Sickle cell anemia, thalassemia, and congenital hemolytic anemias

18 Pages·2016·1.75 MB·English

CHAPTER 11
Sickle cell anemia, thalassemia, and congenital
hemolytic anemias
KeithQuirolo1&ElliottVichinsky1,2
1DepartmentofHematology/Oncology,UCSFBenioffChildren’sHospitalOakland,Oakland,CA,USA
2DepartmentofPediatrics,UniversityofCaliforniaSanFrancisco,SanFrancisco,CA,USA
Eachyear,anestimated300,000infantsarebornwitheitherofthe protectiveagainstmalariawithincreasedprevalenceinsomeareas
twomostcommonhemoglobinopathies:thesicklecelldiseasesor oftheworld. Redcelltransfusions areindicated for bothofthese
the thalassemias. These inherited diseases are the most prevalent hemoglobinopathies. In sickle cell disease, transfusions prevent
monogeneticdisordersworldwide.Sicklecelldiseasemakesup85% and/ortreatcomplicationsandameliorateanemia.Inthethalasse-
of the total infants, and thalassemias the remaining 15%. It is mias,transfusionpreventstheanemiaassociatedwithdecreasedor
increasingly apparent that sickle cell disease and thalassemia absent hemoglobin production.
have become a major health challenge in emerging countries as
moreinfantswithhemoglobinopathiessurvivebeyondinfancyand
intoadulthood. Malaria,bloodgroups,and
Theprevalenceofsignificanthemoglobintrait1(HbS,HbC,Hb hemoglobinopathy
E, Hb D, etc., and β thalassemia and α0 thalassemia) varies from Infectionsthatareendemicandlethalinchildrenareparticularly
about 1% in all of Europe to as high as 18% in all of Africa; the effectivefortheselectionofmutationsthatprovidesurvivaladvan-
prevalence in the American population is 3%. The presence of tage. Malaria is a devastating parasitic disease with a very high
disease is 10.8/1000 in Africans, 0.6/1000 in Americans, and 0.2/ mortality rate among children and pregnant women. Due to the
1000inallofEurope.Halfofthepeopleintheworldwithsicklecell high infection and mortality rates, malaria is an extremelystrong
disease live in three countries: Nigeria, Democratic Republic of force for selection. It is estimated that worldwide there are three
Congo,andIndia.InWestAfrica,about1,000infantsadayareborn billion people at risk for infection; there are 250 million clinical
with sicklecelldisease. episodes of malaria and between one million and 500,000 deaths
In the world’s population, 1.5% are β thalassemia mutation annually.3 Ninety percent of deaths occur in sub-Saharan Africa,
carriers. Hemoglobin E–beta0 thalassemia (Hb E/β0 thalassemia) where many of the hemoglobin polymorphisms and blood group
isthegenotyperesponsibleforapproximatelyone-halfofallsevere variants are found. Mutations providing even a slight survival
β thalassemia worldwide. The distributions of the phenotype and advantagearenumerous,primarilychangingtheredcellmembrane
genotypeofNorthAmericanthalassemiapatientstoday—aswellas and hemoglobin. Without the genetic pressure from malaria,
their transfusion management—are dramatically different from human history and the practice of hematology and transfusion
those in the past decades.2 The majority of patients, previously medicinewouldbemuchdifferentthantheyaretoday.Anunder-
of Mediterranean descent, are now largely of Asian, Indian, and standingofmalariaandthemutationsithascausedlaysafounda-
MiddleEasternorigin.2InThailand,about3,000affectedchildren tion for understanding sickle cell disease, thalassemia, and
arebornannually,withestimatesofabout100,000livingpatients. transfusion therapy ofthehemoglobinopathies.
InsouthernChina,thegenefrequenciesforβ-thalassemiaandfor In Africa between 50,000 and 300,000 years ago, a genetically
Hb E are over 4%, resulting in thousands of annual births of β similarspeciestoPlasmodiumfalciparuminfectingwesterngorillas
thalassemiamajorandhemoglobinHbE/β0thalassemia.Duetothe jumpedspeciesandinfectedhumans.4Itisthoughtthatallofthe
diasporaoccurringinthepastandpresent,sicklecelldiseaseand Plasmodiumspeciesinsub-SaharanAfricajumpedfromchimpan-
thalassemiacan nowbe foundin areasthatare freeofmalaria. zees,macaques,andgorillastohumans.However,thedirectionof
Sicklehemoglobinisastructuralvariantcausingseverediseasein transfertoNewWorldmonkeyscannotbedeterminedforPlasmo-
thehomozygousstateandwhenincombinationwithotherhemo- dium malariae or Plasmodium vivax; the parasite may have been
globin variants. The α and β thalassemias are genetically diverse transmitted from humans to monkeys.5 Currently, there are four
withmorethan200mutationsaccountingfordecreasedproduction species of malaria parasites infecting humans: P. falciparum, P.
ofhemoglobininthoseaffected.Thethalassemiaphenotypevaries vivax,Plasmodiumovale,andP.malariae.P.falciparumisthemost
from mild to severe states of anemia. The heterozygote is mildly commonofthesespecies,occurringinabout40%ofinfections.Itis
Rossi’sPrinciplesofTransfusionMedicine,FifthEdition.EditedbyTobyL.Simon,JeffreyMcCullough,EdwardL.Snyder,BjarteG.Solheim,and
RonaldG.Strauss.
©2016JohnWiley&Sons,Ltd.Published2016byJohnWiley&Sons,Ltd.
126
Chapter11:Sicklecellanemia,thalassemia,andcongenitalhemolyticanemias 127
alsothemostlethal,accountingforthevastmajorityofdeathsand Gerbichbloodgroup13
severe disease. P. vivax may account for another 40% of cases, The Gerbich blood group is expressed on glycophorin C and
causingmorbiditybutnotthemortalityofP.falciparum.6Themost glycophorin D. There are 11 antigens in this group. The gene,
recentjump7isthefifthspeciesofPlasmodiumtoinfecthumans: GYPC,islocatedonchromosome2,2q14>2q21.Bothglycophorins
Plasmodiumknowlesi.Stillconsideredazoonosis,thisPlasmodium areencodedbythisgene.Therearetwoinitiationcodons;initiation
sp. has macaque monkeys as a reservoir, and is known to infect atthefirstcodonresultsinglycophorinC;initiationatthesecond
human populations in Southeast Asia. P. knowlesi infections are codon results in glycophorin D. These glycophorins interact with
reported tobe assevere as thoseofP.falciparum.8 the4.1Rprotein,stabilizingtheredcellmembrane.Areductionof
Theassociationbetweenhematologicaldiseaseandmalariawas these antigens leads to hereditary elliptocytosis. Glycophorin C is
first noted in the 1940s by Haldane9 in the Mediterranean and oneofthereceptorsofP.falciparum(EBA-140).14Therehavebeen
Beet10inAfrica.Sixcommondiseasesareassociatedwithresistance reportsofincreasedGerbichnegativityinthecoastalareasofPapua
to malaria:11 thalassemia (both α and β thalassemia), glucose-6- NewGuinea,anareawheremalariaisendemic.Thereisevidence
phosphate dehydrogenase deficiency, hemoglobin C, Southeast thattheGerbichphenotypeisassociatedwithmalariainfection.14
Asianovalocytosis,andhemoglobinS.Therearesixbloodgroups Thereisnohomologybetweenthisgroupandtheglycophorinsof
with mutations associated with malarial disease: the Duffy blood theMNS system.
group, Gerbich blood group, MNS blood group, Knops blood
group, and possibly ABO and Lewisblood groups. MNSbloodgroupsystem
The MNSblood group system includes three red cellantigens on
twoglycophorins.MandNarefoundonglycophorinA,andSon
Bloodgroups
glycophorinB.ThesetwoglycophorinscarrytworeceptorsforP.
