高亮：traumatic brain injury associated coagulopathy

Dept. of Neurosurgery. Huashan Hospital. Fudan University.

Shanghai Neurosurgical emergency center Liang Gao (高亮 )

TraumaticTraumatic BrainBrain InjuryInjuryAssociatedAssociated CoagulopathyCoagulopathy

Case File 20 year old, female, student. Suffered from traffic accident and

loss of consciousness immediately, transferred to local hospital 30’ later, CT scan showed brain swelling, right occipital bone fracture.2009/06/30

PE: 3mm, light reflex(+), babinski sign (+) ,GCS13. a

2009.06.30 2:17PM

DIAGONOSIS

Mild TBI Right skull base fracture Small subdural hemorrhage t-SAH

DIAGNOSIS-Marshall classification

Computed tomography classification system of head injury Diffuse injury I No visible pathology seen on CT Diffuse injury II Cisterns are present with shift 0-5 mm. No high- or mixed-

density lesion >25 cc.May include bone fragments and foreign bodies

Diffuse injury III (swelling) Cisterns compressed or absent. Shift 0-5 mm. No high- or mixed-density lesion >25 cc

Diffuse injury IV (shift)-Shift >5 mm. No high- or mixed-density lesion >25 cc

Evacuated mass lesion -Any lesion surgically evacuated Nonevacuated mass lesion-High- or mixed-density lesion >25 cc not

surgically evacuated

HIGH RISK !!!!!

2009.07.01

Coma, GCS decrease to 9, pupil diameter 3mm in both sides, light reflex (+), babinski sign in both sides (+);

2009.07.01 18:15PM

2009.07.02 11:12PM

Initial management

GCS decreased to 7

Pupil 3mm, light reaction(+)

Dehydration

DIC management

2009.07.03 10:41AM

Continuous CSF drainage via lumbar puncture !???

GCS decreased to 3. Pupils 1mm, light reaction (+/-) Ventilator support

Traumatic Coagulapathy

Mechanism Diagnosis Management????

2009.07.04 0:45AM

2009.07.07 10:12AM

2009.07.09 0:04AM

Transfer to Shanghai 2009.07.10

GCS3, High fever, support with ventilalar SOS Reasons ?????

二 00

九年七月十三日

2009.07.20

2009.08.20

CoagulopathyCoagulopathy andand TBITBI

ConceptsConcepts ofof hemostasishemostasis CoagulopathyCoagulopathy inin traumatictraumatic brainbrain injuryinjury ReviewReview somesome treatmentstreatments forfor TBI associatedTBI associated

coagulopathycoagulopathy


PrimaryPrimary hemostasishemostasis InitialInitial clotclot FunctionFunction ofof plateletsplatelets SecondarySecondary hemostasishemostasis ThrombinThrombin generationgeneration viavia thethe coagulationcoagulation cascadecascade Cross-linkingCross-linking ofof fibrinfibrin FibrinolysisFibrinolysis ActivationActivation ofof PlasminogenPlasminogen toto PlasminPlasmin tPAtPA

Coagulation CascadeCoagulation Cascade

Cell-basedCell-based Model ofModel of HemostasisHemostasis

Components Endothelial Injury Tissue Factor release Thrombin generation Platelet activationCoagulation factor activationMathews Neurocritical Care, 2006

Coagulopathy andCoagulopathy and TBITBI

CoagulopathyCoagulopathy isis commoncommon inin TBITBI DilutionalDilutional Pre-existingPre-existing coagulationcoagulation abnormalitiesabnormalities AnticoagulantAnticoagulant useuse Warfarin,Warfarin, ASA,ASA, NSAIDS,NSAIDS, PlavixPlavix HypothermiaHypothermia (30-34(30-34 degrees)degrees) IncreasedIncreased fibrinolysisfibrinolysis ThrombocytopeniaThrombocytopenia ImpairedImpaired plateletplatelet functionfunction

