Hemorrhage Caused by Snake Venom Metalloproteinases: A Journey of Discovery and Understanding

Abstract

The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main site of action of SVMPs. After years of debate, biochemical developments demonstrated that all hemorrhagic toxins in viperid venoms are zinc-dependent metalloproteinases. Hemorrhagic SVMPs act by initially hydrolyzing key substrates at the basement membrane (BM) of capillaries. This degradation results in the weakening of the mechanical stability of the capillary wall, which becomes distended owing of the action of the hemodynamic biophysical forces operating in the circulation. As a consequence, the capillary wall is disrupted and extravasation occurs. SVMPs do not induce rapid toxicity to endothelial cells, and the pathological effects described in these cells in vivo result from the mechanical action of these hemodynamic forces. Experimental evidence suggests that degradation of type IV collagen, and perhaps also perlecan, is the key event in the onset of microvessel damage. It is necessary to study this phenomenon from a holistic, systemic perspective in which the action of other venom components is also taken into consideration.

A therapeutic combination of two small molecule toxin inhibitors provides pancontinental preclinical efficacy against viper snakebite

“…Treatments for systemic viper envenoming need to neutralize a number of major classes of hemotoxins, which are found in varying abundances across medically important snake species, and typically include the Zn 2+ -dependent snake venom metalloproteinases (SVMPs), phospholipase A 2 (PLA 2 s) and snake venom serine proteases (SVSPs) 17 . Collectively, these three enzymatic families typically comprise >60% of all toxins found in viper venom proteomes 5 and, in combination, are responsible for: (i) the destruction of local tissue, often resulting in necrosis, (ii) the degradation of the basement and cellular membranes resulting in extravasation, and (iii) the onset of coagulopathy via the activation and breakdown of clotting factors -with the latter two effects often culminating in life-threatening systemic hemorrhage [17][18][19][20] .…”

Evaluation of the geographical utility of Eastern Russell’s viper (Daboia siamensis) antivenom from Thailand and an assessment of its protective effects against venom-induced nephrotoxicity

“…Such protein neo-/sub-functionalization is thought to be underpinned by multiple gene duplication events coupled to accelerated bursts of adaptive evolution [12–14]. Consequently, snake venom PLA 2 s are responsible for several pharmacological activities including neurotoxicity, myotoxicity, anticoagulant effects, smooth muscle relaxation/hypotension and hypersensitivity [15], while SVMP functional activities include the activation of different coagulation factors and the degradation of endothelial cell membranes, resulting in venom-induced consumption coagulopathy and haemorrhage [16]. Other toxin families (e.g.…”

Biochemical and pharmacological characterization of Trimersurus malabaricus snake venom

“…Unexpectedly, hyaluronidase enzyme, termed as spreading factor in snake venom toxicity, was not detected in T. malabaricus venom even in very high concentrations (100 μg/mL) of hyaluronic acid as a substrate (Table 1). PLA 2 and protease activity, which are attributed for several local tissue damages like hemorrhage, edema, and myotoxicity [18][19][20][36][37][38][39] were detected in high amounts (Table 1). In order to understand the role of these hydrolytic enzymes in the induction of local tissue damage, several pharmacological studies such as hemorrhage; edema and myotoxicity were performed using animal models.…”

“…Most pathological events resulting from snakebite are due to protease components that are caused by hemorrhagic metalloproteinases and are capable of hydrolyzing casein and gelatin; the common substrates to measure the protease activity. 18,20 Caseinolytic and gelatinolytic zymogram activity a the distinct translucent bands indicating the presence of multiple enzymatic forms in both the substrates ( Figure 4A). In addition, most snake venom proteases affect coagulation by hydrolyzing the fibrinogen and inducing/prolonging clot formation.…”