An evaluation of procoagulant activity in the peripheral blood of rats treated with monocrotaline pyrrole.
Monocrotaline pyrrole (MCTP), a putative toxic metabolite of the naturally occurring pyrrolizidine alkaloid, monocrotaline, causes pulmonary vascular thrombi that are associated with vascular remodeling, pulmonary hypertension, and right cardioventricular hypertrophy in rats. The thrombi are composed of platelets and fibrin and occur in the absence of vascular necrosis. Since thrombosis may result from excessive procoagulant activity in the systemic circulation, we evaluated the hemostatic system of rats treated with MCTP to determine if a hypercoagulable state developed in the peripheral blood. Male Sprague-Dawley rats received a single, bolus injection of MCTP (3.5 mg/kg) or an equal volume of the N,N-dimethylformamide (DMF) vehicle in the tail vein. Rats were killed at 1, 3, 5, 8, 11, or 14 days after toxin administration, and several markers of lung injury and hemostasis were evaluated. The protein concentration of cell-free bronchoalveolar lavage fluid (BALF) from MCTP-treated rats was slightly elevated at 1 and 3 days. At 5 days the elevation had become more pronounced, and values increased markedly thereafter. The wet lung-to-body-weight ratio and lactate dehydrogenase activity of cell-free BALF from rats treated with MCTP were mildly increased at 3 days. Increases in these markers progressed at 5 days and values reached a plateau thereafter. MCTP-treated rats had moderately increased total nucleated cell counts in BALF at 5 days, and counts increased markedly thereafter. Right cardioventricular hypertrophy was first detected at 8 days in MCTP-treated rats and became more pronounced with time. The prothrombin time and modified prothrombin time of MCTP-treated rats were consistently greater than those of controls. Although statistically different, these values never exceeded the range of normal values. The activated partial thromboplastin time of MCTP and control rats was variable. Only at Day 14 did MCTP-treated rats have significantly longer activated partial thromboplastin times than those of controls, and these values were within the normal range. Rats treated with MCTP had statistically significant elevations in antithrombin 3 activity at Day 8 and of fibrinogen concentration and antithrombin 3 activity at Day 11 that exceeded the normal range. Platelet numbers of both MCTP- and DMF-treated rats were greater than normal on Day 1 but quickly returned to baseline. The plasminogen values of rats treated with MCTP were lower than controls on Day 5 only. These results suggest that the pulmonary vascular thrombi induced by administration of MCTP to rats are not mediated by an excess in procoagulant activity in the peripheral blood.
Schultze
A E
AE
Department of Pathology, Michigan State University, East Lansing 48824.
Wagner
J G
JG
Roth
R A
RA
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D006332:Cardiomegaly / Q000139:chemically induced*; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects*; D008297:Male; D016686:Monocrotaline / Q000031:analogs & derivatives*; D009929:Organ Size / Q000187:drug effects; D010314:Partial Thromboplastin Time; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D011763:Pyrrolizidine Alkaloids; C014114:monocrotaline pyrrole; D016686:Monocrotaline