Coagulopathy Score

SCORE PT(S) aPTT(S

)Platelet Fibrinogen

(mg/dl) D-dimer

(ng/ml)

1 <13.5 28~41 ＞ 150 ＞ 180 < 1000

2 >=13.5 <28, >41

≦ 150 ≦ 180 < 2000

3 >15 ≦ 24, ≧46

≦ 100 ≦ 150 <4000

4 >18 ≧ 61 ≦ 60 ≦ 100 ≧ 4000

Scoring system for diagnosing DIC

Prothrombin Index: the percentage of the present prothrombin complex to its normal level

Time course of coagulopathy in isolated s-TBI

Coagulopathy andCoagulopathy and TBITBI

Coagulopathy isCoagulopathy is moremore frequent in TBIfrequent in TBI ReviewReview ofof 276276 IsolatedIsolated headhead injury injury onon CTCT hadhad aa

17%17% raterate ofof coagulopathy.coagulopathy. CoagulopathyCoagulopathy is highly associated withis highly associated with poor poor

outcomeoutcome in TBI.in TBI. ReviewReview ofof 8K8K TBITBI ptspts revealedrevealed elevatedelevated INRINR toto bebe aa

powerfulpowerful independentindependent prognosticprognostic signsign ofof poorpoor outcome.outcome.

Coagulopathy is highly associated with DTICH.Coagulopathy is highly associated with DTICH.

Murray, Steyerberg et al, J Neurotrauma, 2007Zehtabchi,Sinert et al, Resuscitation, 2008


TBITBI inducedinduced coagulopathycoagulopathy InjuryInjury mediatedmediated releaserelease ofof TissueTissue FactorFactor RelatedRelated toto amountamount ofof tissuetissue injuredinjured FibrinolysisFibrinolysis abnormalitiesabnormalities HypocoagulableHypocoagulable statestate IncreaseIncrease inin sizesize ofof intracranialintracranial hemorrhagehemorrhage HypercoagulableHypercoagulable statestate IncreaseIncrease inin microthrombosismicrothrombosis causingcausing locallocal

ischemiaischemia

TBITBI andand Platelet DysfunctionPlatelet Dysfunction

ComparedCompared toto nonnon-TBITBI traumatrauma andand healthyhealthyvolunteers,volunteers, TBITBI patientspatients had:had:

PlateletPlatelet countcount lowerlower (180(180 vsvs 230230 andand 256)256)

LongerLonger bleedingbleeding timetime (674(674 ss vsvs 350/320350/320 s)s)

DiminishedDiminished plateletplatelet functionfunction usingusing thromboelastographythromboelastography

TBITBI andand HypoperfusionHypoperfusion

Challenge to concept thatChallenge to concept that TF release is TF release is sourcesource ofof TBITBI coagulopathy.coagulopathy.

ProspectiveProspective cohortcohort studystudy (n=39)(n=39) AISAIS ofof brain ,Proteinbrain ,Protein C,C, Thyromodulin Thyromodulin

(Anticoagulants) PT,(Anticoagulants) PT, PTT,ABG(BD>6)PTT,ABG(BD>6)

Cohen, Pittett et al, J of Trauma, Dec 2007


28 of28 of 3939 withwith normalnormal BDBD

NoneNone developeddeveloped coagulopathycoagulopathy

1111 ofof 3939 withwith BDBD >6 >6

ElevatedElevated INRINR


IncreasingIncreasing brainbrain AISAIS hadhad littlelittle effecteffect on on PT/PTT.PT/PTT.

Cohen, Pittett et al, J of Trauma, 2007


IncreasingIncreasing brainbrain AISAIS hadhad littlelittle effecteffect onon ProteinProtein CC oror ThrombomodulinThrombomodulin..


TBI andTBI and HypoperfusionHypoperfusion

IncreasingIncreasing basebase deficitdeficit hadhad significantsignificant effecteffect onon PT/PTT.PT/PTT.



