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COMMENTARYOpen AccessShould we treat sepsis-induced DIC withanticoagulants?AbstractBackground:Disseminated intravascular coagulation(DIC)is a common complication in sepsis because of crosstalkbetween the immune system and the coagulation system.Several anticoagulant agents have been tested in anattempt to improve the survival of patients with sepsis and sepsis-induced DIC.Here,we discuss the rationaleagainst using anticoagulation therapy in septic DIC.Main body of the abstract:Coagulopathy and DIC are associated with increased mortality in sepsis.Severalanticoagulant agents have been tested in an attempt to improve the survival of patients with sepsis and sepsis-induced DIC,but have proven largely ineffective.This is because of two major factors.First,the coagulation systemis complex and closely related to the immune system.When we manipulate one of the factors involved in thesesystems,we may disturb the delicate homeostasis between them.A second factor may be failure to identifypatients who will benefit from anticoagulation therapy.This may be attributed partly to the fact that there is nogold standard for the diagnosis of DIC,and there are consequently several diagnostic criteria,none of which arespecifically designed for sepsis-induced DIC.Application of precision medicine,of the kind currently being appliedin other intensive care fields,may be the key to overcoming these challenges.Until we know the precise targetpopulation,we should not use anticoagulation therapy in sepsis-induced DIC outside a research setting.Short conclusion:There is no strong evidence to support the effectiveness of routine anticoagulation therapy insepsis-induced DIC,and it should not be used clinically until more is known regarding the population of patientswho may benefit from it.Keywords:Disseminated intravascular coagulation,Sepsis,Anticoagulation,Immunothrombosis,Precision medicineBackgroundDisseminated intravascular coagulation(DIC)is an ac-quired syndrome characterized by delocalized intravascularactivation of coagulation arising from a range of differentcauses 1.If sufficiently severe,it can lead to organ dys-function and death.DIC is frequently seen in sepsis becausethe immune system and coagulation system closely interactwith each other 2.Coagulopathy and DIC are associatedwith increased mortality in sepsis 3,4.Therefore,severalanticoagulant agents have been tested in an attempt toimprove the survival of patients with sepsis and sepsis-induced DIC.Here,rationales against using anticoagulationtherapy in septic DIC are discussed.Main textObservational studies suggest a link between the severityofcoagulopathy,organdysfunction,anddeathinpatients with sepsis 3,4.Therefore,it is not surprisingthat several anticoagulant agents have been tested in anattempt to improve the survival of patients with sepsisand sepsis-induced DIC.Such attempts have been un-successful in improving survival in sepsis and septicshock 5,6.By network meta-analysis,Yatabe et al.showed no significant differences in mortality risk whena placebo and four anticoagulants(antithrombin,throm-bomodulin,heparin,or protease inhibitors)were com-pared in patients with sepsis-induced DIC 6.Recently,Vincent et al.reported the results of the SCARLET(Sepsis Coagulopathy Asahi Recombinant LE Thrombo-modulin)phase 3 trial 7.The inclusion criteria of theSCARLET study were based on a post hoc analysis of arandomized placebo-controlled phase 2b study,in which The Author(s).2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License(http:/creativecommons.org/licenses/by/4.0/),which permits unrestricted use,distribution,andreproduction in any medium,provided you give appropriate credit to the original author(s)and the source,provide a link tothe Creative Commons license,and indicate if changes were made.The Creative Commons Public Domain Dedication waiver(http:/creativecommons.org/publicdomain/zero/1.0/)applies to the data made available in this article,unless otherwise stated.Correspondence:yuinatawch.opho.jpDepartment of Intensive Care Medicine,Osaka Womens and ChildrensHospital,840 Murodo-cho,Izumi,Osaka 594-1101,JapanInata Journal of Intensive Care (2020)8:18 https:/doi.org/10.1186/s40560-020-0435-8recombinant human soluble thrombomodulin(rhsTM)had a non-significant effect on the 28-day mortality ratein patients with sepsis and suspected DIC(17.8%vs21.6%in the placebo group)8.Despite including onlypatients with sepsis-associated coagulopathy,the SCARLETtrial failed to demonstrate a reduction in 28-day all-causemortality.Incorporating then-unpublished results of theSCARLET trial,Yamakawa et al.conducted a systematic re-view and meta-analysis of the effects of rhsTM on sepsis-induced coagulopathy 9;reduction in the risk of all-cause28-day mortality in the rhsTM group was not significantlydifferent compared to the control group(relative risk,0.87;95%confidence interval,0.741.03;p=0.10).Why have anticoagulants failed to demonstrate survivalbenefit in sepsis or sepsis-induced DIC?Firstly,the coagu-lation system,traditionally divided into an intrinsic andextrinsic pathway,is not as simple as once thought andclosely related to the immune system 10.Immuno-thrombosis is an evolutionarily conserved mechanism inwhich thrombosis plays a major physiological role in im-mune defense 11.When we manipulate factors involvedin these intertwined systems,we may disturb their delicatehomeostasis