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HEMATOLOGYREVIEWFORSURGICALCRITICALCARE Overview I.BloodandBloodComponents II.MassiveTransfusionandResuscitationofHemorrhagicshock III.AcuteCoagulopathyofTrauma IV.DamageControlResuscitation V.HemostaticAdjuncts VI.CoagulationTesting VII.CoagulationDisorders VIII.AnemiaintheICU IX.ThrombocytopeniaandHIT X.ManagementandReversalofAnti‐coagulantsandAnti‐plateletagents XI.Transfusion‐associatedcomplications I.BloodandBloodComponents A.Redbloodcells(RBC)aretheprimaryO2‐carryingcomponentofwholeblood;300 mL/unit;typicalhematocritof29%;usuallytransfusedin10‐15mL/kg“challenges;” expectedincreaseperunittransfusedisonegram(hemoglobin)or3%(hematocrit); typicalshelf‐lifeupto42days;groupObloodtypeisconsidereduniversaldonor(O negativeforfemalerecipients) B.Plasmaistheprimarysourceofcoagulationfactors;makesup55%ofbloodvolume; 200‐250mL/unit;contains400‐450mgfibrinogen/unit;otherfactorsin60‐70%range; bufferssevereacidosis(viaitshighcitratecontent);“jumbo”plasmaunit700‐800mLfrom singledonor(aphaeresis);FFP‐plasmafrozenwithin8hoursofreceipt;FP24‐plasma frozenwithin24hoursorreceipt;liquidplasma‐neverfrozenplasma;FFPistobeused within24hours,otherwise,relabeledthawedplasma‐previouslyfrozenFFPorFP24with 5dayshelflife;ABplasmaisconsidereduniversaldonor C.Plateletsarederivedfrommegakaryocytesandplayanactiveprocessincoagulation throughclottingfactor,fibrinandendothelialinteractions;releasedas5‐6packs(units) (40‐50mL/unit)fromrandomdonorsorfromsingledonor(aphaeresisunit,200‐250mL) withtypicalcountof80,000platelets;storedatroomtemperatureandonanagitator; traditionalshelf‐lifeof5days;avoidtransfusioninpatientswithTTP(worsensneuro symptomsandrenalfailure),HITandDIC;nouniversaldonorrequired D.Cryoprecipitateisaconcentratedproductobtainedfromplasma;transfusedasapooled units(4‐6unitpools),therefore,typicalbagis80‐100mL;each(10‐15mL)unittypically contains100IUoffactorVIII,250mgoffibrinogen,andadequatestoresofvonWillebrand factor(vWF)andfactorXIII;aswithplasma,compatibilitytestingisnotstrictlynecessary, butABtypeistheuniversalplasmadonor;intheemergencysetting,typicallygivento addresshypofibrinogenemia E.Wholebloodisutilizedinausteresettingswhen(1)bloodsuppliesarestressedor depletedand(2)whendonorscreeningiscompletedandresultsareknownpriorto donation(militarysetting);usualvolumeofeachunitis450‐500mLwhichhasa hematocritof>38%,plateletcount>150,000,100%clottingfactorlevelsand1000mg fibrinogen;mustbetype‐specificproduct II.MassiveTransfusion(MT)andHemorrhage A.Hemorrhageaccountsforgreatestnumberofdeathswithinthefirsthourofarrivalafter injury;exsanguinationisresponsible>80%O.R.deathsand~50%deathsinthefirst24 hoursafterinjury B.MTtraditionallydefinedas10unitsofredbloodcells;otherdefinitionsinclude‐lossof onebloodvolumein24hours,50%bloodvolumelosswithina3hourperiod,orlossof bloodat150mL/min;seenin8‐10%traumapatientsinmilitarysettingand1‐3%inthe civiliansetting C.MTprotocolshavebeendevelopedtoaddressthis;composedofasystemwhereby physicianactivatestheprotocolandpredeterminedbloodandbloodproductsare deliveredinrapidandsustainedmanner;ratiosandunitsdeliveredpercycleare institution‐specific;manycentersalsoemploytheseprotocolsfornon‐traumapatientsas well D.MTprotocolsratiostypicallyincluderedbloodcells,plasma,plateletsand cryoprecipitate.Someusepharmacologicadjunctsaswell.Plasma:RBCratiosaretypically