{"paper_id":"fc3be30d-48bd-4de8-b992-0c807e37d540","body_text":"C A S E R E P O R T Open Access\nSuccessful conservative treatment for\nmassive uterine bleeding with non-septic\ndisseminated intravascular coagulation\nafter termination of early pregnancy in a\nwoman with huge adenomyosis: case\nreport\nFuminori Kimura *, Akimasa Takahashi, Jun Kitazawa, Fumi Yoshino, Daisuke Katsura, Tsukuru Amano and\nTakashi Murakami\nAbstract\nBackground: Adenomyosis is a benign gynecological condition in which endometrial tissue or endometrial-like\ntissue develops within the uterine myometrium. Few cases of disseminated intravascular coagulation has been\nreported in the patients with adenomyosis. Although hysterectomy is indicated for refractory massive uterine\nbleeding in the patients with advanced uterine adenomyosis, conservative treatment is often desired in women in\nthe late reproductive age. Recently such cases are increasing due to the social trend of late marriage.\n(Continued on next page)\n© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,\nwhich permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give\nappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if\nchanges were made. The images or other third party material in this article are included in the article's Creative Commons\nlicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons\nlicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain\npermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nThe Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the\ndata made available in this article, unless otherwise stated in a credit line to the data.\n* Correspondence: kimurafu@belle.shiga-med.ac.jp\nDepartment of Obstetrics and Gynecology, Shiga University of Medical\nScience, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan\nKimura et al. BMC Women's Health           (2020) 20:56 \nhttps://doi.org/10.1186/s12905-020-00924-8\n\n(Continued from previous page)\nCase presentation: A 37-year-old woman with huge adenomyosis, gravida 2 para 0, was referred to our hospital to\nterminate her pregnancy. Acute, non-septic, disseminated intravascular coagulation (DIC) developed after early\npregnancy was terminated in a woman with huge adenomyosis. Massive bleeding and DIC occurred 3 days after\nthe dilatation and curettage. There was no evidence of infection as the cause of the DIC, because neither bacteria\nnor endotoxin could be detected in her blood, and antithrombin 3 (AT3), which would be expected to decrease in\nseptic patients, was not decreased. Hemorrhage in the adenomyotic tissue after the termination presumably\ndeveloped inflammation, with numerous microthrombi and necrosis in the adenomyotic tissue, which subsequently\npromoted coagulation and fibrinolysis, leading to the onset of massive uterine bleeding and DIC. Although severe\nhyperfibrinolysis is observed in peripheral blood, the fibrinolysis state in the uterine myometrium is considered to\nbe even more severe. The newly formed clots for hemostasis under the uterine mucosa could be removed due to\nthe excessive activation of fibrinolytic system happened in the adjacent myometrium, leading to the onset of\nmassive uterine bleeding. Massive bleeding and DIC resolved quickly after the patient was treated with nafamostat\nmesilate, which is effective for both excessive coagulation and fibrinolysis.\nConclusions: Adenomyosis could cause massive bleeding and DIC when pregnancy is terminated. Massive\nbleeding was considered to occur because the excessive fibrinolysis system inside adenomyosis affected the\nadjacent endometrium. Before considering hysterectomy to control refractory uterine bleeding, nafamostat mesilate\nshould be considered as one option, thinking the pathophysiology of the massive bleeding due to uterine\nadenomyosis.