Extravasated platelet aggregation in the livers of rats with drug‑induced hepatic sinusoidal obstruction syndrome

Hirata,Miki; Tajima,Hidehiro; Miyashita,Tomoharu; Miyata,Takashi; Nakanuma,Shinichi; Makino,Isamu; Hayashi,Hironori; Oyama,Katsunobu; Takamura,Hiroyuki; Ninomiya,Itasu; Fushida,Sachio; Nakata,Hiroki; Iseki,Shoichi; Harada,Shinichi; Wakayama,Tomohiko; Ohta,Tetsuo

doi:10.3892/mmr.2017.6407

Extravasated platelet aggregation in the livers of rats with drug‑induced hepatic sinusoidal obstruction syndrome

Authors:
- Miki Hirata
- Hidehiro Tajima
- Tomoharu Miyashita
- Takashi Miyata
- Shinichi Nakanuma
- Isamu Makino
- Hironori Hayashi
- Katsunobu Oyama
- Hiroyuki Takamura
- Itasu Ninomiya
- Sachio Fushida
- Hiroki Nakata
- Shoichi Iseki
- Shinichi Harada
- Tomohiko Wakayama
- Tetsuo Ohta
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Affiliations: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan, Department of Histology and Embryology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan, Center of Biochemical Research, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan, Department of Histology, Faculty of Life Sciences, Kumamoto University, Kanazawa, Ishikawa 920‑8641, Japan
Published online on: March 28, 2017 https://doi.org/10.3892/mmr.2017.6407
Pages: 3147-3152

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Abstract

Oxaliplatin-based chemotherapy plays an important role in the treatment of colorectal liver metastases. Oxaliplatin, however, causes sinusoidal obstruction syndrome (SOS), which is characterized by portal hypertension, splenomegaly, thrombocytopenia, and liver dysfunction. SOS is diagnosed histopathologically by disruption of the sinusoidal endothelium, collagen deposition, fibrosis especially around zone 3, dilatation of the sinusoidal space and congestion. This study assessed the characteristics of a rat model of SOS. SOS was induced in rats by administration of monocrotaline (MCT). Blood chemistries and macroscopic and microscopic findings were compared in rats administered MCT and vehicle (control group). Levels of expression in the liver of CD41, P‑selectin, rat endothelial cell antigen‑1, CD34, and cleaved caspase‑3 were analyzed immunohistochemically. Moreover, livers of these rats were analyzed by electron microscopy. Macroscopically, MCT‑treated rats showed accumulation of bloody ascites and blue liver and were diagnosed with SOS histologically. Serum concentrations of aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.008), total‑bilirubin (P=0.012), direct‑bilirubin (P=0.007), indirect‑bilirubin (P=0.003), lactate dehydrogenase (P<0.001) and hyaluronic acid (P=0.016) were significantly higher, and platelet counts significantly lower (P=0.004), in MCT‑treated than in control rats. The livers of MCT‑treated rats were immunohistochemically positive for CD41 and P‑selectin, suggesting platelet aggregates; for rat endothelial cell antigen‑1 and CD34, suggesting sinusoidal endothelial disorder; and for cleaved caspase‑3, suggesting hepatocyte apoptosis. Electron microscopic findings revealed platelet aggregation in the space of Disse in the MCT group. Extravasated platelet aggregation in Disse's space may be involved in the development of SOS.