inthe1:3‐1:1rangewithplateletsandcryoprecipitateusemorevariable.Well‐developed protocols,irrespectiveoftheratios,havebeenassociatedwithdramaticreductionsin mortality,reductioninmulti‐organfailureandARDS,reductioninoverallbloodandblood componentutilizationandlowerhospitalcharges E.ActivationofMTprotocolsmaybedirectedbyclinicalgestalt,laboratoryorphysiological triggersoravalidatedscoringsystem;use/requestofuncross‐matchedproducthasbeen showntoprecederecognitionofmajorbleedingandMTscenarios,assuch,transfusionof uncross‐matchedproductsshouldactivateaninstitution’sMTprotocol;theTASHandABC scoresarebothvalidatedscoringsystemsthathavebeenshowntopredicttheneedforMT withAUROC0.80‐0.90;thescoreshavegoodPPVandgreatNPV;thesescoringsystems employacombinationofhypotension,tachycardia,(+)FAST,mechanismofinjury,andbase deficit III.AcuteCoagulopathyofTrauma(ACoT) A.ACoThasbeendescribedasanendogenousimpairmentofhemostasisthatoccursearly afterinjury;coagulationabnormalitiesarecommonfollowingmajortraumaandare presentonarrivalin25%ofpatientswithmajortrauma;mortalityamongtrauma patientsisincreaseddramaticallywhenACoTispresent(morethan4‐foldincreasein mortality) B.HallmarkofACoTismicrovascular‐bleedingleadingtomassivebloodloss;purported etiologiesincludehemodilution,majorsurgeryinducingcomplexhemostaticchanges, consumptionofcoagulationfactors,andexcessivefibrinolysis. C.MajorriskfactorsforACoTincludeextensivetissuedamage,shock/acidosis(basedeficit of10orsustainedSBP<90mmHg),largeamountofprehospitalIVfluid(3000mL),and hypothermia(temperature<35 C);ACoTisassociatedwithincreasedtransfusion requirementsandorganfailure IV.DamageControlResuscitation A.Thethreetenetsinclude:permissivehypotension,limitingcrystalloidsanddelivering higherratiosofplasmaandplatelets;toaddressthese,institutionsdevelopedand implementedMTprotocols;however,theratioshavebeenthemoststudiedcomponent B.Allpublishedstudiestodatehavebeennon‐randomizedandmosthavebeen retrospectivereviewsbasedonchangesinpractice;moststudiesonratioshave demonstratedsurvivaladvantagewithincreasingplasma:RBCandplatelet:RBCratios;at thistime,theoptimalratioofplasma:RBCappearstobebetween1:1‐1:2 C.Survivalbiaspotentialhasbeenraisedbyseveralauthors;survivalbiassuggeststhat patientsarenotsurvivingbecausetheyreceivedhigherratiosofproductsbuttheyare receiving(achieving)higherratiosbecausetheyaresurvivinglongenough;thisreaffirms thosewhostatethatthisreflectsanavailabilitybias(“youcan’tgivewhatyoudon’thave”) asoneoftheinitialstudiespointingoutsurvivalbiasdidnotadministerplasmawithinthe first90minutesofarrival D.Duringtheacuteresuscitationphase,increasingvolumesofcrystalloidareassociated withworseoutcomes;theseincludeincreasedfrequencyofandlongertimetorecovery fromALIandARDS,increasedgastrointestinaldysmotilityandanastomoticleakrates, morefrequentcoagulationdisturbancesandhighermortality;thesecomplicationsremain significantevenwhencontrollingforshockandseverityofinjury;thesecomplicationsare morecommon(andseenwithevenlessfluidadministration)intheelderlytraumapatient E.Recentcivilian(USandUK)andmilitaryguidelinesrecommendfluidrestrictive strategiesintheprehospitalsettings,titratingsmallfluidboluses(250mL)forpalpable radialpulsepalpableandnormalmentalstatus;arandomizedtrialfromDuttonetal demonstratedthattherewasnosurvivalbenefitfromresuscitatingpatientswithevidence ofhemorrhagetoaSBP>70mmHgor>100mmHg;arecentpilotstudyfromMorrisonetal