rev bras hematol hemoter. 2017;39(4):364–367
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Case
report
Passenger
lymphocyte
syndrome
in
liver
transplantation
Denise
M.
Brunetta
a,b,∗,
Lilian
M.
de
Albuquerque
a,
Andressa
H.
de
Morais
Batista
b,
Lhais
Helenne
O.
Santos
b,
Dirk
Schreen
a,
Clébia
A.
de
Lima
a,
Denissa
F.G.
Mesquita
a,
Luciana
Maria
de
B.
Carlos
b,
José
Huygens
P.
Garcia
aaUniversidadeFederaldoCeará(UFC),Fortaleza,CE,Brazil
bCentrodeHematologiaeHemoterapiadoCeará(HEMOCE),Fortaleza,CE,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received27March2017
Accepted26July2017
Availableonline26August2017
Introduction
Duetothelimitedavailabilityoforgandonorsandthegrowing
numberofpatientsawaitingorthotopiclivertransplantation
(OLT),non-ABOidenticaltransplantationisoftenperformed,
inanattempttolowerthemorbidityandmortalityratesof
transplantlists.1 MinorABO incompatibilityisdescribed as
thepresenceofnaturallyoccurringABO antibodies against
the recipient red blood cells (RBCs) of the donor. Donor
viable, immunocompetentlymphocytes present withinthe
graft(knownaspassengerlymphocytes)aretransferredand
canproduceantibodiesagainstRBCsif theyarestimulated
shortly after transplant by recipient or transfused red cell
antigens.2,3 Passengerlymphocyte syndrome(PLS)can also
occurduetothetransferoflymphocytesthatproduceother
anti-RBCantibodies.4,5
PLSisassociated withdifferent typesoftransplants. In
solid organ transplants, the incidence of PLS is lowest in
∗ Correspondingauthorat:DivisãodeHematologia,HospitalUniversitárioWalterCantídiodaUniversidadeFederaldoCeará(HUWC-UFC),
RuaCapitãoFranciscoPedro,1290,RodolfoTeofilo,60430-270Fortaleza,CE,Brazil.
E-mailaddress:dbrunetta@hotmail.com(D.M.Brunetta).
kidney, followed by liver and heart-lung transplants.6 PLS
can also occur in allogeneic hematopoietic stem cell
transplantation.7
BiochemicalPLS,indicatedbyaderangementofthe
labo-ratoryparametersofhemolysis,isrelativelycommoninliver
transplantation,affectingupto37%ofthepatientsundergoing
minorABOincompatibleOLT.8ThereforePLSisnotan
uncom-moncauseofanemiainnon-ABOidenticalOLT,butoftengoes
undiagnosed.Theaimofthisarticleistodescribetwocases
ofPLSinlivertransplantationandprovidealiteraturereview
ofthiscomplication.
Case
report
1
A57-year-oldmanwithdiabetes,hypertensionandcoronary
heartdiseasewasdiagnosedwithalcoholiclivercirrhosisin
October2013.Hepresentedwithsevereandfrequentepisodes
ofhepaticencephalopathyandhemorrhagicevents.OLTwas
http://dx.doi.org/10.1016/j.bjhh.2017.07.006
1516-8484/©2017Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.PublishedbyElsevierEditoraLtda.Thisisan
revbrashematolhemoter.2017;39(4):364–367
365
Figure1–Bloodsmearofthepatientwithpassengerlymphocytesyndrome.Fullarrowshowspolychromasia,dottedarrow showsmicrospherocyteandbroadarrowshowserythroblast.
performedusingthepiggybacktechniqueinSeptember2014.
HisMELDscorewas16.ThedonorwasABOgroup O+and
therecipientwasA+.ThepatientreceivedfourA+RBCunits.
Immunosuppressionconsistedofhydrocortisone,tacrolimus
andmycophenolicacid.Hewasdischargedfromthe
hospi-taleightdaysafterthetransplantation,withhemoglobin(Hb)
concentrationof8.52g/dL.
Fourdayslater,hewasreadmittedtothehospitalbecause
of anemic syndrome. His exams showed: Hb of 5.03g/dL,
positivedirectantiglobulintest(DAT–IgG1+,C3d2+),
reticulo-cytosisof393×103/L,lactatedehydrogenase(LDH)of544U/L
(normal range<460U/L) and total bilirubin of 1.24mg/dL.
