PAMPsandDAMPsastriggersforDIC TakashiIto 12 Abstract ThrombosisisgenerallyconsideredharmfulbecauseitcompromisesthebloodsupplytoorgansHoweverrecent studieshavesuggestedthatthrombosisundercertaincirc ID: 334597
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REVIEWOpenAccess PAMPsandDAMPsastriggersforDIC TakashiIto 1,2 Abstract Thrombosisisgenerallyconsideredharmfulbecauseitcompromisesthebloodsupplytoorgans.However,recent studieshavesuggestedthatthrombosisundercertaincircumstancesplaysamajorphysiologicalroleinearlyimmune defenseagainstinvadingpathogens.Thisdefensiveroleofthrombosisisnowreferredtoasimmunothrombosis. Activatedmonocytesandneutrophilsaretwomajorinducersofimmunothrombosis.Monocytesandneutrophilsare activatedwhentheydetectpathogen-associatedmolecula rpatterns(PAMPs)anddamage-associatedmolecular patterns(DAMPs).DetectionofPAMPsandDAMPstriggerstissuefactorexpressiononmonocytesandneutrophil extracellulartrap(NET)releasebyneutrophils,promotingimmunothrombosis.Althoughtissuefactor-mediated andNET-mediatedimmunothrombosisplaysaroleinearlyhostdefenseagainstbacterialdissemination,uncontrolled immunothrombosismayleadtodisseminatedintravascularcoagulation. Keywords: Immunothrombosis,Pathoge n-associatedmolecularpatterns(PAMPs) ,Damage-associatedmolecularpatterns (NETs),Disseminatedintra vascularcoagulation(DIC) Introduction Bloodmustbemaintainedinafluidstateunderphysiologic conditions,butthenchangetoasolidstateaftervascular injury.Thisbalancingactisaccomplishedbyplatelets,co- agulationfactors,anticoagulan tfactors,fibrinolyticfactors, endothelialcells,andpossiblyleukocytes,whichallsupport thedynamicequilibriumthatprovidesproperblood flow[1].Disruptionofthiswell-regulatedbalanceleads topathologicconditions,suchasthrombosisandbleeding. Review Basicmechanismsofhemostasis Plateletsandcoagulationfactorsaretwomajorplayersin hemostasis.Plateletsandcoagulationfactorscirculatein thebloodandbecomeactivatedatsitesofvasculardam- age.Plateletsmonitorvasculardamageusingcell-surface sensorsforsubendothelialcollagenandvonWillebrand factorboundtocollagen.Engagementofthesubendothe- lialmatrixbyplateletsresultsinasequenceofreactions comprisingplateletadhesion,activation,andaggregation, factors,morespecificallycoagulationfactorVII,searchfor sitesofvasculardamagewheresubendothelialtissuefactor isexposed.BindingofcoagulationfactorVIIatotissuefac- torresultsinacascadeofblood-clottingreactions,leading tothrombingenerationandsubsequentfibrindeposition atsitesofvasculardamage(Figure1).Plateletthrombus formationandfibrindepositionoccurconcomitantlyas thrombinactivatesplatelets,andactivatedplateletsexpose phosphatidylserineontheirmembranesurfacetoprovide ascaffoldforblood-clottingenzymecomplexes[3]. Inthehemostaticsystem,thrombingenerationistrig- geredbythefactorVIIa-tissuefactorcomplex,aninducer oftheso-calledextrinsicpathway.Oncesmallamountsof thrombinaregeneratedinthispathway,thrombinplaysa crucialroleintheamplificationandpropagationphasesof coagulationfactorsV,VIII,andXI(Figure1)[1].This leadstoaburstofadditionalthrombingeneration,which isessentialforformingsufficientfibrinandsealingthe sitesofvasculardamage.CoagulationfactorXIIIthen crosslinksfibrinfibers,afundamentalprocessforsta- bilizingfibrinclots.Contactactivationofcoagulation factorXII,anotherimportanttriggerofcoagulationinla- boratorytests,isnotconsideredessentialforhemostasis becausehereditarydeficienciesinfactorXIIarenotasso- ciatedwithabnormalbleeding[4,5].However,factorXII mightbeinvolvedinpathologicalthrombosis[6-8]and Correspondence: takashi@m3.kufm.kagoshima-u.ac.jp 1 DepartmentofEmergencyandCriticalCareMedicine,KagoshimaUniversity GraduateSchoolofMedicalandDentalSciences,Kagoshima,Japan 2 DepartmentofSystemsBiologyinThromboregulation,Kagoshima UniversityGraduateSchoolofMedicalandDentalSciences,Kagoshima, Japan ©2014Ito;licenseeBioMedCentral.