The human blood groups are either receptors for the malaria falciparum:EBA-175onglycophorinAandEBA-1onglycophorin
parasite or are involved in the rosetting of red cells infected with B.Theglycophorinsareencodedonchromosome4,4q28>4q31in
the malarialparasite. sequence GYPA, GYPB, GYPE. These are homologous genes
probablyarisingfromGYPA.Thereisnoevidenceofaglycophorin
Duffybloodgroup ontheredcellmembranearisingfromGYPE.15TheMNSsystemis
TheDuffybloodgroupgenelocus,DARC,isanacronymforDuffy complexwithunequalcrossovers,deletions,geneconversions,and
antigenreceptorforchemokine.Thegeneresidesonthelongarmof point mutations leading to 46 different antigens. It is second in
chromosome1(1q21-q22).Thegenenotationforthebloodgroupis complexityonly totheRh system. SeeTable 11.2.
FY. Polymorphisms are responsible for the Fya and Fyb antigens.
These antigens differ in only one amino acid at position 42: Fya Knopsbloodgroup16
glycine, Fyb aspartic acid. There are four common Duffy pheno-
The Knops blood group is found on the complement receptor 1
types.WithintheDuffybloodgroupsystem,therearesixseparate
(CR1), a glycoprotein present on the red cell as well as other
antigens.12 The Duffy antigen is the receptor for P. vivax and P.
circulatingbloodcells.CR1isoneofagroupofmembraneproteins
knowlesi. The Duffy antigen is also a nonspecific chemokine
termedtheregulatorsofcomplementactivation;theyincludedecay
receptor. SeeTable 11.1.
accelerating factor (DAF/CD55), membrane cofactor protein
The merozoite of P. vivax requires the Duffy-binding protein
(CD46), and membrane inhibitor of reactive lysis (MIRL/CD59).
(PvDBP)inordertobindtotheDARContheredcell.P.vivaxand
CR1alsobindsC4b/C3bimmunecomplexesfortransfertotheliver
P.knowlesigenesencodeforonlyonebindingprotein;theabsence
or spleen where the immune complexes are ingested by macro-
of DARC on the red cell is protective against invasion by these
phages,returningtheredcellstothecirculation.CR1hasabinding
parasites.
siteforP.falciparumentryintothehostredcells.CR1andamalaria
TheDuffynegativealleleinAfricansistheresultofamutationin
redcellmembraneproteinareinvolvedinredcellrosettingduring
the erythroid-specific promoter at position 33 of the GATA-1
cerebralmalaria.
transcription factor region blocking the expression of the Duffy
antigen on red cells. The mutation is in the Fyb allele, designated
ABO,Lewisbloodgroups
erythroid silent: FyEs. The Duffy antigen remains present on ThereisevidencethatP.falciparuminfluencedthedistributionof
somatic cellsin thepresence oftheerythroid silentmutation.
theABObloodgroupstofavorgroupOinareaswhereP.falcipa-
rum was present.17 Group O decreases the adhesive properties of
infectedredcellsrelativetogroupsAandB.18Empirically,thereare
higher rosette levels, increased size, and increased adhesion in
Table11.1 PrevalenceofDuffyAntigens groups A and AB. Group B patients19 have an intermediate
Prevalence%
Table11.2 PlasmodiumReceptors
RedCell African
Phenotype Caucasians Americans Allele
Plasmodiumsp. Parasitereceptor Redcellreceptor
Fy(a+b�) 20∗∗ 10∗∗ FY∗01/Fy∗01
orFY∗A/FY∗A P.vivax Duffybindingprotein DuffyA,DuffyB
Fy(a�b+) 32 20 P.falciparum EBA-175 GlycophorinA(MN)
Fy(a+b+) 48 3 P.falciparum EBA-140 GlycophorinC(Gerbich)
Fy(a�b�) Rare 67% P.falciparum EBA-1 GlycophorinB(Ss,U)
∗∗70–90%ofAsianshavethismutation;FYBESisthenotationfortheerythroid From:JesseQiao,MD,PowerPointpresentation,UTHealthScienceCenter,January
silentGATAmutationprimarilyseeninAfricanAmericans. 28,2013.
128 SectionII:PartI:Redbloodcells
levelofrosettes,withthelowestlevelofrosetteformationbeingseen Betathalassemia
ingroupOindividuals.Itisproposedthatthedistributionofblood Althoughβthalassemiaisprevalentinmalarialareas,theevidence
groupOshouldbehighestinareasofmalariaandlowestinareas forβthalassemiabeingprotectiveagainstmalariaislessconvincing,
withoutmalaria,andthatgroupAshouldbelowerintheseareas, primarilyduetothefactthattheareasaroundtheMediterranean
whichisindeedthecase.BloodgroupOiscommoninequatorial whereβthalassemiahasbeenprevalentarenowfreeofthemalaria
regions, and group A is more common in northern latitudes. parasite. In Africa there are few, if any, published studies of the
Infections with severe malaria are more common in group A1 effectofthesickleβthalassemiaphenotypesonsurvivalinpatients
versusgroupO,eventhoughgroupOismuchmorecommoninthe with malaria. The majority of β mutations in Africans are β plus
populationsstudied.Inhibitionofthiseffectcanbedemonstrated mutations(�88C>Tand�29A>G).InAfricanAmericans,thereare
in vitro using soluble A and B antigen, blocking the PfEMP-1 14βmutations.26Thetwomostcommonβplusmutationsarethe
receptor.ThiscouldalsooccurinvivoduetotheeffectoftheLewis sameasnoted.ThemostcommonβzeromutationisCodon6�A,
genetransferase,whichincreasesthelevelsofAandBantigeninthe alsoseeninAfricans.
serum.20ThiswouldaccountfortheincreasedLe(a�b�)seenin
individuals withAfrican ancestry.
Membranemutation
Enzymopathy
SoutheastAsianovalocytosis
SoutheastAsianovalocytosisdoesnotoccurinAfrica,butheredi-
Glucose-6-phosphatedehydrogenase(G6PD)
deficiency taryelliptocytosishasaprevalenceofupto1.5%insomepopula-
G6PDisexpressedinallcells.Itisthefirstenzymeinthepentose tions.27 There is in vitro evidence that spectrin mutations may
impede the entry of P. falciparum into red cells, but there is no
phosphate pathway and is responsible for the production of the
published clinical evidence ofaneffect onsurvival.28
NADPH needed for the regeneration of reduced glutathione.
Reducedglutathioneconvertshydrogenperoxide(H O )towater.