unless we understand and control for all un-intended effects.We are all too familiar with the fact thatmany clinical trials involving strategies for modifying thesystemic inflammatory response by targeting endogenousmediator molecules have produced negative results 12.Secondly,there has been a failure to identify patients whowould benefit from anticoagulation therapy.The disap-pointing results of the SCARLET trial could be explainedby the fact that sepsis-associated coagulopathy is not thesame as sepsis-induced DIC;coagulopathy is common insepsis but does not necessarily lead to the development ofa widespread coagulopathy that meets the diagnostic cri-teria of DIC 3.A meta-analysis of randomized controlledtrials of anticoagulant therapies in sepsis demonstrated asurvival benefit with anticoagulation only in the subgroupof patients with sepsis-induced DIC,but not in the popu-lation with sepsis-associated coagulopathy 5.In the edi-torial accompanying the SCARLET trial report 13,it isnoted that failure to identify patients who were more likelyto respond favorably to rhsTM could partially explain thelack of efficacy for rhsTM in reducing mortality.However,this does not mean that rhsTM is proven to be effective inreducing mortality when used in patients with confirmedsepsis-induced DIC,and physicians should be reminded ofthe difficulty of identifying patients who may benefit fromrhsTM.Difficulty identifying the right targets for anticoa-gulation therapy can be attributed partly to the ambiguousdiagnostic criteria for DIC.There is no gold standard forDIC diagnosis,and there are several diagnostic criteria;inaddition,none of these criteria were specifically designedfor sepsis-induced DIC 4.Thus,discrimination betweensimple coagulopathy and DIC and the timing of treatmentbecomes somewhat arbitrary,and the optimal cutoffpoints of DIC scoring systems are still under debate 14.Finally,different sepsis phenotypes correlated with host-response patterns and clinical outcomes may explain theheterogeneity of treatment effects 15.How can we overcome the challenges mentioned above?One solution could be the application of precision medi-cine,which is increasingly common in the field of inten-sive care medicine 16.One example is the application ofprognostic and predictive enrichment strategies to findpopulations that could benefit from corticosteroid treat-ments in sepsis 17.Predictive enrichment strategy in-volves identifying endotypes(subclasses of a disease orsyndrome as defined by function or biology)by analyzinggene expression 18.This highly sophisticated methodhas revealed that the endotype of patients with sepsischanges over time,possibly affecting the response of thesepatients to treatment 19.If this dynamic change of endo-type is seen in patients with septic DIC,it may not bebeneficial to administer rhsTM to all patients with septicDIC for a uniform duration.There is hope in the field of DIC.In patients with sepsis,thrombocytopenia on admission was associated with a dis-tinct gene expression pattern that corresponds to a moredisturbed host response 20.Applying a precision medi-cineapproach topatientswithsepsis-inducedDICthroughout the clinical course may help identify patientswho benefit from anticoagulation.Until such measuresbecome available,the best possible targets for anticoagula-tion therapy may be patients fulfilling all three criteria ofsepsis,DIC,and high disease severity 21.Nevertheless,in the absence of robust evidence,anticoagulants shouldonly be used for sepsis-induced DIC in a research settingin order to try and find the right population,timing,dosage,and duration of therapy for effective treatment.ConclusionsThere is no strong evidence to support routine anticoa-gulation therapy in sepsis-induced DIC.While anticoa-gulation therapy may be beneficial for some patients,there are several challenges that need to be overcome inorder to find the right targets of the therapy.Until weknow the precise target population,we should not useanticoagulation therapy in sepsis-induced DIC outside aresearch setting.AbbreviationsDIC:Disseminated intravascular coagulation;rhsTM:Recombinant humansoluble thrombomodulin;SCARLET:Sepsis Coagulopathy Asahi RecombinantLE ThrombomodulinAcknowledgementsNot applicableAuthors contributionsYI wrote the manuscript.The author read and approved the final manuscript.Inata Journal of Intensive Care (2020)8:18 Page 2 of 3FundingNot applicableAvailability of data and materialsNot applicableEthics approval and consent to participateNot applicableConsent for publicationNot applicableCompeting interestsThe author declares that there are no competing interests.Received:20 July 2019 Accepted:23 January 2020References1.Taylor FB,Toh CH,Hoots WK,Wada H,Levi M;Scientific Subcommittee onDisseminated Intravascular Coagulation(DIC)of the International Society onThrombosis and Haemostasis(ISTH).Towards definition,clinical andlaboratory criteria,and a scoring system for disseminated intravascularcoagulation.Thromb Haemost.2001;86:13271330.2.Levi M,van der Poll T.Coagulation and sepsis.Thromb Res.2017;149:3844.3.Lyons PG,Micek ST,Hampton N,Kollef MH.Sepsis-associated coagulopathyseverity predicts hospital mortality.Crit Care Med.2018;46:73642.4.Iba T,Di Nisio M,Levy JH,Kitamura N,Thachil J.New criteria for sepsis-induced coagulopathy(SIC)following the revised sepsis definition:aretrospective analysis of a 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