This page has only limited features, please log in for full access.

Prof. Dr. Vance Nielsen
University of Arizona

Basic Info


Research Keywords & Expertise

0 Coagulation
0 Heavy Metals
0 Snake venom
0 Thrombelastography
0 Heme mediated regulation

Fingerprints

Coagulation
Thrombelastography
Snake venom

Honors and Awards

The user has no records in this section


Career Timeline

The user has no records in this section.


Short Biography

The user biography is not available.
Following
Followers
Co Authors
The list of users this user is following is empty.
Following: 0 users

Feed

Letter to the editor
Published: 08 May 2021 in Journal of Thrombosis and Thrombolysis
Reads 0
Downloads 0
ACS Style

Vance G. Nielsen. Ruthenium chloride inhibits the anticoagulant activity of the phospholipase A2-dependent neurotoxin of Mojave rattlesnake Type A venom. Journal of Thrombosis and Thrombolysis 2021, 1 -3.

AMA Style

Vance G. Nielsen. Ruthenium chloride inhibits the anticoagulant activity of the phospholipase A2-dependent neurotoxin of Mojave rattlesnake Type A venom. Journal of Thrombosis and Thrombolysis. 2021; ():1-3.

Chicago/Turabian Style

Vance G. Nielsen. 2021. "Ruthenium chloride inhibits the anticoagulant activity of the phospholipase A2-dependent neurotoxin of Mojave rattlesnake Type A venom." Journal of Thrombosis and Thrombolysis , no. : 1-3.

Journal article
Published: 28 April 2021 in International Journal of Molecular Sciences
Reads 0
Downloads 0

Procoagulant snake venoms have been inhibited by the ruthenium containing compounds CORM-2 and RuCl3 separately, presumably by interacting with critical histidine or other sulfur-containing amino acids on key venom enzymes. However, combinations of these and other platinoid containing compounds could potentially increase, decrease or not affect the procoagulant enzyme function of venom. Thus, the purpose of this investigation was to determine if formulations of platinoid compounds could inhibit venom procoagulant activity and if the formulated compounds interacted to enhance inhibition. Using a human plasma coagulation kinetic model to assess venom activity, six diverse venoms were exposed to various combinations and concentrations of CORM-2, CORM-3, RuCl3 and carboplatin (a platinum containing compound), with changes in venom activity determined with thrombelastography. The combinations of CORM-2 or CORM-3 with RuCl3 were found to enhance inhibition significantly, but not in all venoms nor to the same extent. In sharp contrast, carboplatin-antagonized CORM-2 mediated the inhibition of venom activity. These preliminary results support the concept that platinoid compounds may inhibit venom enzymatic activity at the same or different molecular sites and may antagonize inhibition at the same or different sites. Further investigation is warranted to determine if platinoid formulations may serve as potential antivenoms.

ACS Style

Vance Nielsen. Modulation of Diverse Procoagulant Venom Activities by Combinations of Platinoid Compounds. International Journal of Molecular Sciences 2021, 22, 4612 .

AMA Style

Vance Nielsen. Modulation of Diverse Procoagulant Venom Activities by Combinations of Platinoid Compounds. International Journal of Molecular Sciences. 2021; 22 (9):4612.

Chicago/Turabian Style

Vance Nielsen. 2021. "Modulation of Diverse Procoagulant Venom Activities by Combinations of Platinoid Compounds." International Journal of Molecular Sciences 22, no. 9: 4612.

Article
Published: 02 January 2021 in Journal of Thrombosis and Thrombolysis
Reads 0
Downloads 0

In recent years a variety of metals (cadmium, chromium, copper, iron) have been demonstrated to modulate coagulation in vitro and in vivo. One group of metals, the platinoids, have not been assessed, and such investigation is justified given the thromboembolic phenomena associated with platinum-based chemotherapy. Thus, the goal of the present investigation was to assess the effects of carboplatin, cisplatin (platinum compounds), NAMI-A, and ruthenium chloride (ruthenium compounds) on human plasmatic coagulation. Human plasma was exposed to clinically relevant, equimolar concentrations of the aforementioned platinum and ruthenium compounds, with changes in plasmatic coagulation assessed via thrombelastography. The first series of experiments demonstrated no significant modulation of coagulation by the platinum compounds, while NAMI-A demonstrated mild hypercoagulability and ruthenium chloride exerted marked hypercoagulability. A second series of experiments utilizing a variety of specialized modifications of thrombelastography focused on ruthenium chloride revealed that this compound enhances prothrombin activation. While the hypercoagulability associated with platinum compounds in vivo do not appear to have a basis in plasmatic biochemistry, it appears that ruthenium compounds can exert procoagulant properties by enhancing the common pathway of human plasmatic coagulation. Future investigation of Ru based chemotherapeutic agents in development to assess procoagulant activity as part of evaluating their potential clinical safety is warranted.

