Nagashima2002 - Simulating blood coagulation inhibitory effects
Mathematical model of blood coagulation and the effects of inhibitors of Xa, Va:Xa and IIa.
- Studies on the different modes of action of the anticoagulant protease inhibitors DX-9065a and Argatroban. I. Effects on thrombin generation.
- Nagashima H
- The Journal of biological chemistry , 12/ 2002 , Volume 277 , Issue 52 , pages: 50439-50444
- New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., Tokyo 104-8369, Japan. firstname.lastname@example.org
- The present study began with mathematical modeling of how inhibitors of both factor Xa (fXa) and thrombin affect extrinsic pathway-triggered blood coagulation. Numerical simulation demonstrated a stronger inhibition of thrombin generation by a thrombin inhibitor than a fXa inhibitor, but both prolonged clot time to a similar extent when they were given an equal dissociation constant (30 nm) for interaction with their respective target enzymes. These differences were then tested by comparison with the real inhibitors DX-9065a and argatroban, specific competitive inhibitors of fXa and thrombin, respectively, with similar K(i) values. Comparisons were made in extrinsically triggered human citrated plasma, for which endogenous thrombin potential and clot formation were simultaneously measured with a Wallac multilabel counter equipped with both fluorometric and photometric detectors and a fluorogenic reporter substrate. The results demonstrated stronger inhibition of endogenous thrombin potential by argatroban than by DX-9065a, especially when coagulation was initiated at higher tissue factor concentrations, while argatroban appeared to be slightly less potent in its ability to prolong clot time. This study demonstrates differential inhibition of thrombin generation by fXa and thrombin inhibitors and has implications for the pharmacological regulation of blood coagulation by the anticoagulant protease inhibitors.
|Nagashima2002.xml||SBML L2V4 representation of Nagashima2002 - Simulating blood coagulation inhibitory effects||58.52 KB||Preview | Download|
|Fig2_AC_1.jpg||Simulation result with k37 set to zero. Simulating Xa-inhibitor. Simulating both k37 and k41 set to zero results in no thrombin generation in 1000s.||29.08 KB||Preview | Download|
|Fig2.jpg||Simulation result with non-zero kinetic rates||28.54 KB||Preview | Download|
|Fig2_AC_2.jpg||Simulation result with k41 set to zero. Alternative simulation Xa-inhibitor. Simulating both k37 and k41 set to zero results in no thrombin generation in 1000s.||28.00 KB||Preview | Download|
|Nagashima2002.cps||Model COPASI file. Attempt at reproducing figure 2. Current model file encoded with non-zero kinetic parameters (k37, k41, k43). Attempt to reproduce figure 2 A,C by setting k37 and/or k41 to zero to simulate Xa-inhibitor as these parameters relate to Xa-Inhibitor complex dissociation rate. IIa-inhibitor simulated by setting parameter k43 to zero as this parameter encodes IIa-Inhibitor complex dissocation rate.||133.68 KB||Preview | Download|
|Fig2_BD.jpg||Simulation result with k43 set to zero. Simulating IIa-inhibitor.||28.26 KB||Preview | Download|