title: Extravasated platelet aggregation in the livers of rats with drug‑induced hepatic sinusoidal obstruction syndrome.
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.
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Tajima
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Miyashita
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakanuma
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Makino
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Oyama
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamura
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Itasu
authors.initials: I
authors.lastname: Ninomiya
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Fushida
authors.affiliation: Department of Histology and Embryology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nakata
authors.affiliation: Department of Histology and Embryology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Iseki
authors.affiliation: Center of Biochemical Research, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.affiliation: Department of Histology, Faculty of Life Sciences, Kumamoto University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Wakayama
authors.affiliation: Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D053148:Caspase 3 / Q000378:metabolism; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D016686:Monocrotaline / Q000633:toxicity*; D019007:P-Selectin / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018952:Antigens, CD34; D019007:P-Selectin; D040201:Platelet Membrane Glycoprotein IIb; D016686:Monocrotaline; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D053148:Caspase 3; D001663:Bilirubin