Laboratorycoagulationvalues(plateletcount,partial
throm-boplastintime,prothrombintime)wereallwithinthenormal
ranges.Ultrasoundscreeningwasperformedandtherewas
noevidenceofintra-abdominalbleeding.AnABOdiscrepancy
wasfoundandanti-A1antibodiesweredetectedintheeluate
andintheserum,withtitrationof4+.Thepatientreceived
fourleukoreducedRBCunits(twoofA2bloodtypeandtwoof
Obloodtype)accordingtotheprotocolfortransfusionofliver
transplantrecipientsinourinstitutionandhisclinical
condi-tionimproved.Hewasdischargedfivedayslaterwithstable
Hbandasymptomatic.
Case
report
2
A 13-year-old girl was diagnosed with acute liver failure,
Child C(12) with PELD 32 in August 2015. She underwent
OLTwithnoexcessivebleedingorothercomplications.The
recipientblood typewasB+and donorbloodtypewas O+.
Immunosuppressionconsistedofhydrocortisone,tacrolimus
andmycophenolicacid.Thepatientwasdischargedfromthe
hospitaleightdaysaftersurgery.OnDay11post-transplant
herHbconcentrationwas9.54g/dL.
On day 13, she was readmitted because of a
sud-den decrease in Hb concentration. Her exams showed:
Hb of 5.8g/dL, positive DAT (IgG2+), reticulocytosis of
240.19×103/l(normalvalue<89.0×103/L),LDHof798U/L
(normalvalue<460U/L),totalbilirubinof2.51mg/dL,indirect
bilirubinof1.55mg/dLwithnoevidenceofbleedingin
abdom-inalultrasound.Spherocytesanderythroblastswerenotedon
theperipheralsmear(Figure1).AnABOdiscrepancywasfound
andanti-Bantibodiesweredetectedinserumandeluate.The
patientreceivedfolicacidandhydrationwithimprovementof
clinicalconditionandhemoglobinlevelsafterthreedays.She
wasdischargedaftersevendays.Thepost-transplant
reeval-uationonDay26showedanHbconcentrationof11.1g/dL.
Discussion
Liver transplantation can be associated with many
hema-tological abnormalities.2 Graft-versus-host disease,
post-transplant lymphoproliferative malignancies, thrombotic
microangiopathy, hemophagocytic syndrome induced by
infections and PLSare amongthe hematological
complica-tionsoflivertransplantation.2Sinceanemiacanoccurinmore
than50%oflivertransplantrecipients,9thedifferential
diag-nosisofanemiaandjaundicealsoincludesinferiorvenacava
andhepaticveinthrombosis,portalveinthrombosis,hepatic
artery thrombosisand stenosis, biliary complications, and
infectionsorsepsis.10
PLSisawell-knownsyndromeofimmunehemolysis
fol-lowing allogeneic hematopoieticstem cell11 or solid organ
transplantations, such as kidney,12,13 liver4 and heart-lung
transplants.4,14PatientsofA,BorABbloodgroupsmayreceive
organs from ABO-compatible, but non-identical donors.15
TheseminorABOincompatibletransplantationsoccurmore
frequentlyin:(a)theuseofallograftsfromlivedonors,(b)acute
liverfailure,(c)urgentre-transplantsand(d)ABbloodgroup
patients.PLSismorefrequentwithdonorOandrecipientA.14
BothofourpatientshadPLSduetominorABOincompatibility
366
revbrashematolhemoter.2017;39(4):364–367The frequency of PLS after minor ABO
incompatibil-ity organ transplantation depends on the lymphoid mass
transplanted14 withlymphocytes accountingforalmost 4%
ofthelivermass.16TheincidenceofPLSisabout13.5%13in
kidneyand70%inheartandinlungtransplants.17 Ramsey
etal.describedanincidenceof37%ofPLSinliver
transplan-tationinaretrospectiveanalysisof1000patients.8Another
recent retrospective study at a transplant center in Spain
detected12 PLSinatotalof1217OLT.18 Tenpatients of56
OLTwithminorABO incompatibilitydevelopedPLS(17.9%)
andtwopatientsof147caseswithminorRh
incompatibil-itydevelopedthesyndrome(1.40%).18Ontheotherhand,ina
prospectiveanalysisofelevenABOorRhDmismatchedliver
transplantations,ElAnsaryetal.foundonlytwoPLSwith
anti-bodiesdirectedagainstABOorRhDintheserumoreluate.19
Although,apositiveDATwasencounteredinsixoftheeleven
patients.19
ThePLS may be considered a type ofgraft-versus-host
disease,according to Audet et al.,3 where donor
immuno-competent memory B lymphocytes escape from immune
surveillanceoftheimmunosuppressedrecipientandare
stim-ulatedtoproduceantibodiesdirectedagainstRBC antigens
(oroftransfused RBC),causing hemolysis.The importance
ofdonor-derivedmemory B lymphocyteswithinthe
trans-planted organ is highlighted by two case series,4,20 as
hemolysiswas observed inmore than oneorgan recipient
fromthesamedonor.
