Pulsion, Excalez MAB member Fresenius, Ashai Kasei consultancy

julia.wendon@kcl.ac.uk

AcuteLiverFailure:whattomorrowmaybring?

JuliaWendonKingsCollegeLondonandKingsCollegeHospital

London

Definitions

Aetiology

Managementoforgandysfunctions

Whotoconsiderfortransplantation

Acute Liver Failure

Bernaletal,Lancet2010

Hyperacute <7daysAcute1-4weeksSubacute4-12weeks

Hperacute +acuteHE,cerebraloedema

Subacutejaundice,asciteslateHE

Acute Liver Failure

Primary liver injury

Coagulaopthy

Encephalopathy

No preexisting liver disease

ALF:Aetiology

Bernal&WendonNEJM2013Incidence:1.6-6.2million/year

BonemarrowstainedforTcellmarkerCD3insituhybridizationforEBV

Transfer issues1. Early transfer to a Tp centre2. Elective ventilation if GCS

changing or < 8-93. Observe pupils4. Fluid 5. Noradrenaline6. Mannitol for pupil abnormalities

Cardiovascularsupportandmanagement

RetrogradecerebralandcoronaryperfusionFullsupportnonativecardiacfunctionNopulsatility

ECMO & liver disease

LIVERNEEDINGECMO N= ECMOsurvival %

Survivaltodischarge(or90days)

%

ALLliverpatients 20 16 80% 13* 65%

11ALF,7electiveOLT,2CLD …ofwhich12VV,8VAwithbeing5eCPR

ALLelectivelivertransplants 7 6 86% 6 86%

3VV,3VA …ofwhich1waseCPR

ALLlivertransplants 15 11 73% 8 53%

9VV,6VA …ofwhich4wereeCPR

*OnelatedeathfromHATat5months

ALF & ECMO - Demographics

Aetiology Age Gender

1 SALF† 23 F

2 Avascular* 29 M

3 POD 17 F

4 PPOD‡ 26 F

5 HH** 29 M

6 Status/POD 44 M

7 Wilsons 11 M

†Sub-acute liver failure*Penetrating trauma, HA ligated, prolonged Pringle manoeuvre‡Polypharmacy OD**Suspected myocarditis and hepatitis

ALF & ECMO - Severity of liver disease

ASTIU/L INR Lactate Bilirubin HEIII-IV

All 8531 6 13.1 282 6SALF 57 5.4* 8 312 1

Avascular 6000 3* 12 159 1

POD 9966 9.7 11 325 1

PPOD 12650 5.35* 18 227 1

HH 12200 6.1* 15 219 unknown

StatusHH 18180 5* 13.2 94 1

Wilsons 667 7.36* 14.4 636 1

*INR supported

6/7 (86%) ptsfulfilled KCHcriteria for ELT

Extra-hepatic organ failure

All VVSOFA 22 (20-24)

CPR 5 (71%)

RRT 7 (100%)

ICH 6 (86%)

Plt 40 (20-77)

Norepinephrine μg/kg/min

1.02 + other

PPlat 37 (32-40)

Murray 3.8 (3-4)

Outcomes – ALF & ECMO

ECLSduration WeanedECLS Dischargeor90dsurvival

All 8d(1-20) 6/7(86%) 5/7(71%)

VVECMO 11d(5-20) 4/5(80%) 3/5(60%)

VAECMO 5d(4-6) 2/2(100%) 2/2(100%)

ECMOpreELT 8d(3-21) 3/4(75%) 2/4(50%)*

• 86% wean rate• 71% 90 day survival off ECMO• All patients transplanted (n = 4) survived OLT procedure• 100% had excellent early graft function – normal D1 lactate• One died at 5 months from HAT

RenalNaLactateGlu

Minimal effects of acute liver injury/acute liver failure onhemostasis as assessed by thromboelastography

R. Todd Stravitz1,⇑, Ton Lisman3, Velimir A. Luketic1, Richard K. Sterling1, Puneet Puri1,Michael Fuchs1, Ashraf Ibrahim2, William M. Lee4, Arun J. Sanyal1

1Section of Hepatology and Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA; 2Department ofAnesthesiology, Virginia Commonwealth University, Richmond, VA, USA; 3Department of Surgery, University Medical Center Groningen,

University of Groningen, Groningen, The Netherlands; 4Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center,Dallas, TX, USA

