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.