ACS Style

Vance G. Nielsen. Platinoid effects on human plasmatic coagulation kinetics: a viscoelastic analysis. Journal of Thrombosis and Thrombolysis 2021, 51, 577 -583.

AMA Style

Vance G. Nielsen. Platinoid effects on human plasmatic coagulation kinetics: a viscoelastic analysis. Journal of Thrombosis and Thrombolysis. 2021; 51 (3):577-583.

Chicago/Turabian Style

Vance G. Nielsen. 2021. "Platinoid effects on human plasmatic coagulation kinetics: a viscoelastic analysis." Journal of Thrombosis and Thrombolysis 51, no. 3: 577-583.

Journal article
Published: 23 April 2020 in International Journal of Molecular Sciences
Reads 0
Downloads 0

The demonstration that carbon monoxide releasing molecules (CORMs) affect experimental systems by the release of carbon monoxide, and not via the interaction of the inactivated CORM, has been an accepted paradigm for decades. However, it has recently been documented that a radical intermediate formed during carbon monoxide release from ruthenium (Ru)-based CORM (CORM-2) interacts with histidine and can inactivate bee phospholipase A2 activity. Using a thrombelastographic based paradigm to assess procoagulant activity in human plasma, this study tested the hypothesis that a Ru-based radical and not carbon monoxide was responsible for CORM-2 mediated inhibition of Atheris, Echis, and Pseudonaja species snake venoms. Assessment of the inhibitory effects of ruthenium chloride (RuCl3) on snake venom activity was also determined. CORM-2 mediated inhibition of the three venoms was found to be independent of carbon monoxide release, as the presence of histidine-rich albumin abrogated CORM-2 inhibition. Exposure to RuCl3 had little effect on Atheris venom activity, but Echis and Pseudonaja venom had procoagulant activity significantly reduced. In conclusion, a Ru-based radical and ion inhibited procoagulant snake venoms, not carbon monoxide. These data continue to add to our mechanistic understanding of how Ru-based molecules can modulate hemotoxic venoms, and these results can serve as a rationale to focus on perhaps other, complementary compounds containing Ru as antivenom agents in vitro and, ultimately, in vivo.

ACS Style

Vance G. Nielsen. Ruthenium, Not Carbon Monoxide, Inhibits the Procoagulant Activity of Atheris, Echis, and Pseudonaja Venoms. International Journal of Molecular Sciences 2020, 21, 2970 .

AMA Style

Vance G. Nielsen. Ruthenium, Not Carbon Monoxide, Inhibits the Procoagulant Activity of Atheris, Echis, and Pseudonaja Venoms. International Journal of Molecular Sciences. 2020; 21 (8):2970.

Chicago/Turabian Style

Vance G. Nielsen. 2020. "Ruthenium, Not Carbon Monoxide, Inhibits the Procoagulant Activity of Atheris, Echis, and Pseudonaja Venoms." International Journal of Molecular Sciences 21, no. 8: 2970.

Journal article
Published: 18 March 2020 in International Journal of Molecular Sciences
Reads 0
Downloads 0

Using thrombelastography to gain mechanistic insights, recent investigations have identified enzymes and compounds in Naja and Crotalus species’ neurotoxic venoms that are anticoagulant in nature. The neurotoxic venoms of the four extant species of Dendroaspis (the Black and green mambas) were noted to be anticoagulant in nature in human blood, but the mechanisms underlying these observations have never been explored. The venom proteomes of these venoms are unique, primarily composed of three finger toxins (3-FTx), Kunitz-type serine protease inhibitors (Kunitz-type SPI) and

ACS Style

Vance G. Nielsen; Michael T. Wagner; Nathaniel Frank. Mechanisms Responsible for the Anticoagulant Properties of Neurotoxic Dendroaspis Venoms: A Viscoelastic Analysis. International Journal of Molecular Sciences 2020, 21, 2082 .

AMA Style

Vance G. Nielsen, Michael T. Wagner, Nathaniel Frank. Mechanisms Responsible for the Anticoagulant Properties of Neurotoxic Dendroaspis Venoms: A Viscoelastic Analysis. International Journal of Molecular Sciences. 2020; 21 (6):2082.

Chicago/Turabian Style

Vance G. Nielsen; Michael T. Wagner; Nathaniel Frank. 2020. "Mechanisms Responsible for the Anticoagulant Properties of Neurotoxic Dendroaspis Venoms: A Viscoelastic Analysis." International Journal of Molecular Sciences 21, no. 6: 2082.