2 2
ItistheonlyNADPHsourceintheredbloodcellprotectingitfrom
oxidativedamage.ItislocatedontheXchromosome(Xq28).G6PD Structuralhemoglobinmutations
isthemostcommonenzymopathyinhumans.Thediseaseaffects
malesandfemaleswhoarehomozygotes;insomecases,G6PDcan HemoglobinE
affect heterozygotes due to lyonization. The gene is polymorphic First described in 1954, hemoglobin E is a structural thalassemic
with140differentvariants.ThenormalalleleisB.Therearethree mutationthatispredominantinSoutheastAsia.HemoglobinEis
allelesinAfrica:B,A,A�.ThetwoAalleleshave85%and12%of the result of a point mutation at codon 26 of the β globin gene
normal activity; only the A� allele provides protection against (Glu>Lys).Althoughthisthalassemiaiscommoninmalarialareas,
malaria.21 The A allele differs from B by one amino acid, and itisnotclearhowthismutationwouldprotectagainstP.falciparum
the A� from A by one amino acid. The A� is always on an A malaria. Thesered cellsmay be lesssusceptible toinvasion.29
background, which may be required for malaria protection. The
mostsevereformofG6PDistheMediterraneanallele,alsoaone- HemoglobinC
amino-acidsubstitution,producingonly3%activity.Itisfoundin HemoglobinCoccursalmostexclusivelyinWestAfrica,havinga
theMediterranean, India, and Indonesia. frequencyof50%intheIvoryCoast.UnlikehemoglobinS,where
thereisadisadvantageforthehomozygote,thereappearstobeno
selective disadvantage to the homozygote CC or the heterozygote
Thalassemia AC. Hemoglobin C is not as effective in the prevention of severe
malariacomparedtohemoglobinS,whichisprobablywhyitisnot
Alphathalassemia more prevalent in sub-Saharan Africa. Both AC and CC are
Alphathalassemiaisthemostcommonsingle-genediseaseinthe protective, with levels of protection differing depending upon
world.Fourcommonmutationsleadtoαthalassemia,andallareα reports.30,31 Protection from severe malaria is due to a decreased
globingenedeletions.InAfrica,themostcommondeletionis�α3.7. parasitesurvivalinCCcellsandchangesintheredcellsurfacein
Thedeletiontypeshavenotbeenstudiedintermsoftheirprotective CC and AC red cells, particularly PfEMP1, leading to decreased
effect against malaria. It is assumed they are equally effective. cyto-adherence and an increase in acquired immunity.32 This
Homozygous α+ thalassemia (�α/�α) has been found to be theoryhasbeenquestioned33inareportthattherewasnoincrease
protective against severe malaria. In some malarial areas, such as in antibody response between AS and AC children infected with
partsofIndiaandAsia,theincidenceofhomozygousαthalassemia malaria. The presence of hemoglobin C in the erythrocyte alters
is80%.Insub-SaharanAfrica,theincidenceis50%orlessinspiteof the red cell membrane as well as hindering the development of
endemicseveremalaria.Thisisthoughttobeduetothenegative P.falciparum withinthe cell.34
effect(negativeepistasis)ofthecombinationofhemoglobinASand
αthalassemia.22InchildrenwithhomozygoushemoglobinA,both HemoglobinS
the α thalassemia heterozygous23 and homozygous24 forms are HemoglobinS(ß6Glu6Val,GAG>GTG)iscommoninWestand
protective.Theprotectiveeffectisadecreaseofdiseaseprogression Central Africa wheremalaria isendemic. Themore prevalent the
fromparasitemiatoseveremalaria.Theactualbiologyofthiseffect malaria, the more prevalent is this hemoglobin mutation. Hemo-
has not been defined, but there is decreased rosette formation, globinSalsooccursinNorthAfrica,theMediterranean,andIndia.
increased phagocytosis,25 and increased immune recognition in α ItisestimatedthatthehemoglobinSmutationoccurredasrecently
thalassemiared cells. as 250–700 years or as long ago as 1750 years. The mutation for
Chapter11:Sicklecellanemia,thalassemia,andcongenitalhemolyticanemias 129
hemoglobinSoccurredmuchmorerecentlythanthemutationfor Sicklecelldiseaseisbothavasculopathy,withredcelladhesionto
hemoglobinC,whichisestimatedtohaveoccurred3000yearsago. thevascularendothelium,andahemolyticanemiawithplasmafree
HemoglobinShasbecomethedominantmutationduetosuperior hemoglobinandmicroparticles.Aseachofthesepathologieshasa
protection against P.falciparum inthe heterozygote. separatediseasemanifestation,therehasbeenaproposed“pheno-
HemoglobinASishighlyprotectiveagainstmalaria.35Arecent typic”modelofsicklecelldiseaseinwhichoneortheotherofthese
study36showedthathemoglobinASwas90%effectiveinprevent- features predominates. See Figure11.1.
ing malaria in 2591 children with severe malaria compared to a Hemoglobin S can polymerize in the presence of other hemo-
groupof2048controlchildreninGhana.Inthisstudy,ACwasonly globin variants as well as hemoglobin A. These combinations are
associated with a decrease in cerebral malaria. Although AS is referredtoassicklecelldiseaseiftheycauseclinicalsymptomsor
clearlyprotectiveagainstseveremalaria,itisnotknownhowsickle have the potential to cause symptoms. Hemoglobin S combined
hemoglobin provides this protection. There are several mecha- with hemoglobin C, DLos Angeles, β thalassemia, OArab, or CHORI
nismsthatcouldaccountfortheprotectionaffordedbyAS.Mostof causesymptomaticsicklecelldisease.Theonlycommonhemoglo-
the research has been done in areas where P. falciparum is bin-inhibitingpolymerizationishemoglobinF.Thesicklepheno-
prevalent. typeisaffectedbycoinheritanceofαthalassemia43andbythelevel
RedcellsinfectedwithP.falciparumhaveincreasedpolymeriza- ofhemoglobin F.44
tion of hemoglobin and have an intracellular environment that ThemostcommonsicklecombinationsareSS,SC,Sβ0,andSβ+
decreases parasite growth. This could be due to high levels of thalassemia. β0 refers to a thalassemia major mutation, and β+
potassium, elevated levels ofhemoglobin, ormicroRNA that may refers to a mutation in which there is decreased hemoglobin A
reduce growth by inhibiting mRNA transcription in the parasite. production, with S being the dominant hemoglobin. It would be
There is also decreased rosetting of infected AS red cells in the expected that S β+ thalassemia would be a relatively benign
circulation,likelyduetoareducedexpressionofsurfaceadherence combination, but this is not necessarily true. There are at least
proteins. The expression of these adherence proteins, such a P. 14β+mutationscommonlyoccurringinAfricanAmericans.26The
falciparum membrane protein-1 (PFWMP1), leadsto cycloadher- mutationsproduceawiderangeofhemoglobinAconcentrationsin
ence and increased endothelial activation in infected persons. the red cell, determining the phenotypic expression of this
Recently,37 a murine model has shown that heme oxygenase I combination.
inductionbyhemolysiswiththeproductionofCOcreatestolerance Even though the genotype of homozygous S is the same, the
tomalariaandcouldbeanothermechanismofprotectionprovided phenotype is not.45 There are many variables that influence the
byhemoglobinAS.TheexpressionofthehemeoxygenaseIgene, phenotype,46 the level of fetal (F) hemoglobin and an α gene
Hmox1,isincreasedbyplasmafreehemoglobin.HemeoxygenaseI deletion being the two most common. However, there are bio-
has been shown to be protective in inflammatory disease.38 The markersthatcouldpotentiallychangethephenotypicpresentation
protection against severe malaria is due to the effect of carbon of sickle cell disease. Biomarkers in sickle cell disease have been
monoxideonsignaltransductionbybindingironintheprosthetic reviewed, and although there are over one hundred variables
groups’effectormoleculesandtheinhibitionofhemereleasefrom consideredaspossiblebiomarkersofseverity,onlythemostcom-
hemoglobin. There is no decrease in parasitemia, but there is monlyusedlaboratorytestsareclinicallyrelevant:completeblood
tolerance induced by heme oxygenase I production of CO. This count with reticulocyte count, renal and hepatic function testing,
mechanismcouldalsoexplainthedecreaseinmalariamortalityin and urine albumin–creatinine ratios are the most useful.47 Initial
the thalassemias and inG6PD deficiency. steps have been taken in genome-wide surveys to find single
nucleotide polymorphisms associated with severity, but clinical
relevance has not been found to be associated with most of these
HemoglobinSSpathophysiology single nucleotide polymorphisms.48
Unlike homozygous hemoglobin C, which results in the crystalli- Itisusuallynotpossibletopredicttheseverityofachild’scourse
zation of hemoglobin at normal oxygen tension, homozygous withsicklecelldisease.InareviewofthedatafromtheCooperative
hemoglobinSresultsinhemoglobinpolymerizationatlowoxygen Study of Sickle Cell Disease, pain, persistent leukocytosis, and
tension. Polymerization can also occur at low pH and with tem- anemia in children under the age of 24 months were associated
perature elevation. Hemoglobin S polymerization distorts the red with poor outcome in the long term.49 Other predictors of poor
cellmembrane,disruptingtheasymmetryfoundinthenormalred outcomeinsicklecelldiseaseareanabnormaltranscranialDoppler
cellmembrane.Whentheredcellmembranelosesitsasymmetry,39 (TCD) velocity (predicting stroke in children homozygous for
phosphatidylserine is exposed on the surface of the red cell. This hemoglobin S or with S β0 thalassemia) or an elevated tricuspid
exposureleadstoahypercoagulable40stateandactivatesthecellular jetvelocity onanechocardiogram in adults.