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1	Rubbia-Barandt L, Audard V, Sartoretti P, Roth AD, Brezault C, Le Charpentier M, Dousset B, Morel P, Soubrane O, Chaussade S, et al: Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 15:460–466. 2004. View Article : Google Scholar : PubMed/NCBI
2	Hubert C, Fevaille C, Sempoux C, Horsmans Y, Humblet Y, Machiels JP, Zech F, Ceratti A and Gigot JF: Prevalence and clinical relevance of pathological hepatic changes occurring after neoadjuvant chemotherapy for colorectal liver metastases. Surgery. 147:185–194. 2010. View Article : Google Scholar : PubMed/NCBI
3	Vauthey JN, Pawlik TM, Ribero D, Wu TT, Zorzi D, Hoff PM, Xiong HQ, Eng C, Lauwers GY, Mino-Kenudson M, et al: Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 24:2065–2072. 2006. View Article : Google Scholar : PubMed/NCBI
4	Tamandl D, Klinger M, Eipeldauer S, Herberger B, Kaczirek K, Gruenberger B and Gruenberger T: Sinusoid obstruction syndrome impairs long-term outcome of colorectal liver metastases treated with resection after neoadjuvant chemotherapy. Ann Surg Oncol. 18:421–430. 2011. View Article : Google Scholar : PubMed/NCBI
5	Robinson SM, Wilson CH, Burt AD, Manas DM and White SA: Chemotherapy associated liver injury in patients with colorectal liver metastases: A systemic review and meta-analysis. Ann Surg Oncol. 19:4287–4299. 2012. View Article : Google Scholar : PubMed/NCBI
6	Aloysius MM, Zaitoun AM, Beckingham IJ, Neal KR, Aithal GP, Bessell EM and Lobo DN: The pathological response to neoadjuvant chemotherapy with FOLFOX-4 for colorectal liver metastases: A comparative study. Virchows Arch. 451:943–948. 2007. View Article : Google Scholar : PubMed/NCBI
7	Nakano H, Oussoultzoqlou E, Rosso E, Casnedi S, Chenard-Neu MP, Dufour P, Bachellier P and Jaeck D: Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg. 247:118–124. 2008. View Article : Google Scholar : PubMed/NCBI
8	Jardim DL, Rodorigues CA, Novis YA, Rocha VG and Hoff PM: Oxaliplatin-related thrombocytopenia. Ann Oncol. 23:1937–1942. 2012. View Article : Google Scholar : PubMed/NCBI
9	Miura K, Nakano H, Sakurai J, Kobayashi S, Koizumi S, Arai T, Shimamura T, Makizumi R, Yamada K, Miyajima N, et al: Splenomegaly in FOLFOX-naïve stage IV or recurrent colorectal cancer patients due to chemotherapy- associated hepatotoxicity can be predicted by the aspartate aminotransferase to platelet ratio before chemotherapy. Int J Clin Oncol. 16:257–263. 2011. View Article : Google Scholar : PubMed/NCBI
10	Klieger PM, Tamandl D, Herberger B, Faybik P, Fleichmann E, Maresch J and Gruengerger T: Evaluation of chemotherapy-associated liver injury in patients with colorectal cancer liver metastases using indocyanine green clearance testing. Ann Surg Oncol. 18:1644–1650. 2011. View Article : Google Scholar : PubMed/NCBI
11	Sato S, Nakano H, Ishida Y and Otsubo T: The aspartate aminotransferase to platelet ratio before chemotherapy predicts adverse events for FOLFOX and XELOX regimens including bevacizumab as the first-line therapy for stage IV, recurrent and metastatic colorectal cancer. J Gastrointest Oncol. 4:203–209. 2013.PubMed/NCBI
12	Narita M, Oussoultzoglou E, Chenard MP, Fuchshuber P, Rather M, Rosso E, Addeo P, Jaeck D and Bachellier P: Liver injury due to chemotherapy-induced sinusoidal obstruction syndrome is associated with sinusoidal capillarization. Ann Surg Oncol. 19:2230–2237. 2012. View Article : Google Scholar : PubMed/NCBI