\nKeywords: Adenomyosis, Case report, Disseminated intravascular coagulation, Termination of pregnancy, abortion,\nBackground\nDisseminated intravascular coagulation (DIC) is a coagu-\nlopathy that can occur in a large number of clinical con-\nditions, including malignant tumors and obstetrical\nevents [ 1–5]. However, few cases of DIC have been re-\nported in benign diseases, especially intrauterine diseases\n[6–8]. Adenomyosis is a benign gynecological condition\nin which endometrial tissue or endometrial-like tissue\ndevelops within the uterine myometrium [ 9–11]. A case\nof non-septic DIC that occurred after termination of\nearly pregnancy in a woman with huge adenomyosis is\npresented. The DIC occurred during the period when\nlevels of pregnancy-related hormones and substances\nwere diminishing. The clinical course strongly suggested\nthat the massive bleeding was related to the occurrence\nof excessive fibrinolysis. Although hysterectomy is indi-\ncated for massive uterine bleeding in patients with ad-\nvanced uterine adenomyosis, conservative treatment is\noften desired in women in the reproductive age. Re-\ncently, such cases have been increasing due to the social\ntrend of late marriage. The administration of nafamostat\nmesilate, which is effective for both excessive coagula-\ntion and fibrinolysis, should be considered as one option\nwhen massive bleeding caused by excessive fibrinolysis\ndue to huge adenomyosis occurs in patients who want\nto preserve their uterus.\nCase presentation\nA 37-year-old woman, gravida 2, para 0, was referred to\nour hospital for termination of early pregnancy. She suf-\nfered from huge adenomyosis and had been treated with\na GnRH agonist for 15 months in total. She also had a\nhistory of transfusion due to severe uterine hemorrhage\nwhen a miscarriage occurred at the age of 33 years.\nOn initial ultrasonography examination, the total\nthickness of her uterus was found to be over 10 cm, and\nextensive distribution of heterogeneous echogenicity was\ndiffusely detected in both the posterior and anterior\nwalls, as well as at the fundus. A 3-cm gestational sac\nwith fetal heart movement, compatible with a gestational\nage of 6 weeks, was also detected in the uterine cavity\n(Fig. 1). In Japan, women have right to terminate preg-\nnancy in early stage because of the socio-economic rea-\nson. In the present case, the woman was not married at\nthat time and wanted to terminate the pregnancy due to\nfinancial reason. She was admitted, with dilatation and\ncurettage performed gently under ultrasonographic guid-\nance after the length of the uterine cavity was estimated\nto be 8.5 cm with a sonde, which was not very enlarged.\nThere was little bleeding during the procedure. To pre-\nvent infection, 1 g of cefmetazole (CMZ) was adminis-\ntered intravenously twice in the perioperative period.\nThe patient recovered well and was discharged the next\nday. When the patient was reviewed in the morning 3\ndays after the procedure, she had slight uterine bleeding\nwith no pain or fever. Laboratory tests were as follows:\nwhite blood cells (WBCs) 8.0 × 10 3 (3.3 × 103–9.0 × 103/\nμl), hemoglobin (Hb) 8.8 (11.5 –15.0 g/dl), platelets 24 ×\n104 (12 × 104 – 40 × 104 /μl), C-reactive protein (CRP)\n0.9 mg/dl (< 0.5 mg/dl), anti-thrombin 3 (AT3) 108 (80 –\n130%), thrombin antithrombin III complex (TAT) 10.9\n(< 3.0 ng/ml), D-dimer 6.1 (< 1.0 μg/ml), plasminogen\nKimura et al. BMC Women's Health           (2020) 20:56 Page 2 of 6\n\nactivator inhibitor-1 (PAI-1) 91.4 (< 50 ng/ml), and plas-\nmin α2-plasmin inhibitor complex (PIC) 0.8 (0.4 –0.8 μg/\nml) (Fig. 2a, b). However, she developed abdominal pain\nthat night, and the symptom gradually worsened. The\namount of uterine bleeding also increased dramatically.