Background & Aims: Patients with acute liver injury/failure (ALI/ALF) are assumed to have a bleeding diathesis on the basis of ele-vated INR; however, clinically significant bleeding is rare. Wehypothesized that patients with ALI/ALF have normal hemostasisdespite elevated INR.Methods: Fifty-one patients with ALI/ALF were studied prospec-tively using thromboelastography (TEG), which measures thedynamics and physical properties of clot formation in wholeblood. ALI was defined as an INR P1.5 in a patient with no pre-vious liver disease, and ALF as ALI with hepatic encephalopathy.Results: Thirty-seven of 51 patients (73%) had ALF and 22patients (43%) underwent liver transplantation or died. Despitea mean INR of 3.4 ± 1.7 (range 1.5–9.6), mean TEG parameterswere normal, and 5 individual TEG parameters were normal in32 (63%). Low maximum amplitude, the measure of ultimate clotstrength, was confined to patients with platelet counts<126 ! 109/L. Maximum amplitude was higher in patients withALF than ALI and correlated directly with venous ammonia con-centrations and with increasing severity of liver injury assessedby elements of the systemic inflammatory response syndrome.All patients had markedly decreased procoagulant factor V andVII levels, which were proportional to decreases in anticoagulantproteins and inversely proportional to elevated factor VIII levels.

Conclusions: Despite elevated INR, most patients with ALI/ALFmaintain normal hemostasis by TEG, the mechanisms of whichinclude an increase in clot strength with increasing severity ofliver injury, increased factor VIII levels, and a commensuratedecline in pro- and anticoagulant proteins.! 2011 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.

Introduction

Acute liver injury and acute liver failure (ALI/ALF) are syndromesdefined by ‘‘coagulopathy’’ on the basis of increased prothrombintime (PT)/INR; ALF represents a more severe liver injury resultingin hepatic encephalopathy [1]. Thrombocytopenia frequentlyaccompanies ALI/ALF, although its pathogenesis remains poorlydefined [2]. Consequently, patients with ALI/ALF have beenassumed to have a bleeding diathesis [3], even though most ser-ies report a low incidence of spontaneous, clinically significantbleeding [4]. Although invasive procedures such as intracranialpressure (ICP) monitor placement are also rarely associated withbleeding complications (<5% [5]), coagulation factor and platelettransfusion remain a routine practice despite potential adverseeffects [6].

In patients with cirrhosis, who also have thrombocytopeniaand elevated INR, a concept of ‘‘re-balanced hemostasis’’ has beenproposed to explain the fact that patients rarely bleed outside ofthe consequences of portal hypertension [7]. As shown by Tripodi[8], thrombin generation is normal in patients with cirrhosis pro-vided that thrombomodulin is added to the reaction mixture toactivate the anticoagulant protein C system. These and otherauthors have explained the maintenance of hemostasis inpatients with cirrhosis by the fact that decrements in procoagu-lant proteins are matched by decrements in anticoagulant pro-teins, such as proteins C and S, and antithrombin (AT) [9].

In contrast to conventional coagulation tests such as the PT/INR and the activated partial thromboplastin time (aPTT) whichassay only clot formation time in a plasma environment, throm-boelastography (TEG) assesses overall hemostasis, the cumulativeeffects of procoagulant and anticoagulant proteins, fibrinogen,platelets, and red blood cells. Component measurements of the

Journal of Hepatology 2012 vol. 56 j 129–136

Keywords: Acute liver failure; Coagulopathy; Hepatic encephalopathy; Hemos-tasis; Thromboelastography.Received 26 January 2011; received in revised form 29 March 2011; accepted 6 April2011; available online 19 May 2011⇑ Corresponding author. Address: Section of Hepatology, P.O. Box 980341,Virginia Commonwealth University, Richmond, VA 23298-0341, USA. Tel.: +1804 828 4060; fax: +1 804 828 4945.E-mail address: rstravit@vcu.edu (R.T. Stravitz).Abbreviations: ALI, acute liver injury; ALF, acute liver failure; INR, internationalnormalized ratio of prothrombin time; TEG, thromboelastogram/thromboelas-tography; PT, prothrombin time; ICP, intracranial pressure; AT, antithrombin;aPTT, activated partial thromboplastin time; R-time, reaction time of TEG; K-time,kinetic time of TEG; MA, maximum amplitude of TEG; SIRS, systemic inflamma-tory response syndrome; WBC, white blood cell count; LY-30, clot lysis in 30 min;CVVH, continuous veno-veno hemofiltration; BMI, body mass index; APAP, ace-taminophen (paracetamol); MAP, mean arterial pressure; OLT, orthotopic livertransplantation; TFS, transplant-free survival; MELD, model for end-stage liverdisease score; ADAMTS13, a disintegrin and metalloprotease with thrombospon-din type-1 motifs 13; vWF, von Willebrand factor.

