Deep Vein Thrombosis (DVT) · Pulmonary Embolism (PE) — Comprehensive Quantitative Systems Pharmacology Model
Venous thromboembolism (VTE) — encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) — is the third most common cardiovascular disease after myocardial infarction and stroke, affecting 1-2 per 1,000 adults annually. PE carries a 30-day mortality of 1–3% (up to 30% for massive PE) and 2–4% of survivors develop chronic thromboembolic pulmonary hypertension (CTEPH).
This QSP model integrates:
- Virchow's Triad (stasis / endothelial injury / hypercoagulability)
- Full coagulation cascade (extrinsic + intrinsic + common pathways)
- Platelet activation (GPIb, GPVI, PAR1/4, GPIIb/IIIa)
- Natural anticoagulants (AT-III, Protein C/S, TFPI)
- Fibrinolysis (tPA/uPA-plasmin-D-dimer axis, PAI-1, TAFI)
- Multi-drug PK/PD: Rivaroxaban · Apixaban · Dabigatran · Warfarin · Enoxaparin
| File | Description |
|---|---|
vte_qsp_model.dot |
Graphviz mechanistic map (12 clusters, 140+ nodes) |
vte_qsp_model.svg |
SVG (interactive/vector) |
vte_qsp_model.png |
PNG 150 dpi |
vte_mrgsolve_model.R |
mrgsolve ODE model (19 compartments, 6 scenarios) |
vte_shiny_app.R |
Shiny dashboard (6 tabs) |
vte_references.md |
57 PubMed references |
The .dot file contains 12 subgraph clusters:
| # | Cluster | Key Nodes |
|---|---|---|
| ① | Virchow's Triad & Risk Factors | Stasis, Endothelial Injury, Hypercoagulability; FV Leiden, PT G20210A, APS, OCP |
| ② | Vascular Endothelium | TF expression, vWF release, PGI2/NO, TM, EPCR, tPA, PAI-1 |
| ③ | Extrinsic Pathway (TF) | TF exposed, FVII/FVIIa, TF-FVIIa tenase, TFPI inhibition |
| ④ | Intrinsic Pathway (Contact) | FXII → kallikrein → FXIa → FIXa, FVIII/FVIIIa, Intrinsic Tenase |
| ⑤ | Common Pathway / Thrombin | FXa, Prothrombinase, Thrombin (FIIa), Fibrinogen → Fibrin cross-linked |
| ⑥ | Platelet Activation | GPIb/GPVI, PAR1/4, ADP/P2Y12, TXA2, GPIIb/IIIa, PS exposure |
| ⑦ | Natural Anticoagulants | AT-III/Heparan sulfate, APC-Protein S, TFPI-FXa |
| ⑧ | Fibrinolysis | Plasminogen, tPA/uPA, Plasmin, PAI-1, α2-antiplasmin, TAFI, D-dimer |
| ⑨ | Drug PK | Rivaroxaban (2-cmt), Apixaban (1-cmt), Dabigatran, Warfarin, Enoxaparin, Alteplase |
| ⑩ | Drug PD | FXa inhibition (DOAC), DTI (Dabigatran), VKA (Warfarin VK cycle), Heparin-AT |
| ⑪ | Lab Monitoring | PT/INR, aPTT, Anti-Xa, TT/ECT, D-dimer, Thrombin generation |
| ⑫ | Clinical Endpoints | Proximal/Distal DVT, Low-risk PE, Submassive PE, Massive PE, CTEPH, PTS |
| Compartment | Drug | Key Parameters |
|---|---|---|
RIV_GUT, RIV_CENT, RIV_PERIPH |
Rivaroxaban | Ka=1.2/h, CL=4.8L/h, V1=33L, t½=5-9h |
APIX_CENT |
Apixaban | Ka=0.78/h, CL=3.3L/h, V1=23L, t½=12h |
DABI_CENT |
Dabigatran | Ka=0.35/h, F=6.5%, CL=8.5L/h (renal), t½=12-17h |
WARF_CENT |
Warfarin | Ka=0.9/h, CL=0.2L/h (CYP2C9), t½=36h |
ENOX_CENT |
Enoxaparin | Ka=0.23/h, CL=0.82L/h, F=92% SC |
| Compartment | Represents |
|---|---|
FXa_ACT |
Active Factor Xa (inhibited by DOAC/LMWH-AT) |
FIIa_ACT |
Active Thrombin (inhibited by dabigatran/FXa cascade) |
FIBRIN_FORM |
Fibrin formation/lysis balance |