elementsofthebloodandvascularendothelium.Thedistortionalso
leads to rigidity of the membrane and hemolysis. Hemolysis
increases plasma red cell arginase and plasma free hemoglobin,
depletingnitricoxide41anddecreasingcyclicguanosinemonophos- Clinicalreviewofsicklecelldisease/
phate. Hemolysis and red cell membrane instability increases red transfusionindications
cellmembranemicroparticlesintheplasma.Thesechangesinthe Red cell transfusion has been a therapy for sickle cell disease for
redcellmembraneandtheactivationofcellularelementsandthe decades,becomingmoreprevalent sincetheinstitution ofnucleic
vascularendotheliumaccountformanyoftheclinicalfindingsin acidamplificationtechnology(NAT),leukoreduction,androutine
sickle cell disease. Other modifiers of sickle cell disease42 include red cell phenotyping for transfusion. There are numerous indica-
proteins S and C deficiency, α thalassemia,43 fetal hemoglobin tionsfortransfusioninchildrenandadultswithsicklecelldisease.
production, nutritional factors, as well as others that influence Reviewedarethemostcommonindicationsfortransfusionanda
the phenotypic expression ofsicklecelldisease. briefdescription ofeach.
130 SectionII:PartI:Redbloodcells
Figure11.1 “Phenotypic”modelofsicklecelldisease.
studyleadingtotheSTOPStudy,therewerestrokesinchildrenwith
Cerebrovasculardisease(stroke)
TAMMv much less than 200cm/sec.54 It would be prudent to
Cerebralvasculardiseaseisthemostcommonindicationforthetransfusionof evaluate patients with MRI–MRA–Perfusion scans and treat
childrenwithsicklecelldisease.Strokeandcerebralvasculardiseasecanbe patients with persistently elevated conditional TCD TAMMv
prevented by transfusion in children who have an abnormal transcranial with either hydroxyurea (no findings on MR study) or chronic
Doppler.Childrenwhohavepreexistingcerebralvasculardiseaseatdiagnosis redcelltransfusion(findingsonMRstudy).Patientswithcerebral
willlikelyhaveprogressivecerebralvasculardisease.Thereisanincreasedrisk
vascularpathologyshouldbetransfusedforlife.Childrenwhohave
of progressive hemorrhagic stroke in adults who are treated with chronic
normalTCDstudiescannotbeconsideredatnoriskforstrokeas
transfusiontherapyforstroke.
MRI–MRA studies have shown ischemia and cerebral vascular
disease inthese children as well.55 SeeTable 11.3.
Strokeprevention Onceinstituted,transfusiontherapyshouldnotbediscontinued
StrokeriskforchildrenwithhomozygoushemoglobinSis200times abruptly. The STOP II study was discontinued by the data safety
that for children without sickle cell anemia.50 It is estimated that monitoringboardduetoanincreasedrateofstrokeandreversionto
10%ofchildrenwillhaveastrokebeforetheageof20years.Stroke abnormalTCDinthenon-transfusedgroup.56Theearlyeventsin
risk continues with age, with hemorrhagic stroke more common
between theages of20and 30years.51
The STOP I study revealed that TCD screening beginning Table11.3 TranscranialDopplerScreening
betweentwo andthree yearsofageinchildren withhomozygous
hemoglobinSorSβ0thalassemiapredictsincreasedriskofstroke. TAMMv1 Treatment Imaging
Theinstitutionofchronicredcelltransfusiontherapyforabnormal Normal <170cm/sec Screenannually Follow2
timed average mean maximum (TAMMv) can prevent brain Conditional 170cm/sec Institutetransfusion BrainMRI–MRA–
injury.52 Children with abnormal transcranial velocity (TAMMv therapy perfusionscan
Abnormal 200cm/sec Institutetransfusion BrainMRI–MRA–
>200cm/sec) frequently have normal brain magnetic resonance therapy perfusionscan
imagingandangiography(MRI–MRA),butthisdoesnotindicate
they are at decreased risk of stroke. The elevation of the TAMM 1TimedaveragemeanmaximumvelocityperSTOPIstudy.
2ConsiderMRI–MRAatagefiveyearstoscreenforoccultischemicorcerebral
velocity is proportional to the risk of stroke.53 In the preliminary
vasculardiseasepertheSITstudy.
Chapter11:Sicklecellanemia,thalassemia,andcongenitalhemolyticanemias 131
this study may have been related to reticulocytosis following the Transfusion
discontinuation of transfusion, although this has not been The goal of transfusion therapy is to decrease hemoglobin S by
documented. dilutioninsimpletransfusionandbyremovalofaffectedcellsand
Children who appear normal on physical examination and by replacement in red cell exchange. For acute events, the post-
history are at risk for so-called silent stroke or occult cerebral transfusion percentage of hemoglobin S is optimally less than
infarct.57Thirtypercentofchildrenwithhomozygoushemoglobin 30%. During chronic transfusion, the goal for the pretransfusion
S will have evidence of occult infarct on MRI.58 There is an hemoglobinSisbetween30and35%.Thehemoglobinshouldnot
undefined increased risk of stroke or increased occult infarcts be above 11g/dl with simple transfusion. With red cell exchange,
in these children, even if they have a normal TCD. The risk of the goalfor hemoglobin should be 9g/dl, which in some patients
stroke in children with preexisting occult cerebral ischemia was willleadtoareductioninironoverload.Redcellexchangeisthe
studied in the SIT Study (Silent Cerebral Infarct Multi-Center preferred initialtreatment foracute stroke.
Clinical Trial).59 In this study, it was shown that the risk of a
further increase in size (3mm or more) of the initial area of
ischemia, or of stroke, was reduced by 58% in the transfusion Ophthalmologiccomplications
armcomparedtothecontrolarm.Thiswouldmeanthat13patients
Transfusionisindicatedforretinalarterialocclusionwithvisualloss,particularly
wouldhavetobetreatedforthreeyearstopreventoneevent.The ifblindnessisapossibility.Transfusionforinvasiveretinalsurgeryisindicated.
optimum age and frequency for screening with MRI for occult Lasertherapyforroutinemanagementofsicklecellvascularretinopathydoes
ischemicinjuryarenotknown.Bysixyearsofage,theprevalenceof notrequiretransfusion,althoughpatientswithseveresickleretinopathywith
brainischemiais27%.TCDaswellasanMRIatMRIatagefive visuallossshouldbeconsideredfortransfusion.HemoglobinSCpatientswould
yearsandfurtherMRI–MRA–Perfusionscansifthechilddemon- requireredcellexchangetransfusion.
strated soft neurologic signs or had decreased academic achieve-
ment atschool.