notedthatpatientswithpenetratingtorsotraumawhowererandomizedtoanintra‐ operativeMAPof>50mmHghadlessbloodloss,receivedlesstotalfluidsandlessblood productsthanthoserandomizedtoMAP>65mmHg V.HemostaticAdjuncts A.Internal‐Pharmacologic FactorVIIa InitiallydevelopedforuseinHemophilia,subsequentlyusedinlife‐threatening hemorrhagefromtrauma,surgery,liverfailure.Wasalsoshowntohavearoleinreducing strokevolumehemorrhage.Exceptionallyexpensiveduetoitsrecombinantnature.Dosing scheduleneverwellelucidated. Trialintraumastoppedprematurelyduetofutility.Hasbeeneffectivelyshowntoreduce transfusionrequirementsbutNEVERtoreducemortality.Beingusedlessandlessdueto expenseandconcernforside‐effectprofile(thromboticevents) ProthrombinComplexconcentrates Again,notdesignedforuseintrauma,buthavebeenusedsuccessfullyinanecdotalcasesof patientsnotrespondingtohemostaticresuscitation.Thecorrectdosagestillneedsto elaboratedaswellastheexactpatientpopulationthatmaybenefitfromthisdrug. B.External Multipleagentshavebeenusedbothonandoff‐labelwithmixedresults.Oneearlyfailure wasWoundstat,whichwaswithdrawnduetoaconcernregardingthrombosesofnearby vessels. Quikclot–oneofthefirsttomarket.Initiallyingranuleform,thenrepackagedintoa “teabag”.InitialproductHIGHLYexothermic,thenreformulated.Firstgenerationgranules veryeffective,butatpriceoftissuedamage.Makershavemovedintothirdgeneration dressingsnow,andareconcentratinglessonQuikclotbutstillcommerciallyavailable. CombatGauze–Kaolinimpregnatedgauzeroll.Forexternaluseonly,butcanbe packedintolargehemorrhagingwounds,orintothenasalcavityforexample.Trueefficacy unclearincontrollingbleedingintraumapatientswithACoT.Nowcarriedextensivelyby army–madebysamemanufacturersasquikclot. C.Internal–ORadjuncts Thrombin/Fibringlues Usemostlyrestrictedtotheoperatingroom.Moreeffectiveinslowlyoozingbroad surfacesthanlargevolumeorinjuredvessels.Certainlyhavearole,butoneproducthas notbeenshowntohavesignificantsuperiorityoveranother. Collagengauzes,granules Surgicel/Nugauze–oxidizedcellulose.Effectiveforminorsurfacebleeding.Cheap andnon‐toxic.Canevenbeleftinsidethepatient,andwillreabsorb.Bacteriostatic. Othergranules,powdersavailable.Noneeffectiveformajorbleeding. VI.CoagulationTesting A.Rapididentificationofclottingabnormalitiesappearscriticaltoimprovingsurvival; unfortunately,themajorityoftestsfocusonsinglepartofclottingcascade;prothrombin time(PT)andINRreflectdefectsorintegrityoftheintrinsicpathwaywhilepartial thromboplastintime(PTT)reflectstheextrinsicpathway;intherapidlybleedingand unstablepatient,thesetestsareoftenrenderedworthlessduetolongintervalsinherentin drawingblood,processingspecimen,andobtainingresults B.PT,INR,andPTTreflectsonlystatusofplasmaproteins;thesestudiesneglectthe contributionoftheothercomponentsofwholeblood;PT,INR,andPTTmayindicatea certaindegreeofcoagulopathyand,whenmarkedlyelevated,correlatewithworse outcomes;however,thesetestswereneverdevelopedorintendedforfollowingpatients withacutecoagulopathyfromtrauma;thesetestsweredevelopedandvalidatedinpatients beingtreatedwithoral(warfarin‐PTandINR)orintravenous(heparin‐PTT) anticoagulants;whilePTTmayoccasionallybeprolongedwithneweranticoagulants (dabigatran,rivaroxaban),PTandINRarenormal;othercoagulationtests(plateletand fibrinogencount)arelimitedbytheirpurequantitativevaluesandlackoftestingof functionorqualitativeassessment C.Multiplepoint‐of‐carecoagulationdeviceshavebeendeveloped;unfortunately,these