13	Morine Y, Shimada M and Utsunomiya T: Evaluation and management of hepatic injury induced by oxaliplatin-based chemotherapy in patients with hepatic resection for colorectal liver metastasis. Hepatol Res. 44:59–69. 2013. View Article : Google Scholar : PubMed/NCBI
14	Lalor PF, Herbert J, Bicknell R and Adams DH: Hepatic sinusoidal endothelium avidly binds platelets in an integrin-dependent manner, leading to platelet and endothelial activation and leucocyte recruitment. Am J Physiol Gastrointest Liver Physiol. 304:G469–G478. 2013. View Article : Google Scholar : PubMed/NCBI
15	Tajima H, Ohta T, Miyashita T, Nakanuma S, Matoba M, Miyata T, Sakai S, Okamoto K, Makino I, Kinoshita J, et al: Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver. Mol Clinic Oncol. 3:555–558. 2015.
16	Narita M, Hatano E, Ikai I, Miyagawa-Hayashino A, Yanagida A, Nagata H, Asechi H, Taura K and Uemoto S: A phosphodiesterase III inhibitor protects rat liver from sinusoidal obstruction syndrome through heme oxygenase-1 induction. Ann Surg. 249:806–813. 2009. View Article : Google Scholar : PubMed/NCBI
17	Prié S, Stewart DJ and Dupuis J: EndothelinA receptor blockade improves nitric oxide-mediated vasodilation in monocrotaline-induced pulmonary hypertension. Circulation. 97:2169–2174. 1998. View Article : Google Scholar : PubMed/NCBI
18	Nakamura K, Hatano E, Narita M, Miyagawa-Hayashino A, Koyama Y, Nagata H, Iwaisako K, Taura K and Uemoto S: Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9. Hepatology. 57:1037–1043. 2012. View Article : Google Scholar
19	DeLeve LD, McCuskey RS, Wang X, Hu L, McCuskey MK, Epstein RB and Kanel GC: Characterization of a reproducible rat model of hepatic veno-occlusive disease. Hepatology. 29:1779–1791. 1999. View Article : Google Scholar : PubMed/NCBI
20	Suzuki M, Bachelet-Violette L, Rouzet F, Beilvert A, Autret G, Maire M, Menager C, Louedec L, Choqueux C, Saboural P, et al: Ultrasmall superparamagnetic iron oxide nanoparticles coated with fucoidan for molecular MRI of intraluminal thrombus. Nanomedicine (Lond). 10:73–87. 2015. View Article : Google Scholar : PubMed/NCBI
21	Wisse E, De Zanger RB, Charels K, Van Der Smissen P and McCuskey RS: The liver sieve: Considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology. 5:683–692. 1985. View Article : Google Scholar : PubMed/NCBI
22	Fina L, Molgaard HV, Robertson D, Bradley NJ, Monaghan P, Delia D, Sutherland DR, Baker MA and Greaves MF: Expression of the CD34 gene in vascular endothelial cells. Blood. 75:2417–2426. 1990.PubMed/NCBI
23	Couvelard A, Scoazec JY, Dauge MC, Bringuier AF, Potet F and Feldmann G: Structural and functional differentiation of sinusoidal endothelial cells during liver organogenesis in humans. Blood. 87:4568–4580. 1996.PubMed/NCBI
24	Kuntz E and Kuntz HD: Textbook and Atlas: History, Morphology, Biochemistry, Diagnostics, Clinic, TherapyHepatology. 3rd. Springer Medizin Verlag; Heidelberg: 2008, View Article : Google Scholar
25	Wakayama T, Nakata H, Kurobo M, Sai Y and Iseki S: Expression, localization, and binding activity of the ezrin/radixin/moesin proteins in the mouse testis. J Histochem Cytochem. 57:351–362. 2009. View Article : Google Scholar : PubMed/NCBI
26	Jelliffe DB, Bras G and Stuart KL: Veno-occlusive disease of the liver. Pediatrics. 14:334–339. 1954.PubMed/NCBI
27	Campos-Varela I, Castells L, Dopazo C, Pérez-Lafuente M, Allende H, Len O, Llopart L, Vargas V and Charco R: Transjuglar intrahepatic portsystemic shunt for the treatment of sinusoidal obstruction syndrome in a liver transplant recipient and review of the literature. Liver Transpl. 18:201–205. 2012. View Article : Google Scholar : PubMed/NCBI
