,Hangzhou310000,therelationshipbetweenperipheralregulatoryTcells(Tregs)andPTRremainsunclear.
:Weretrospectivelystudiedthefrequencyofalloimmunizationagainst
Emails:******@;3202110@
.
Monoclonalantibodysolid-­phaseplateletantibodytest(MASPAT)kitswereused
Fundinginformation

fromZhejiangProvincePublicWelfareandCD4+CD25+CD127−Tcellsweredetectedbyflowcytometry,whiletransform-
TechnologyApplicationResearchProject
(grantnumberLGD19H080002)andOpeninggrowthfactor-beta­(TGF-β­)andinterleukin(IL)-­17cytokinesweredetectedby
FoundationofKeyLaboratoryofBloodenzyme-­linkedimmunosorbentassay.
SafetyResearchofZhejiangProvince
(grantnumber2020KF002)Results:Atotalof399patientswhomettheinclusioncriteriawereenrolledforthe
,10(%)
werepositiveforplateletantibodiesbeforetransfusionand47(%)became
antibody-­
significantlyhigherinpatientswithhematologicaldiseaseascomparedwithother
diseasegroups(p < ).Refractorinessandalloimmunizationoccurredin77(%)
and22(%)patients,+,
+++−
CD8,andCD4CD25CD127TcellnumbersandplasmalevelsofTGF-β­1andIL-­17
betweenpatientswithPTRandthecontrolgroup.
Conclusions:Refractorinesswascommoninpatientsundergoingmultipleplatelet
transfusions(%),%,
TregsinperipheralbloodmaynotplayakeyroleinPTR.
KEYWORDS
alloimmunization,plateletantibodies,plateletrefractoriness,platelettransfusions,regulatory
Tcells
1 | INTRODUCTIONPLTtransfusiontherapyisalloimmunizationtodonorPLTantigens,
predominantlyhumanleukocyteantigen(HLA)classIand,insome
Platelet(PLT)transfusionisanessentialtherapytomaintainhemo-cases,humanPLTantigens(HPA),,
,onesequelaofwhicharedirectedagainsttheHLA,HPA,andCD36presentonthe
ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-­NonCommercial-­NoDerivsLicense,whichpermitsuseanddistributionin
anymedium,providedtheoriginalworkisproperlycited,theuseisnon-­commercialandnomodificationsoradaptationsaremade.
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 | ;00:e23864.
/
2of8 |   SONGetal.
TABLE1 Patientcharacteristicsatstudyentry
plateletsurface,cancreatearefractorystate,wherebytransfused
PLTsarerapidlyclearedintherecipientduetoopsonizationbyan-Characteristic
1,2
–­N(%)399()
However,themechanismsunderlyingcellularresponsesthatre-Age
sultinalloantibodyproductionafterallogeneicPLTtransfusionas
Median(interquartilerange)57(46–­69)
wellastheeffectsofalloantibodiesonimmune-­mediatedPLTre-
Agegroup–­N(%)
,4
16–2­934()
AlloimmunizationtotransfusedPLTsrequiresprimingandac-
30–3­939()
tivationofCD4+Tcellsspecificforpeptidesderivedfromplatelet
40–4­948()

plasmacellsthatproduceimmunoglobulinG(IgG)antibodiesthatbind50–5­994()
PLTsurfaces,leadingtoplatelettransfusionrefractoriness(PTR).560–6­992()
RegulatoryTcells(Tregs)contributetothemaintenanceofperipheral70–7­969()
immunetolerance;defectsinthesearethoughttoplayaroleinthe>7923()
6
-Sex–­N(%)
+
hibitionofCD4TcellactivationandproliferationmaybemediatedbyMale231()
thesecretionoftheinhibitorycytokinesinterleukin(IL)-­10andtrans-Female168()
forminggrowthfactor-­beta(TGF-β­).TregsareessentialregulatorsofGender/pregnancy–­N(%)
self-­toleranceanddirectlysuppressacquiredimmuneresponsesin
Maleandfemale(nulliparous)243()

Female(≥1pregnancy)156()
theproductionofPLTalloantibodiesanditsassociationswithTregs;6,8
Weight–­kg
however,itisnotfullyelucidatedtowhatextendtheproportionof
Median(interquartilerange)60(53–­66)
TregsandrelatedcytokinesinperipheralbloodisassociatedwithPTR.
Previousclinicalstudieshavedescribedtherelationshipsbe-Height–­cm
tweenthenumberofPLTtransfusions,PLTalloimmunization,andMedian(interquartilerange)165(160–­170)
refractorinessinmultiplyplatelet-­
ReduceAlloimmunizationtoPlatelets(TRAP)involvedadministra-Median(interquartilerange)
%ofpatientswithacute(–­)
2
myeloidleukemiareceivingleukoreduced,single-­donor,apheresisBodysurfacearea–­m
PLTsduringinductiontherapybecamealloimmunized;8%devel-Median(interquartilerange)(–­)
,only5%ofpatientsbecamealloimmunizedinDisease–­N(%)
theProphylacticPlateletDoseonTransfusionOutcomes(PLADO)Acuteleukemia126()
10,11
()
Atotalof52HLA-­A,96HLA-­B,and61HLA-­DRB1alleleswereMultiplemyeloma27()
,toour
Myelodysplasticsyndrome29()
knowledge,baselinedataarelimitedregardingtheincidenceofPLT
Lymphoma83()