Article
Published: 02 November 2019 in Journal of Thrombosis and Thrombolysis
Reads 0
Downloads 0

Bee venom phospholipase A2 (PLA2) has potential for significant morbidity. Ruthenium (Ru)-based carbon monoxide releasing molecules (CORM) inhibit snake venoms that are anticoagulant and contain PLA2. In addition to modulating heme-bearing proteins with carbon monoxide, these CORM generate reactive Ru species that form adducts with histamine residues resulting in changes in protein function. This study sought to identify anticoagulant properties of bee venom PLA2 via catalysis of plasma phospholipids required for thrombin generation. Another goal was to determine if Ru-based CORM inhibit bee venom PLA2 via carbon monoxide release or via potential binding of reactive Ru species to a key histidine residue in the catalytic site of the enzyme. Anticoagulant activity of bee venom PLA2 was assessed via thrombelastography with normal plasma. Bee venom PLA2 was then exposed to different CORM and a metheme forming agent and anticoagulant activity was reassessed. Using Ru, boron and manganese-based CORM and a metheme forming agent, it was demonstrated that it was unlikely that carbon monoxide interaction with a heme group attached to PLA2 was responsible for inhibition of anticoagulant activity by Ru-based CORM. Exposure of PLA2 to a Ru-based CORM in the presence of histidine-rich human albumin resulted in loss of inhibition of PLA2. Ru-based CORM likely inhibit bee venom PLA2 anticoagulant activity via formation of reactive Ru species that bind to histidine residues of the enzyme.

ACS Style

Vance G. Nielsen. The anticoagulant effect of Apis mellifera phospholipase A2 is inhibited by CORM-2 via a carbon monoxide-independent mechanism. Journal of Thrombosis and Thrombolysis 2019, 49, 100 -107.

AMA Style

Vance G. Nielsen. The anticoagulant effect of Apis mellifera phospholipase A2 is inhibited by CORM-2 via a carbon monoxide-independent mechanism. Journal of Thrombosis and Thrombolysis. 2019; 49 (1):100-107.

Chicago/Turabian Style

Vance G. Nielsen. 2019. "The anticoagulant effect of Apis mellifera phospholipase A2 is inhibited by CORM-2 via a carbon monoxide-independent mechanism." Journal of Thrombosis and Thrombolysis 49, no. 1: 100-107.

Journal article
Published: 30 September 2019 in International Journal of Molecular Sciences
Reads 0
Downloads 0

Snake venom enzymes of the L-amino acid oxidase (LAAO) class are responsible for tissue hemorrhage, edema, and derangement of platelet function. However, what role, if any, these flavoenzymes play in altering plasmatic coagulation have not been well defined. Using coagulation kinetomic analyses (thrombelastograph-based), it was determined that the LAAO derived from Crotalus adamanteus venom displayed a procoagulant activity associated with weak clot strength (no factor XIII activation) similar to thrombin-like enzymes. The procoagulant activity was not modified in the presence of reduced glutathione, demonstrating that the procoagulant activity was likely due to deamination, and not hydrogen peroxide generation by the LAAO. Further, unlike the raw venom of the same species, the purified LAAO was not inhibited by carbon monoxide releasing molecule-2 (CORM-2). Lastly, exposure of the enzyme to phenylmethylsulfonyl fluoride (PMSF) resulted in the LAAO expressing anticoagulant activity, preventing contact activation generated thrombin from forming a clot. In sum, this investigation for the first time characterized the LAAO of a snake venom as both a fibrinogen polymerizing and an anticoagulant enzyme acting via oxidative deamination and not proteolysis as is the case with thrombin-like enzymes (e.g., serine proteases). Using this thrombelastographic approach, future investigation of purified enzymes can define their biochemical nature.

ACS Style

Vance G. Nielsen. Characterization of L-amino Acid Oxidase Derived from Crotalus adamanteus Venom: Procoagulant and Anticoagulant Activities. International Journal of Molecular Sciences 2019, 20, 4853 .

AMA Style

Vance G. Nielsen. Characterization of L-amino Acid Oxidase Derived from Crotalus adamanteus Venom: Procoagulant and Anticoagulant Activities. International Journal of Molecular Sciences. 2019; 20 (19):4853.

Chicago/Turabian Style

Vance G. Nielsen. 2019. "Characterization of L-amino Acid Oxidase Derived from Crotalus adamanteus Venom: Procoagulant and Anticoagulant Activities." International Journal of Molecular Sciences 20, no. 19: 4853.

Letter to the editor
Published: 17 July 2019 in Journal of Thrombosis and Thrombolysis
Reads 0
Downloads 0
ACS Style

Vance G. Nielsen. Lethal concentrations of mercury or lead do not affect coagulation kinetics in human plasma. Journal of Thrombosis and Thrombolysis 2019, 48, 697 -698.

AMA Style

Vance G. Nielsen. Lethal concentrations of mercury or lead do not affect coagulation kinetics in human plasma. Journal of Thrombosis and Thrombolysis. 2019; 48 (4):697-698.

Chicago/Turabian Style

Vance G. Nielsen. 2019. "Lethal concentrations of mercury or lead do not affect coagulation kinetics in human plasma." Journal of Thrombosis and Thrombolysis 48, no. 4: 697-698.