IncreasingIncreasing basebase deficitdeficit hadhad significantsignificant effecteffect onon ProteinProtein CC andand ThyromodulinThyromodulin (anticoagulants).(anticoagulants).



HypoperfusionHypoperfusion maymay bebe significantsignificant contributorcontributor toto coagulopathycoagulopathy inin TBI.TBI.

GiveGive additionaladditional supportsupport toto hypotensionhypotension worsensworsens outcomeoutcome in why TBI.in why TBI.

AdequateAdequate andand earlyearly resuscitationresuscitation fieldfield asaswellwell asas thethe EDED isis critical.critical.

WarfarinWarfarin andand TBITBI

TBITBI inin patientspatients usingusing warfarin.warfarin.

ICHICH inin warfarinwarfarin usersusers hadhad 48%48% mortality.mortality.

ComparedCompared toto ICHICH w/ow/o warfarinwarfarin mortalitymortality ofof 10%.10%.


AllAll traumatrauma patientspatients onon warfarinwarfarin werewere quicklyquickly evaluatedevaluated andand treatedtreated byby protocolprotocol withwith 4-64-6 unitsunits FFPFFP..


ProtocolProtocol drivendriven warfarinwarfarin reversalreversal decreaseddecreased timetime toto INRINR correctioncorrection (INR(INR <1.6).<1.6).


ProtocolProtocol drivendriven warfarinwarfarin reversalreversal decreaseddecreased incidenceincidence ofof ICHICH progressionprogression..


ProtocolProtocol drivendriven warfarinwarfarin reversalreversal decreaseddecreased mortalitymortality fromfrom 48%48% toto 10%10%.

Both deaths in the treatment group had>10 hour delay in initiation due to transfer issues

Warfarin-relatedWarfarin-related hemorrhagehemorrhage

Warfarin-relatedWarfarin-related hemorrhagehemorrhage

WarfarinWarfarin doublesdoubles ICH mortality.ICH mortality. WarfarinWarfarin increasesincreases riskrisk ofof hematomahematoma

expansion. Bleedingexpansion. Bleeding continuescontinues

overover aa longerlonger period.period.

Flibotte et al. Neurology, 2004


IncreasingIncreasing useuse ofof warfarinwarfarin forfor strokestroke preventionprevention inin elderlyelderly LessLess studiedstudied thanthan warfarin-relatedwarfarin-related non-non- traumatictraumatic ICHICH ProgressionProgression ofof hematomahematoma common,common, eveneven whenwhen initiallyinitially

smallsmall ProgressionProgression increasesincreases mortalitymortality riskrisk ReversalReversal seemsseems toto decreasedecrease progressionprogression NoNo randomizedrandomized trialstrials What’sWhat’s thethe smallestsmallest amountamount ofof traumatictraumatic intracranialintracranial

hemorrhagehemorrhage thatthat doesn’tdoesn’t needneed toto bebe reversed?reversed? LocationLocation specificspecific ?


Ivascu Journal of Trauma 2005

FFP REVERSAL PROTOCAL

INRINR correctedcorrected withinwithin 2424 hourshours (<(< 1.4)1.4)–– ShorterShorter medianmedian timetime toto FFPFFP initiationinitiation (90(90 v.v. 210210 min)min)–– 1212 ofof 6969 (17%)(17%) notnot reversedreversed byby 2424 hourshoursThisThis experienceexperience neitherneither uniqueunique nornor acceptableacceptableLogisticsLogistics ofof FFPFFP oror reversalreversal agentagent itself?itself?

CoagulopathyCoagulopathy ReversalReversal

PrinciplePrinciple:

anyany intracranialintracranial hemorrhagehemorrhage inin patientpatient onon warfarinwarfarin (with(with INRINR >> 1.4)1.4) shouldshould bebe consideredconsidered “life-threatening”.“life-threatening”.