haveonlybeenformallyevaluatedwithpatientsonoralanti‐coagulants;inaddition,these PT/INRpoint‐of‐caredevicesdemonstrategoodcorrelationatlowervalues(INR<2.0)but showconsiderablevariability(andpoorcorrelation)atvalueshigherthan2.0 D.Wholeblood‐based,viscoelastictestinghasrecentlygainedpopularity,thoughthe technologyhasbeenaroundfor>50years;boththrombelastography(TEG)androtational thromboelastometry(ROTEM)areavailableintheUSforevaluatingtheACoT;inboth,a smallsampleofbloodisaddedtoacuvetteandtheclottingprocessisinitiatedbythe additionofoneoracombinationofactivators(kaolin,tissuefactor,calciumchloride);these testshavebeenshowntocorrelatenotonlywithpooroutcomes,but,moreimportantly, withplasma,plateletandcryoprecipitate/fibrinogentransfusions;TEGhasalsobeen showntopredicthypercoagulability,specificallyin‐hospitalvenousthromboembolism, myocardialinfarction,andstroke E.TheTEGvaluesgeneratedinclude:ACTandr‐value(representingthetimebetweenstart oftheassayandinitialclotformation),k‐time(timetoreachspecifiedclotstrength),alpha‐ angle(slopeoftracingthatrepresentsrateofclotformation),maximalamplitude(greatest amplitudeoftracing,reflectsabsoluteclotstrength),andtheLY30(whichrepresentsclot stabilityandthe%amplitudereduction30minaftermaximalamplitudeachieved); ROTEMvaluesinclude:in‐TEM(representsintrinsicpathwayactivation),hep‐TEM (assessestheintrinsicpathway’sintegritywithheparininfluenceremoved),ex‐TEM (representsextrinsicpathwayactivity),fib‐TEM(inhibitionofplatelets),andap‐TEM (representingtheamountoffibrinolysis) F.ProlongationoftheTEG’sACTandr‐valueandtheROTEM’sin‐TEMandex‐TEMfactor reflectfactordeficiencyorseverehemodilution(usuallytreatedwithplasmaorfactor concentrates);prolongedk‐timeordecreasedalpha‐anglecorrelatewithstatesof hypofibrinogenemia(usuallytreatedwithcryoprecipitateorfibrinogenconcentrates); decreasedmaximalamplitudebyTEGandfib‐TEMbyROTEMcorrespondwithplatelet defectsordecreasedactivity(usuallytreatedwithplatelettransfusion);increasedLY30or ap‐TEMareseenincasesofhyperfibrinolysis(treatedwithamino‐caproicacidor tranexamicacid) VII.CoagulationDisorders A.HemophiliaAisasex‐linkedrecessive,factorVIIIdeficiencyassociatedwithprolonged PTTandnormalPT(treatedwithfactorVIIIorcryoprecipitate);hemophiliaBisalsoasex‐ linkedrecessivefactorIXdeficiencyassociatedwithprolongedPTTandnormalPT (treatmentwithfactorIXorcryoprecipitate) B.vonWillebrand’sdiseaseisthemostcommoncongenitalbleedingdisorder;several types,rangingfromminimalbleedingtooverthemorrhage;whiletypeIandIIare autosomaldominant,typeIIIisrecessive;boththePT/PTTcanbenormal,checkbleeding time(ristocetintest);typeIandIIaretreatedwithcryoprecipitateandDDAVP,whiletype IIIistreatedwithcryoprecipitateorVIII:vWFconcentrate;insemi‐electivesettings,keyto treatmentistheadministrationofcryoprecipitate(sixunits)approximatelysixhoursprior tointervention VIII.AnemiaintheICU A.85%ofpatientswhoareintheICUforlongerthanaweekwillendupreceivingablood transfusion.However,theTRICCtrialin1999showedthatarestrictivetransfusion strategyofkeepingpatient’shemoglobinsbetween7‐9g/dLwasaseffectiveas10‐12g/dL andinsomepatientswasadvantageous.Therewasimprovedsurvivalinlessinjuredand younger(<55years)cohorts. B.Transfusioninthenon‐bleedingICUpatientshouldconsistofasingleunitofPRBCata time,followedbylaboratorytestingtoassesswhethertransfusionoffurtherunitsistruly necessary. C.Thereisadose‐dependentrelationshipbetweenthetransfusionofbloodproductsand