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons AttributionLicense(http://creativecommons.org/licenses/by/4.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycredited.TheCreativeCommonsPublicDomain Dedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle, unlessotherwisestated. Ito JournalofIntensiveCare (2014)2:65 DOI10.1186/s40560-014-0065-0 couldbeauniquedrugtargetsuitableforpreventing thrombosiswithoutaffectingnormalhemostasis[5]. Thepropagationofahemostaticplugcanbetermi- natedwhenitreachesintactendothelium.Endothelial cellsexpressseveralanticoagulants,includingthrombo- modulin(TM),tissuefactorpathwayinhibitor(TFPI), andheparansulfate(Figure2)[9,10].Uponbindingto TM,thrombinlosesitsabilitytoactivateplatelets,fi- brinogen,andcoagulationfactorsV,VIII,XI,andXIII [11].Furthermore,thethrombin-TMcomplexactivates proteinC,whichinturnstopsthrombingenerationby inactivatingcoagulationfactorsVaandVIIIa.Endothe- lialcellsalsosynthesizeanddisplayheparansulfate proteoglycansontheirsurface,whichbindtoTFPIand antithrombin(AT),inhibitingthefactorVIIa-tissuefac- torcomplex,factorXa,andthrombinactivity[10].Thus, endothelialcellsplayaroleinregulatingthespatial localizationofhemostaticplugs.Disruptionofthiswell- Figure1 Basicmechanismsofcoagulation. CoagulationfactorVIIsearchesforsitesofvasculardamagewheresubendothelialtissuefactoris exposed.Tissuefactorisexpressedonthesurfaceoffibroblastsandpericytesinthesubendothelialspace.BindingofcoagulationfactorVIIato tissuefactorresultsinacascadeofblood-clottingreactions,leadingtothrombingeneration(theinitiationpathway).Oncesmallamountsof thrombinaregeneratedinthispathway,thrombinplaysacrucialroleintheamplificationandpropagationphasesofcoagulationbyactivating coagulationfactorsV,VIII,andXI(theamplificationpathway).Thisleadstoaburstofadditionalthrombingeneration,whichisessentialforform ing sufficientfibrinandsealingthesitesofvasculardamage.CoagulationfactorXIIIthencrosslinksfibrinfibers,afundamentalprocessforstabil izingfibrin clots.Contactactivationofcoagulationfactor XII,anotherimportanttriggero fcoagulationinlaboratorytests,isnotconsideredessentialfor hemostasis. Figure2 Anticoagulantpropertiesofendothelialcells. Endothelialcellsexpressseveralanticoagulants,includingthrombomodulin(TM),tissue factorpathwayinhibitor(TFPI),andheparansulfate.UponbindingtoTM,thrombinlosesitsabilitytoactivateplatelets,fibrinogen,andcoagula tion factorsV,VIII,XI,andXIII.Furthermore,thethrombin-TMcomplexactiv atesproteinC,whichinturnstopsthrombingenerationbyinactivating coagulationfactorsVaandVIIIa.Endothelialcells alsosynthesizeanddisplayheparansulfatepr oteoglycansontheirsurface,whichbindtoTFPI andantithrombin(AT),inhibitingthefactorVIIa-tissuefactorcomplex,factorXa,andthrombinactivity. IIa thrombin, PS proteinS. Ito JournalofIntensiveCare (2014)2:65 Page2of9 