Article
Published: 23 May 2019 in Journal of Thrombosis and Thrombolysis
Reads 0
Downloads 0

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.

ACS Style

Vance G. Nielsen. Carbon monoxide inhibits the anticoagulant activity of Mojave rattlesnake venoms type A and B. Journal of Thrombosis and Thrombolysis 2019, 48, 256 -262.

AMA Style

Vance G. Nielsen. Carbon monoxide inhibits the anticoagulant activity of Mojave rattlesnake venoms type A and B. Journal of Thrombosis and Thrombolysis. 2019; 48 (2):256-262.

Chicago/Turabian Style

Vance G. Nielsen. 2019. "Carbon monoxide inhibits the anticoagulant activity of Mojave rattlesnake venoms type A and B." Journal of Thrombosis and Thrombolysis 48, no. 2: 256-262.

Article
Published: 06 April 2019 in Journal of Thrombosis and Thrombolysis
Reads 0
Downloads 0

Lizards in the genus Heloderma are the most ancient venomous reptiles, with a traceable lineage nearly 100 million years old. The proteome of the venom of three of the remaining species (Heloderma suspectum, H. exasperatum, H. horridum) are very conserved, with kallikrein-like activity present to cause critical hypotension to immobilize and outright kill prey. Kallikrein-like activity would be expected to activate the contact protein pathway of coagulation, which would be detectable with thrombelastography in human plasma. Thus, it was proposed to determine if kallikrein-like activity could be detected with thrombelastography, and if this activity could be inhibited by carbon monoxide (CO) via a putative heme-based mechanism. Procoagulant activity of each venom was assessed via thrombelastography with normal plasma, and kallikrein-like activity confirmed with FX-depleted plasma. Venom was then exposed to carbon monoxide releasing molecule-2 (CORM-2) or its inactive releasing molecule to assess CO inhibition. All three venoms demonstrated kallikrein-like activity with the same potency and inhibition of activity by CO. In conclusion, the present work documented that procoagulant, kallikrein-like activity containing venoms of the oldest species of venomous reptiles was inhibited by CO, potentially via heme modulation. This is also the first identification and characterization of a kallikrein-like enzyme utilizing coagulation factor-depleted plasma to assess venom that inflicts hypotension. Future investigations will continue to define the vulnerability of venom enzymatic activities to CO.

ACS Style

Vance G. Nielsen; Nathaniel Frank. The kallikrein-like activity of Heloderma venom is inhibited by carbon monoxide. Journal of Thrombosis and Thrombolysis 2019, 47, 533 -539.

AMA Style

Vance G. Nielsen, Nathaniel Frank. The kallikrein-like activity of Heloderma venom is inhibited by carbon monoxide. Journal of Thrombosis and Thrombolysis. 2019; 47 (4):533-539.

Chicago/Turabian Style

Vance G. Nielsen; Nathaniel Frank. 2019. "The kallikrein-like activity of Heloderma venom is inhibited by carbon monoxide." Journal of Thrombosis and Thrombolysis 47, no. 4: 533-539.

Review
Published: 06 February 2019 in Toxins
Reads 0
Downloads 0

Snakebite with hemotoxic venom continues to be a major source of morbidity and mortality worldwide. Our laboratory has characterized the coagulopathy that occurs in vitro in human plasma via specialized thrombelastographic methods to determine if venoms are predominantly anticoagulant or procoagulant in nature. Further, the exposure of venoms to carbon monoxide (CO) or O-phenylhydroxylamine (PHA) modulate putative heme groups attached to key enzymes has also provided mechanistic insight into the multiple different activities contained in one venom. The present investigation used these techniques to characterize fourteen different venoms obtained from snakes from North, Central, and South America. Further, we review and present previous thrombelastographic-based analyses of eighteen other species from the Americas. Venoms were found to be anticoagulant and procoagulant (thrombin-like activity, thrombin-generating activity). All prospectively assessed venom activities were determined to be heme-modulated except two, wherein both CO and its carrier molecule were found to inhibit activity, while PHA did not affect activity (Bothriechis schlegelii and Crotalus organus abyssus). When divided by continent, North and Central America contained venoms with mostly anticoagulant activities, several thrombin-like activities, with only two thrombin-generating activity containing venoms. In contrast, most venoms with thrombin-generating activity were located in South America, derived from Bothrops species. In conclusion, the kinetomic profiles of venoms obtained from thirty-two Pan-American Pit Viper species are presented. It is anticipated that this approach will be utilized to identify clinically relevant hemotoxic venom enzymatic activity and assess the efficacy of locally delivered CO or systemically administered antivenoms.

ACS Style

Vance G. Nielsen; Nathaniel Frank; Sam Afshar. De Novo Assessment and Review of Pan-American Pit Viper Anticoagulant and Procoagulant Venom Activities via Kinetomic Analyses. Toxins 2019, 11, 94 .