GoalGoal –– normalizenormalize coagulationcoagulation

– – (not(not hypercoaguable)hypercoaguable)

– – PracticalPractical approach:approach: normalnormal INRINR ASAPASAP

WarfarinWarfarin ReversalReversal AgentsAgents

WarfarinWarfarin – – VitaminVitamin KK antagonistantagonist – – VitVit KK isis cofactorcofactor inin gg–carboxylation–carboxylation ofof coagulationcoagulation

factorsfactors II,II, VII,VII, IX,IX, XX (and(and ProPro CC && S)S) OptionsOptions – – DirectlyDirectly competecompete byby givinggiving VitaminVitamin KK – – ReplaceReplace nativenative coagulationcoagulation factorsfactors (FFP,(FFP, PCC)PCC) – – BypassBypass centralcentral partpart ofof coagulationcoagulation cascadecascade (rVIIa)(rVIIa)

Schulman. Anticoagulants and their reversal. Transfusion Medicine Reviews 21;2007Steiner. Intracerebral hemorrhage associated with oral antiocoagulant therapy. Stroke 37;2006

VitaminVitamin KK

OralOral oror parenteralparenteral PlasmaPlasma half-lifehalf-life 1.5-31.5-3 hourshours FullFull effecteffect atat 12-2412-24 hourshours afterafter administrationadministration DoseDose –– 1010 mgmg oral,oral, sc,sc, oror IVIV CostCost -cheap-cheap UtilityUtility forfor urgenturgent warfarinwarfarin reversalreversal –– poorpoor DueDue toto shortshort durationduration ofof otherother replacementreplacement agentsagents

shouldshould bebe givengiven asas partpart ofof allall reversalreversal protocolsprotocols

FreshFresh FrozenFrozen PlasmaPlasma

““StandardStandard approach”approach” AllAll coagulationcoagulation factorsfactors inin non-concentratednon-concentrated formform MustMust do:do: ABOABO compatibilitycompatibility testing,testing, ThawingThawing

(~20(~20 min)min) DifficultDifficult toto givegive enoughenough volumevolume toto correctcorrect INRINR >> 55 VolumeVolume loadload (800-3500(800-3500 mlml forfor fullfull correction)correction) CostCost –– moderate,moderate, ~200~200 cccc unitunit UtilityUtility forfor urgenturgent warfarinwarfarin reversalreversal –– poorpoor duedue toto

logisticslogistics (time(time andand volume)volume) ShouldShould stillstill probablyprobably bebe givengiven asas partpart ofof allall

reversalreversal protocolsprotocols becausebecause itit containscontains allall factorsfactors

ProthrombinProthrombin ComplexComplex ConcentrateConcentrate

DryDry preparationpreparation –– ~20~20 minmin toto reconstitute;reconstitute; nono compatibilitycompatibility testingtesting oror thawingthawing

AtAt leastleast 1616 differentdifferent prepspreps worldwideworldwide SomeSome withwith relativelyrelatively lessless VIIVII oror IXIX DoseDose –– variousvarious recsrecs 30-5030-50 IU/kg;IU/kg; singlesingle bolusbolus dosedose

(~50(~50 ml)ml) CostCost –– expensiveexpensive UtilityUtility forfor urgenturgent warfarinwarfarin reversalreversal –– goodgood ProblemsProblems –– availability;availability; riskrisk ofof thrombosis;thrombosis; viralviral reductionreduction doesdoes notnot eliminateeliminate prionsprions

rFVIIarFVIIa

Off-labelOff-label useuse WorksWorks inin non-warfarinnon-warfarin ICH?ICH? RapidRapid reconstitution,reconstitution, lowlow volumevolume DoseDose -- ???,???, reportsreports havehave usedused 5-3205-320 µg/kgµg/kg CostCost –– veryvery expensiveexpensive UtilityUtility forfor urgenturgent warfarinwarfarin reversalreversal –– goodgood •• ProblemsProblems –– riskrisk ofof thrombosis,thrombosis, INRINR

correctioncorrection withoutwithout eliminatingeliminating bleedingbleeding riskrisk (thromboelastography(thromboelastography better?)better?)