\nShe consulted our hospital again 5 days after the proced-\nure because of severe abdominal pain and massive uter-\nine bleeding. Her body temperature was 37.1 °C. There\nwas marked tenderness of the uterus, and massive uter-\nine bleeding continued. Her WBC count was 19.2 × 10 3/\nμl, and her platelet count was decreased to 5.3 × 10 4 /μl.\nOther laboratory tests were as follows: Hb 7.5 g/dl, CRP\n24.1 (< 0.5 mg/dl), AT3 87%, TAT 36.0 ng/ml, D dimer\n111.1 μg/ml, PAI-1 27.3 ng/ml, and PIC 13.7 μg/ml (Fig.\n2a, b). These findings strongly suggested that the patient\nwas developing DIC. Endotoxin was not detected in her\nblood, and no bacterial colonies grew in peripheral blood\nand uterine blood cultures. The Chlamydia trachomatis\nantibody titer was also not elevated. She was re-admitted\nto hospital and treated with nafamostat mesilate (200\nmg/day) for 60 h, which has effects against both exces-\nsive coagulation and fibrinolysis, and cefmetazole (2 g/\nday) for 2 days. A decrease in bleeding was observed in a\nfew hours. There was rapid improvement of her symp-\ntoms of abdominal pain and uterine bleeding and the la-\nboratory data (Fig. 2a, b). Without surgical intervention,\nthe patient was discharged on the fourth days after the\nsecond admission.\nDiscussion and conclusions\nIn the present case, the clinical course and laboratory\ndata strongly suggested that the DIC was unrelated to\ninfection. First, symptoms of abdominal pain usually\npersist for several days after the start of treatment in the\ncase of severe uterine infection, but the symptoms di-\nminished rapidly after the administration of cefmetazole\nand nafamostat mesilate in the present case. Second, no\ncolonies grew or were detected on peripheral blood and\nuterine blood cultures, and endotoxin was neither de-\ntected in her blood. Third, the serum level of AT3 was\nnot decreased so much, and PAI-1 was not increased\nwhen the patient complained of abdominal ache,\nwhereas these parameters should be markedly decreased\nand markedly elevated, respectively, in a case of septic\nDIC. Accordingly, mechanisms other than infection are\nthought to have been responsible for her DIC. Thus,\nadenomyosis was thought to be the main cause of DIC\nafter the termination of early pregnancy, although it is\ndifficult to reliably deny other causes.\nAdenomyosis is a benign condition, but it is known to\ncause hypermenorrhea, dysmenorrhea, and infertility [ 9–\n11]. Hypermenorrhea may be due to increased area of\nthe uterine cavity, disturbance of uterine contraction,\nand hemorrhage from the adenomyosis tissue to the\nuterine cavity [ 12]. Inflammation and hemorrhage are\nknown as potential causes of dysfunctional coagulation\nand fibrinolysis [ 13–15]. Recently, the occurrence of\nDIC in a patient with adenomyosis during menstruation\nwas reported [ 7]. This report suggested that local\nhemorrhage inside the adenomyosis and subsequent\nthrombosis formation contributed to the development of\nacute DIC. We recently reported activation of the fibrin-\nolysis system during menstruation and its relationship to\nmicrothrombi inside adenomyosis in patients with large\nadenomyosis, and we suggested that intramural\nhemorrhage in the adenomyosis lesion blocked vessels,\nFig. 1 Ultrasound image of patient ’s uterus at the first visit. The uterus was more than 10 cm in the thickness, and heterogeneous echogenicity\ncould be diffusely detected throughout the myometrium. The uterine cavity was not enlarged and was rather narrow. It contained a 3 cm of\ngestational sac with fetal heart movement\nKimura et al. BMC Women's Health           (2020) 20:56 Page 3 of 6\n\nleading to multiple microthrombi and ischemic damage\nto