Plasma protein C activity is enhanced by arsenic but inhibited by fluorescent humic acid associated with blackfoot disease.

Blackfoot disease is a peripheral vascular disease causally related to the fluorescent humic acid found in the drinking water of endemic areas in Taiwan. We compared the effects of humic acid (HA) purified from the well water of Blackfoot disease endemic areas with the effects of commercial humic acid (Aldrich) as well as trivalent arsenic (As2O3) on protein C activity, which plays an important role in regulation of blood coagulation and fibrinolysis. Humic acid, either purified from drinking water or obtained commercially, dose-dependently inhibited both activated protein C activity and the activation of protein C induced by Protac, a snake venom-derived protein C activator. In contrast to humic acid, arsenic oxide dose-dependently enhanced both activated protein C activity and the Protac-stimulated activation of protein C. In the presence of humic acid the enhancement effect of arsenic oxide was completely abolished, resulting in concentration-dependent inhibition of protein C activity. Therefore, the results of this study indicate that humic acid is a potent protein C inhibitor even in the presence of arsenic, which enhances the protein C activity. Since protein C is a potent anticoagulant and profibrinolytic agent, acquired defects of protein C induced by humic acid might cause a thrombophilic or hypercoagulable state. Whether this is one of the possible mechanisms of humic acid-induced thrombotic disorders in Blackfoot disease needs to be further characterized.