regulatedbalanceleadstothrombusformationinsidebloodvessels(i.e.,thrombosis)[1].ImmunothrombosisMicrovascularthrombosisisafrequentcomplicationofcriticalillnessconditions,suchassepsis,trauma,andma-lignancy[12].Thrombosisisgenerallyconsideredharmfulbecauseitcompromisesthebloodsupplytoorgans.How-ever,recentstudieshavesuggestedthatthrombosisundercertaincircumstancesplaysamajorphysiologicalroleinimmunedefense[13,14].Thisdefensiveroleofthrombosisisnowreferredtoasimmunothrombosis[13].Thrombusformationandinnateimmunityarecloselylinked[15].Uponinjury,multicellularorganismsfacetwomajorcrises:bleedingandinfection.Toovercomethesecrises,multicellularorganismshavedevelopedhemostaticsystemsandimmunesystems.Inhorseshoecrabs,asinglehemocytetypecirculatesintheiropencirculatorysystemandplayssignificantrolesinbothhemostasisandinnateimmunity[16].Thehemocytesreleaseprocoagulantserineproteasezymogenswhentheydetectlipopolysaccharide(LPS)ontheirsurface.Theactivationofthesezymogenstriggersthecoagulationcascade,whichultimatelyconvertscoagulogenintoinsolublecoagulingels[17].Coagulinclotsareimportantnotonlyforsealinginjuredsitesbutalsofortrappinginvadingpathogensandsupportinganti-microbialdefense.Thus,thehemocytesofhorseshoecrabscandetectandrespondsensitivelytoLPS,maintaininghemostasisandhostdefenseagainstinvadingpathogens.Horseshoecrabhemocytesarenowusedforlaboratorymeasurementsofendotoxins.Coagulationsystemsinmammalsalsoplayimportantrolesinimmunedefense.Fibrinogen-deficientmicedisplayimpairedcytokineproduction,suppressedneutrophilre-cruitment,increasedbacterialburden,andincreasedmor-talityafterbacterialinoculation[18,19].Furthermore,micepretreatedwithanticoagulants,suchascoumadinorhiru-din,alsodisplayincreasedbacterialburdenandmortalityfollowingbacterialinoculation[18,20].Thesephenotypesindicateprotectiverolesofcoagulationsystemsduringearlyhostdefenseagainstbacterialdissemination.Inhumans,coagulationsystemsarealsoactivatedduringinfection[21].However,itremainstobedeterminedwhetheranticoagulanttherapyimprovesorworsenstheclinicaloutcomesofpatientswithinfectiousdiseases.Plateletshaveimportantrolesinfightinginfections.Uponbacterialinfection,plateletsrapidlyaccumulateonthesurfaceofbacteriacaughtbyKupffercells[22].Theplatelet-mediatedencasementofbacteriarestrictstheirescapefromKupffercells.Thiseventprecedesleukocyterecruitmentandcontributestoearlyhostdefenseagainstinfectioninmice.Plateletsareabletoreleaseantimicrobialmoleculesandproinflammatorymediators,whichmayfurthersupporthostdefenseagainstinfection[23].Inhumans,thrombocytopeniaisincreasinglyrecognizedasanindependentriskfactorforseriousinfections[23].Furthermore,antiplatelettherapymaybeassociatedwithincreasedincidenceofcommunity-acquiredpneumonia[24],althoughitmayalsobeassociatedwithbetterout-comesinpatientswithsevereinfections[25,26].Theseobservationssuggestthatplateletsmaybeimportantinearlyhostdefenseagainstinvadingpathogensbeforein-fectiousdiseasesdevelopbutmaybedeleteriousifin-fectionsprogresstosevereformswithorganfailure.Todate,fourmechanisticmodelshavebeenproposedforhowimmunothrombosisprovidesprotectionagainstinvad-ingpathogens(Figure3)[13].First,immunothrombosislimitsmicrobialdisseminationbyretainingmicrobeswithinthrombi.Inthisregard,coagulationfactorXIIIcrosslinksbacteriatofibrinfibers,leadingtoimmobilizationandkill-ingofbacteriainsidetheclot[27].Second,thrombiformprotectivebarricadesinsideand/oraroundbloodvesselsthatlimitmicrobialmovementinandoutofthevessels[20].Third,fibrin,fibrinogen,andfibrin/fibrinogendeg-radationproductspromoterecruitmentandactivationofleukocytes,suchasneutrophilsandmacrophages,coord-inatingcellularimmuneresponsestopathogensatsitesofinfection[28].Fourth,intravascularthrombiyieldadis-tinctcompartmentwhereantimicrobialpeptidesarecon-centratedandhaveincreasedopportunitiestocomeintocontactwithpathogens.Antimicrobialpeptidescanbereleasednotonlybyleukocytesbutalsobyplateletsandcoagulationsystemsduringtheprocessofimmu-nothrombosis[23,29].TriggersforimmunothrombosisWhatarethetriggersforimmunothrombosis?Duringthecourseofinfections,plateletsandcoagulationfactorscanbecomeactivatedevenintheabsenceofcontactwithsubendothelialcollagenandtissuefactor.Itisnowwidelybelievedthatinsteadofsubendothelialcollagenandtissuefactor,neutrophilsandmonocytescouldserveasthetrig-gersforimmunothrombosis(Figure4)[13].Monocytesareapotentialsourceoftissuefactorincirculatingblood[30].Incontrasttosubendothelialtissuefactorconstitutivelyexpressedonfibroblastsandpericytes,monocyte-associatedtissuefactorexpressionisnormallyverylowandincreasesinresponsetopathogenstimuli[31].GeneticreductionoftissuefactorexpressiononleukocytesreducesLPS-inducedthrombingeneration[32,33],suggestingthattissuefactoronleukocytesacti-vatescoagulationinresponsetopathogenstimuli.Fur-thermore,lowtissuefactorexpressionresultsinbacterialdisseminationandpooroutcomesfollowingbacterialinoculation[18].Thesefindingsindicatethatmonocyte-associatedtissuefactorisanimportantinducerofimmunothrombosis.JournalofIntensiveCarePage3of9 Neutrophilsandneutrophilextracellulartraps(NETs) areotherinducersofimmunothrombosis[13].Inresponse topathogenstimuli,neutrophilsinitiateaprograminvolv- ingrearrangementofthenuclearandgranulararchitecture, leadingtoextracellularreleaseofNETs.NETsarecom- posedofweb-likestructuresofDNAandantimicrobial proteinssuchashistones,neutrophilelastase,andmyelo- peroxidase,andhavetheabilitytoentrapandkillmicrobes [34,35].NETsarealsoabletoactivatecoagulationfac- torXII[8],inactivateanticoagulantTFPI[20],andpro- videascaffoldforplateletbindingandaggregation[36], allofwhichpromotethrombusformation[37].Block- adeofNETactivitybyDNaseorantibodiesagainst DNA-histonecomplexesresultsindecreasedthrombus formation[20,38,39]andincreasedmicrobialdissemination [20,40-42],indicatingthatNETsplayacriticalrolein immunothrombosis. PAMPsandDAMPs Asmentionedabove,activatedmonocytesandneutro- philsaretwomajorinducersofimmunothrombosis. Therefore,thenextquestioniswhatactivatesmonocytes andneutrophilstoinduceimmunothrombosis? Pathogen-associatedmolecularpatterns(PAMPs)and damage-associatedmolecularpatterns(DAMPs)might beresponsible. TheadaptiveimmunesystemcomposedofTandB lymphocytesmonitorsnon-selfantigensusingantigen- specificreceptors.Self-reactivelymphocytesaredeleted earlyinlife,andresiduallymphocytesestablishasurveil- lancesystemfornon-selfantigens.Althoughthissystem ishighlyspecificandeffectivefornon-selfantigenelimin- ation,itisnotperfectbecauseimmuneresponsesagainst harmlessnon-selfcomponents,suchasfetusesorfood- stuffs,canbedeleteriousandshouldbeavoided[43].Innate immunecells,includingmonocytesandneutrophils,em- ployadifferentsurveillance system.Theymonitorcommon molecularpatternsofmicrobes(PAMPs)and/ormolecules fromdamagedcellsofhostorigin(DAMPs)usingpattern recognitionreceptors(PRRs)andonlyactivatetheadaptive immunesystemiftheydetectPAMPsand/orDAMPs. Thus,theinnateandadaptiveimmunesystemsdevelopa mutuallycomplementaryrelationship,andtheoverallim- munesystemconstructsasurveillancesystemforinfec- tiousnon-selfand/ordamagingnon-selfantigens[43,44]. PAMPs,comprisingmolecularstructuresuniqueto microbes,aresubjecttoi nnateimmunemonitoringby thehost.Forexample,cellwallcomponents,suchas LPSand -glucan,orflagellarcomponents,suchas flagellin,arerecognizedasPAMPs,andPAMPdetec- tionbyPRRstriggersproinflammatoryandantimicrobial responsesininnateimmunecells[45].PAMPdetection Figure3 Fourmechanisticmodelsexplainin ghowimmunothrombosisprovidesprotectionagainstinvadingpathogens. (1)Immunothrombosis limitsmicrobialdisseminationbycontainingmicrobeswithinthrombi.