28	Yao L, Yao ZM and Yu T: Influence of BOL on hyaluronic acid, laminin and hyperplasia in hepatofibrotic rats. World J Gastroenterol. 7:872–875. 2001. View Article : Google Scholar : PubMed/NCBI
29	Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y and Zychlinsky A: Neutrophil extracellular traps kill bacteria. Science. 303:1532–1535. 2001. View Article : Google Scholar
30	Merza M, Hartman H, Rahman M, Hwaiz R, Zhang E, Renström E, Luo L, Mörgelin M, Regner S and Thorlacius H: Neutrophil extracellular traps induce trypsin activation, inflammation and tissue damage in mice with severe acute pancreatitis. Gastroenterology. 149:1920–1931, e8. 2015. View Article : Google Scholar : PubMed/NCBI
31	Sakai S, Tajima H, Miyashita T, Nakanuma S, Makino I, Hayashi H, Nakagawara H, Kitagawa H, Fushida S, Fujimura T, et al: Sivelestat sodium hydrate inhibits neutrophil migration to the vessel wall and suppresses hepatic ischemia reperfusion injury. Dig Dig Sci. 59:787–794. 2014. View Article : Google Scholar
32	Nakanuma S, Miyashita T, Hayashi H, Tajima H, Takamura H, Tsukada T, Okamoto K, Sakai S, Makino I, Kinoshita J, et al: Extravasated platelet aggregation in liver zone 3 may correlate with the progression of sinusoidal obstruction syndrome following living donor liver transplantation: A case report. Exp Therap Med. 9:1119–1124. 2015.
33	Takamura H, Nakanuma S, Hayashi H, Tajima H, Kakinoki K, Kitahara M, Sakai S, Makino I, Nakagawara H, Miyashita T, et al: Severe veno-occlusive disease/sinusoidal obstruction syndrome after deceased-donor and living-donor liver transplantation. Transplant Proc. 46:3523–3535. 2014. View Article : Google Scholar : PubMed/NCBI
34	Pai RK, van Besien K, Hart J, Artz AS and O'Donnell PH: Clinicopathologic features of late onset veno-occlusive disease/sinusoidal obstructive syndrome after high dose busulfan and hematopoietic cell transplantation. Leuk Lymphoma. 53:1552–1557. 2012. View Article : Google Scholar : PubMed/NCBI
35	Carreras E, Grañena A and Rozman C: Hepatic veno-occlusive disease after bone marrow transplant. Blood Rev. 7:43–51. 1993. View Article : Google Scholar : PubMed/NCBI
36	Battinelli EM, Markens BA and Italiano JE Jr: Release of angiogenesis regulatory proteins from platelet alpha granules: Modulation of physiologic and pathologic angiogenesis. Blood. 118:1359–1368. 2011. View Article : Google Scholar : PubMed/NCBI
37	Cui S, Shibamoto T, Liu W, Takano H and Kurata Y: Effects of platelet- activating factor, thromboxane A2 and leukotriene D4 on isolated perfused rat liver. Prostaglandins Other Lipid Mediat. 80:35–45. 2006. View Article : Google Scholar : PubMed/NCBI
38	Narmada BC, Chia SM, Tucker-Kellogg L and Yu H: HGF regulates the activation on TGF-β1 in rat hepatocytes and hepatic stellate cells. J Cell Physiol. 228:393–401. 2013. View Article : Google Scholar : PubMed/NCBI
39	Parenti A, Brogelli L, Filippi S, Donnini S and Ledda F: Effect of hypoxia and endothelial loss on vascular smooth muscle cell responsiveness to VEGF-A: Role of fit-1/VEGF-receptor-1. Cardiovasc Res. 55:201–212. 2002. View Article : Google Scholar : PubMed/NCBI
40	Oates JA, FitzGerald GA, Branch RA, Jackson EK, Knapp HR and Roberts LJ II: Clinical implications of prostaglandin and thromboxane A2 formation (1). N Eng J Med. 319:689–698. 1988. View Article : Google Scholar
41	Attal M, Huguet F, Rubie H, Huynh A, Charlet JP, Payen JL, Voigt JJ, Brousset P, Selves J and Muller C: Prevention of hepatic veno-occlusive disease after bone marrow transplantation by continuous infusion of low-dose heparin: A prospective, randomized trial. Blood. 79:2834–2840. 1992.PubMed/NCBI