CLOT_SIZE |
Thrombus burden (0-100%) |
PLASMIN_ACT |
Fibrinolytic plasmin activity |
DDIMER_CONC |
D-dimer (ng/mL) — fibrinolysis marker |
VK_OX, VK_RED |
Vitamin K cycle (Warfarin indirect PD) |
FVII_POOL, FX_POOL, FII_POOL |
VK-dependent factor pools (%, t½ 5-60h) |
- FXa Inhibitors: Hill Emax model; Rivaroxaban EC50=12 ng/mL; Apixaban EC50=5 ng/mL
- Dabigatran: Direct thrombin inhibition; EC50=35 ng/mL
- Warfarin: Indirect response via VK reduction → ↓ factor synthesis (γ-carboxylation)
- LMWH: ATIII activation → FXa inhibition; EC50=0.35 IU/mL Anti-Xa
- Dabigatran CL adjusted:
CL_eff = CL_DABI × (eGFR/90)^0.85 - Enoxaparin CL adjusted:
CL_eff = CL_ENOX × (eGFR/90)^0.65
| # | Scenario | Regimen | Clinical Setting |
|---|---|---|---|
| 1 | DVT: Rivaroxaban | 15 mg BID × 21d → 20 mg QD | Acute DVT (confirmed) |
| 2 | PE: Apixaban | 10 mg BID × 7d → 5 mg BID | Acute PE (stable) |
| 3 | Warfarin + Bridge | Warfarin 5 mg QD + Enoxaparin 1 mg/kg BID × 10d | Classic bridging therapy |
| 4 | Prophylaxis: Enoxaparin | 40 mg QD SC × 14d | Post-surgical VTE prevention |
| 5 | Extended: Rivaroxaban | 10 mg QD × 180d | Secondary VTE prevention |
| 6 | CKD: Dabigatran | 110 mg BID (GFR 30 vs. 90) | Renal impairment sensitivity |
| Tab | Content |
|---|---|
| ① Patient Profile | Demographics, Virchow's Triad risk factors, Wells score (DVT/PE), treatment duration recommendation, drug selection based on contraindications |
| ② Drug PK | Rivaroxaban/Apixaban/Enoxaparin/Dabigatran/Warfarin plasma profiles; Cmax/trough info boxes; renal impairment comparison |
| ③ Coagulation PD | FXa/FIIa inhibition, thrombin generation (ETP), Warfarin factor depletion/INR, Emax concentration-effect curves |
| ④ Thrombus Dynamics | Clot resolution over time, fibrin-plasmin balance, D-dimer normalization; info boxes for Day 7/30/90 clot % |
| ⑤ Scenario Comparison | Side-by-side 6-scenario comparison on any endpoint; efficacy/safety summary table |
| ⑥ Biomarker Dashboard | INR, Anti-Xa, D-dimer, coagulation cascade activity; biomarker interpretation guide |
# 1. Install dependencies
install.packages(c("mrgsolve", "dplyr", "ggplot2", "tidyr", "shiny",
"shinydashboard", "plotly", "DT", "purrr"))
# 2. Run mrgsolve simulation (6 scenarios)
source("vte_mrgsolve_model.R")
# 3. Launch Shiny dashboard
shiny::runApp("vte_shiny_app.R")# 4. Render mechanistic map
dot -Tsvg vte_qsp_model.dot -o vte_qsp_model.svg
dot -Tpng -Gdpi=150 vte_qsp_model.dot -o vte_qsp_model.png| Parameter | Value | Clinical Source |
|---|---|---|
| Rivaroxaban Cmax (15 mg fed) | ~270 ng/mL | Mueck et al., 2011 |
| Apixaban EC50 (FXa inhib.) | 5 ng/mL | Frost et al., 2013 |
| Dabigatran t½ (GFR 90) | 12-17h | Stangier et al., 2008 |
| Warfarin FVII t½ | ~5.7h (earliest INR rise) | Holford, 1986 |
| Enoxaparin Tmax Anti-Xa | 3-5h (SC) | Hulot et al., 2004 |
| DVT 3-month recurrence (unprovoked) | ~10% | Kyrle et al., 2004 |
| PE CTEPH rate | 2-4% | Pengo et al., 2004 |
CC BY 4.0 — QSP Disease Model Library | pipetcpt/qsp
Model generated 2026-06-23 by Claude Code Routine (CCR)