(2)T hrombiformprotectivebarricadesin sideand/oraroundbloodvesselst hatlimit microbialmovementinandoutofthevessels.(3)Fibrin,fibrinogen,andfi brin/fibrinogendegradationproductspromoterecruitmentandactivati onof leukocytes,suchasneutrophilsandmacrophages,coordinatingcellulari mmuneresponsestopathogensatsitesofinfection.(4)Intravascularthr ombiyield adistinctcompartmentwhereantimicrobialpep tidesareconcentratedandhave increasedopportunitiestocomeintocontactwithpathogens. Ito JournalofIntensiveCare (2014)2:65 Page4of9 alsotriggerstissuefactorexpressiononmonocytes [30,33]andNETreleasebyneutrophils[38],promoting immunothrombosis. DAMPsareendogenousmoleculesthatarenormally foundinsidecells,unlessreleasedbydamage.Undernor- malconditions,DAMPsarehiddenfromrecognitionby innateimmunecells.However,underconditionsofcellular stressorinjury,DAMPscanbereleasedintotheextracel- lularspacefromdamagedcells,activatinginnateimmune cells[46].PrototypicalDAMPsincludenuclearproteins suchashighmobilitygroupbox1(HMGB1)[47,48]and histones[49],purinemetabolitessuchasATP[50,51]and uricacid[52,53],andmitochondrialcomponentssuchas formylpeptidesandmitochondrialDNA[54].Detection oftheseDAMPsbyPRRs,suchasToll-likereceptorsand inflammasomes,triggersinflammation,whichisimportant foreradicationofinvadingpathogens,clearanceofdead cells,andregenerationofdamagedtissue[55].DAMPs alsotriggerintravascularthrombusformation[50],pos- siblybyinducingtissuefactorexpressiononmonocytes [56],elevatingtissuefactorprocoagulantactivity[57,58], andpromotingplateletaggregation[59]. Immunothrombosisbeyondcontrol Althoughimmunothrombosismightbeimportantinearly hostdefenseagainstbacterialdissemination,uncontrolled immunothrombosismightbedetrimentaltothehost. Disseminatedintravascularcoagulation(DIC)occursin 25% 50%ofpatientswithsepsisandisassociatedwith pooroutcomes[12,60].DICischaracterizedbywidespread microvascularthrombosiswithexhaustionofcoagulation factorsandplatelets[61].Monocyte-associatedtissue factorandneutrophil-derivedNETsarepredisposing factorsforDIC[20,32,38,40,62],indicatingthatDIC mightbeanadvancedstageofimmunothrombosiswherein theimmunesystemisnolongerabletorestrictPAMP/ DAMPspreadingandimmunothrombosisbecomesover- whelmed[13]. Asmentionedabove,tissuefactor-inducedcoagulation isimportantforpreventingbacterialdissemination[18]. However,excessivecoagulopathycanbedetrimental[63], andpharmacologicalinhibitionoftissuefactororgenetic reductionoftissuefactorexpressionoftenrescuesanimals fromsepsis-associatedlethalcoagulopathy[32,33,62].Simi- larly,eliminationofNETscandecreaseorgandamage [38,40],althoughNETsareimportantforpreventing bacterialdissemination[40-42].Thesefindingssupport theconceptthatimmunothrombosiscanbedetrimental ifitbecomesoverwhelmed. ThesameistrueforDAMPs.AlthoughDAMPshave beneficialrolesinimmunityandtissuerepair[44,64],ex- cessiveDAMPscanbedetrimental.Serumandplasma HMGB1levelsareelevatedinpatientswithsepsisand/or DIC[65,66]andarecorrelatedwithDICscores. Figure4 Triggersforimmunothrombosis. DetectionofPAMPsandDAMPstriggersNETreleasebyneutrophilsandtissuefactorexpressionon monocytes,promotingimmunothrombosis.NETsareabletoactivatecoagulationfactorXII,inactivateanticoagulantTFPI,andprovideascaffold