Mesoscale Simulations of Thrombin Activation and Fibrin Formation in Microvascular and In Vitro Settings

TL;DR

This work tackles how microvascular flow, geometry, and transport interact with simplified coagulation networks to control early thrombin generation and fibrin formation. It embeds two validated reduced schemes for intrinsic and extrinsic pathways into a mesoscale compositional SDPD framework that resolves fluid momentum and multispecies ADR dynamics. Key findings show that transport-reaction coupling creates spatial heterogeneity in thrombin and fibrin that is not captured by outlet thrombin curves, with Pe, Re, injury size, and fibrinogen levels modulating clot initiation and growth; cap-like geometries and surface-mediated fluxes can markedly amplify coagulation. The approach offers a unified, multiscale platform for thrombosis modeling and blood diagnostics, with potential for future extensions toward thrombus mechanics and patient-specific simulations.

Abstract

Blood coagulation is governed by tightly regulated reaction networks that unfold within a flowing, heterogeneous microvascular environment. Reduced kinetic models of the intrinsic and extrinsic pathways have seen limited in vitro validation, and their behavior within spatially resolved flow fields remains largely unexplored. Here, we embed two established reduced networks into a recently proposed mesoscale particle-based framework that resolves fluid momentum transport alongside multispecies advection-diffusion-reaction dynamics. We investigate the initiation phase of coagulation by simulating thrombin formation in microvascular geometries and in vitro assays, and we assess the framework's ability to reproduce thrombin generation curves (TGCs) under physiologically relevant conditions. We further examine how variations in fibrinogen levels - an important determinant of clot structure and a biomarker for inflammation and thrombosis - affect thrombin and fibrin formation. Overall, this study provides a unified computational approach for analysing how biochemical kinetics interact with transport processes, offering insights relevant to thrombosis modeling and blood diagnostics.

Figures (9)

• Figure 1: Flowchart of the coagulation network during the initiation phase. The extrinsic pathway (blue) is triggered by tissue trauma, while the intrinsic pathway (pink) begins with Factor XII activation. Both converge at Factor X activation to Factor Xa, leading to thrombin (IIa) generation. Thrombin cleaves fibrinogen (I) into fibrin (Ia) and initiates three positive feedback loops (Factors V, VIII, XI; green dashed lines). Major inhibitors, including TFPI and Antithrombin, are shown in red.
• Figure 2: Simulation domains for in vivo and in vitro studies. (a) Two rectangular channel domains ($L_x=$55, $H=$10) for in vivo simulations. The dashed outline marks the homogeneous (hom.) domain. The heterogeneous domain includes "injury" particles (red) to trigger coagulation; a semicircular cap (pink) represents quiescent particle clusters. 13,260 is the total count of fluid particles (blue). (b) Cuvette for in vitro tests, with 6,426 fluid particles; TF (red) initiates coagulation, static cuvette walls (gray).
• Figure 3: (a) Intrinsic pathway: Evolution of mean concentration profiles for Factor Xa, prothrombin (II), and thrombin (IIa). Solid lines show MATLAB ode15s results, and circles denote SDPD simulations; the inset highlights Xa and IIa peaks. (b,c) Extrinsic pathway: Evolution of mean concentrations in the reduced extrinsic network chen2019reduced. Panel (b) shows all species (log scale), and (c) focuses on thrombin forms: strongly bound (${}^{\gamma}\mathrm{S}$), weakly bound (${}^{\mathrm{E}}\mathrm{S}$), free, and total.
• Figure 4: Influence of Pe (10,70) under low Re=0.02. (a) Maximum concentrations of species Xa (blue) and IIa (yellow) over time, with solid lines for Pe$=$10 and filled squares for Pe$=$70. The red vertical lines highlight the time of maximal absolute IIa peak occurrence, $t^*_{\mathrm{peak}}$. (b) Mean Xa and IIa concentration profiles at the channel outlet; magenta lines indicate $t^*_{\mathrm{max}}$. (c–d) Normalized IIa concentration scatter plots at $t^*_{\mathrm{peak}}$ for Pe$=$10 and Pe$=$70, respectively, with matched axis ranges. The SDPD length scale is nondimensionalized by the channel height $H$. (e–f) IIa concentration histograms: lilac for values at $t^*_{\mathrm{peak}}$ in (c–d), red for values at $t^*_{\mathrm{max}}$.
• Figure 5: (a) Evolution of thrombin (IIa) concentration at the channel outlet for different Reynolds numbers (Re$=$0.02, 0.08, 0.1, and 0.5) with Pe$=$100. Markers indicate Re$=$0.02 (square), Re$=$0.08 (circle), Re$=$0.1 (diamond) and Re$=$0.5 ($|$). (b) Spatial distribution of IIa in the in vivo domain at $t^* =$ 5000 for the each Re value, fading the channel outlet $x$-slab where local averages are computed. A consistent rainbow color scale is used across all cases for direct comparison.