Pathogenesis of hemorrhage induced by hemorrhagic proteinase IV from timber rattlesnake (Crotalus horridus horridus) venom.

The effects on the vascular system of a purified toxin, hemorrhagic proteinase IV, from Crotalus horridus horridus venom were studied with emphasis on the pathogenesis of hemorrhage. White mice were injected intramuscularly with sublethal doses of the hemorrhagic toxin, and tissue samples were obtained at 5 and 30 min, 3 and 24 hr after the injection. There was a good correlation between amount of toxin injected and amount of hemorrhage. Microscopically, extensive areas of hemorrhage around muscle and adipose cells were observed just 5 min after injection. At later time periods the changes were similar, but the hemorrhage was more extensive. Many vessels were plugged by aggregations of platelets. Electron microscopy showed that endothelial cells of capillaries were affected to various degrees. Some were swollen and had plasma membranes that formed large blebs; others were thin and disrupted. In vessels where the intercellular junctions could be observed, they were intact even when the endothelial cells were damaged or ruptured, indicating hemorrhage per rhexis instead of per diapedesis. Basal lamina were often disorganized or absent. Both intravascular and extravascular fibrin deposition were commonly observed. Hemorrhagic proteinase IV from C. h. horridus venom induces hemorrhage per rhexis and platelet aggregation within 5 min of intramuscular injection into mice, and marked fibrin deposition within 30 min of injection.