the myometrium, resulting in activation of the fibrin-\nolysis system [ 16]. Although severe hyperfibrinolysis is\nobserved in peripheral blood, we speculate the fibrinolysis\nstate in the uterine myometrium is considered to be even\nmore severe. The newly formed clot for hemostasis under\nthe uterine mucosa could be removed due to the excess fi-\nbrinolytic substance(s) from the adjacent myometrium,\nFig. 2 a. Changes in hemoglobin levels, white blood cell counts, platelets counts and levels of antithrombin 3. At 3 days after the procedure, the\nhemoglobin (Hb) level and the platelet count was slightly decreased from the initial data. The white blood cell (WBC) count and the level of\nantithrombin 3 (AT3) was in normal range. At fifth day of post procedure, the Hb level was decreased and the platelet count was markedly\ndecreased. The WBC count was markedly increased although the level of AT3 was still in normal range. After the treatment of nafamostat\nmesylate and cefmetazole, the data were recovered. b. Changes in levels of D-dimer, thrombin antithrombin3 complex, plasminogen activator\ninhibitor-1 and plasmin α2-plasmin inhibitor complex. The level of plasminogen activator inhibitor-1 (PAI-1) and the level of thrombin\nantithrombin 3 complex (TAT) was increased by the third day after the procedure, while the level of D-dimer and the level of plasmin α2-plasmin\ninhibitor complex (PIC) were in normal range. The levels of D-dimer, TAT and PIC increased markedly on the fifth day although the level of PAI-1\nstarted to decease. Treatment with nafamostat mesilate led to rapid improvement of the levels of D-dimer, TAT and PIC\nKimura et al. BMC Women's Health           (2020) 20:56 Page 4 of 6\n\nleading to the onset of massive uterine bleeding. Difficulty\nof the treatment of uterine adenomyosis might be that\nuterine adenomyosis produces fibrinolytic substances, that\ndirectly effect on the endometrium that lies on adjacent\nadenomyosis. Moreover, a similar adenomyosis case of\nacute DIC that developed after dilation and curettage was\nreported [8]. The clinical course improved after treatment\nwith tranexamic acid, blood transfusions, and subtotal\nhysterectomy. The authors also stated that activation of\nthe coagulation system, microthrombus formation, myo-\nmetrial necrosis, exhaustion of coagulation factors, and\nhyperfibrinolysis might play crucial roles in the develop-\nment of DIC [ 8].\nIn the present case, the increase of sex steroid hor-\nmones due to pregnancy could have affected the adeno-\nmyosis tissue and resulted in the production of more\nmicrothrombi than usual menstruation. The patient did\nnot complain of abdominal pain until 3 days after the\nprocedure. In addition, 3 days after the procedure, AT3\nwas in the normal range. The Hb level and platelet\ncount were slightly decreased, and PAI-1 was increased\nto 91.4 ng/ml. TAT and D dimer increased slightly to\n10.9 ng/ml and 6.1 μg/ml, respectively, while PIC was\nunchanged. PAI-1 inhibits the serine protease tissue\nplasminogen activator (tPA) and is thus an inhibitor of\nfibrinolysis. As it inhibited activation of blood fibrinoly-\nsis, DIC might not occur at that time. Five days after the\nprocedure, the Hb level and platelet count were de-\ncreased, and PAI-1 was decreased to 27.3 ng/ml in nor-\nmal range. However, TAT was increased to 36.0 ng/ml,\nand D dimer and PIC were increased to 111.1 μg/ml and\n13.7 μg/ml, respectively, although AT3 was still in the\nnormal range. Based on these data, the patient could be\ndiagnosed as developing DIC with both excess coagula-\ntion and fibrinolysis. We thought that a large number of\nthrombi had already formed 3 days after the procedure.