Res Pract Thromb Haemost. 2026 Aug 3;10(6):106884. doi: 10.1016/j.rpth.2026.106884. eCollection 2026 Aug.
ABSTRACT
BACKGROUND: Altered fibrin clot architecture is a distinct signature in cardiovascular diseases. To determine the origin and importance of these alterations, a fundamental understanding of normal plasma clotting mechanisms is essential. While biochemical and structural aspects of fibrin formation are individually well documented, their mechanistic link lacks a quantitative description.
OBJECTIVES: This study addresses two questions: How does fibrin architecture vary with tissue factor concentration ([TF]) in normal plasma, and can a simple mechanistic relationship between fibrin structure and thrombin generation be extracted?
METHODS: The structuring of clots formed in TF-triggered normal pooled plasma and IIa-triggered fibrinogen was compared by varying the trigger concentrations. Architecture was quantified using confocal microscopy (pore size) and fibrinography (nanostructure). Thrombin kinetics were monitored using thrombinography.
RESULTS: Although purified and plasma clots appeared morphologically identical, their ultrastructural parameters showed fundamentally different sensitivities to trigger concentrations. In purified systems, a 100-fold [IIa] increase induced a 30-fold decrease in protofibril number (N Final) and a 5-fold change in pore size. Conversely, plasma clots exhibited remarkable robustness: a 40-fold increase in [TF] resulted in only a 2-fold change in N Final, with little pore size evolution. Crucially, by applying inverted purified data to plasma structural data, we predicted thrombin concentrations during the exponential growth phase of plasma calibrated automated thrombinography curves.
CONCLUSIONS: Our findings show that the unique functional shape of the thrombin burst, rather than the trigger concentration, governs plasma fibrin architecture. This inherent robustness supports the existence of a "normal" clot structure and the potential of fibrinography as a robust structural biomarker candidate.
PMID:42825136 | PMC:PMC13629324 | DOI:10.1016/j.rpth.2026.106884