thedevelopmentofcomplications,particularlynosocomialinfections.The immunosuppressiveeffectofbloodtransfusionhasbeenwellstudiedandislikelythe causeofthisincreasedincidence.ThereforeinthestableICUpatient,eachtransfusion shouldbecarefullyweighedastoitspotentialbenefitandrisks. D.Thecaveatofcourseisthatpatientswhoareactivelybleedingfromwhateversourcee.g. GIhemorrhage,trauma,etc.shouldbeaggressivelyresuscitated,preferablyusingthe principlesofdamagecontrolresuscitationasalreadydetailed. E.Ethryopoetinandothersimilarmedicationsshouldbelimitedonlytopatientswith chronickidneydiseasesandanemiafromcancerorblooddyscrasias.Theirefficacyin raisingthehemoglobinoftheaverageICUpatientislimited(10%inonestudy),andtheir expensedoesnotjustifytheiruse.Concernregardingthromboticeventshasalsoledthe FDAtoattachablackboxwarningtothesedrugs. IX.ThrombocytopeniaandHIT A.Asmanyas33%ofpatientadmittedtotheintensivecareunitwilldevelopsomedegree of thrombocytopenia duringtheirhospitalization. However,the most feared cause due to the associated serious thrombotic sequelae is heparin‐induced thrombocytopenia. HIT is divided into 2 types: a benign, nonimmune mediated form (type I) and an immune‐ mediatedform(typeII). B.TypeIthrombocytopeniamaybeobservedinupto25%ofpatients1to4daysafterthe initiation of heparin therapy, particularly in the postoperative setting. This nonimmune thrombocytopenia(generallyassociatedwithaplateletcountof100/Lto130/Lx109/L)is transient,asymptomatic,andappearstobecausedbyadirectplateletagglutinatingeffect ofheparin.Thisformisself‐limitingandgenerallyself‐resolvingwithoutanytherapeutic adjustment. C. type II HIT, or “true” HIT, is an antibody‐ mediated syndrome that most commonly appearswithin5daysto14daysfromtheinitialheparinadministration.HITisaserious prothrombotic disease caused by heparin‐dependent antibodies that trigger platelet aggregation by binding to molecular complexes formed by platelet factor 4 (PF4) and heparin D.TheriskofdevelopingHeparin‐inducedThrombocytopenia(HIT)isaffectedbytypeof heparinused(withhighestriskassociatedwithbovineUFH,followedbyporcineUFH,and lower risk for LMWH), the duration of heparin exposure (maximal risk for treatments lasting4daysto14days),ahistoryofrecentheparinexposure(withinthepast100days), the patient setting (postoperative vs. medical vs. pregnancy), and the patient’s sex (estimated 1.5 to 2 times higher relative risk in women compared with men, possibly becauseofincreasedimmuneresponses). E.HITcanbeconfirmedbythepresenceofanti‐PF4antibodies,whicharedetectedbyan ELISAbloodtest. F. When HIT is strongly suspected or confirmed, all heparins should be stopped. This includes the removal of heparin‐coated intravascular catheters and the suspension of heparinflushes.Ifthepatientrequiresanticoagulationforwhateverreason,Fondaparinux canbeusedforDVTprophylaxisandArgatrobanforfullanticoagulationinstead. X.ManagementandReversalofAnti‐coagulantsandAnti‐plateletagents A.WarfarincanbeeffectivelyreversedbytheuseofeitherFreshFrozenPlasma(FFP)ora ProthrombinComplexConcentrate(PCC).ThedegreeofnormalizationoftheINRbyeach unitofFFPisdifficulttopredictandwilldependoncirculatingbloodvolume Thisisoneofthereasonsthatitistheauthor’spreferencetoreverseWarfarinwithaPCC< unlesstherearepressingneedstogivethepatientvolumeinaddition. B.IndicationsforPCCtransfusioninclude: a) Anypatientwithseriousorlife‐threateningbleeding(intracranial,gastrointestinal, retroperitoneal,etc.)duetowarfarinmaybeconsideredfortherapyaftermeeting anyoneofthecriteriabelow. b) Patientisunabletotoleratethevolumeoffreshfrozenplasma(FFP)neededforINR reversal(e.g.CHF).Patientstypicallyrequire2‐4LofFFPforadequatereversal c) CriticalpatientsthatcannottoleratethetimerequiredforreversalwithFFP.Note thatinfusionofFFPmaytake3‐6hoursdependingontherateofinfusionandthe volumerequiredforreversal.CompleteINRreversalmaybedelayedinsome circumstances d) INRisrefractorytostandarddosesofFFP C.Dosing ThereareonlytwocommerciallyavailablePCCsforuseintheUSA–Profilnine,Bebulin ReversalofINRtypicallyoccurswithin10minutesofinfusion.TheINRmaybecheckedat 30minutesanddoserepeatedifneeded. DosingforProfilnineshownbelow(dependentonINR) InitialINR<5:Dose=25unitsperkg RecheckINR10to20minutesafterdrugadministration.Mayre‐dose25unitsperkgto achieveagoalINR≤1.5.IfINR>1.5after2doses,giveFFPtoachievegoalINR InitialINR≥5:Dose=50unitsperkg RecheckINR10to20minutesafterdrugadministration.IfINR>1.5,giveFFPtoachieve goalINR AllpatientswhoreceivePCCmustbegivenVitaminK10mgIVasaninfusion.Failure toadministerVitaminKmayresultinareboundincreaseinINRafter6hours. C.Antiplateletdrugs Aspirin, Clopidogrel, Ticlodipine and Prasugrel all irreversibly inhibit platelet function thereforetheirhalf‐liveislessimportantthanthefactthatforeachdayafterinterruption ofanyoftheseagents,∼10%to14%ofnormalplateletfunctionisrestored. Most authorities recommend that full strength aspirin should be held for a minimum of seven days prior to major abdominal surgery. The American College of Chest Physicians recommends7to10daysinthelatestversionofitsguidelinespublishedin2012. CurrentrecommendationsbythemanufacturersofPlavis(Clopidogrel)aretodiscontinue thedrugforfivedayspriortoelectivesurgery. There is anecdotal data to support the use of platelet transfusion to support the irreversibleeffectsofplateletinhibitionbyPlavixorAspirin,butnorandomizedcontrolled trials. In the circumstance described above, it would be reasonable to transfuse platelets during the operative case to reduce the risk of intra‐operative blood loss. Other rescue strategies have included administration of DDAVP, cryoprecipitate, and even Methylprednisolone. D.DabigatranandRivaroxaban Unfortunately,todatetherearenoknownsimpleandeffectivewaystoreversethe anticoagulanteffectsofthedirectthrombininhibitor,Dabigatran.Researchhassofar shownthattheavailablePCCsintheUShavenotbeenabletoreliablyreversethe anticoagulanteffect.TheyareNOTrecommendedasfirstlinetherapyinthesepatients. Currently,2011ACCF/AHAguidelinesrecommendthatpatientswithseveredabigatran‐ associatedhemorrhagebetransfusedwithfreshfrozenplasma(FFP)and/orpackedred bloodcells(pRBC)asnecessary.However,thisiswithoutanyclinicalorlaboratory evidencethatFFPtransfusioniseffectiveinthesepatients. Themanufacturersthemselvesinrecommendemergencydialysisasthemosteffective treatmentforreversalofthisagent,with60%ofthedrugsupposedlybeingremovedin2‐3 hours.However,thisobviouslymaynotalwaysbefeasibleintheemergencysetting,and willlikelyinvolveplacingacentralvenouscatheterfordialysisaccessinafully anticoagulatedpatient.Thisneverthelessremainsthemostreliableoptionforreversalof thisanticoagulant. Rivaroxabanhasbeenshowninsomeresearchtobeatleastpartiallyreversedby administrationofPCCandmaythereforeachievesomefavorinthefuturebecauseofthis