Thrombocytopenia50()
ThisreportassessedthedevelopmentofPLTantibodiesinpre-
Solidtumor31()
viouslyuntreatedpatientsreceivingPLTtransfusionsandexamined
Other46()
theassociationsofTlymphocyte,Blymphocyte,TGF-β­,andIL-­17
–­N(%)
Chemotherapyorradiation302()
Othersupportivecare97()
2 | MATERIALSANDMETHODS
thefirstPLTtransfusionduringthecourseofstudy;and(2)available
 | Patientinclusioncriteriadiagnosticandclinicalinformation,includingclinicalcharacteristics,
post-­PLTtransfusionincrements(within4 hand/or18–­24 h),PLT
Therecordsof399patientswhomettheinclusioncriteriabetweenantibodyscreening,priorhistoryofpregnancyorbloodtransfusion,
January1,2013,andDecember31,2017wereretrospectivelyre--­uptimewas
-definedasthetimeelapsedfromthefirsttolastPLTtransfusion.
tientcharacteristicsareshowninTable -
asfollows:(1)

SONGetal.   | 3of8
assesstherelationshipbetweenTregsandPTR, | Bloodcomponentpreparationand
andrandomlyselected24patientswithhematologicdisease(meantransfusion
age, years)andPTRtoformtheresearchgroup,including12
patientswithacuteleukemia,7withlymphoma,and5withmyelod-BloodcomponentswerepreparedattheBloodCenterofZhejiang
,;theupperlimit
hematologicaldiseaseandwithoutPTR( years),in-ofresidualleukocyteswas5 × 108whitebloodcells(WBCs)/bag,
cluding17patientswithacuteleukemia,10patientswithlymphoma,whilethevolumeofapheresisPLTswasapproximately250–­300 ml/
-,asingleplateletunitcontained≥ × 1011
tainedfromthereviewboardoftheSirRunRunShawHospital,platelets.
(RBCs)(non-­leukoreduced)wereadminis-
teredatahemoglobinlevelof<70 g/
was20 × 109/Linpatientsreceivingsupportivetherapyonly(eg,
 | Definitionsofalloimmunizationandforacuteleukemia)and30 × 109/-
refractorinessceivedABO-­compatibleapheresisPLTsandwererandomizedtore-
ceiveeitheralowdose(≤ × 1011/m2)orahighdose(> × 1011/
AlloimmunizationwasdefinedasthedevelopmentofPLTantibodiesm2)ofPLTs.
inpatientspreviouslynegativeforPLTantibodiesduringthestudy
(CCI)wasdefinedasCCI
(≤4 h)<5orCCI(18–­24 h)< | Studyendpoints
astheoccurrenceofalowCCIintwoconsecutivePLTtransfusions.
CCIwascalculatedasfollows11:TheprimaryendpointswerePTRandPLTantibodypositivitybefore
thediagnosisofrefractoriness.
9
CCI=plateletincrement10∕L
×bodysurfaceaream2∕plateletstransformed(1011).

 | Statisticalanalysis
Bodysurfaceareawascalculatedasfollows: × height
142
(cm) +  × weight(kg)−-
siswasperformedusingSPSSforWindows,
significancewasconsideredatp < .
 | PLTantibodyassay
PatientphlebotomytimebeforePLTtransfusion:Serumsamples3 | RESULTS
wereobtainedfromclottedbloodfollowingcentrifugationat1000 g
for10 -­ | PatientenrollmentandPLTtransfusions
plateletantibodytest(MASPAT)kits(Sanquin)wereusedtoscreen
forplateletantibodiesaccordingtothemanufacturer',399patientswhomettheinclusioncri-
PLTswerescreenedusingthefollowingantigens:HPA-­1(a,b);HPA-­
2(a,b);HPA-­3(a,b);HPA-­4(a);HPA-­5(a,b);HLA-­A1,2,3,30,31,68;thepatientswas57 years(interquartilerange,46–­69 years).Among
HLA-­B7,35,38,44,51,57,60;andHLA-­C3,-­transfused399patients,156hadahistoryofpregnancy.
ThepatientsreceivedamedianoffivePLTtransfusions(interquar-
tilerange,2–­11)andthreeRBCtransfusions(interquartilerange,
 | Tcellandcytokinedetection1–­7).Themediandurationoffollow-­up(fromthefirsttolasttrans-
fusion)was20 weeks(interquartilerange,2–­51)(Table 2).

ofthesecellswasperformedbyflowcytometryusingthefollow-
ingmonoclonalantibodies:CD3−FITC,CD4−PE,CD8−APC-C­y7, | Alloimmunizationandrefractoriness
CD25−APC,CD127−PE-­Cy7,andmouseIgG1APCandIgG1PE-­Cy7
asnegativecontrol(allfromBDBiosciences).Tregswerecharacter-Ofthe399patientsincludedinthestudy,77(%)hadrefractori-
izedbyCD4+CD25+CD127−
percentagesoftheCD4+-(%).Additionally,35ofthe322(%)non-­refractorypa-
tionsofTGF-β­andIL-­17weredetectedbyenzyme-­linkedimmuno-
sorbentassayaccordingtothemanufacturer'sinstructions(TibikangasignificantincreaseinalloimmunizationinthepatientswithPTR
).(p < )(Table 3).
4of8 |   SONGetal.
TABLE2 TheeffectsofplatelettransfusionsTABLE3 Plateletantibodyandplateletrefractoriness
CharacteristicNon-­PTR
patientsPTRpatients
Totalplatelettransfusionsnumber–­N2946
PlateletantibodiesN(%)N(%)p
Platelettransfusions()
Negativepatients287()55()
Median(interquartilerange)5(2–­11)(n = 342)
11
Platelettransfusions–­10()Positivepatients35()22()<
Median(interquartilerange)(–­)(n = 57)
Platelettransfusions–­1011(