rFVIIarFVIIa inin TBITBI

LevelLevel II trauma,trauma, retrospective,retrospective, 44 years.years. 681681 severesevere TBITBI patients.patients. 6363 initiallyinitially coagulopathiccoagulopathic (INR(INR >1.4)>1.4) .. 2929 receivedreceived rFVIIarFVIIa vs.vs. 3434 nono rFVIIa.rFVIIa. MeanMean age,age, ISS,ISS, GCS,GCS, INRINR

Stein, Scalea et al, J Trauma, 2008


TimeTime toto interventionintervention (median)(median)

rFVIIarFVIIa 144144 minutesminutes

nono rFVIIarFVIIa 446446 minutesminutes (p(p == 0.0003)0.0003)



FFPFFP givengiven priorprior toto interventionintervention (median)(median)

rFVIIarFVIIa 22

nono rFVIIarFVIIa 66 (p(p == 0.0006)0.0006)



MortalityMortality inin isolatedisolated TBITBI

rFVIIarFVIIa 33.3%33.3%

nono rFVIIarFVIIa 52.9%52.9% (p(p == 0.24)0.24)



ThromboebolicThromboebolic comlictionscomlictions

rFVIIa --6rFVIIa --6

nono rFVIIa --6rFVIIa --6 (p=(p= 0.7590.759))


GuidelinesGuidelines forfor WarfarinWarfarin ReversalReversal

USUS -- ChestChest 133133 (Suppl(Suppl 175S),175S), 2008:2008:

InIn patientspatients withwith life-threateninglife-threatening bleedingbleeding “hold“hold warfarinwarfarin therapytherapy andand givegive FFP,FFP, PCC,PCC, oror rVIIarVIIa supplementedsupplemented withwith vitaminvitamin KK (10(10 mgmg byby slowslow IVIV infusion).infusion). Repeat,Repeat, ifif necessary,necessary, dependingdepending onon INRINR (Grade(Grade 1c).”1c).”

ReversingReversing heparinheparin UnfractionatedUnfractionated heparinheparin – – ActsActs atat IIa/XaIIa/Xa – – ProtamineProtamine 11 mgmg perper 100100 UU heparinheparin receivedreceived withinwithin last 2last 2 hourshours

(max(max 5050 mg)mg) LowLow molecularmolecular weightweight heparinheparin – – ActsActs atat XaXa – – NoNo directdirect reversalreversal agentagent ProtamineProtamine 11 mgmg perper 11 mgmg enoxaparinenoxaparin receivedreceived withinwithin pastpast 88 hourshours

(max(max dosedose 5050 mg)?mg)? CheckCheck factorfactor XaXa levellevel -rFVIIa?-rFVIIa? FewFew casecase reportsreports DirectDirect thrombinthrombin inhibitorsinhibitors (e.g(e.g argatroban)argatroban) – – NoNo reversalreversal agentagent

AntiplateletAntiplatelet AgentsAgents ExtremelyExtremely widelywidely usedused agentsagents–– ASA,ASA, clopidogrel,clopidogrel, ASAASA ++

DPDP ICHICH –– thethe wordword isis stillstill outout – – StudiesStudies conflictconflict regardingregarding impactimpact onon hematomahematoma growthgrowth

andand outcome----outcome---- IndependentIndependent predictorpredictor ofof death,death, likelylikely duedue toto hematomahematoma enlargementenlargement

--No--No effecteffect onon outcomeoutcome oror hematomahematoma expansionexpansion inin CHANTCHANT placeboplacebo groupgroupTBITBI –– eveneven lessless knownknown thanthan withwith ICHICH – – MayMay bebe associatedassociated withwith ongoingongoing bleedingbleeding andand ↑↑

mortality,mortality, espesp inin elderlyelderly – – Everybody’sEverybody’s afraidafraid ofof clopidogrelclopidogrel andand surgerysurgery

SaloheimoSaloheimo StrokeStroke 2006;2006;NeurologyNeurology 20092009

AntiplateletAntiplatelet agentsagents –– WhatWhat totoDo?Do?