\nConsidering the changes of PIC and D dimer, fibrinolysis\nwas excessive with increased coagulation after 3 days of\nthe procedure. Therefore, we thought that a large num-\nber of microthrombi had formed inside the adenomyotic\ntissue around 3 days after the procedure, which subse-\nquently led to the rapid onset of DIC with excessive fi-\nbrinolysis. Since severe fibrinolysis dysfunction was\nconfirmed in the peripheral blood, it was presumed that\nthe fibrinolysis dysfunction inside the uterus was further\nenhanced. For this reason, massive uterine bleeding oc-\ncurred, and it is thought that a rapid decrease in the Hb\nlevel and a decrease in the platelet count were observed.\nFour cases of cerebral infarcts associated with adeno-\nmyosis have been reported [ 17]. Interestingly, 2 of the 4\npatients had systemic embolism, and another patient had\nthrombi in the brachiocephalic trunk and left subclavian\nartery. The levels of coagulation markers were reported to\nbe elevated in the acute phase. The authors speculated\nthat patients with adenomyosis might be potentially at risk\nof developing infarcts associated with hypercoagulability\nrelated to menstruation-related coagulopathy or increased\ntissue factors. Moreover, a case of uterine infarction inside\nuterine adenomyosis following biochemical pregnancy\nwas reported [ 18]. Necrotic myometrium due to focal\nuterine infarction was suspected based on pelvic magnetic\nresonance imaging.\nIn the present case, nafamostat mesilate was adminis-\ntered because the coagulation function was still acti-\nvated, and nafamostat mesilate has effects against both\nexcessive coagulation and fibrinolysis to prevent the de-\nvelopment of infarcts [ 19, 20]. Administration of hepa-\nrins alone to fibrinolytic DIC (DIC with a strong\nfibrinolytic activation) rather promotes bleeding [ 21–23].\nBoth gabexate mesilate (FOY) and nafamostat mesylate\nare synthetic serine protease inhibitors and exhibit\nantithrombin-independent anticoagulant activity [ 22–\n26]. However, FOY does not have strong effect to inhibit\nfibrinolytic activity. Nafamostat mesylate is characterized\nby a strong effect of inhibiting not only the activation of\ncoagulation but also the activation of fibrinolysis [ 24–\n26]. For this reason, it is an extremely effective thera-\npeutic agent for fibrinolytic DIC. To treat excessive fi-\nbrinolysis, we could choose to administer a drug with\nonly antifibrinolytic action, such as tranexamic acid.\nHowever, we thought that it might increase the risk of\ndeveloping infarcts. Nafamostat mesilate can be expected\nto suppress new redundant production of microthrombi\ninside adenomyotic tissue. In our view, a drug affecting\nboth coagulation and fibrinolysis should be considered\nwhen massive bleeding occurs in patients with huge ade-\nnomyosis. Moreover, nafamostat mesylate has a short\nhalf-life of 5 –8 min and we can quickly switch treatment\nstrategy to surgery if it is judged to be ineffective [ 21,\n27].\nShe was very grateful that she saved her uterus as she\nwas unmarried and desired to get a child in future.\nTo the best of our knowledge, this is the first report of\nsuccessful conservative treatment of acute non septic\nDIC after termination of early pregnancy in a woman\nwith adenomyosis. The clinical course strongly suggested\nthat bleeding inside the adenomyotic tissue promoted\nexcessive coagulation and fibrinolysis, which was then\nrelated to the development of DIC. Although severe\nhyperfibrinolysis is observed in peripheral blood, the fi-\nbrinolysis state in the myometrium is considered to be\neven worse. The newly formed clot for hemostasis under\nthe uterine mucosa could be removed due to the excess\nfibrinolytic system in the adjacent myometrium and\ncould cause massive bleeding. This case serves as a\nwarning that