forplateletbindingandaggregation,allofwhichpromotethrombusformation.Apartofmonocyte-associatedtissuefactorisreleasedinthe formofmicroparticlesanddeliveredintodevelopingthrombi. Ito JournalofIntensiveCare (2014)2:65 Page5of9 ExtracellularHMGB1stimulatestissuefactorexpres-siononmonocytes,inhibitsproteinCactivation,andpromotesmicrovascularthrombosisdevelopment[56].AntibodiesorantagonistscapableofneutralizingHMGB1reduceorgandamageandimprovesurvivalofsepticmice[65,67,68],indicatingthatexcessiveHMGB1circulatinginthebloodisdetrimental.Plasmahistonelevelsarealsoele-vatedinpatientswithsepsisandDIC[69,70].Extracellularhistonestriggerplateletaggregation,fibrindeposition,thromboticocclusionofmicrovessels,andexhaustionofcoagulationfactorsandplatelets[70].Extracellularcell-freeDNA(cfDNA)alsoactsasaDAMP[71].PlasmacfDNAlevelsareelevatedinpatientswithseveresepsis,es-peciallyinnon-survivorsandhavebetterprognosticutilitythanAcutePhysiologyandChronicHealthEvaluation(APACHE)IIscores,MultipleOrganFailureAssessment(SOFA)scores,andotherbiomarkers[72].ThemajorityofplasmacfDNAisderivedfromthehost[72,73],althoughsomeoriginatesfrombacteria,fungi,andviruses.cfDNAisthemajorstructuralcomponentofNETs,andcfDNA/NETscanpromotethrombingeneration,inpart,throughactivationofcoagulationfactorXII[39,74].DepletionofcfDNA/NETsbyDNasetreatmentimpedesearlyimmuneresponses[75],suggestingthatcfDNA-mediatedimmuno-thrombosismightbeimportantinearlyhostdefenseagainstbacterialdissemination.Insepticconditions,theprocoagulant-anticoagulantbalancebecomesdisturbed.Whiletissuefactor-andNET-associatedprocoagulantactivityisincreasedduringsepsis,anticoagulantproteins,suchasTM,proteinC,andAT,canbeseverelycompromised[60,76-78].Furthermore,fibrinolysisisattenuatedinsepticconditions,inpartthroughincreasedplasminogenactivatorinhibitortype-1(PAI-1)releasefromendothelialcells[60].Thus,disturb-anceoftheprocoagulant-anticoagulantbalance,withincreasesinprocoagulanttissuefactorandNETsanddecreasesinanticoagulantsandfibrinolyticcapacity,isthekeyfeatureofsepsis-associatedDIC.TherapeuticoptionsforDICThecornerstoneformanagingDICremainsthemanage-mentoftheunderlyingcauses,suchassepsis,inmostWesterncountries[61].Accordingly,thereisnomentionofDICintheSurvivingSepsisCampaignguidelines,com-prisinginternationalguidelinesformanagementofseveresepsisandsepticshock[79].Consequently,anticoagulantdrugsmightbeusedforthetreatmentofsepsis,butnotforDICitselfinthosecountries.ActivatedproteinC(APC)isanaturalanticoagulantthatcandampenthrombingenerationbyinactivatingcoagula-tionfactorsVaandVIIIa(Figure2).APCalsoexertscyto-protectiveeffects,inpartthroughactivationofendothelialcellprotease-activatedreceptor1[80].Drotrecoginalfa(activated),arecombinanthumanAPC(rhAPC),usedtobetheonlyapproveddrugassociatedwithsignificantlyim-provedsurvivalofpatientswithseveresepsis,basedonalarge-scale,randomized,double-blind,placebo-controlled,multicentertrial(PROWESSstudy)[81].However,theini-tialsuccesswasnotreplicatedinsubsequenttrialsofdro-trecoginalfa(activated)inpatientswithseveresepsisandlowriskofdeath[82],childrenwithseveresepsis[83],andpatientswithsepticshock[84],andthisdrughasnowbeenwithdrawnfromthemarket[85].PossiblereasonsforthisfailureincludetheincreasedriskofseriousbleedingintherhAPCgroupandlowerplacebomortalityratescomparedwiththeoriginalPROWESSstudy,makingitdifficulttodemonstratebeneficialeffectsofrhAPC.TMisananticoagulantcofactorthatconvertsthrom-binintoanAPCgenerator(Figure2).