title: Hematological and morphological investigation of thrombogenic mechanisms in the lungs of phenylhydrazine-treated rats.
abstract: Abnormality in hematological condition including hemolytic disorders has been suggested one of the risk factor of pulmonary thrombosis. We previously reported that phenylhydrazine (PHZ) could induce acute thrombosis in the rat lung. In this study, time-related hematological and histopathological changes were evaluated in PHZ-treated rats to reveal the pathogenesis of pulmonary thrombosis in hemolytic condition. Male Sprague-Dawley rats were administered PHZ at 40 mg/kg/day daily for up to 4 days (n=6). At 24 h after the last administration (i.e. on days 1, 2, 3, or 4), animals were euthanized and samples were subjected to hematology, light microscopy, and electron microscopy. PHZ-treated rats developed severe anemia on day 1 or later. On day 2 and after, congestion in the alveolar septa corresponding to accumulation of deformed/ghost erythrocytes in the alveolar capillaries was observed, which was the earliest change that preceded thrombus formation. Focal fibrin deposition in the alveolar septa was noted on day 3 and it expanded widely by day 4, while endothelial injury were minimally noted just on day 4. These congestive/thrombotic changes were predominant in the pulmonary capillaries. Changes in hemostatic parameters were noted only on day 4; which were prolonged prothrombin time and activated partial thromboplastin time, greatly increased plasma thrombin-antithrombin complex levels with statistical significance, and slightly decreased fibrinogen levels. In conclusion, the trigger of acute pulmonary thrombosis in PHZ-treated rats was considered to be regional stasis resulting from blockage caused by the deformed erythrocytes, and subsequent systemic hemostatic disruption.
authors.affiliation: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1, Kazusakamatari, Kisarazu, Chiba 292-0818, Japan. sato.hiroko@mc.mt-pharma.co.jp
authors.forename: Hiroko
authors.initials: H
authors.lastname: Sato
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sakairi
authors.forename: Hisako
authors.initials: H
authors.lastname: Fujimura
authors.forename: Jiro
authors.initials: J
authors.lastname: Sugimoto
authors.forename: Eisuke
authors.initials: E
authors.lastname: Kume
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kitamura
authors.forename: Kimimasa
authors.initials: K
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D016877:Oxidants / Q000633:toxicity; D010659:Phenylhydrazines / Q000633:toxicity; D011655:Pulmonary Embolism / Q000139:chemically induced / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000139:chemically induced / Q000473:pathology*
chemical_list: D016877:Oxidants; D010659:Phenylhydrazines; C030299:phenylhydrazine