Research Article

recognized in patients with ALF: despite elevated INR, they rarelybleed. Nevertheless, the management of such patients oftenincludes repletion of coagulation factors and platelets, introduc-ing the possibility of adverse effects (volume overload, transfu-sion-associated lung injury, thrombosis), and added expense.Our results clearly demonstrate that most patients with ALI/ALFhave normal clot formation by TEG despite admission INR rang-ing from 1.5 to 9.6, levels which would likely prompt coagulationfactor repletion prior to an invasive procedure.

TEG parameters in patients with ALI/ALF reflect specificphases of blood clot formation and are associated with specificaspects of the clinical syndrome. The R-time mirrors activationof the coagulation cascades and procoagulant factor levels. Con-sistent with the well-recognized importance of the INR and factorV in predicting outcome in patients with ALF [21,22], the R-timedirectly correlated with the SIRS, specific laboratories which pre-dict poor outcome (lactate and phosphate), complications of theALI/ALF syndrome other than hepatic encephalopathy, and pooroutcome. R-time was significantly higher in patients with infec-tion, those requiring CVVH, and in those with bleeding complica-tions. The TEG was, in fact, more sensitive than the INR forpredicting bleeding, since the INR was not significantly differentin those who bled and those who did not (p = 0.14). This observa-tion supports those of Chau et al. [23], who noted that variceal re-bleeding in patients with cirrhosis was predicted by TEG but notINR. Similarly, the platelet count, factor levels, and fibrinogenconcentration were similar in patients who bled and those whodid not, although the aPTT was significantly longer in the former(65 vs. 47 s; p = 0.016). Thus, monitoring the R-time by TEG or theaPTT would seem a more appropriate assessment of bleeding riskin patients with ALI/ALF than the INR.

In contrast to the R-time, the K-time, a-angle, and MA corre-spond to fibrin formation and platelet activation, and were asso-ciated with different complications of ALI/ALF. These parametersbecome more ‘‘hypercoagulable’’ with increasing SIRS, venousammonia, and the presence of hepatic encephalopathy. The find-

Table 2. Correlation of TEG parameters with coagulation parameters, SIRS components, and admission laboratories in patients with ALI/ALF. Data representcorrelation coefficients (Pearson r values), with negative numbers denoting inverse correlation. All laboratory and clinical data were collected at the time of TEG.

Feature R time K time α-Angle Maximum amplitude

Coagulation Parameters:INR 0.32* 0.17 -0.24 -0.23PTT 0.60**** 0.07 -0.07 -0.06Platelets 0.01 -0.50*** 0.58**** 0.73****Fibrinogen -0.22 -0.44** 0.34* 0.57****Factor V -0.30* -0.25 0.24 0.34*Factor VII 0.08 -0.02 -0.06 0.17Factor VIII -0.27 -0.31* 0.38** 0.33*Protein C Activity -0.19 0.02 -0.14 -0.04Protein S Activity -0.14 0.11 -0.20 -0.14Antithrombin Activity -0.14 -0.02 -0.06 0.17SIRS Components:Pulse 0.18 -0.43** 0.29* 0.44**Respirations 0.46*** -0.34* 0.15 0.31*Temperature -0.20 0.03 0.02 -0.06WBC 0.29* -0.13 0.19 0.30*Chemistries:Lactate 0.58**** 0.16 -0.23 0.01Ammonia (venous) 0.13 -0.37** 0.38** 0.38**Phosphate 0.47*** -0.04 0.00 0.25Creatinine 0.11 -0.05 0.13 0.23Total Bilirubin -0.14 -0.16 0.22 0.10

⁄p <0.05, ⁄⁄p <0.01, ⁄⁄⁄p <0.001, ⁄⁄⁄⁄p 60.0001 indicates significant correlation.