BecauseTMises-sentialforpreventingintravascularcoagulation[86]anditsexpressioniscompromisedduringsepsis[76],substi-tutionwithrecombinanthumansolubleTM(rhsTM)isapromisingtreatmentforpatientswithsepsisandDIC.AlthoughtheanticoagulantactionofTMismainlymedi-atedbyAPC,rhsTMtreatmentmayhavesomeadvantagesoverrhAPC.First,rhsTMmayhavelessriskofbleedingcomplicationsthanrhAPCbecauseitisacofactoranddoesnotactasananticoagulantwhennothrombinexists[87].Second,theAPC-independentactionsofrhsTMmightconferabenefit.Theseactionsincludesequestra-tionofPAMPs[88],DAMPs[68,70,89],andcomple-ments[90]throughthelectin-likedomainofrhsTM[91].Inarandomized,double-blind,parallel-grouptrialtoevalu-ateDICresolutionrates,rhsTMwassignificantlysuperiortoheparinforDICimprovement[92].The28-daymortalityrateswereassessedasasecondaryendpointinthestudyandwere28.0%fortherhsTMgroupand34.6%fortheheparingroup(difference:6.6%;95%CI:24.6to11.3)inpatientswithDICandinfection.Thus,rhsTMhasbeenapprovedinJapanfortreatmentofDIC,althoughfur-therstudiesareneededtoconfirmthatrhsTMimprovesclinicaloutcomesinpatientswithsepsis-associatedDIC.Post-marketingretrospectiveobservationalstudiessug-gestedthatrhsTMtherapymightbeassociatedwithbetteroutcomes[93-95],andaninternational,multicenter,ran-domized,double-blind,placebo-controlled,phase3clinicaltrialforrhsTMisnowinprogress.Severesepsispatientswithcoagulopathyarescheduledtobeevaluatedinthistrial,onthegroundsthatmortalityratesofsepsispatientswithoutorgandysfunctionarerelativelylowanditisthusdifficulttoevaluatetreatmentbenefitsonmortalityinthesepatients,andthatpatientswithcoagulopathymightgaingreaterbenefitsfromanticoagulanttherapy[96].ATisthemostabundantanticoagulantproteincircu-latingintheblood.ATisrapidlydepletedintheearlyphasesofsepsisthroughdecreasedsynthesis,increasedde-struction,andenhancedclearancebythrombin-ATcom-plex(TAT)formation[77,78].AThasanti-inflammatoryJournalofIntensiveCarePage6of9 andanticoagulantproperties.HeparinenhancestheanticoagulantactivityofATbutmaydiminishanti-inflammatoryeffectsofAT[97].Theeffectsofhigh-doseATtreatmentinpatientswithseveresepsiswereinves-tigatedintheKyberSepttrial,alarge-scale,randomized,double-blind,placebo-controlled,phase3clinicaltrial[98].However,itshowedthathigh-doseAThadnoeffecton28-dayall-causemortalityandwasassociatedwithin-creasedriskofhemorrhagewhenadministeredwithheparin.Thereissomeevidencetosuggesttreatmentben-efitsofATinsubgroupsofpatientsnotreceivingcon-comitantheparinandcomplicatedwithDIC[98-100].TheefficacyandsafetyofATneedtobeconfirmedinfurtherstudies.ConclusionsImmunothrombosisplaysanimportantroleinearlyim-munedefenseagainstinvadingpathogens.DICisconsid-eredtobeanadvancedstageofimmunothrombosis,wheretheimmunesystemisnolongerabletorestrictPAMP/DAMPspreadingandimmunothrombosisbecomesover-whelmed.Inthisstage,thrombosisisdetrimentalbecauseitcausesmultipleorganfailure.Althoughanticoagulantdrugs,suchasAPC,TM,andAT,arepromisingoptionsfortreatmentofsepsis-associatedDIC,noneofthemhavebeenshowntoimprovetheoutcomesofpatientswithsepsis.Thekeytosuccessmaybetheselectionofproperpatients,propertiming,andproperdosages.pathogen-associatedmolecularpatterns;DAMPs:damage-associatedmolecularpatterns;NETs:neutrophilextracellulartraps;DIC:disseminatedintravascularcoagulation;TM:thrombomodulin;TFPI:tissuefactorpathwayinhibitor;AT:antithrombin;LPS:lipopolysaccharide;PRRs:patternrecognitionreceptors;HMGB1:highmobilitygroupbox1;cfDNA:cell-freeDNA;APACHEII:AcutePhysiologyandChronicHealthEvaluationII;SOFA:SequentialOrganFailureAssessment;PAI-1:plasminogenactivatorinhibitortype-1;APC:activatedproteinC;rhAPC:recombinanthumanactivatedproteinC;rhsTM:recombinanthumansolublethrombomodulin;TAT:thrombin-antithrombincomplex.CompetinginterestsTIholdsanendowedfacultypositioninthrombosisresearchandhasreceivedfundsfromMedipolisMedicalResearchInstitute,ShinNipponBiomedicalLaboratories,AsahiKaseiPharma,andAsahiKaseiMedical.AcknowledgementsThisworkwassupportedinpartbyaresearchgrantfromtheJapanSocietyforthePromotionofScience(Grant-in-Aid24390402).Received:3October2014Accepted:13November2014Published:31December20141.BorissoffJI,SpronkHM,tenCateH:Thehemostaticsystemasamodulatorofatherosclerosis.NEnglJMed2.JacksonSP,NesbittWS,KulkarniS:SignalingeventsunderlyingthrombusJThrombHaemost3.FurieB,FurieBC:Mechanismsofthrombusformation.NEnglJMed4.RatnoffOD,ColopyJE:Afamilialhemorrhagictraitassociatedwithadeficiencyofaclot-promotingfractionofplasma.JClinInvest5.ColmanRW:Arehemostasisandthrombosistwosidesofthesamecoin?JExpMed6.RenneT,PozgajovaM,GrunerS,SchuhK,PauerHU,BurfeindP,GailaniD,NieswandtB:DefectivethrombusformationinmicelackingcoagulationfactorXII.JExpMed7.KleinschnitzC,StollG,BendszusM,SchuhK,PauerHU,BurfeindP,RenneC,GailaniD,NieswandtB,RenneT:TargetingcoagulationfactorXIIprovidesprotectionfrompathologicalthrombosisincerebralischemiawithoutinterferingwithhemostasis.JExpMed8.vonBruhlML,StarkK,SteinhartA,ChandraratneS,KonradI,LorenzM,KhandogaA,TirniceriuA,ColettiR,KollnbergerM,ByrneRA,LaitinenI,WalchA,BrillA,PfeilerS,ManukyanD,BraunS,LangeP,RieggerJ,WareJ,EckartA,HaidariS,RudeliusM,SchulzC,EchtlerK,BrinkmannV,SchwaigerM,PreissnerKT,WagnerDD,MackmanN,etalMonocytes,neutrophils,andplateletscooperatetoinitiateandpropagatevenousthrombosisinmiceinvivo.JExpMed9.AirdWC:Spatialandtemporaldynamicsoftheendothelium.JThrombHaemost10.PoberJS,SessaWC:EvolvingfunctionsofendothelialcellsinNatRevImmunol11.EsmonCT:Theregulationofnaturalanticoagulantpathways.Science12.LeviM,TenCateH:Disseminatedintravascularcoagulation.NEnglJMed13.EngelmannB,MassbergS:Thrombosisasanintravasculareffectorofinnateimmunity.NatRevImmunol14.PfeilerS,MassbergS,EngelmannB:Biologicalbasisandpathologicalrelevanceofmicrovascularthrombosis.ThrombRes(Suppl1):S3515.DelvaeyeM,ConwayEM:Coagulationandinnateimmuneresponses:canweviewthemseparately?16.MutaT,IwanagaS:TheroleofhemolymphcoagulationininnateCurrOpinImmunol17.CereniusL,SoderhallK:Coagulationininvertebrates.JInnateImmun18.LuoD,SzabaFM,KummerLW,PlowEF,MackmanN,GailaniD,SmileyST:Protectiverolesforfibrin,tissuefactor,plasminogenactivatorinhibitor-1,andthrombinactivatablefibrinolysisinhibitor,butnotfactorXI,duringdefenseagainstthegram-negativebacteriumYersiniaenterocolitica.JImmunol19.SunH,WangX,DegenJL,GinsburgD:ReducedthrombingenerationincreaseshostsusceptibilitytogroupAstreptococcalinfection.20.MassbergS,GrahlL,vonBruehlML,ManukyanD,PfeilerS,GoosmannC,BrinkmannV,LorenzM,BidzhekovK,KhandagaleAB,KonradI,KennerknechtE,RegesK,HoldenriederS,BraunS,ReinhardtC,SpannaglM,PreissnerKT,EngelmannB:Reciprocalcouplingofcoagulationandinnateimmunityvianeutrophilserineproteases.NatMed21.GüntherA,MosaviP,HeinemannS,RuppertC,MuthH,MarkartP,GrimmingerF,WalmrathD,Temmesfeld-WollbrÜCkB,SeegerW:fibrinformationcausedbyenhancedprocoagulantanddepressedfibrinolyticcapacitiesinseverepneumonia.AmJRespCritCareMed22.WongCH,JenneCN,PetriB,ChrobokNL,KubesP:Nucleationofplateletswithblood-bornepathogensonKupffercellsprecedes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