JWS Online

bungay3

bungay3

 Detail
 Download

Reactions

LB1

Factor II lipid binding

II_f + {100.0}LIPID > II_l

LB10

Factor IXa lipid binding

IXa_f + {100.0}LIPID > IXa_l

LB11

Factor X lipid binding

X_f + {100.0}LIPID > X_l

LB12

Factor Xa lipid binding

Xa_f + {100.0}LIPID > Xa_l

LB13

APC lipid binding

APC_f + {100.0}LIPID > APC_l

LB14

PS lipid binding

PS_f + {100.0}LIPID > PS_l

LB15

Factor VIIIai lipid binding

VIIIai_f + {100.0}LIPID > VIIIai_l

LB16

Factor Vai lipid binding

Vai_f + {100.0}LIPID > Vai_l

LB17

PC lipid binding

PC_f + {100.0}LIPID > PC_l

LB2

Factor mIIa lipid binding

mIIa_f + {100.0}LIPID > mIIa_l

LB3

Factor V lipid binding

V_f + {100.0}LIPID > V_l

LB4

Factor Va lipid binding

Va_f + {100.0}LIPID > Va_l

LB5

Factor VII lipid binding

VII_f + {100.0}LIPID > VII_l

LB6

Factor VIIa lipid binding

VIIa_f + {100.0}LIPID > VIIa_l

LB7

Factor VIII lipid binding

VIII_f + {100.0}LIPID > VIII_l

LB8

Factor VIIIa lipid binding

VIIIa_f + {100.0}LIPID > VIIIa_l

LB9

Factor IX lipid binding

IX_f + {100.0}LIPID > IX_l

R1

TF_VIIa binding

VIIa_l + TF_l > TF_VIIa_l

R10

Xa_VIII binding

Xa_l + VIII_l > VIII_Xa_l

R10b

Factor VIII activation

VIII_Xa_l > Xa_l + VIIIa_l

R11

IIa_f + V_l > V_IIa_l

R11b

V_IIa_l > IIa_f + Va_l

R12

IIa_f + VIII_l > VIII_IIa_l

R12b

VIII_IIa_l > IIa_f + VIIIa_l

R13

II_l + Xa_Va_l > Xa_Va_II_l

R14

mIIa_l + Xa_Va_l > Xa_Va_mIIa_l

R15

Xa_Va_II_l > Xa_Va_mIIa_l

R15b

Xa_Va_mIIa_l > IIa_f + Xa_Va_l

R16

Xa_l + VII_l > VII_Xa_l

R16b

VII_Xa_l > Xa_l + VIIa_l

R17

IIa_f + XI_f > XI_IIa_l

R17b

XI_IIa_l > IIa_f + XIa_l

R18

VIIIa_l + APC_PS_l > APC_PS_VIIIa_l

R18b

APC_PS_VIIIa_l > VIIIai_l + APC_PS_l

R19

Va_l + APC_PS_l > APC_PS_Va_l

R19b

APC_PS_Va_l > Vai_l + APC_PS_l

R2

TF_VII binding

VII_l + TF_l > TF_VII_l

R20

Xa_f + TFPI_f > TFPI_Xa_l

R21

TF_VIIa_l + TFPI_Xa_l > TFPI_Xa_TF_VIIa_l

R22

AT_f + IXa_f > IXa_AT_f

R23

AT_f + Xa_f > Xa_AT_f

R24

AT_f + IIa_f > IIa_AT_f

R25

mIIa_l + V_l > V_mIIa_l

R25b

V_mIIa_l > mIIa_l + Va_l

R26

mIIa_l + VIII_l > VIII_mIIa_l

R26b

VIII_mIIa_l > mIIa_l + VIIIa_l

R27

TM_l + IIa_f > IIa_TM_l

R28

PC_l + IIa_TM_l > IIa_TM_PC_l

R28b

IIa_TM_PC_l > APC_l + IIa_TM_l

R29

AT_f + mIIa_f > mIIa_AT_l

R3

IX_TF_VIIa binding

IX_l + TF_VIIa_l > TF_VIIa_IX_l

R30

PS_l + APC_l > APC_PS_l

R31

IX_l + XIa_l > XIa_IX_l

R31b

XIa_IX_l > IXa_l + XIa_l

R3b

Factor IX activation

TF_VIIa_IX_l > TF_VIIa_l + IXa_l

R4

X_TF_VIIa complex formation

X_l + TF_VIIa_l > TF_VIIa_X_l

R4b

Factor X activation

TF_VIIa_X_l > TF_VIIa_Xa_l

R4c

Factor Xa release

TF_VIIa_Xa_l > Xa_l + TF_VIIa_l

R5

Xa_TF_VII binding

Xa_l + TF_VII_l > TF_VII_Xa_l

R5b

TF_VII activation

TF_VII_Xa_l > Xa_l + TF_VIIa_l

R6

VIIIa_IXa binding

VIIIa_l + IXa_l > IXa_VIIIa_l

R7

Va_Xa binding

Va_l + Xa_l > Xa_Va_l

R8

X_IXa_VIIIa complex formation

X_l + IXa_VIIIa_l > IXa_VIIIa_X_l

R8b

Factor X activation

IXa_VIIIa_X_l > Xa_l + IXa_VIIIa_l

R9

V_Xa binding

