A Lauterio

E Halac

H Saito

H Wang

J Yoshimura

JC Hong

JL Vincent

K Hata

K Kimura

K Yamakawa

M Hayakawa

M Mohri

M Nagato

M Vivarelli

RP Cauley

S Sakamoto

Koichi Kimura

Tomoharu Yoshizumi

Shinji Itoh

Norifumi Harimoto

Takashi Motomura

Noboru Harada

Akihisa Nagatsu

Toru Ikegami

Mizuki Ninomiya

Yuji Soejima

Yoshihiko Maehara

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CASE REPORT Open AccessEfficacy of recombinant thrombomodulinfor DIC after deceased donor livertransplantation: a case reportKoichi Kimura*, Tomoharu Yoshizumi, Shinji Itoh, Norifumi Harimoto, Takashi Motomura, Noboru Harada,Akihisa Nagatsu, Toru Ikegami, Mizuki Ninomiya, Yuji Soejima and Yoshihiko MaeharaAbstractBackground: Disseminated intravascular coagulation (DIC) after liver transplantation (LT) is a difficult complication.We report a case of disseminated intravascular coagulation after deceased donor liver transplantation (DDLT)treated with recombinant thrombomodulin (rTM).Case presentation: A 30-year-old woman underwent right tri-segment split graft DDLT for acute liver failure. Shedeveloped disseminated intravascular coagulation on post-operative day 5 with fever. Computed tomographyrevealed necrosis of hepatic segment IV, and her acute-phase disseminated intravascular coagulation score wasseven points. She was given rTM, and the inflammation, liver function, and coagulation disorders immediatelyimproved. However, pleural effusion drainage from the chest tube became bloody on post-operative day 11, andrTM was discontinued. She progressed well and was discharged from the hospital on post-operative day 28. rTM isan effective treatment for disseminated intravascular coagulation; however, rTM for cases with coagulationdisorders, which can occur after liver transplantation, has both risks and benefits.Conclusions: We report a case of DIC after LT, in which rTM was potentially effective. Further studies are needed todetermine the appropriate dosages, duration, and additional considerations for rTM therapy in liver transplantationpatients.Keywords: Deceased donor liver transplantation, Split graft, Recombinant thrombomodulin, Disseminatedintravascular coagulationBackgroundSplit liver transplantation (LT) is one of few surgicaloptions to expand the donor pool and address organshortages and increasing wait list mortality rates [1].However, split LT is associated with problems relatedto the surgical technique and possible complications.Hong et al. reported that the adult 10-year patient sur-vival rate was significantly lower for split extendedright-liver graft compared with adult whole-liver andliving donor right-liver graft [2]. Halac et al. showedthat the most frequent complications in split LT were bil-iary complications, followed by vascular complicationsand segment IV necrosis [3]. These complications couldlead to disseminated intravascular coagulation (DIC) andpoor outcomes after split LT.Recombinant thrombomodulin (rTM) has excellentanticoagulant activity and is a known therapy for DIC.Recent reports have shown the superiority of rTM overlow-dose heparin for treating DIC and that rTM has sev-eral activities, including anti-inflammatory effects as wellas its anticoagulant activity [4].We present a patient with DIC who was treated withrTM after deceased donor liver transplantation (DDLT)with right tri-segment split graft.Case presentationThe patient was a 30-year-old female with jaundice.Blood analysis at a local hospital revealed severe liverfailure, and she was transferred to our hospital. She was* Correspondence: cubicseal@gmail.comDepartment of Surgery and Science, Graduate School of Medical Sciences,Kyushu University, Fukuoka 812-8582, Japan© 2016 The Author(s). 