YouYou getget toto pickpick 1.1. NothingNothing 2.2. GiveGive plateletplatelet transfusiontransfusion 3.3. GiveGive DDAVPDDAVP 4.4. GiveGive rFVIIarFVIIa 5.5. CheckCheck plateletplatelet functionfunction assayassay andand dodo 2/3/42/3/4 ifif

abnormalabnormal 6.6. CheckCheck bleedingbleeding timetime andand dodo 2/3/42/3/4 ifif

abnormalabnormal 7.7. RescanRescan andand dodo 2/3/42/3/4 ifif hematomahematoma expandsexpands 8.8. CheckCheck plateletplatelet functionfunction assayassay (PFA-10(PFA-10 )

TBI-inducedTBI-induced CoagulopathyCoagulopathy

TBI-initiatedTBI-initiated consumptiveconsumptive coagulopathycoagulopathy (DIC)(DIC)

– – BalanceBalance betweenbetween thrombosisthrombosis andand hemostasishemostasis

– – Acutely,Acutely, hemostasishemostasis andand preventionprevention ofof ongoingongoing bleedingbleeding isis prioritypriority

INR & TBI craniotomy

Methods: We performed a 2-year (2005-2006) retrospective study of adult blunt trauma patients with traumatic brain injury who presented coagulopathic (international normalized ratio [INR] >1.3) and required emergent craniotomy. We compared patients who did (rFVIIa group) and did not (no-rFVIIa group) receive rFVIIa to correct coagulopathy before craniotomy.

Brown et al. Recombinant Factor VIIa for the Correction of Coagulopathy Before Emergent Craniotomy in Blunt Trauma Patients. Journal of Trauma-Injury Infection & Critical Care,2010


METHODS: The clinical and laboratory features of a prospectively followed up case-series of 15 patients with traumatic ICB (mainly isolated SDHs) and coagulopathy (INR) >1.3 treated with rFVIIa in our institution are presented, along with a review of the literature regarding the role of rFVIIa in neurosurgical patients with ICB.

RESULTS: All 15 patients suffered a SDH (4 of 15 had a combined ICB) and coagulopathy (mean INR, 2.34 +/- 0.83; thrombocytopenia rate, 20%), which was attributed to anticoagulants in 46.7%. The mean INR decreased to 1.5 +/- 0.14 after standard therapy and 0.92 +/- 0.1 after rFVIIa therapy.

Bartal C. J Trauma. 2007 Oct;63(4):725-32.

rFVIIa INR & emergency Craniotomy

METHODS: nine patients with coagulopathy requiring urgent neurosurgical intervention were reviewed retrospectively. Each patient was given a dose ranging from 40 to 90 microg/kg of rFVIIa before undergoing surgery. Pre-rFVIIa coagulation and post-rFVIIa coagulation parameters were obtained. Once correction of the coagulopathy was verified, each patient underwent the appropriate neurosurgical procedure. 20 minutes after infusion of the medication showed normalization of values.

Park P. Neurosurgery. 2003 Jul;53(1):34-8;


METHODS: The trauma registry was used to identify patients with severe TBI who were admitted during a 4-year period and were coagulopathic at admission (international normalized ratio, INR >/=1.4) and required a neurosurgical procedure.

Stein. J Trauma. 2008 Mar;64(3):620-7;

Coagulopathy & PLT

PLT

高亮：traumatic brain injury associated coagulopathy

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