Journal of thrombosis and haemostasis : JTH · 2026
Thrombin-dependent nanoscale architecture and fibrinolytic remodeling of hydrated fibrin clots revealed by expansion microscopy.
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Pan Xiang, Chen Edith, Stelter Cole, Nagaswami Chandrasekaran, Weisel John W, Kim Oleg V
Аннотация
BACKGROUND: Fibrin network architecture governs clot stability, permeability, and susceptibility to fibrinolysis, yet nanoscale characterization of hydrated fibrin structures remains challenging.
OBJECTIVE: To apply expansion microscopy (ExM) for quantitative subdiffraction-resolution imaging of fixed, hydrated fibrin architecture and determine how fibrin structure varies with thrombin, regulates clot permeability, and remodels during fibrinolysis.
METHODS: Fibrin structure in human platelet-free plasma clots was quantified across thrombin concentrations (0.3-1.5 U/mL) and during tissue-type plasminogen activator-induced internal fibrinolysis using ExM, with validation against confocal, stimulated emission depletion, and scanning electron microscopy. Fiber diameter, pore size, porosity, and clot permeability were measured to relate nanoscale structure to macroscopic transport.
RESULTS: Increasing thrombin produced progressively thinner fibers, without altering network porosity, indicating redistribution of fibrin mass at constant void fraction. In contrast, pore area decreased monotonically and exhibited a strong linear relationship with clot permeability, suggesting that pore geometry, rather than bulk porosity, is closely associated with hydraulic transport under constant fibrinogen concentration. Fiber diameters measured by ExM closely matched those by stimulated emission depletion and were systematically larger than scanning electron microscopy values, consistent with preservation of hydrated ultrastructure. During fibrinolysis, ExM resolved spatiotemporal remodeling of fibrin networks, including fiber thinning during active lysis followed by increased heterogeneity, apparent fiber bundling, and marked pore enlargement in late lysis.
CONCLUSIONS: These findings define a nanoscale structural sequence linking thrombin-regulated polymerization and fibrinolytic degradation to macroscopic clot function and establish ExM as a robust platform for quantitative analysis of fibrin architecture in hydrated plasma clots.
OBJECTIVE: To apply expansion microscopy (ExM) for quantitative subdiffraction-resolution imaging of fixed, hydrated fibrin architecture and determine how fibrin structure varies with thrombin, regulates clot permeability, and remodels during fibrinolysis.
METHODS: Fibrin structure in human platelet-free plasma clots was quantified across thrombin concentrations (0.3-1.5 U/mL) and during tissue-type plasminogen activator-induced internal fibrinolysis using ExM, with validation against confocal, stimulated emission depletion, and scanning electron microscopy. Fiber diameter, pore size, porosity, and clot permeability were measured to relate nanoscale structure to macroscopic transport.
RESULTS: Increasing thrombin produced progressively thinner fibers, without altering network porosity, indicating redistribution of fibrin mass at constant void fraction. In contrast, pore area decreased monotonically and exhibited a strong linear relationship with clot permeability, suggesting that pore geometry, rather than bulk porosity, is closely associated with hydraulic transport under constant fibrinogen concentration. Fiber diameters measured by ExM closely matched those by stimulated emission depletion and were systematically larger than scanning electron microscopy values, consistent with preservation of hydrated ultrastructure. During fibrinolysis, ExM resolved spatiotemporal remodeling of fibrin networks, including fiber thinning during active lysis followed by increased heterogeneity, apparent fiber bundling, and marked pore enlargement in late lysis.
CONCLUSIONS: These findings define a nanoscale structural sequence linking thrombin-regulated polymerization and fibrinolytic degradation to macroscopic clot function and establish ExM as a robust platform for quantitative analysis of fibrin architecture in hydrated plasma clots.