AMA Style

Vance G. Nielsen, Nathaniel Frank, Sam Afshar. De Novo Assessment and Review of Pan-American Pit Viper Anticoagulant and Procoagulant Venom Activities via Kinetomic Analyses. Toxins. 2019; 11 (2):94.

Chicago/Turabian Style

Vance G. Nielsen; Nathaniel Frank; Sam Afshar. 2019. "De Novo Assessment and Review of Pan-American Pit Viper Anticoagulant and Procoagulant Venom Activities via Kinetomic Analyses." Toxins 11, no. 2: 94.

Article
Published: 29 October 2018 in Journal of Thrombosis and Thrombolysis
Reads 0
Downloads 0

Snake venom contains a myriad of classes of enzyme which have been investigated for medicinal and toxinological purposes, including phospholipase A2 (PLA2), which is responsible for anticoagulant, myotoxic and neurotoxic effects. Given the importance of PLA2, the purposes of the present investigation were to characterize the coagulation kinetic behavior of a PLA2 purified from Crotalus adamanteus venom (Ca-PLA2) in human plasma with thrombelastography and determine if carbon monoxide could inhibit its activity. Coagulation kinetics were determined in human plasma with a range of Ca-PLA2 activity (0–2 U/ml) via thrombelastography. Then, using carbon monoxide releasing molecule-2 or its inactivated molecule (0 or 100 µM), the vulnerability of Ca-PLA2 activity to carbon monoxide mediated inhibition was assessed. Lastly, the inhibitory response of Ca-PLA2 activity to exposure to carbon monoxide releasing molecule-2 (0–100 µM) was determined. Ca-PLA2 activity degraded the velocity of clot growth and clot strength in an activity dependent, exponential manner. Carbon monoxide inhibited Ca-PLA2 activity in a concentration dependent fashion, with loss of detectable activity at 100 µM of carbon monoxide releasing molecule-2. These findings, while preliminary, open the possibility that other PLA2 contained in snake venom with multiple toxicities (e.g., myotoxin, neurotoxin) may be heme bearing and CO-inhibitable, which have profound potential basic and clinical science implications.

ACS Style

Vance G. Nielsen. Carbon monoxide inhibits the anticoagulant activity of phospholipase A2 purified from Crotalus adamanteus venom. Journal of Thrombosis and Thrombolysis 2018, 47, 73 -79.

AMA Style

Vance G. Nielsen. Carbon monoxide inhibits the anticoagulant activity of phospholipase A2 purified from Crotalus adamanteus venom. Journal of Thrombosis and Thrombolysis. 2018; 47 (1):73-79.

Chicago/Turabian Style

Vance G. Nielsen. 2018. "Carbon monoxide inhibits the anticoagulant activity of phospholipase A2 purified from Crotalus adamanteus venom." Journal of Thrombosis and Thrombolysis 47, no. 1: 73-79.

Article
Published: 21 August 2018 in BioMetals
Reads 0
Downloads 0

Envenomation by vipers with hemotoxic enzymes continues to be a worldwide source of morbidity and mortality. The present work examined the effects of exposure of venom enzymes to carbon monoxide and O-phenylhydroxylamine, agents that modulate the biometal heme, by forming carboxyheme and metheme, respectively. Four venoms obtained from medically important, diverse snake venom found in Africa, Asia and Australia were analyzed. The species that had venom tested in human plasma with thrombelastography and heme modulating agents were Deinagkistrodon acutus, Protobothrops mucrosquamatus, Dispholidus typus and Pseudonaja textilis. These venoms varied four hundred-fold in potency (ng-µg/ml) to exert procoagulant effects on human plasma; further, there was species specific variability in venom inhibition after exposure to carboxyheme or metheme agents. Lastly, using a wide range of carbon monoxide concentrations, it was determined that the factor V component of P. textilis venom was likely inhibited before the factor X component. Further investigation using this thrombelastograph-based, venom “kinetomic” methodology involving heme modulation will demonstrate in time its laboratory and clinical utility.

ACS Style

Vance G. Nielsen; Nathaniel Frank. Differential heme-mediated modulation of Deinagkistrodon, Dispholidus, Protobothrops and Pseudonaja hemotoxic venom activity in human plasma. BioMetals 2018, 31, 951 -959.

AMA Style

Vance G. Nielsen, Nathaniel Frank. Differential heme-mediated modulation of Deinagkistrodon, Dispholidus, Protobothrops and Pseudonaja hemotoxic venom activity in human plasma. BioMetals. 2018; 31 (6):951-959.

Chicago/Turabian Style

Vance G. Nielsen; Nathaniel Frank. 2018. "Differential heme-mediated modulation of Deinagkistrodon, Dispholidus, Protobothrops and Pseudonaja hemotoxic venom activity in human plasma." BioMetals 31, no. 6: 951-959.