The incidence of retinopathy is the greatest in hemoglobin SC
Apreliminarystudyindicatedtherewasanassociationbetween disease(33%)andSβ0thalassemia(13%),andlowestinhomozy-
mildlyelevatedbloodpressures,anemia,andsilentinfarct.60Chil-
gousS(3%).69Overtheageof30years,43%ofSCpatientsand13%
drenwhohaveabnormalsleepstudieswithobstructiveorcentral
of SS patients will have retinopathy. Hyphemia70 is a medical
apnea are at increased risk for stroke.61 Overall, children with
emergency in both sickle cell disease and sickle cell trait causing
hemoglobinSShaveacumulativeriskofcerebralvasculardisease
glaucoma and blindness. Retinal artery occlusion,71 suspected or
of49.9%by theageof14years.62 confirmed, isan indication fortransfusion.
Strokeriskisincreasedforatleasttwoweeksfollowinganepisode
ofacutechestsyndrome.Posteriorleukoencephalopathyhasbeen
reportedwithacutechestsyndrome63andisassociatedwithblood Transfusion
transfusion,corticosteroidadministration,andfluidoverloadwith Transfusion is initiated until a definitive diagnosis is determined
hypertension. Blood pressures for patients with sickle cell disease and a long-term care plan made. Retinal arterial occlusion is an
are lower than normal.64 Blood pressure should be closely moni- indicationforchronictransfusiontherapy.Patientswithhemoglo-
toredinpatientswhoarereceivingbloodtransfusionforacutechest bin SC or SS with elevated hemoglobin are transfused by red cell
syndrome or another catastrophic event requiring red cell exchange.ThepercentageofhemoglobinSshouldbelessthan40%,
transfusion. andforSCitisconvenienttouseagoalofhemoglobinAgreater
TheSTOPstudiesshowedthatstrokeriskisdecreasedandacute than60%.
strokes can be prevented by chronic red cell transfusion therapy.
There is evidence that preexisting cerebral vascular disease is
progressive in spite of appropriate chronic red cell transfusion Respiratorydisease72
therapy.65,66TheTWiTCHStudyrevealedthat,inselectedpatients, Thereisnoindicationfortransfusionforobstructiveorrestrictivelungdiseasein
switching from transfusion to hydroxyurea did not lead to an patientswithsicklecelldisease.Severelyanemicadultswhohaverestrictivelung
increase in the TAMMv on transcranial Doppler compared to diseasemaybenefitfromtransfusiontoimproveoxygenation.Obstructiveor
central sleep apnea are risk factors for stroke. Transfusion for central sleep
transfusion.Thestudydidnotshowthattherewasequalprotection
apneadependsontheclinicalassessment.Echocardiographyshouldbeper-
fromstrokewith thischange in therapy.
formedtoevaluateforpulmonaryhypertension,andnighttimeoxygenadmin-
istrationshouldbeconsidered.
Secondarystrokeprevention
Overtstrokehasbecomelesscommoninchildrenandyoungadults
since the institution of transcranial Doppler screening. Chronic Childrenandadultswithsicklecelldiseaseareatincreasedriskfor
transfusion therapy is not completely protective for progressive obstructiverestrictivelung disease andasthma.73 Asthmais a risk
cerebralvasculardiseaseandstroke66thatispresentwhentransfu- factorforacutechestsyndromeandforstroke.74Childrenfrequently
siontherapyisinitiated.Childrenandadultswhohaveseverebrain presentwithbothrestrictiveandobstructivedisease75onpulmonary
injuryfollowingacompletedstrokeshouldbeplacedontransfusion functiontestingwithoutsymptoms.Nitricoxidedepletionoccursin
for life. Red cell exchange can eliminate or decrease iron burden both sickle cell disease and asthma.76 Treatment for asthma is
inpatientswithovertstrokeonchronictransfusion.67Itshouldbe recommendedforchildrenwithsicklecelldiseasewhohaveahistory
thepreferredmethodforchronictransfusiontherapyforsecondary ofacutechestsyndromeandabnormalpulmonaryfunctiontesting.72
prevention of stroke. The SWITCH study would suggest that Children and adults with respiratory disease would benefit from
patients who have overt stroke or cerebral vascular disease are hydroxyureatherapytoreducetheincidenceofacutechestsyndrome.
morelikelytohaveagoodoutcomewithtransfusionandchelation Tonsillectomyandadenoidectomyforsleepapneawithhypoxia
versus hydroxyurea andphlebotomy.68 areconsideredhigh-risksurgeries,andpreoperativetransfusionis
132 SectionII:PartI:Redbloodcells
indicated.77 A sleep study will determine whether nocturnal Acutechestsyndrome
hypoxia is persistent in a patient who has had a tonsillectomy Acutechestsyndrome87accountsforabout25%ofhospitaladmis-
andadenoidectomy.78Nocturnaloxygenadministrationshouldbe sionsandisaleadingcauseofdeathinsicklecelldisease.Recurrent
instituted,andthepatientevaluatedforpulmonaryhypertension.In episodesofacutechestsyndromecancauselungscarringleadingto
the absence of severe anemia, transfusion is not indicated for restrictivelungdiseaseinchildrenandadultswithsicklecelldisease.
patients with abnormalpulmonary functiontesting. Obstructive75 pulmonary disease is common when pulmonary
function is formally evaluated. Children and adolescents may not
have symptoms ofobstructivedisease. Asthma isarisk factor for
Cardiopulmonary: pulmonary hypertension and acute acutechestsyndrome.72Acutechestsyndromeisariskfactorfor
chestsyndrome encephalopathy88andstroke.89Acutechestsyndromecandevelop
Transfusionforacutechestsyndromecanbelifesaving.Transfusionforpul- within72hoursofapainfuleventinadults.Elevatedphospholipase
monaryhypertensionmaybeindicatediftreatmentwithsildenafilisconsid- A2,inconjunctionwithfeverandrespiratorysymptoms,predicts
ered,asthereisanassociationbetweentheuseofsildenafilandincreasedpain acute chest syndrome, and expectant transfusion may arrest its
in sickle cell disease. Transfusion alone may decrease pulmonary arterial development.90,91
pressure. TheNationalAcuteChestSyndromeStudyGroupreviewedthe
commonfeaturesandevaluationofacutechestsyndromeinsickle
cell disease.87
Pulmonaryhypertensionhasbeenaknowncomplicationofsickle
(cid:129) Patients should be continuously monitored, and transfusion
celldiseaseforover30years.79Itisonlyrecently80thatpulmonary
should be considered if there is a new infiltrate and oxygen
hypertensionhasbecomeamajorfocusinthetreatmentofsickle
saturation is lessthan 90–95%.
cell disease. The interest has increased as the pathophysiology of
(cid:129) Chestpainandlowoxygensaturation,withoutinfiltrate,should
pulmonary hypertension has become understood81 and there are
bethethresholdforconsideringpulmonaryemboliasacauseof
therapies for pulmonary hypertension that were not available
these symptoms.
previously. Screening by cardiac echocardiogram beginning at
theageof10–15yearsisrecommended.Adultswhohavepulmo-
nary artery pressures estimated to be 25mmHg (Trjet 2.5m/sec.)
