Nagashima2002 - Simulating blood coagulation inhibitory effects

  public model
Model Identifier
BIOMD0000000747
Short description
Mathematical model of blood coagulation and the effects of inhibitors of Xa, Va:Xa and IIa.
Format
SBML (L2V4)
Related Publication
  • 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 , PubMed ID: 12496240
  • New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., Tokyo 104-8369, Japan. nagasxop@daiichipharm.co.jp
  • 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.
Contributors
Submitter of the first revision: Matthew Roberts
Submitter of this revision: Krishna Kumar Tiwari
Modellers: Matthew Roberts, Krishna Kumar Tiwari

Metadata information

is (2 statements)
BioModels Database MODEL1807230003
BioModels Database BIOMD0000000747

isDescribedBy (1 statement)
PubMed 12496240

isVersionOf (1 statement)
Gene Ontology blood coagulation

hasProperty (2 statements)
Mathematical Modelling Ontology Ordinary differential equation model
Taxonomy Homo sapiens

Curation status
Curated
Modelling approach(es)
ordinary differential equation model
Tags

Connected external resources

Name Description Size Actions

Model files
Nagashima2002.xml SBML L2V4 representation of Nagashima2002 - Simulating blood coagulation inhibitory effects - normal system (without inhibitors on) 124.63 KB Preview | Download

Additional files
Nagashima2002.cps COPASI file for control condition (without inhibitor) 169.15 KB Preview | Download
Nagashima2002.sedml SEDML file for control condition 3.53 KB Preview | Download

  • Model originally submitted by : Matthew Roberts
  • Submitted: Jul 23, 2018 4:24:22 PM
  • Last Modified: Jul 10, 2019 5:11:01 PM
Revisions
  • Version: 6 public model Download this version
    • Submitted on: Jul 10, 2019 5:11:01 PM
    • Submitted by: Krishna Kumar Tiwari
    • With comment: Automatically added model identifier BIOMD0000000747
  • Version: 4 public model Download this version
    • Submitted on: Jul 10, 2019 1:11:33 PM
    • Submitted by: Krishna Kumar Tiwari
    • With comment: Automatically added model identifier BIOMD0000000747
  • Version: 2 public model Download this version
    • Submitted on: Jul 23, 2018 4:24:22 PM
    • Submitted by: Matthew Roberts
    • With comment: Edited model metadata online.

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
TF VIIa

Coagulation Factor VII Human ; Tissue Factor 		0.005 nmol
Xa

Coagulation Factor X Human 		0.0 nmol
Xa VIII

Coagulation Factor VIII ; Coagulation Factor X Human 		0.0 nmol
VIIIa IXa

Coagulation Factor IX Human ; Coagulation Factor VIII 		0.0 nmol
Va

Coagulation Factor V 		0.0 nmol
Va Xa

Coagulation Factor X Human ; Coagulation Factor V 		0.0 nmol
Va Xa Xa Inhibitor

Coagulation Factor X Human ; Coagulation Factor V ; EC 3.4.21.6 (coagulation factor Xa) inhibitor 		0.0 nmol
Reactions
Reactions Rate Parameters
TF_VIIa_IX => TF_VIIa + IXa compartment*k03*TF_VIIa_IX k03 = 0.47
Xa + VIII => Xa_VIII compartment*(k07*Xa*VIII-k08*Xa_VIII) k08 = 2.1; k07 = 0.1
Xa => Xa_inact compartment*k34*Xa k34 = 0.011
TF_VIIa + IX => TF_VIIa_IX compartment*(k01*TF_VIIa*IX-k02*TF_VIIa_IX) k02 = 2.2; k01 = 0.1
Xa_VIII => Xa + VIIIa compartment*k09*Xa_VIII k09 = 0.023
VIIIa + IXa => VIIIa_IXa compartment*(k13*VIIIa*IXa-k14*VIIIa_IXa) k14 = 0.17; k13 = 0.1
Va + Xa_Xa_Inhibitor => Va_Xa_Xa_Inhibitor compartment*(k38*Va*Xa_Xa_Inhibitor-k39*Va_Xa_Xa_Inhibitor) k38 = 0.1; k39 = 0.1
Va_Xa_II => Va_Xa + IIa compartment*k28*Va_Xa_II k28 = 35.0
Va_Xa + Xa_Inhibitor => Va_Xa_Xa_Inhibitor compartment*(k40*Va_Xa*Xa_Inhibitor-k41*Va_Xa_Xa_Inhibitor) k41 = 3.0; k40 = 0.1
Xa + Va => Va_Xa compartment*(k24*Xa*Va-k25*Va_Xa) k24 = 0.1; k25 = 0.1
Curator's comment:
(added: 10 Jul 2019, 13:11:15, updated: 10 Jul 2019, 13:11:15)
Model created and simulated using COPASI 4.24 (build 197). Inhibitor Xa and IIa need to be given different concentration (0,30,100,300,1000,3000) to reproduce the literature results. Data exported foster situation and plot generated using Microsoft excel. Submitted xml and cps file is of normal system without Inhibitors. One need to switch-on the inhibitors to test the impact.