Journal article
Published: 08 August 2018 in Toxins
Reads 0
Downloads 0

Geographic isolation and other factors result in evolution-driven diversity of the enzymatic composition of venom of pit vipers in the same genus. The present investigation sought to characterize venoms obtained from such genetically diverse Ovophis and Trimeresurus pit vipers utilizing thrombelastographic coagulation kinetic analyses. The coagulation kinetics of human plasma were assessed after exposure to venom obtained from two Ovophis and three Trimeresurus species. The potency of each venom was defined (µg/mL required to equivalently change coagulation); additionally, venoms were exposed to carbon monoxide (CO) or a metheme-inducing agent to modulate any enzyme-associated heme. All venoms had fibrinogenolytic activity, with four being CO-inhibitable. While Ovophis venoms had similar potency, one demonstrated the presence of a thrombin-like activity, whereas the other demonstrated a thrombin-generating activity. There was a 10-fold difference in potency and 10-fold different vulnerability to CO inhibition between the Trimeresurus species. Metheme formation enhanced fibrinogenolytic-like activity in both Ovophis species venoms, whereas the three Trimeresurus species venoms had fibrinogenolytic-like activity enhanced, inhibited, or not changed. This novel “venom kinetomic” approach has potential to identify clinically relevant enzymatic activity and assess efficacy of antivenoms between genetically and geographically diverse species.

ACS Style

Vance G. Nielsen; Nathaniel Frank; Ryan W. Matika. Effects of Heme Modulation on Ovophis and Trimeresurus Venom Activity in Human Plasma. Toxins 2018, 10, 322 .

AMA Style

Vance G. Nielsen, Nathaniel Frank, Ryan W. Matika. Effects of Heme Modulation on Ovophis and Trimeresurus Venom Activity in Human Plasma. Toxins. 2018; 10 (8):322.

Chicago/Turabian Style

Vance G. Nielsen; Nathaniel Frank; Ryan W. Matika. 2018. "Effects of Heme Modulation on Ovophis and Trimeresurus Venom Activity in Human Plasma." Toxins 10, no. 8: 322.

Comparative study
Published: 08 August 2018 in Human & Experimental Toxicology
Reads 0
Downloads 0

Venomous snake bite and subsequent coagulopathy is a significant source of morbidity and mortality worldwide. The gold standard to treat coagulopathy caused by these venoms is the administration of antivenom; however, despite this therapy, coagulopathy still occurs and recurs. Of interest, our laboratory has demonstrated in vitro and in vivo that coagulopathy-inducing venom exposed to carbon monoxide (CO) is inhibited, potentially by an attached heme. The present investigation sought to determine if venoms derived from snakes of the African genera Atheris, Atractaspis, Causus, Cerastes, Echis, and Macrovipera that have no or limited antivenoms available could be inhibited with CO or with the metheme-inducing agent, O-phenylhydroxylamine (PHA). Assessing changes in coagulation kinetics of human plasma with thrombelastography, venoms were exposed in isolation to CO or PHA. Eight species were found to have procoagulant activity consistent with the generation of human thrombin, while one was likely fibrinogenolytic. All venoms were significantly inhibited by CO/PHA with species-specific variation noted. These data demonstrate indirectly that the heme is likely bound to these disparate venoms as an intermediary modulatory molecule. In conclusion, future investigation is warranted to determine if heme could serve as a potential therapeutic target to be modulated during treatment of envenomation by hemotoxic enzymes.

ACS Style

V G Nielsen; N Frank. Role of heme modulation in inhibition of Atheris, Atractaspis, Causus, Cerastes, Echis, and Macrovipera hemotoxic venom activity. Human & Experimental Toxicology 2018, 38, 216 -226.

AMA Style

V G Nielsen, N Frank. Role of heme modulation in inhibition of Atheris, Atractaspis, Causus, Cerastes, Echis, and Macrovipera hemotoxic venom activity. Human & Experimental Toxicology. 2018; 38 (2):216-226.

Chicago/Turabian Style

V G Nielsen; N Frank. 2018. "Role of heme modulation in inhibition of Atheris, Atractaspis, Causus, Cerastes, Echis, and Macrovipera hemotoxic venom activity." Human & Experimental Toxicology 38, no. 2: 216-226.

Article
Published: 21 June 2018 in Journal of Thrombosis and Thrombolysis
Reads 0
Downloads 0

Copper poisoning is associated with severe multiorgan injury and potentially death if chelation therapy is not administered. Of interest, while important gastrointestinal and urinary tract hemorrhage is associated with copper poisoning, very little is known concerning the nature of copper induced coagulopathy. Using thrombelastography, we assessed changes in coagulation kinetics in human plasma following exposure to copper concentrations encountered during poisoning. While time to commence coagulation was not compromised, both velocity of thrombus growth and final strength were diminished. This result was duplicated with one concentration of copper in factor XIII deficient plasma. This pattern of coagulation kinetic response was interpreted as copper mediated fibrinogen dysfunction, perhaps via oxidation of key fibrinogen disulfide bridges. Lastly, experiments wherein glutathione was added implicated copper generated radical oxygen species as one of the mechanisms responsible for compromised coagulation kinetics. While chelation therapy is the key to survival following copper poisoning, perhaps this and future investigations of how copper affects coagulation may provide insight into effective supportive therapy for patients with active bleeding.