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.Kimura et al. Surgical Case Reports  (2016) 2:81 DOI 10.1186/s40792-016-0208-8diagnosed as having acute liver failure of unknownetiology and underwent medical treatment, includingplasma exchange and transfusion; however, her liverfunction did not improve. LT was planned, but therewas no suitable living donor, and she was placed on theDDLT wait list. DDLT was performed with right tri-segment split graft 13 days later. At the time of abdom-inal closure, the transplanted graft showed ischemia insegment IV. The graft volume to the standard liver vol-ume ratio was 123.4 % (graft volume = 1381 g), the coldischemic time was 10 h and 32 min, the warm ischemictime was 50 min, and the anhepatic time was 1 h and5 min. The native liver showed subtotal necrosis.Although no severe complications occurred after sur-gery, she developed a fever and increased total bilirubinlevel on post-operative day (POD) 5 (Fig. 1). Bloodanalysis revealed decreased platelets, coagulation ab-normalities, and severe inflammation. Computed tom-ography on POD 6 revealed necrosis of segment IV ofthe transplanted graft (Fig. 2). She was diagnosed ashaving DIC based on the Japanese acute-phase DICscore (seven points) [5], and rTM was begun at 380 U/kg/day. Thereafter, inflammation, liver function, andcoagulation abnormalities dramatically improved andthe fever resolved (Figs. 1 and 3). However, on POD 12,the pleural effusion drainage from the chest tube be-came bloody. The anticoagulant effect of rTM was con-sidered the cause and was discontinued. On POD 14,the pleural effusion drainage became serous, and onPOD 19, the quantity of pleural effusion was minimaland the chest tube was removed. Thereafter, she madegood progress and was discharged from hospital onPOD 28.DiscussionrTM was effective for DIC after DDLT with right tri-segment split graft in this case, and we believe that ne-crosis of segment IV of the split graft caused the DIC.DIC is a severe possible complication after LT and is asystemic disorder characterized by continuous intravas-cular coagulation related to an underlying disease. Theliver produces most of the body’s coagulation factors,fibrinolytic compounds, and coagulation inhibitor fac-tors. However, the dramatic coagulation disorders andfibrinolysis seen with DIC occur systemically after livertransplantation. Coagulation and fibrinolysis are markedlydegraded in end-stage liver failure patients well beforesurgery, and these functions are degraded further aftersurgery because of the intra-operative anhepatic time anddelayed time to improved graft function. After transplant-ation, the competing effects of acute inflammation withcoagulation and fibrinolysis lead to thrombotic microangi-opathy and systemic inflammatory response syndromemaking it difficult to grasp the disease symptoms andtreatment [6].Cauley et al. [7] recently aimed to determine the currentrisk of graft failure in adult recipients after split LT by ana-lyzing data from the United Network for Organ Sharingregistry, assessing 889 split liver grafts performed from1995 to 2010. Similar to previous analyses from the USA,the authors noted a significantly increased risk of graftfailure in split grafts compared with whole grafts. In Japan,Sakamoto et al. showed that complications related to theoperation were more frequent in split LT. They reportedthat the occurrence of bile leakage in extended right-lobegrafts was generally related to the viability of segment IV.The blood supply to segment IV, which arises primarily0500100015002000353637383940-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Body temperature( )ALT(U/l)T-Bil(mg/dl)0510152025T-Bil(mg/dL) ALT(U/L)surgerypostoperative dayfever39.1T-Bil(mg/dL)ALT(U/L)BT( )BT( )chest drain tubeshowed bloody solutionrTM 380 U/kg/dayFig. 