Transfusion
haveanincreasedriskofmorbidityandmortality.80Patientswith
For patients who present with acute chest syndrome and severe
pulmonary artery pressures of 30mmHg or higher should be anemia, simple transfusion may be sufficient to increase oxygen-
consideredforcardiaccatheterizationtodeterminetruepulmonary
ation and reduce risk of more severe disease. Hyperviscosity and
hypertension.82 If it is determined that a patient has elevated hypervolemia can complicate simple transfusion.92 Patients who
pulmonary pressures with increased pulmonary artery vascular
present with an elevated hemoglobin (8g/dl or higher) should
resistance, they are considered for treatment. Sildenafil (a phos-
receive an exchange transfusion as the initial therapy. Neurologic
phodiesterasetype5inhibitor)wasshowntoincreasepainepisodes changes63duringacutechestsyndromearemorefrequentinadults
inpatientswithsicklecelldiseaseduringtheWalkPHaSSTStudy,
and are an indication for exchange transfusion as stroke risk is
which was terminated by the US National Institutes of Health.
increased during, as well as following, an episode of acute chest
Treatmenthasnotbeenstudiedbeyondsildenafilalone.Onestudy
syndrome. There is an association between blood transfusion,
ofbosentanshowedthatthistherapywaswelltoleratedinsicklecell
corticosteroiduse,andstroke/posteriorleukoencephalopathy,usu-
disease.83
ally precipitated byhypertension.
Arecentstudy82hasshownthattheincidenceofcardiaccathe-
terization-proven pulmonary hypertension is much less frequent
thanestimatedbyechocardiogram.Inthisstudy,thosepatientswho Redcellexchangetransfusion
werediagnosedashavingpulmonaryhypertensionwereolder,had Red cell exchange transfusion93 is the safest and most effective
increased six-minute walk, increased N-terminal pro brain natri- methodoftransfusionforsevereacutechestsyndrome.Itprovides
ureticpeptide,andevidenceofincreasedhemolysis.Only1.5%of for isovolumetric red cell exchange without changes in viscosity.
398patientshadincreasedpulmonaryarterialresistance,andonly TheendhematocritandpercentageofhemoglobinSarepredictably
24 had evidence of pulmonary hypertension by capillary wedge obtained. The transfusion goal should be a reduction in the
pressure. It is not known what significance elevated echocardio- percentageofhemoglobinSto30%orlesswithanendhematocrit
graphictricuspid-regurgitation jetvelocityisinpediatricpatients. of9–10g/dl.Ventilatedpatientsshouldhaveanendhematocritof
Inadult patients, itis ariskfactor formorbidity and mortality. 10g/dl.
Chronictransfusionforsixmonthsfollowingasevereepisode
Transfusion84 of acute chest syndrome is reasonable therapy. Hydroxyurea
Fordocumentedpulmonaryarteryhypertension,transfusionalone should be considered for all patients who have had an episode
ofacutechestsyndrome,particularlyiftheyhaveobstructivelung
hasbeensuccessfulinreducingpulmonaryarterypressuresinsome
cases.85 Sildenafil could be added to transfusion if transfusion disease.72
therapy was not effective. In pediatric patients, hydroxyurea has
beenfoundtobeeffectiveinasmallstudy.86Thereisnoconsensus
Immunedysfunction/sepsisrisk
astotheoptimaltherapyfordocumentedpulmonaryhypertension.
Aspirin has been recommended for splenectomized patients to Childrenandadultswhoaresepticfrequentlyhaveaprecipitousdropintheir
prevent pulmonary hypertension due to platelet aggregation in hemoglobin. Patients who appear septic should have a type and screen at
thelungs.Therehavebeennostudiesoftheeffectivenessofaspirin presentationintheeventtheyneedanemergenttransfusion.
forthis indication.
Chapter11:Sicklecellanemia,thalassemia,andcongenitalhemolyticanemias 133
Infectionremainsthemostcommoncauseofdeathatallagesin priapism during childhood and adolescence, but the actual inci-
sicklecelldisease.94Patientswithsicklecelldiseasehavedecreased denceisunknown.Priapismleadstopermanentischemicdamage
abilitytoopsonizebacteria,95and95%ofchildrenhomozygousfor and impotence.104 Severe priapism prognosticates a more severe
hemoglobinSdevelopfunctionalasplenia96bytheageoffiveyears. course of sickle cell disease.104 Priapism may be induced by
FunctionalaspleniaoccursinhemoglobinSCatanolderagewith hemolysis.105 There are no reports of priapism in the setting of
muchhigherPITTcounts.97Theincidenceofinfectionisgreatest delayedhemolytictransfusionreactions(DHTRs)orothersettings
ininfancyandearlychildhood,thendecreaseswithage.Theeffect ofhemolysis.
of pneumococcal vaccine98 and penicillin prophylaxis99 has
decreasedtheincidenceofdeathfromoverwhelmingpneumococ-
calsepsisinsicklecelldisease.Childrenwithsicklecelldiseaseare Transfusion
morelikelytohavebacteremia100withacutechestsyndrome,they Transfusions,bothsimpleandexchange,havenotbeenshownto
are at risk for pyelonephritis and urosepsis, and they have an have an effect on acute priapism.106 There have been reports of
increasedincidenceofosteomyelitis101withsalmonella.Children neurologiceventswhentreatingpriapismwithexchangetransfu-
with sickle cell disease can appear deceptively nontoxic with sion107duetoincreasedviscosityandfluidoverload.Patientswith
infectionsthatprovefatal. arenalallograftshouldhaveeithersimpleorexchangetransfusion
for graft protection. The hemoglobin should be kept between 9
Transfusion and 10g/dl with a percentage of hemoglobin S between 30 and
Intheabsenceofmultiorganfailure,simpletransfusiontomaintain 40%.108
the hemoglobin between 9 and 10g/dl is recommended. Severe
sepsis with multiorgan failure would be an indication for red cell
Gastrointestinal
exchangetodecreasethepercentageofhemoglobinSto30%with
an endhemoglobin of9 to10g/dl. Thereisnoindicationfortransfusionasnutritionalsupportforpatientswho
havegrowthorpubertaldelay.Transfusion forchildren oradultswhohave
hepaticdiseasemaybeindicated.
Renaldisease
Transfusion for renal disease would include patients with declining renal Common gastrointestinal complications in sickle cell disease are
functionandanemiaandpatientswithakidneytransplant.Priapismhasnot
cholelithiasis, cholecystitis, choledocholithiasis, hepatic sequestra-
beenreportedtorespondtotransfusion. tion, and intestinal ischemia.109 Surgical emergencies occur as
frequentlyin sicklecell diseaseas inotherpopulations.
Renal disease is common in children and adults with sickle cell Hepaticdiseaseisrelativelycommoninsicklecelldisease.110The
disease.102Totalrenalbloodflowisincreasedinsicklecelldisease pathology includes viral hepatitis, hepatic sequestration, hepatic
duetoanemia,withhyperfiltrationpresentininfantsbyaboutone ironinjury,andintrahepaticcholestasis.111Duringhepaticseques-
year of age. Microalbuminuria is present in about 30%of adoles- tration,thetransaminasesareelevatedaswellasthebilirubin,and
cents. The inability to concentrate urine (hyposthenuria) is theALT(alanineaminotransferase)canremainelevatedforseveral
extremelycommoninsicklecelldisease,andithasbeenreported weeks. Overtransfusion in hepatic sequestration hasledto hyper-
tobereversedinchildhoodwithchronictransfusiontherapy.Both viscositymorbidity.112Intrahepatic cholestasis isarare complica-
proximalanddistaltubulardiseaseispresentinpatientswithsickle tionofsicklecelldisease.Exchangetransfusionhasbeensuccessful
cell disease. Distal tubule dysfunction causes a mild renal tubular insomecases.113Liverbiopsyiscontraindicatedinthepresenceof
acidosis. Proximal tubular disease causes an increase in tubular hepaticcongestionandcoagulopathy.Elevationofbilirubinabove
secretionmakingcreatinineapoorindicatorofglomerularfiltration 13mg/dlwithapredominantlydirectcomponentcanbeasignof
rate.Microscopichematuriaiscommon,frankbleedingcanfollow intrahepaticcholestasis,asometimesfatalcomplicationofsicklecell
renal papillary necrosis. Blood loss from renal papillary necrosis disease.111Bilirubinlevelsgreaterthan30mg/dlorhighercanlead
mayappeartobesevere,butitgenerallydoesnotrequiretransfu- tohepatorenal syndrome and death.
sion. An uncommon complication of papillary necrosis is hydro-
nephrosis dueto ureter obstruction.