0 1 2 3 430

40

50

60

70

80

Max

imum

ampl

itude

(mm

)

SIRS (N)

Fig. 2. Maximum amplitude of clot formation according to the number ofSIRS concurrently determined in patients with acute liver injury/failure onadmission to study. Data represent mean values with lower/higher 95%; width ofcolumns reflect number of patients with indicated number of SIRS (p = 0.024 fortrend).

JOURNAL OF HEPATOLOGY

Journal of Hepatology 2012 vol. 56 j 129–136 133

LiverInt 2013

Coagulation

JournalofHepatology2012vol.57780–786Mallett etal

KarvellasIntensiveCareMed2009Clin Gastroenterol Hepatol.2014Nov;12(11)

Antibioticprophylaxisdoesnotdecreasebloodstreaminfectionsnotimpactuponmortality

Bacteraemia wasassociatedwithmortalityInUSAstudyascomparedtoUKstudy

Functionalmonocyte deactivationinALF

0

200

400

600

800

1000

1200

0 20 40 60 80

hladr

ObservedLogarithmic

IL-1

0 pg

/ml r= -0.8; p<0.001

↓monocyteHLA-DR,↑circulatingIL-10

Strongcorrelationwithseverityofliverinjury,organfailure&outcome

Antoniades etal,Hepatology‘06;BerryetalLiv Int ‘10

Monocytopaenia inALF

Monocytes Neutrophils

Antoniades etal,Hepatology 2012

HepaticmicroenvironmentfavorsresolutioninflammationIncreasedIL6,10,TGFbetaNodifferenceforIl-1,INF,IL-12,17,23

ALFplasmaexertsanti-inflammatoryeffectsonmonocytes/macrophages

• IncubationofhealthyvolunteerCD14+monocytesandmonocyte-derivedmacrophageswithALFplasma(24-48hours)

• LPSstimulation(100mcg/ml)&TNF-a,IL-6,IL-10levels

Antoniadesetal, gastroenterology2016

ALF

LPS

SequentialandregionalSLPIvariations

*p=0.03

Inflamed liver is a source of production of SLPI

Antoniadesetal,Hepatology.2014Apr;59(4):1564-76

SLPIMainphysiologicaltargetisneutrophilelastase/inhibitneut releasedproteasesduringtissueinjuryAmelioratingtissueinjury/woundhealingInhibitsmonocytedrivenTcellproliferation/Th1responses(Guerrieri etal,Immunology‘11)

Canwealtertheseobservations?HEPATOLOGY2014;59:1564-1576

• SecretoryLeucocyteProteaseInhibitor– anti-inflammatorymediatorintissuemicroenvironment– macrophageNF-kB– MacrophagessecreteSLIPfollowingphagocytosisofapoptoticcells– Immunemodulatoryroleinsepsis

Antoniades CG

NH4cutoff124:pH,cerebraloedema+NH4predictoutcomeBhatiaVGut2005

ClemmensenetalHepatology1999;29:648-653

BernalWHepatology2007

GradeIII/IVcomaYoungpeopleHaemodynamic instability;pressorsFever,SIRS,lowNaElevatedNH4(>150)Renalfailure

Non-Acetaminophen 33/170 (19%)Acetaminophen 55/210 (26%)

BernalWHepatology2008 2007

Reduction in ICPin treatment group(p<0.005)

Murphy et al Hepatology 2004;39(2):464-70

Reduced risk of intracranialhypertension (p<0.05)

HypertonicsalineandCerebraloedemaRandomizedcontroltrialGradeIVHEwithICPbolt

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LarsenetalJournalofHepatology 2016

CD68(Yellow)andFibrin(Red

PE resulted in a significant decrease in circulating histone –associated DNAMonocytes

PE reduce TNF vs SoC and IL-6Early PE reduced surface expression of

CD163 (p=0.0250), CD64 (p=0.0042)CCR7 (p=0.0008)

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Lymphocytesno change in numbers CD8-T, NK-T, NK – cells,regulatory T Decreased production of IL-10, IL-4 and TGF-B following endotoxin challenge

Transplantationandprognosticmarkers

Gut2012;61:1068e1075

RameshKumar,

Bernaletal2016

D1:INR6.5 risingto8.5,CK150K,ALT9,000,ARF,lactate6- D2INR5,lactate3.0,ALT7000

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70%successfulweaningofImmunosuppression

4/8survivedwithoutOLT

Teamsmakethingsworkjulia.wendon@kcl.ac.uk