Factor X activating Atractaspis snake venoms and the relative coagulotoxicity neutralising efficacy of African antivenoms

Abstract

Atractaspis snake species are enigmatic in their natural history, and venom effects are correspondingly poorly described. Clinical reports are scarce but bites have been described as causing severe hypertension, profound local tissue damage leading to amputation, and deaths are on record. Clinical descriptions have largely concentrated upon tissue effects, and research efforts have focused upon the blood-pressure affecting sarafotoxins. However, coagulation disturbances suggestive of procoagulant functions have been reported in some clinical cases, yet this aspect has been uninvestigated. We used a suite of assays to investigate the coagulotoxic effects of venoms from six different Atractaspis specimens from central Africa. The procoagulant function of factor X activation was revealed, as was the pseudo-procoagulant function of direct cleavage of fibrinogen into weak clots. The relative neutralization efficacy of South African Antivenom Producer's antivenoms on Atractaspis venoms was boomslang>>>polyvalent>saw-scaled viper. While the boomslang antivenom was the most effective on Atractaspis venoms, the ability to neutralize the most potent Atractaspis species in this study was up to 4-6 times less effective than boomslang antivenom neutralizes boomslang venom. Therefore, while these results suggest cross-reactivity of boomslang antivenom with the unexpectedly potent coagulotoxic effects of Atractaspis venoms, a considerable amount of this rare antivenom may be needed. This report thus reveals potent venom actions upon blood coagulation that may lead to severe clinical effects with limited management strategies.

Comparison of Methods for Measuring Protein Concentration in Venom Samples

“…However, in complex, unknown mixtures, it is hard to correctly estimate this parameter, and thus the calculated values can be very different from the true ones. Nevertheless, this method is commonly used in snake venom studies [46][47][48].…”

Novelty in three-finger toxin evolution

“…The other well-studied nonfront-fanged snake venom is that of Dispholidus typus, the dangerously toxic boomslang, which is primarily composed of P-III snake venom metalloproteinases and so contributes relatively few sequences to our data [21,118]. Among the front-fanged snakes, the stereotypical toxins for each lineage are something besides ten-cysteine 3FTx: viperid venoms are primarily enzymatic [119], [120], and atractaspidine venoms by blood-pressure-affecting serotoxin peptides and procoagulant enzymes [121][122][123]. Together, these factors make it so that there are far more ten-cysteine 3FTx known from Boiga than any other snake lineage.…”

A blood bond: evolutionary, pathophysiological and biodiscovery implications of coagulotoxic snake venoms

“…Procoagulation and the varying effects of anticoagulation are the major focal points of this thesis. Procoagulant toxins can be simplified into four groups: prothrombin activators (Bos and Camire, 2010;Joseph and Kini, 2002;Kini, 2005a;Kornalik and Blombäck, 1975;Pirkle et al, 1972;Rogalski et al, 2017;Rosing and Tans, 1992;Yamada et al, 1996), Factor X activators (Chen et al, 2008;Joseph and Kini, 2002;Oulion et al, 2018;Tans and Rosing, 2002;Yamada et al, 1997), Factor V activators (Bos and Camire, 2010;Bos et al, 2016;Rosing et al, 2001;Williams et al, 1994;Zdenek et al, 2019), and thrombin-like enzymes (Cho et al, 2001;Esnouf and Tunnah, 1967;Huang et al, 2011;Lin et al, 2009;Nielsen, 2016b;Teng, 1976, 1978;Pradniwat and Rojnuckarin, 2015;Tan, 2010;Tan et al, 2012;Zhang et al, 2007), while anticoagulants can affect any number of factors singularly or synergistically, such as blocking clotting enzymes while activating Protein C (Bakker et al, 1993;Esmon et al, 1987;Jin and Gopinath, 2016;Kisiel et al, 1987;Kogan et al, 1993;Nakagaki et al, 1990). These types of activators or inhibitors have been found and isolated from a number of varying families and species of venomous snakes.…”

“…Procoagulant species of venomous snakes are responsible for devastating effects upon the coagulation systems of envenomed patients. These venoms activate clotting factor zymogens (Factor X or prothrombin) to generate endogenous thrombin, resulting in the production of stable fibrin clots Oulion et al, 2018;Rogalski et al, 2017;Sousa et al, 2018;Zdenek et al, 2019).…”

“…including Hoplocephalus, Notechis, Oxyuranus, Paroplocephalus, Pseudonaja, and Tropidechis Oulion et al, 2018;Rogalski et al, 2017;Sousa et al, 2018;Zdenek et al, 2019).…”