ACS Style

Vance G. Nielsen; Timothy D. Ward; Paul M. Ford. Effects of cupric chloride on coagulation in human plasma: role of fibrinogen. Journal of Thrombosis and Thrombolysis 2018, 46, 359 -364.

AMA Style

Vance G. Nielsen, Timothy D. Ward, Paul M. Ford. Effects of cupric chloride on coagulation in human plasma: role of fibrinogen. Journal of Thrombosis and Thrombolysis. 2018; 46 (3):359-364.

Chicago/Turabian Style

Vance G. Nielsen; Timothy D. Ward; Paul M. Ford. 2018. "Effects of cupric chloride on coagulation in human plasma: role of fibrinogen." Journal of Thrombosis and Thrombolysis 46, no. 3: 359-364.

Article
Published: 20 June 2018 in Journal of Thrombosis and Thrombolysis
Reads 0
Downloads 0

Aminocaproic acid (EACA) availability has recently been decreased whereas tranexamic acid (TXA) is still available as an antifibrinolytic agent to decrease blood loss associated with procedures involving cardiopulmonary bypass (CPB) by inhibiting plasmin mediated platelet activation. Given that the clinical inclination is to substitute TXA for EACA, we sought to compare the antifibrinolytic efficacy of the two agents using the clinically accepted molar ratio of EACA:TXA (7.9:1) that prevents platelet activation in a viscoelastic based system under a variety of conditions in human plasma; 25–50% therapeutic concentration (EACA 32.5–65 µg/ml, TXA 5–10 µg/ml) in the presence of 1500–3000 IU tissue-type plasminogen activator, with 0–50% dilution of plasma with buffer. In all equipotent concentrations, TXA provided superior antifibrinolytic action compared to EACA. It is hoped that this work will serve as a rationale to further investigate these and other similar agents, especially now in a time of unpredictable unavailability of key medications needed to optimize patient care. It is also our wish that these data assist perfusionists, anesthesiologists and cardiothoracic surgeons with their consideration of using an antifibrinolytic agent when managing complex patients with hypercoagulable states (e.g., ventricular assist device explant, infective endocarditis) undergoing CPB.

ACS Style

Vance G. Nielsen; Paul M. Ford. The ratio of concentrations of aminocaproic acid and tranexamic acid that prevent plasmin activation of platelets does not provide equivalent inhibition of plasmatic fibrinolysis. Journal of Thrombosis and Thrombolysis 2018, 46, 365 -370.

AMA Style

Vance G. Nielsen, Paul M. Ford. The ratio of concentrations of aminocaproic acid and tranexamic acid that prevent plasmin activation of platelets does not provide equivalent inhibition of plasmatic fibrinolysis. Journal of Thrombosis and Thrombolysis. 2018; 46 (3):365-370.

Chicago/Turabian Style

Vance G. Nielsen; Paul M. Ford. 2018. "The ratio of concentrations of aminocaproic acid and tranexamic acid that prevent plasmin activation of platelets does not provide equivalent inhibition of plasmatic fibrinolysis." Journal of Thrombosis and Thrombolysis 46, no. 3: 365-370.

Article
Published: 14 May 2018 in BioMetals
Reads 0
Downloads 0

It has been recently demonstrated that the hemotoxic venom activity of several species of snakes can be inhibited by carbon monoxide (CO) or a metheme forming agent. These and other data suggest that the biometal, heme, may be attached to venom enzymes and may be modulated by CO. A novel fibrinogenolytic metalloproteinase, named CatroxMP-II, was isolated and purified from the venom of a Crotalus atrox viper, and subjected to proteolysis and mass spectroscopy. An ion similar to the predicted singly charged m/z of heme at 617.18 was identified. Lastly, CORM-2 (tricarbonyldichlororuthenium (II) dimer, a CO releasing molecule) inhibited the fibrinogenolytic effects of CatroxMP-II on coagulation kinetics in human plasma. In conclusion, we present the first example of a snake venom metalloproteinase that is heme-bound and CO-inhibited.

ACS Style

Montamas Suntravat; Paul R. Langlais; Elda E. Sánchez; Vance G. Nielsen. CatroxMP-II: a heme-modulated fibrinogenolytic metalloproteinase isolated from Crotalus atrox venom. BioMetals 2018, 31, 585 -593.