adenomyosis might induce DIC with exces-\nsive fibrinolysis after termination of pregnancy as a trig-\nger and the usefulness of nafamostat mesilate to treat it\nKimura et al. BMC Women's Health           (2020) 20:56 Page 5 of 6\n\nin patients with huge adenomyosis who want to preserve\ntheir uterus. Before considering hysterectomy to control\nrefractory uterine bleeding, nafamostat mesilate should\nbe considered as one option, thinking the pathophysi-\nology of the massive bleeding due to uterine adenomyo-\nsis. Conservative treatment can be considered in the\ncase of “women who wants to conserve her fertility ”.\nAbbreviations\nAT3: Anti thrombin 3; CMZ: Cefmetazole; CRP: C-reactive protein;\nDIC: Disseminated intravascular coagulation; FOY: Gabexate mesylate;\nHb: Hemoglobin; PAI-1: Plasminogen activator inhibitor-1; PIC: Plasmin α2-\nplasmin inhibitor complex; TAT: Thrombin antithrombinIIIcomplex; tPA: serine\nprotease tissue plasminogen activator; WBC: White blood cell\nAcknowledgements\nNothing to disclose.\nAuthors’ contributions\nConception and design: FK; acquisition of data: FK, JK, FY, DK, TA; the analysis\nof data: FK, JK, FY, DK, TA, interpretation of data: FK, AT; drafting the\nmanuscript: FK; substantively revised it: TA; final approval of the version: TM.\nAll authors read and approved the final manuscript.\nFunding\nNo funding was obtained for this study.\nAvailability of data and materials\nWe can provide the raw data. The datasets used and/or analysed during the\ncurrent study available from the corresponding author on reasonable\nrequest.\nEthics approval and consent to participate\nOur institute allows us to report a case report in journals if the patient\nagrees to it.\nConsent for publication\nWe obtained informed written consent to report the clinical information\nfrom the patient. Informed written consent was obtained for publication.\nCompeting interests\nThe authors declare that they have no competing interests.\nReceived: 4 October 2019 Accepted: 10 March 2020\nReferences\n1. Feinstein DI. Disseminated intravascular coagulation in patients with solid\ntumors. Oncology. 2015;29:96 –102.\n2. Levi M. Management of cancer-associated disseminated intravascular\ncoagulation. Thromb Res. 2016;140(Suppl 1):S66 –70.\n3. Franchini M, Di Minno MN, Coppola A. Disseminated intravascular\ncoagulation in hematologic malignancies. Semin Thromb Hemost. 2010;36:\n388–403.\n4. Cunningham FG, Nelson DB. Disseminated intravascular coagulation\nsyndromes in obstetrics. Obstet Gynecol. 2015;126:999 –1011. https://doi.org/\n10.1097/AOG.0000000000001110.\n5. Erez O, Mastrolia SA, Thachil J. Disseminated intravascular coagulation in\npregnancy: insights in pathophysiology, diagnosis and management. Am J\nObstet Gynecol. 2015;213:452 –63. https://doi.org/10.1016/j.ajog.2015.03.054.\n6. Antovic J, Bakic M, Milicevic R, Gojkovic G, Blombäck M. Activation of the\ncoagulation system occurs within rather than outside cutaneous\nhaemangiomas. Acta Paediatr. 2001;90:1137 –40.\n7. Nakamura Y, Kawamura N, Ishiko O, Ogita S. Acute disseminated\nintravascular coagulation developed during menstruation in an\nadenomyosis patient. Arch Gynecol Obstet. 2002;267:110 –2.\n8. Zhang J, Xiao X, Luo F, Shi G, He Y, Yao Y, Xu L. Acute disseminated\nintravascular coagulation developed after dilation and curettage in an\nadenomyosis patient: a case report. Blood Coagul Fibrinolysis. 2013;24:771 –\n3. https://doi.org/10.1097/MBC.0b013e3283641917.\n9. García-Solares J, Donnez J, Donnez O, Dolmans MM. Pathogenesis of\nuterine adenomyosis: invagination or metaplasia? Fertil Steril. 2018;109:371 –\n9. https://doi.org/10.1016/j.fertnstert.2017.12.030.\n10. Pontis A, D ’Alterio MN, Pirarba S, de Angelis C, Tinelli R, Angioni S.