A comprehensive model for the coagulation network in humans
T. Wajima (1, 2), G.K. Isbister (3, 4), S.B. Duffull (1)
(1) School of Pharmacy, University of Otago, Dunedin, New Zealand, (2) Clinical Pharmacology & Pharmacokinetics, Shionogi & Co. Ltd., Japan, (3) Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle Hospital, Australia, (4) Menzies School of Health Research, Charles Darwin University, Australia
Introduction: Coagulation is an important process in haemostasis. Experimental tests of clotting are difficult to conduct and interpret, because (a) haemostasis is a complex series of interactions including positive feedforward, negative feedforward, positive feedback and negative feedback processes and (b) the reaction rates range are a wide time frame of seconds to days. A mathematical representation of the system therefore serves as a direct source from which cause-effect relationships can be assessed as well as providing quantitative information.
Objectives: To develop a mechanistic quantitative model for the comprehensive humoral coagulation network.
Methods: A full mathematical derivation of a multi-compartmental model for the coagulation network was developed based on individual mechanistic components described in the literature. The model consists of a series of 51 ordinary differential equations. The model includes components for describing the time-courses of coagulation factors by extrinsic and intrinsic pathway activation, as well as the in vitro coagulation tests of prothrombin time (PT, often reported as international normalized ratio [INR]) and activated partial thromboplastin time (aPTT). The model also includes the components related to vitamin K cycle and antithrombin-III:heparin complex for simulating the profiles for drug therapies of warfarin, heparins and vitamin K. The model was applied for simulation of INR (PT) and aPTT tests for the data from the literature [1] and for simulating time-courses of coagulation factors after envenomation by the taipan snake bite. [2]
Results: The model accurately describes the time courses of coagulation factors following in vivo activation (snake bite data) as well as of in vitro blood coagulation tests of PT and aPTT. The model predicts the concentration-time and time-effect profiles for warfarin, heparins and vitamin K in humans as well as the effects of various haemophilias.
Conclusions: The model developed in this study is the first comprehensive description of the in vivo coagulation network and the time course of changes in the clotting factors. The model was effective at describing the time courses of effects of anticoagulants (warfarin and heparins). The model would be useful for clinical situations and for drug development.
References:
[1] Pohl et al, Haemostasis. 1994. 24: 325-337
[2] Lalloo et al. Blood Coagul. Fibrinolysis. 1995. 6, 65-72
