Carbon monoxide inhibits the anticoagulant activity of Mojave rattlesnake venoms type A and B

The Mojave rattlesnake is a unique species of pit viper that expresses either a highly potent phospholipase A₂ (PLA₂)-dependent neurotoxin containing venom nearly devoid of fibrinogenolytic metalloproteinases (venom type A) or a hemotoxic venom with a high percentage of metalloproteinases and PLA₂ without any neurotoxin present (venom type B) depending on its geographical location in the Southwestern United States and Mexico. Given that PLA₂ have been demonstrated to affect coagulation, it was hypothesized that the anticoagulant effects of both type A and B venoms could be assessed by thrombelastography, and determination made if these venoms were heme modulated. Both venom types were exposed to carbon monoxide releasing molecule-2 or its inactivated molecule (0 or 100 µM) in isolation and then placed in human plasma with consequent coagulation kinetics assessed by thrombelastography. It was determined that type A venom was twice as potent as an anticoagulant compared to type B venom, and that both venoms were inhibited by carbon monoxide releasing molecule-2 but not its inactivated molecule. Given the lack of proteolytic activity of type A venom and the dependence of neurotoxicity on PLA₂ activity, it may be possible that carbon monoxide could inhibit neurotoxicity based on inhibition of PLA₂ anticoagulant activity. These data may serve as the rationale for extension of these observations into animal models to determine if CO may inhibit not just hemotoxic venom, but also PLA₂-dependent neurotoxic venom.