2008 - Marseille - France

PAGE 2008: Applications
Stephen Duffull

A system model for the clotting cascade challenges clinical management of snake bites.

PP Tanos(1), SB Duffull(1,2), CMJ Kirkpatrick(1), DG Lalloo(3), GK Isbister (4)

(1) School of Pharmacy, University of Queensland, Brisbane, Australia. School of Pharmacy, University of Otago, Dunedin, New Zealand, (3) Liverpool School of Tropical Medicine, UK. (4) Menzies School of Health Research, Charles Darwin University, Darwin.

Introduction: A procoagulant toxin is found in taipan snake venom. This toxin activates the coagulation cascade and causes venom-induced consumptive coagulopathy (VICC). This condition is associated with an initial phase of unopposed consumption of clotting factors including fibrinogen, followed by a prolonged period of hypocoagulation. Snake bite antivenom is the main stay of treatment.

Objectives: 1. To develop a system model for the clotting cascade that is sufficiently detailed to fully describe the effects of VICC. 2. To use the model to describe the change in the turnover of the clotting factors in the coagulation cascade due to introduction of a procoagulant toxin. 3. To use the model to investigate the influence of snake-bite antivenom.

Methods: A review of the literature was performed to identify relevant articles describing the clotting cascade. The production, elimination and activation of each of the clotting factors/proteins were described by a set of turnover models. The model was built in MATLAB (ver 2006b). Deterministic simulations were undertaken to assess the performance of the model to describe the time course of change of 12 clotting factors/proteins for which data were available from a prior study of 74 patients [1]. This study was not included in the original model building. The model was then used to simulate the effects of antivenom in different clinical settings.

Results: A system model was developed based on literature findings and included 35 compartments. The model performed well in predicting the concentration of clotting factors over time following taipan envenomation. Simulations from the model revealed that the upper limit of the half-life of the toxin in the blood was approximately 1 hour although based on the data available it was estimated to be closer to 10-15 minutes. Simulations from the model also indicated that unless the antivenom is given almost immediately, it is unlikely to influence either the extent or recovery time of the coagulation profile.

Conclusions: The developed model described the available data well. The model predicts the use of antivenom, although accepted as the therapy of choice, may have a more limited role in the treatment of VICC caused by taipans than previously believed. Recent independent data on the half-life of the venom supports the models estimate.

[1] Lalloo et al. Blood Coagul Fibrinolysis 1995; 6: 65-72.

Reference: PAGE 17 (2008) Abstr 1272 [www.page-meeting.org/?abstract=1272]
Oral Presentation: Applications