Crotalus atrox venom preconditioning increases plasma fibrinogen and reduces perioperative hemorrhage in a rat model of surgical brain injury

Abstract

Perioperative bleeding is a potentially devastating complication in neurosurgical patients, and plasma fibrinogen concentration has been identified as a potential modifiable risk factor for perioperative bleeding. The aim of this study was to evaluate preconditioning with Crotalus atrox venom (Cv-PC) as potential preventive therapy for reducing perioperative hemorrhage in the rodent model of surgical brain injury (SBI). C. atrox venom contains snake venom metalloproteinases that cleave fibrinogen into fibrin split products without inducing clotting. Separately, fibrinogen split products induce fibrinogen production, thereby elevating plasma fibrinogen levels. Thus, the hypothesis was that preconditioning with C. atrox venom will produce fibrinogen spilt products, thereby upregulating fibrinogen levels, ultimately improving perioperative hemostasis during SBI. We observed that Cv-PC SBI animals had significantly reduced intraoperative hemorrhage and postoperative hematoma volumes compared to those of vehicle preconditioned SBI animals. Cv-PC animals were also found to have higher levels of plasma fibrinogen at the time of surgery, with unchanged prothrombin time. Cv-PC studies with fractions of C. atrox venom suggest that snake venom metalloproteinases are largely responsible for the improved hemostasis by Cv-PC. Our findings indicate that Cv-PC increases plasma fibrinogen levels and may provide a promising therapy for reducing perioperative hemorrhage in elective surgeries.

Crotalus atrox disintegrin reduces hemorrhagic transformation by attenuating matrix metalloproteinase‐9 activity after middle cerebral artery occlusion in hyperglycemic male rats

“…Interestingly, some snake venoms contain both pro‐coagulant and anti‐coagulant proteins. We previously demonstrated that whole C. atrox venom reduces perioperative hemorrhage in a rat model of surgical brain injury (Kim et al, ). Therefore, we hypothesized that there would be a protein(s) which could be harnessed for therapeutic benefit to protect against hemorrhagic transformation.…”

“…Each analyzed fraction was reduced with dithiothreitol and alkylated with iodoacetamide (Kim et al, ). Proteins were digested with proteomics‐grade porcine pancreatic trypsin (Sigma–Aldrich) and then desalted (C18 ZipTips, EMD Millipore, Billerica, MA, USA).…”

Surgically-induced brain injury: where are we now?

“…Hemorrhage is a critical issue in neurosurgery and is implicated in contributing to SBI [9,44]. Firstly, intraoperative bleeding causes local ischemic insult and systemically plagues the cardiovascular system.…”

“…In the following sections, we expand on the concept of preconditioning and propose the use of venom-derived proteins as a preconditioning therapy for SBI. [35,44,45,67,68], it has often been noted that clinical translation is limited since many injuries occur spontaneously. In the last few decades, the potential of PC, especially for scheduled (or elective) surgeries, has become a real focus in hopes of developing an effective therapy.…”

“…Because of the complex nature of the venoms these investigators used, and also the presence of immunogenic proteins in these venoms, there is a need to study a PLA 2 -rich venom such as that of P. papuanus. Kim et al [44] further demonstrated that venom with hemorrhagic effects can mitigate intra-and post-operative brain hemorrhage. Because of the unique mixture of inflammatory and platelet-aggregating effects of P. papuanus venom, we view this venom as a prime therapy for SBI, which preliminary studies are bearing out.…”