AMA Style

Montamas Suntravat, Paul R. Langlais, Elda E. Sánchez, Vance G. Nielsen. CatroxMP-II: a heme-modulated fibrinogenolytic metalloproteinase isolated from Crotalus atrox venom. BioMetals. 2018; 31 (4):585-593.

Chicago/Turabian Style

Montamas Suntravat; Paul R. Langlais; Elda E. Sánchez; Vance G. Nielsen. 2018. "CatroxMP-II: a heme-modulated fibrinogenolytic metalloproteinase isolated from Crotalus atrox venom." BioMetals 31, no. 4: 585-593.

Article
Published: 23 November 2017 in BioMetals
Reads 0
Downloads 0

Envenomation by hemotoxic enzymes continues to be a major cause of morbidity and mortality throughout the world. With regard to treatment, the gold standard to abrogate coagulopathy caused by these venoms is still the administration of antivenom; however, despite antivenom therapy, coagulopathy still occurs and recurs. Of interest, this laboratory has demonstrated in vitro and in vivo that coagulopathy inducing venom derived from snakes of the family Viperidae exposed to carbon monoxide (CO) is inhibited, potentially by an attached heme. The present investigation sought to determine if venoms derived from snakes of the Elapidae family (taipans and cobras) could also be inhibited with CO or with the metheme inducing agent, O-phenylhydroxylamine (PHA). Assessing changes in coagulation kinetics of human plasma with thrombelastography, venoms from Elapidae snakes were exposed in isolation to CO (five species) or PHA (one specie) and placed in human plasma to assess changes in procoagulant or anticoagulant activity. The procoagulant activity of two taipan venoms and anticoagulant activity of three cobra venoms were significantly inhibited by CO. The venom of the inland taipan was also inhibited by PHA. In sum, these data demonstrate indirectly that the biometal heme is likely bound to these disparate venoms as an intermediary modulatory molecule. In conclusion, CO may not just be a potential therapeutic agent to treat envenomation but also may be a potential modulator of heme as a protective mechanism for venomous snakes against injury from their own proteolytic venoms.

ACS Style

Vance G. Nielsen; Nathaniel Frank; Ryan W. Matika. Carbon monoxide inhibits hemotoxic activity of Elapidae venoms: potential role of heme. BioMetals 2017, 31, 51 -59.

AMA Style

Vance G. Nielsen, Nathaniel Frank, Ryan W. Matika. Carbon monoxide inhibits hemotoxic activity of Elapidae venoms: potential role of heme. BioMetals. 2017; 31 (1):51-59.

Chicago/Turabian Style

Vance G. Nielsen; Nathaniel Frank; Ryan W. Matika. 2017. "Carbon monoxide inhibits hemotoxic activity of Elapidae venoms: potential role of heme." BioMetals 31, no. 1: 51-59.

Article
Published: 09 September 2017 in Journal of Thrombosis and Thrombolysis
Reads 0
Downloads 0

While snake venom derived enzymes, such as the thrombin-like activity possessing ancrod, have been used to treat thrombotic disease by defibrinogenating patients, the therapeutic potential of fibrinogenolytic snake venom enzymes, such as those derived from Crotalus atrox, have not been fully explored. However, one of the potential risks of administering fibrinogenolytic enzymes to effect defibrinogenation is hemorrhage secondary to hypofibrinogenemia. The present investigation sought to determine if human fibrinogen modified with carbon monoxide (CO) and iron (Fe) could resist degradation by C. atrox venom as has been seen in vitro in a recently developed rabbit model of envenomation. Compared with unmodified human fibrinogen, CO/Fe modified fibrinogen administered prior to envenomation had significantly shorter onset of coagulation and greater strength; however, when administered after envenomation, there was no differences between the two types of fibrinogen. Of interest, when administered after envenomation, both types of fibrinogen delayed the onset of coagulation while increasing plasma clot strength, a mixed effect likely secondary to formation of fibrinogen degradation products. Further preclinical investigations are needed to further define the benefits and risks of the use of fibrinogenolytic enzymes as defibrinogenating agents, as well as the risks of the “biochemical brakes” used to modulate the activity or substrate of the fibrinogenolytic enzyme.

ACS Style

Vance G. Nielsen. Effects of purified human fibrinogen modified with carbon monoxide and iron on coagulation in rabbits injected with Crotalus atrox venom. Journal of Thrombosis and Thrombolysis 2017, 44, 481 -488.

AMA Style

Vance G. Nielsen. Effects of purified human fibrinogen modified with carbon monoxide and iron on coagulation in rabbits injected with Crotalus atrox venom. Journal of Thrombosis and Thrombolysis. 2017; 44 (4):481-488.

Chicago/Turabian Style

Vance G. Nielsen. 2017. "Effects of purified human fibrinogen modified with carbon monoxide and iron on coagulation in rabbits injected with Crotalus atrox venom." Journal of Thrombosis and Thrombolysis 44, no. 4: 481-488.