Xa_l + V_l > V_Xa_l

R9b

Factor V activation

V_Xa_l > Xa_l + Va_l

Parameters

Global parameters

Fixed species

Initial values

Functions and Rules

Events

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


Species:

Reactions:

Middle-click: pin/unpin nodes
Shift-click: pool/unpool species
Right-click: context menu
Apply alternate model layout to overlapping elements in current model:

log scales

y-axis min/max

x-axis min/max

A mathematical model of lipid-mediated thrombin generation.

  • Sharene D Bungay
  • Patricia A Gentry
  • Rodney D Gentry
Math Med Biol 2003; 20 (1): 105-129
Abstract
Thrombin is an enzyme that is generated in both vascular and non-vascular systems. In blood coagulation, a fundamental process in all species, thrombin induces the formation of a fibrin clot. A dynamical model of thrombin generation in the presence of lipid surfaces is presented. This model also includes the self-regulating thrombin feedback reactions, the thrombomodulin-protein C-protein S inhibitory system, tissue factor pathway inhibitor (TFPI), and the inhibitor, antithrombin (AT). The dynamics of this complex system were found to be highly lipid dependent, as would be expected from experimental studies. Simulations of this model indicate that a threshold lipid level is required to generate physiologically relevant amounts of thrombin. The dependence of the onset, the peak levels, and the duration of thrombin generation on lipid was saturable. The lipid concentration affects the way in which the inhibitors modulate thrombin production. A novel feature of this model is the inclusion of the dynamical protein C pathway, initiated by thrombin feedback. This inhibitory system exerts its effects on the lipid surface, where its substrates are formed. The maximum impact of TFPI occurs at intermediate vesicle concentrations. Inhibition by AT is only indirectly affected by the lipid since AT irreversibly binds only to solution phase proteins. In a system with normal plasma concentrations of the proteins involved in thrombin formation, the combination of these three inhibitors is sufficient both to effectively stop thrombin generation prior to the exhaustion of its precursor, prothrombin, and to inhibit all thrombin formed. This model can be used to predict thrombin generation under extreme lipid conditions that are difficult to implement experimentally and to examine thrombin generation in non-vascular systems.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000334) Biomodels notes: Thrombin generation model. Factors are denoted by their numbers, with _l and _f suffixes depending on whether they are lipid-bound or fluid phase. Vesicle concentration is derived from LIPID (concentration of head groups) using the formula [vesicle] * 4*10nm^2*pi / 0.74nm^2 per head group. The model was integrated and simulated using Copasi 4.6.32 and plotted using Matplotlib to reproduce figure 4 of the article. JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. No additional changes were made.