Toxins in thrombosis and haemostasis: potential beyond imagination

Abstract

Summary. Exogenous factors isolated from venoms of snakes and saliva of haematophagous animals that affect thrombosis and haemostasis have contributed significantly to the development of diagnostic agents, research tools and life-saving drugs. Here, I discuss recent advances in the discovery, structural and functional characterisation, and mechanism of action of new procoagulant and anti-haemostatic proteins. In nature, these factors have evolved to target crucial ÔbottlenecksÕ in the coagulation cascade and platelet aggregation. Several simple protein scaffolds are used to target a wide variety of target proteins and receptors exhibiting functional divergence. Different protein scaffolds have also evolved to target identical, physiologically relevant key enzymes or receptors exhibiting functional convergence. At times, exogenous factors bind to the same target protein, but at distinct sites, to differentially attenuate their functions exhibiting mechanistic divergence within the same family of proteins. The structure-function relationships of these factors are subtle and complicated but represent an exciting challenge. These studies provide ample opportunities to design highly specific and precise ligands to achieve desired biological target function. Although only a small number of them have been characterised to date, the molecular and mechanical diversities of these exogenous factors and their contributions to understanding molecular and cellular events in thrombosis and haemostasis as well as developing diagnostic and research tools and therapeutic agents, is outstanding. Based on the current status, I have attempted to identify future potential and prospects in this area of research.

A Review of Thrombosis and Antithrombotic Therapy in Microvascular Surgery

“…Antithrombotic agents in development include, rivaroxaban [59], glycoprotein II/III antagonists [60], different snake venoms [61], clopidogrel [62] and recombinant tissue factor pathway inhibitors [33]. …”

Expression of a new serine protease from Crotalus durissus collilineatus venom in Pichia pastoris and functional comparison with the native enzyme

“…The mechanism by which thrombin-like enzymes induce blood clotting is closely related to the ability of these enzymes to cleave Aα and Bβ chains of fibrinogen, leading to the formation of insoluble fibrin monomers (Lu et al 2005;Serrano and Maroun 2005;Kini 2011 Fig. 7 Catalytic activity of native and recombinant collinein-1 upon chromogenic substrates The substrate hydrolysis was determined spectrophotometrically at 405 nm after 40 min of reaction at 37°C.…”

Toxin synergism in snake venoms

“…These two toxins combine to form a hemextin AB complex, which inhibits the TF.VIIa complex formed between freshly exposed tissue factor and factor VIIa, thereby synergistically abrogating the formation of blood clots (Banerjee et al, 2005, Kini, 2006, Kini, 2011) (conceptually similar to Figure 2D). Opposite procoagulant effects are observed for the prothrombin activator, Pseutarin C, from P.…”