ThePLS usually has a sudden onset14 of between four
days4andthreeweeksaftertransplantation,2andthe
clini-calpresentationofPLSrangesfrommildandcompensated
hemolysistosevere andpossibly fatalanemia withkidney
failure.18,21ThepatientofCaseReport1wasdiagnosedwith
PLSonthe12thdayandofCaseReport2,onthe15thdayafter
OLT.TheyhadsignificantdecreasesinHbconcentrationwith
alteredhemolysisscreenandnoevidenceofbleedingtojustify
theanemia.
BesidesadecreaseinHbconcentration,laboratory
abnor-malities in PLS include alterations in hemolysis markers
suchasincreasedindirectbilirubinandLDH,decreased
hap-toglobin, inadditionto thepresenceofa positiveDAT.14,21
Bothpatientsdescribedhereinhadanemic symptomswith
verymildjaundice,hardlynoticedatphysicalexamination,
althoughindirectbilirubinwasincreased.Theyalsohadthe
otherabnormalitiesfoundinPLSsuchasreticulocytosis,
ele-vatedLDHandpositiveDAT(oneIgGandC3d;theotherIgG).
The presence of an antibody with a known specificity
againstahostRBCantigenintheserum and/orinthe
elu-ateisnecessaryfordiagnosis.6,22BothourpatientshadABO
discrepanciesinbloodtestsandtherewereantibodiesagainst
ABOantigensintheeluate(anti-A1inthefirstcaseand
anti-Binthe second case).AlthoughmostcasesofPLSare due
toABOincompatibility,otherantibodiesagainstredcell
anti-gens suchasRh,23 Kell,4,20,24 Kidd5 and Duffy20 havebeen
described.
Thediseaseisoftenself-limiting,usuallyresolvingwithin
three months, because the passenger lymphocytes do not
engraftandthereisafinitetimeduringwhichtheviable
lym-phocytescanproliferate.2,6 However,Fungetal.describeda
severecaseofPLSafterOLTthatonlyresolvedwith
splenec-tomyalmostoneyearafterthediagnosis.23
Treatment issupportiveand consistsofsimple
transfu-sionswithbloodproductsofdonorbloodgroupand,insevere
cases, erythrocytapheresis can be performed23 to remove
incompatible recipient-origin red blood cells and,
conse-quently,theamountofthetargetantigen.2Rituximabhasalso
been usedwith reportedsuccess.25 Steroidshave notbeen
showntobeofbenefitintreatinghemolysisinthissetting.21
Bothourpatientsimprovedwithinafewdayswithsupportive
therapyandthemaintenanceofthesamedoseofprednisone
theywere already using. Thepatient inCaseReport1was
elderlywithcoronaryheartdiseaseandhisHbdecreasedto
5.03g/dLsohereceivedfourRBCunitsmatchedtotheliver
donor.ThepatientofCaseReport2didnotreceiveRBC
trans-fusions.
AsanemiaisafrequentfindinginpatientsundergoingOLT,
thetransplantationteammustalwaysconsiderPLSinpatients
withabruptdecreases ofHbconcentrationsand nosignof
bleeding,particularlyiftherecipientreceivedanorganfrom
aminorABOincompatibilitydonor,orifthedonorwastested
positiveinRBCantibodyscreening.Furthermore,thesetwo
casesillustratewell that PLSis usuallya self-limiting
con-ditionandthechangeintheimmunosuppressiveschemeis
notalwaysrequired,sinceitmayincreasetheriskof
infec-tivecomplicationsthatarealreadycommonintransplanted
patients.Perhapsamoreaggressivetreatmentisonlyjustified
inhemolysiswithrenalrepercussion,inthepatientswhere
itisnotpossibletomaintainsafelevelsofhemoglobinonly
withtransfusions orinthosewithhemolysispersistingfor
periodslongerthantwoweeks,duringwhichtimePLSusually
resolves.
r
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