Renal findingsin sicklecell diseaseinclude: Transfusion
(cid:129) Decreased abilitytoconcentrate urine; The most common surgical diagnosis in patients with sickle cell
(cid:129) Decreased abilitytoexcrete potassium; diseaseischolelithiasis.114Thecomplicationsofthissurgery have
(cid:129) Inability tolower urine pH;and beenreported.115Redcellexchangetransfusionmaybeeffectivefor
(cid:129) Hematuria/papillary necrosis. intrahepatic cholestasis.
Risk factors forrenal failureinclude:
(cid:129) Anemia, proteinuria, and hematuria.
Skeletal(avascularnecrosis/osteomyelitis)
Acuterenalfailurecanoccurinsicklecelldiseaseduringepisodesof
sepsis and multiorgan failure. Rhabdomyolysis can occur with Thereisnoindicationfortransfusionforavascularnecrosis ofbone.Hyper-
dehydrationandhasbeendescribedduringacutepainfulepisodes. viscosityoccurringduringsimpletransfusioncould,theoretically,contributeto
avascular necrosis. Microparticle formation has been implicated in avascular
Exchange transfusion and dialysis arelifesaving.
necrosis.116
Priapism
Priapism is a common symptom in sickle cell disease.103 It is Bone in sickle cell101 disease is a major area of pathology. Bone
estimated that as many as 40% of males will have an episode of infarctsareperhapsthemostcommonsourceofsevereacutepainin
134 SectionII:PartI:Redbloodcells
patientswithsicklecelldisease.Infarctscancausenervecompres- Transfusion
sion,117digitalshorteningfollowingdactylitis,andavascularnecro- Simple transfusion is indicated for anemia due to parvovirus
sisofboththeshouldersandthehips.Ribinfarcts118arethoughtto aplasticanemia.Cautioustransfusionforsequestrationwithatarget
contribute to acute chest syndrome, sternal infarcts are common, hemoglobin of8–9g/dlis thesafest approachto these patients.
andthevertebralbodies119insicklecelldiseaseowetheirpeculiar
shape todamagefromnecrosis.
Surgery
Ithasbeenshowninaprospectiverandomizedtrialthattransfusionpriorto
Transfusion
surgerydecreasesmorbidityandmortality.
Hipreplacementisthemostcommonorthopedicsurgeryinsickle Surgeryiscommoninsicklecelldisease.114Cholelithiasisandosteonecrosisare
cell disease.120 Shoulder replacement is much less common.121 themostcommonindicationsforsurgery.Patientswithsicklecelldiseasehave
Simple transfusion is recommended in the absence of elevated manyriskfactorsformorbidityduringsurgery:Acutechestsyndromeisthemost
hemoglobin,inwhichcasearedcellexchangecouldbeconsidered. common,andsomepatientsmayhavestrokerisk,althoughstrokeasacompli-
cationofsurgeryisuncommon.Hyposthenuriacanleadtodehydrationinthe
sicklecellpatientsawaitingsurgery.Rhabdomyolysiscanoccurduetodehydration
Integument(skinulcers) andprolongedpositioningduringsurgery.Painmanagementisnotusuallya
problemfollowingsurgery.Transfusionisthestandardofcareforsurgerywitha
Transfusionhasbeenusedtoincreaseoxygenationforpatientswithchronicskin
prolongedanesthesiatime.Surgerythathas along anesthesiatimeleadsto
ulcers.Thereisbettertherapyfortreatment,althoughtransfusionfollowingskin atelectasis,increasingtheriskofacutechestsyndromepostoperatively.
graftingcouldbehelpfultodecreasemicrovascularocclusion.
Transfusionguidelinesforsurgeryhavebeenreportedforthegeneralpatient
with sickle cell disease, but not for patients who have comorbid condi-
tions.77,130,120 Surgical procedures can be classified as low, medium, and
Themostcommonproblemoftheskininsicklecelldiseaseisskin
highrisk.
ulcers.122Theyareusuallyduetoskintrauma,notrecalledbythe (cid:129) Low(transfusionnotindicated):Eyes(laserforretinopathy),skin(minor,
patient. There may be a relationship between skin ulceration and biopsy),nose,ears(tympanostomytubes),anddental(whenanesthesiais
hydroxyurea inadult patients.123 lessthanonehour,orconscioussedationorlocalanalgesiaisused);
(cid:129) Mediumtohigh:Headandneckwithpossibleairwayedema(tonsillectomy-
adenoidectomy),genitourinarysystem,andintraabdominal(laparoscopic)
Transfusion (whenthegeneralanesthesiaismorethanonehour);and
Bloodtransfusionhasbeenusedinthetreatmentofskinulceration. (cid:129) High:intracranial,vertebral,cardiovascular,andintrathoracic,orthe
Thereareanecdotalreportsofothertherapies:124vascularflaps,125 anesthesiaisgreaterthanfourhours.
specialdressings,126and arginine butyrate.127
Preoperative:HydrationwhenNPO(nilperos),transfusion,teachingthe
useoftheincentivespirometer,andexpectationsforcarefollowing
Hematologic(severeanemia) surgery.131Undiagnosedasthmaisacommonriskfactorfor
perioperativecomplications.Therefore,screeningforbronchoreactive
Childrenandadultswithanemiaandalowreticulocytecountduetoinfectionor lungdiseaseandpreventativeuseofbronchodilatorsisrecommended.
othercausemaybenefitfromtransfusion.Childrenwithparvovirusinfection Bloodtransfusiontoahemoglobinof10g/dlisrecommendedfor
requiretransfusioniftheyhavesevereanemiawithaninadequatereticulocyte mediumandhigh-risksurgeriestopreventcomplications.132For
count.Splenicandhepaticsequestrationrequiretransfusion. hemoglobinSCorothersicklecelldiseasepatientswithhemoglobin
10g/dlorhigher,exchangetransfusionshouldbeconsidered,
particularlyinpatientswithhemoglobinSS,Sβ0thalassemia,andSC
Sickle cell anemia and sickle β0 thalassemia can have significant whoaretohavehigh-riskorprolongedprocedures.
anemia.Patientswithsickleβthalassemiahavemicrocytosis,making Intraoperative:133Warmroom,warmblood,andmeticulousfluid
thediagnosisofirondeficiencyproblematic.128Aoneortwoαgene management.
deletion (always trans in African Americans) will lead to micro- Postoperatively:Painmanagement,fluidmanagement,andevaluationof
cytosis.Patients with severe anemia(hemoglobin of5g/dl orless) anyrespiratoryorneurologicsymptoms.Incentivespirometryevery2
hours,andoxygentherapytomaintainoxygensaturationover95%.
shouldbetransfusedtoimproveoxygendeliveryandpreventcom-
Commonpostoperativecomplicationsofsurgeryinclude:134
plicationsofanemia.Chronicanemiaresultsinavascularoverloaded
(cid:129) Acutechestsyndrome;
state, and transfusion should be performed cautiously. Patients
(cid:129) Fluidoverload;
otherwisewellwithabriskreticulocytecountandsafehemoglobin (cid:129) Alloimmunization;
canbemonitored.Otheretiologiesofanemiashouldbeconsidered. (cid:129) Rhabdomyolysis;and
Achildpresentingwithanenlargedspleenorliverisdiagnosticof (cid:129) Neurologiccomplications.
splenic or hepatic sequestration: Both are life-threatening. Parvo-
virusisthenextmostcommonetiologyofacuteanemiainchildren.