\nAdenomyosis: a systematic review of medical treatment. Gynecol\nEndocrinol. 2016;32:696–700.\n11. Struble J, Reid S, Bedaiwy MA. Adenomyosis: a clinical review of a\nchallenging gynecologic condition. J Minim Invasive Gynecol. 2016;23:164 –\n85. https://doi.org/10.1016/j.jmig.2015.09.018.\n12. Devlieger R, D'Hooghe T, Timmerman D. Uterine adenomyosis in the\ninfertility clinic. Hum Reprod Update. 2003;9:139 –47.\n13. Krychtiuk KA, Kastl SP, Speidl WS, Wojta J. Inflammation and coagulation in\natherosclerosis. Hamostaseologie. 2013;33:269 –82.\n14. Simmons J, Pittet JF. The coagulopathy of acute sepsis. Curr Opin\nAnaesthesiol. 2015;28:227 –36.\n15. Reikerås O, Borgen P. Activation of markers of inflammation, coagulation\nand fibrinolysis in musculoskeletal trauma. PLoS One. 2014;9:e107881.\n16. Yamanaka A, Kimura F, Yoshida T, Kita N, Takahashi K, Kushima R, et al.\nDysfunctional coagulation and fibrinolysis systems due to adenomyosis is a\npossible cause of thrombosis and menorrhagia. Eur J Obstet Gynecol\nReprod Biol. 2016;204:99 –103. https://doi.org/10.1016/j.ejogrb.2016.07.499.\n17. Yamashiro K, Tanaka R, Nishioka K, Ueno Y, Shimura H, Okuma Y, et al.\nCerebral infarcts associated with adenomyosis among middle-aged women.\nJ Stroke Cerebrovasc Dis. 2012;21:910.e1 –5. https://doi.org/10.1016/j.\njstrokecerebrovasdis.2011.10.017.\n18. Lee JY, Hwang KR, Won KH, Lee DY, Jeon HW, Moon MH. Uterine infarction\nin a patient with uterine adenomyosis following biochemical pregnancy.\nClin Exp Reprod Med. 2014;41:174 –7. https://doi.org/10.5653/cerm.2014.41.4.\n174.\n19. Shimada M, Matsumata T, Shirabe K, Kamakura T, Taketomi A, Sugimachi K.\nEffect of nafamostat mesilate on coagulation and fibrinolysis in hepatic\nresection. J Am Coll Surg. 1994;178:498 –502.\n20. Sundaram S, Gikakis N, Hack CE, Niewiarowski S, Edmunds LH Jr, Koneti Rao\nA, et al. Nafamostat mesilate, a broad spectrum protease inhibitor,\nmodulates platelet, neutrophil and contact activation in simulated\nextracorporeal circulation. Thromb Haemost. 1996;75:76 –82.\n21. Choi JY, Kang YJ, Jang HM, Jung HY, Cho JH, Park SH, et al. Nafamostat\nMesilate as an Anticoagulant During Continuous Renal Replacement\nTherapy in Patients With High Bleeding Risk: A Randomized Clinical Trial.\nMedicine (Baltimore). 2015;94:e2392.\n22. Taneichi A, Fujiwara H, Mizoguchi Y, Machida S, Nonaka H, Takei Y, et al.\nDisseminated intravascular coagulopathy caused by uterine leiomyoma with\nsarcoma-like findings on magnetic resonance imaging. Case Rep Obstet\nGynecol. 2014;2014:978743.\n23. Mukaiyama H, Shionoya S, Ikezawa T, Kamiya T, Hamaguchi M, Saito H.\nAbdominal aortic aneurysm complicated with chronic disseminated\nintravascular coagulopathy: a case of surgical treatment. J Vasc Surg. 1987;6:\n600–4.\n24. Asakura H. Classifying types of disseminated intravascular coagulation:\nclinical and animal models. J Intensive Care. 2014;2:20.\n25. Fujii S, Hitomi Y. New synthetic inhibitors of C1r, C1 esterase, thrombin,\nplasmin, kallikrein and trypsin. Biochim Biophys Acta. 1981;661:342 –5.\n26. Aoyama T, Ino Y, Ozeki M, Oda M, Sato T, Koshiyama Y, et al.\nPharmacological studies of FUT-175, nafamstat mesilate. I. Inhibition of\nprotease activity in in vitro and in vivo experiments. Jpn J Pharmacol. 1984;\n35:203–27.\n27. Shimokawa Miyama T, Yoshioka C, Minami K, Okawa T, Hiraoka H, Itamoto K,\net al. Nafamostat mesilate is not appropriate as an anticoagulant during\ncontinuous renal replacement therapy in dogs. J Vet Med Sci. 2010;72:363 –\n7.\nPublisher’sN o t e\nSpringer Nature remains neutral with regard to jurisdictional claims in\npublished maps and institutional affiliations.\nKimura et al. BMC Women's Health           (2020) 20:56 Page 6 of 6","source_license":"CC0","license_restricted":false}