1 Post-operative changes in body temperature, total bilirubin levels, and alanine aminotransferaseKimura et al. Surgical Case Reports  (2016) 2:81 Page 2 of 4from the left-side vasculature, may be sacrificed duringthe splitting procedure and may increase the risk of paren-chymal necrosis and bile leakage with an incidence ofapproximately 20–30 %. Segment IV-related complica-tions may be directly associated with high rates of graftloss and mortality [8]. These data might include cases thatdevelop DIC after surgery with necrotic areas in the graft,as in our case. Post-operative DIC can also occur follow-ing hepatectomy because liver partition and portal veinligation for staged hepatectomy can cause post-operativeischemia in segment IV [9]. Monitoring hepatectomy pa-tients for post-operative DIC is important with intra-operative visible hepatic ischemia.rTM is a novel anticoagulant agent composed of the ac-tive, extracellular domain of thrombomodulin that regu-lates the imbalanced coagulation system by reducingexcessive activation of thrombin [10]. In Japan, it has beenreported that rhTM potentially reduces the morbidity andmortality in patients with sepsis-induced DIC [11–13].Similarly, an international phase IIb clinical trial of rTMin patients with sepsis and suspected DIC [14] suggestedthat this treatment is both efficacious and safe, stimulatingenthusiasm for the application of rTM in critical care.rTM also has an inhibitory effect on high-mobility groupbox 1 (HMGB1) by an anti- inflammatory action [15].HMGB1 is an intranuclear protein that was originallyidentified as a DNA-binding protein but has since beenrecognized as a late-phase mediator during sepsis [16].HMGB1 is also known to act as a pro-coagulant as well asa pro-inflammatory mediator for septic organ dysfunction.Hepatocyte nuclei contain high levels of HMGB1, whichis released into the blood after ischemic-reperfusion injuryto the liver and hepatocyte necrosis [17]. Therefore, rTMis a useful treatment for DIC after LT.ConclusionsIn conclusion, we report a case of DIC after DDLT withright tri-segment split graft, in which rTM was potentiallyeffective. Further investigations are needed to confirm theFig. 2 Computed tomographic images on POD 6 showing necrosis of segment IV of the transplanted graftpostoperative day0123456785 6 7 8 9 10 11 12Japanese acute phase DIC score Fig. 3 Japanese acute-phase DIC scores from on POD 5 to 12Kimura et al. Surgical Case Reports  (2016) 2:81 Page 3 of 4efficacy of rTM for DIC after LT and to consider rTM thestandard treatment for DIC in LT recipients.AbbreviationsDDLT, deceased donor liver transplantation; DIC, disseminated intravascularcoagulation; HMGB1, high-mobility group box 1; LT, liver transplantation;POD, post-operative day; rTM, recombinant thrombomodulinFundingNone.Availability of data and materialsNone.Authors’ contributionsKK; drafting of the manuscript. TY; study design and concept. SI, NH, TM, AN,TI, MN, YS; critical revision of the manuscript. YM; final approval of themanuscript. All authors read and approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNone.Ethics approval and consent to participateNone.Received: 8 June 2016 Accepted: 28 July 2016References1. Lauterio A, Di Sandro S, Concone G, De Carlis R, Giacomoni A, De Carlis L.Current status and perspectives in split liver transplantation. World JGastroenterol. 2015;21:11003–15.2. Hong JC, Yersiz H, Farmer DG, Duffy JP, Ghobrial RM, Nonthasoot B, CollinsTE, Hiatt JR, Busuttil RW. Longterm outcomes for whole and segmental livergrafts in adult and pediatric liver transplant recipients: a 10-yearcomparative analysis of 2,988 cases. J Am Coll Surg. 2009;208:682–9.3. Halac E, Dip M, Quiñonez E, Alvarez F, Espinoza JL, Romero P, Nievas F,Maurette R, Luque C, Matus D, Surraco P, Fauda M, McCormack L, MatteraFJ, Gondolesi G, Imventarza O. Split liver transplantation: report of right andleft graft outcomes from a multicenter Argentinean group. Liver Transpl.2016;22:63–70.4. Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R,Hirayama A, Matsuda T, Asakura H, Nakashima M, Aoki N. Efficacy and safetyof recombinant human soluble thrombomodulin (ART-123) in disseminatedintravascular coagulation: results of phase III, randomized, double-blindclinical trial. J Thromb Haemost. 2007;5:31–41.5. Hayakawa M, Yamakawa K, Saito S, et al. Recombinant human solublethrombomodulin and mortality in sepsis-induced disseminated intravascularcoagulation. A multicentre retrospective study. Thromb Haemost. 