A CANINE MODEL FOR HEPATIC VENOOCCLUSIVE DISEASE

Hepatic venoocclusive disease is a frequent lethal complication of bone marrow transplantation. It has also been associated with hepatic irradiation and administration of chemotherapeutic agents without BMT. The pathogenesis and therapy of VOD are unclear. The present studies were directed at developing a canine model for VOD. Three groups of dogs were studied. Group one consisted of 8 dogs in which monocrotaline (MC) was administered at 125 mg/kg orally on an intermittent schedule. In 7 of the 8 dogs 6 to 9 doses of drug were administered between 42 and 110 days. Group 2 consisted of 6 dogs receiving busulfan 2 mg/kg/day for 172 5 days, when platelet counts decreased to < 5 x 10(4)/mm3 or clinical bleeding occurred. Group 3 consisted of 2 dogs receiving 24 Gy and 4 dogs receiving 36 Gy of whole-liver irradiation. Seven of 8 dogs in group 1 developed significant liver function abnormalities and evidence of portal hypertension. Histologic findings of VOD were present at autopsy. Group 2 dogs failed to develop clinical or laboratory liver abnormalities, but 3 of 6 animals had minimal histologic evidence of VOD. Three of 6 dogs in group 3 receiving 36 Gy developed hepatic dysfunction and had findings of fibrosis at autopsy. It was concluded that MC administration produced consistent clinical and histologic features of VOD in dogs. Changes occurring after busulfan or total-liver irradiation administration were less reproducible. Dogs are a suitable large-animal model for studies of VOD.