title: Carbon monoxide releasing molecule-2 inhibition of snake venom thrombin-like activity: novel biochemical "brake"?
abstract: A complication of defibrinogenation therapy with snake venom enzymes such as ancrod is hypofibrinogenemia associated bleeding secondary to no human-derived inhibitor being available to inactivate or diminish the activity of such enzymes. Of interest, ancrod contains a critical histidine residue without which enzymatic activity is inhibited, and carbon monoxide has been demonstrated to inhibit biomolecular function by interacting with histidine moieties in ion channels. We tested the hypothesis that exposure of three different snake venoms containing serine proteases with thrombin-like activity (which included ancrod) to carbon monoxide derived from carbon monoxide releasing molecule-2 would diminish their effects on plasmatic coagulation as assessed by thrombelastography. In the case of the Malayan pit viper and Eastern diamondback rattlesnake venoms, carbon monoxide diminished the effects of thrombin-like activity. In contrast, timber rattlesnake venom demonstrated enhancement of "thrombin-generating" activity with simultaneous loss of thrombin-like activity in response to carbon monoxide exposure. These findings may serve as the rational basis for not just continuing to investigate the potential of snake venom enzymes as clinical defibrinogenating agents, but to also to assess the potential to stop such agents from becoming a catalytic "runaway train" by judicious application of a biochemical "brake" such as carbon monoxide.
authors: Department of Anesthesiology, The University of Arizona College of Medicine, 1501 North Campbell Avenue, P.O. Box 245114, Tucson, AZ, 85724-5114, USA. vgnielsen333@gmail.com.
authors: Vance G
authors: VG
authors: Nielsen
authors: Department of Anesthesiology, The University of Arizona College of Medicine, 1501 North Campbell Avenue, P.O. Box 245114, Tucson, AZ, 85724-5114, USA.
authors: Charles M
authors: CM
authors: Bazzell
mesh_terms: D000721:Ancrod / Q000037:antagonists & inhibitors; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002248:Carbon Monoxide / Q000494:pharmacology* / Q000627:therapeutic use; D003435:Crotalid Venoms / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D057057:Serine Proteases; D015842:Serine Proteinase Inhibitors; D013916:Thrombelastography; D013917:Thrombin / Q000378:metabolism
chemical_list: D003435:Crotalid Venoms; D005343:Fibrinolytic Agents; D009942:Organometallic Compounds; D015842:Serine Proteinase Inhibitors; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D057057:Serine Proteases; D000721:Ancrod; D013917:Thrombin
keywords: Carbon monoxide; Fibrinogen depleting agent; Histidine; Snake venom serine protease; Thrombelastography