theoreticaladvantage. XI.Transfusion‐associatedcomplications Thesecanrunthegamutofanyofthefollowingconditions: A. B. C. D. E. F. Hemolytictransfusionreaction Febrilenon‐hemolytictransfusionreaction Allergicreactions Bacterial/Viral/Prioncontamination Fluidoverload TRALI A.Thiscanbeacuteorimmediate,whenitusuallyoccurswithin24hoursoftransfusion, andtheeffectsaregenerallyintravascular.Oritmaypresentinadelayedfashionafter1‐10 days,whentheeffectsaremostlyextravascular.Symptomscommonlyincludefeverand chillsinbothforms,butDIC,hemodynamicinstabilityandrenalfailureismuchmore commonwithintravascularhemolysis Overallincidenceis1:12,000‐25,000,withamortalityof1:650,000. B.Febrilereactionsarecommon,approx.1:100‐1:200,andarethoughttobeduetonon‐ toxicimmunecomplexes.TheeffectsareusuallyremediatedwithtreatmentusingBenadryl /Tylenol C.Allergicreactions(urticarial)arealsofairlycommon,withanincidenceofapproximately 1:200.Theyshouldbetreatedasaboveandthetransfusionshouldbestopped. Bothofthesecomplicationsshouldalwaysbereportedtobloodbankincasethey representthemoreseriousbutlesslikelyconcernforbacterialcontamination. D.Infectiousrisksarenowverylow,theexactriskdependingonthecontaminantbeing considered.ForexampleHIVisaslowas1in2.6million,whileHepatitisCisalsointhe sameballparkof1in2.6million.HepatitisBissomewhathigherriskat1in600,000,while exactfiguresforBacterialcontaminationaredifficulttocomeby,asitisveryrare.West Nileviruscouldtheoreticallybetransmittedbuttheriskisnotyetknown,asinalsothe casewithRabies.DespitethepolicyoftheUSbloodbankstodeferdonorsfromtheUK, therehaveasyetbeennodescribedreportsoftransmissionofnewvariantCreutzfield‐ JakobDiseasebybloodproductadministration E.Circulatoryoverloadisprobablyclinicallyunder‐recognized,andmayhaveanincidence ashighas1:700.Symptomsusuallydevelopwithinhours,andthepopulationmostatrisk istheelderlywithpoorcardiopulmonarystatus.Forunknownreasons,itismorelikely withautologoustransfusion.Theriskcanbeminimizedbyslowingthetransfusiondownto runover4hours,andtheadditionofpreorpostdiuresis. F.TRALIorTransfusion‐Relatedacutelunginjuryhasbecomeaseriousproblem,withan incidenceof1in1700‐5000.Itcanbelifethreatening,andprobablynowrepresentsthe No.1causeoftransfusionrelateddeaths,aswellasbeingaleadingcauseofmorbidity.Itis relatedtoPlasma‐containingbloodproducttransfusions,withFFP>Platelets>RedCells> CRYO>IVIG. Criteriaforitsdiagnosisinclude: i) ii) iii) iv) v) vi) Anacuteonset‐duringorwithin6hrs.ofTransfusion Hypoxemia;anO2sat<90%atroomair,oraPaO2/FiO2ratioof<300mmHg BilateralinfiltratesonChestX‐ray NoevidenceofLeftAtrialHypertension NopreexistingAcuteLungInjurybeforeTransfusion NotemporalrelationshiptoalternativeriskforALI Treatmentissupport,withintubationasnecessaryforhypoxemia,diuresisastoleratedto addwiththepulmonaryedema.Someauthoritieshaveadvocatedtheuseofsteroids,but thereislittledatatosupporttheiruseinTRALI.80%ofpatientswillrecoverwithnormal lungfunction,andfuturetransfusionsarenotnecessarilyanissue. ItisimportantincasesofTRALItoreportthistothebloodbanksothatthedonorplasma canbeidentified,andbothdonorandrecipienttestedforthepresenceofantibodies.This mayleadtothedonorbeingdeferred.Plasmafrommultiparousfemaleshasamuchhigher riskforcausingTRALI,suchthattheUnitedKingdomforexamplehasmovedtocollecting plasmafrommalesonly.Studieshaveshownthatthisapproachcansignificantlyreducethe incidenceofTRALIwhenadoptedbyabloodbank.