2016;3:115.6. Hata K, Tanaka H, Uemoto S. DIC during perioperative liver transplantation.Thromb Med. 2014;2:142–9.7. Cauley RP, Vakili K, Fullington N, Potanos K, Graham DA, Finkelstein JA, KimHB. Deceased-donor split-liver transplantation in adult recipients: is thelearning curve over? J Am Coll Surg. 2013;217:672–84.8. Sakamoto S, Kasahara M, Ogura Y, Inomata Y, Uemoto S. Japanese LiverTransplantation Society Current status of deceased donor split livertransplantation in Japan. J Hepatobiliary Pancreat Sci. 2015;22:837–45.9. Vivarelli M, Vincenzi P, Montalti R, Fava G, Tavio M, Coletta M, Vecchi A,Nicolini D, Agostini A, Ahmed EA, Giovagnoni A, Mocchegiani F. ALPPSprocedure for extended liver resections: a single centre experience and asystematic review. PLoS One. 2015;10:e0144019.10. Mohri M, Sugimoto E, Sata M, Asano T. The inhibitory effect of recombinanthuman soluble thrombomodulin on initiation and extension ofcoagulation—a comparison with other anticoagulants. Thromb Haemost.1999;82:1687–93.11. Yamakawa K, Ogura H, Fujimi S, Morikawa M, Ogawa Y, Mohri T, NakamoriY, Inoue Y, Kuwagata Y, Tanaka H, Hamasaki T, Shimazu T. Recombinanthuman soluble thrombomodulin in sepsis-induced disseminatedintravascular coagulation: a multicenter propensity score analysis. IntensiveCare Med. 2013;39:644–52.12. Yamakawa K, Fujimi S, Mohri T, Matsuda H, Nakamori Y, Hirose T, Tasaki O,Ogura H, Kuwagata Y, Hamasaki T, Shimazu T. Treatment effects ofrecombinant human soluble thrombomodulin in patients with severesepsis: a historical control study. Crit Care. 2011;15:R123.13. Yoshimura J, Yamakawa K, Ogura H, Umemura Y, Takahashi H, Morikawa M,Inoue Y, Fujimi S, Tanaka H, Hamasaki T, Shimazu T. Benefit profile ofrecombinant human soluble thrombomodulin in sepsis-induceddisseminated intravascular coagulation: a multicenter propensity scoreanalysis. Crit Care. 2015;19:78.14. Vincent JL, Ramesh MK, Ernest D, LaRosa SP, Pachl J, Aikawa N, Hoste E,Levy H, Hirman J, Levi M, Daga M, Kutsogiannis DJ, Crowther M, Bernard GR,Devriendt J, Puigserver JV, Blanzaco DU, Esmon CT, Parrillo JE, Guzzi L,Henderson SJ, Pothirat C, Mehta P, Fareed J, Talwar D, Tsuruta K, Gorelick KJ,Osawa Y, Kaul I. A randomized, double-blind, placebo-controlled, Phase 2bstudy to evaluate the safety and efficacy of recombinant human solublethrombomodulin, ART-123, in patients with sepsis and suspecteddisseminated intravascular coagulation. Crit Care Med. 2013;41:2069–79.15. Nagato M, Okamoto K, Abe Y, Higure A, Yamaguchi K. Recombinant humansoluble thrombomodulin decreases the plasma high-mobility group box-1protein levels, whereas improving the acute liver injury and survival rates inexperimental endotoxemia. Crit Care Med. 2009;37:2181–6.16. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J,Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E,Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, SamaA, Tracey KJ. HMG-1 as a late mediator of endotoxin lethality in mice.Science. 1999;285:248–51.17. Kimura K, Shirabe K, Yoshizumi T, Takeishi K, Itoh S, Harimoto N, Ikegami T,Uchiyama H, Okano S, Maehara Y. Ischemia-reperfusion injury in fatty liver ismediated by activated NADPH oxidase 2 in rats. Transplantation. 2016;100:791–800.Submit your manuscript to a journal and beneﬁ t from:7 Convenient online submission7 Rigorous peer review7 Immediate publication on acceptance7 Open access: articles freely available online7 High visibility within the ﬁ eld7 Retaining the copyright to your article    Submit your next manuscript at 7 springeropen.comKimura et al. Surgical Case Reports  (2016) 2:81 Page 4 of 4

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Efficacy of recombinant thrombomodulin for DIC after deceased donor liver transplantation: a case report

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Efficacy of recombinant thrombomodulin for DIC after deceased donor liver transplantation: a case report

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