Overtransfusioncanleadtohyperviscosityandmorbiditywhen
treating sequestration; blood may be released from the congested
Pain
organ,increasing thehematocrittodangerously highlevels.Chil-
dren who have life-threatening splenic sequestration should be Transfusionasaninterventionforanacute,uncomplicated,painepisodehas
transfused on a monthly basis to prevent recurrence and should notbeenstudied.Forpatientswhohavechronicpain,atrialoftransfusionmay
have a laparoscopic splenectomy as soon as they have been fully allowpatientstobepainfreewhiletheyarewithdrawnfrompainmedications
immunized. There is significant morbidity in children who have and learning other coping skills. It is not recommended that patients be
maintainedonbothtransfusionandopioidmedicationsforpainunlessthere
hepaticsequestration.Hepatorenalsyndromeshouldbeentertained
isaphysiologicindicationsuchasavascularnecrosis.
asapossible complication.129
Chapter11:Sicklecellanemia,thalassemia,andcongenitalhemolyticanemias 135
Painisthepathognomonicsymptomofsicklecelldisease.135Pain
Table11.4 SickleCellDiseaseIndicationsforTransfusion
in sickle cell disease is not necessarily sickle cell vaso-occlusive
pain. CerebralVascular
Acute pain thatissickle cellrelated includes: Disease
(cid:129) Acute painful episodes; Strokeprevention Transfusionbysimpleorredcellexchangefor
cerebralvasculardisease,occultbrainischemia,
(cid:129) Acute chestsyndrome; abnormalTCD
(cid:129) Priapism; Secondarystroke Transfusionbysimpleorredcellexchangeforstroke
(cid:129) Cholecystitis (ascending cholangitis); prevention
Ophthalmologic Transfusionforarterialinfarct
(cid:129) Dactylitis; complications
(cid:129) Left upper quadrant pain:splenic sequestration/infarct; Respiratorydisease Noindicationfortransfusion
(cid:129) Right upper quadrantpain: hepatic sequestration; Cardiopulmonary
(cid:129) Skin ulcer (even before skinbreakdown); disease
Pulmonary Redcellexchangeforcatheterizationproven
(cid:129) Painwithinternalrotationofthehip:earlyavascularnecrosisof hypertension pulmonaryhypertension
hip; and Acutechest Simpletransfusionforlowhemoglobin,redcell
(cid:129) Pain with armextension: shoulder avascular necrosis. syndrome exchangeifclinicallysevereorforelevated
hemoglobinatpresentation
Chronic pain that issicklecell related includes: Immune Simpletransfusionforsevereanemia
(cid:129) Avascular (osteo)necrosis (non-acute); dysfunctionsepsis
(cid:129) Arthropathies (vertebral infarcts/collapse); Renaldisease Considertransfusionforsevereanemia
(cid:129) Legulcers (chronic); Priapism Transfusionnotproveneffective
Skeletal Transfusionnoteffective
(cid:129) Chronic osteomyelitis; Integument Considertransfusionforsevereanemia
(cid:129) Intractable chronic pain; and Severeanemia
(cid:129) Neuropathic pain. Parvoviralinfection Simpletransfusionforanemia
Splenicsequestration Simpletransfusion
Hyperhemolysis Avoidtransfusionifpossible
Surgery Transfusiontohemoglobinof10g/dl
Transfusion Pain Transfusionnotproventobeeffective
Afallinhemoglobinandhyperhemolysiscanoccurduringpainful Pregnancy Rolefortransfusion,redcellexchangemaybe
eventsinpatientswithsicklecelldisease.136Transfusionshouldbe beneficial
judicially used in the event of anemia occurring during a painful
episode.Transfusioncanbeusedduringaperiodofweaningfrom
chronic pain medication. It is not recommended to treat chronic
Thalassemia
pain with both transfusionand opioid.
The thalassemias are the most common monogenetic diseases
worldwide.146Thesesyndromesareclassifiedaccordingtowhether
themutationcausingthedefectaffectstheαglobingeneclusteror
Pregnancy137 theβglobingenecluster.Thereisoneβglobingeneclusteroneach
There is controversy concerning transfusion during pregnancy. Studies have chromosome 11 (β/β). Duplicated α gene clusters occur on chro-
shownthereislittletonobenefittothefetus,butthatmothershavelesspainful mosome 16 (αα/αα). Mutations in the globin genes reduce or
events when transfused during the latter half of pregnancy compared to eliminate the synthesis of the respective globin molecule. The
nontransfused women with sickle cell disease. 138 Pregnancy carries a high majority of α gene mutations are deletional, although structural
riskforthemotherandfetuscomparedtonormalwomen.Maternalcomplica- mutationsoccur.Thereareabout100αgenemutationsreported.β
tions occur even in the chronically transfused patient. Chronic transfusion globinmutationsareprimarilypointmutationsleadingtoabsentβ
shouldbeconsideredforallwomenduringpregnancy. globinsynthesis(β0mutations)ordecreasedβglobinsynthesis(β+
mutations). There are well over 200 β globin gene mutations.
Structural variants of the globin genes can lead to thalassemic
Some young women do relatively well with pregnancy,139 but
genecombinations.Therearealsodeletionsofβglobinregulatory
generally there is an increase in morbidity.140 Pregnancy-related
elementsandoftheothergenesintheβglobinclusterthatleadto
complications occur more frequently in women with hemoglobin
changes in expression of the gamma globin gene (HPFH). The β
SS.Transfusionhasbeenofferedtowomeninthelasttrimesterof
globin gene cluster is also regulated by genes on distant chromo-
pregnancy,butshouldbeofferedearlyifthereisanycomorbidity.
somessuch asBCL11A, KLF1, and others.
Thereisnoindicationthatthisimprovesfetaloutcome,butitdoes
decrease complications for the mother.141–143 A recent study of
partialexchangetransfusionsduringpregnancyrevealedthat,even βThalassemia147
withtransfusion,thereisstillanincreaseinmorbidityforwomen
β thalassemia presents with a diverse phenotype. Among this group are
with sickle cell disease during pregnancy.144 Some studies have
individualswhodonotrequireregulartransfusionbutdorequireintermittent
shown that red cell exchange transfusion significantly decreases transfusionduringillness,andindividualswhorequirelifelongchronictransfu-
morbidity and mortality duringpregnancy.138,145 siontherapy.Thegoaloftransfusionisnormalgrowthanddevelopmentandthe
prevention of complications of ineffective erythropoiesis. Iron accumulation
fromtransfusionand/orineffectiveerythropoiesisisamajorproblemforpatients
Transfusion withβthalassemia.
Transfusions for complications of pregnancy are indicated to
prevent morbidity and mortality. Consider prophylactic simple
red cell transfusion during pregnancy. Red cell exchange may The major predictor of the β thalassemic phenotype is the
provide anadditional benefit.See Table11.4. α/β-globin chain imbalance with more severe disease in those