Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed - Dynamic and structural approaches by confocal microscopy

Abnormal fibrin architecture is thought to be a determinant factor of hypof ibrinolysis. However, because of the lack of structural knowledge of the pr ocess of fibrin digestion, relationships between fibrin architecture and hy pofibrinolysis remain controversial. To elucidate further structural and dy namic changes occurring during fibrinolysis, cross-linked plasma fibrin was labeled with colloidal gold particles, and fibrinolysis was followed by co nfocal microscopy. Morphological changes were characterized at fibrin netwo rk and fiber levels. The observation of a progressive disaggregation of the fibrin fibers emphasizes that fibrinolysis proceeds by transverse cutting rather than by progressive cleavage uniformly around the fiber, Plasma fibr in clots with a tight fibrin conformation made of thin fibers were dissolve d at a slower rate than those with a loose fibrin conformation made of thic ker (coarse) fibers, although the overall fibrin content remained constant. Unexpectedly, thin fibers were cleaved at a faster late than thick ones. A dynamic study of FITC-recombinant tissue plasminogen activator distributio n within the fibrin matrix during the course of fibrinolysis showed that th e binding front was broader in coarse fibrin clots and moved more rapidly t han that of fine plasma fibrin clots. These dynamic and structural approach es to fibrin digestion at the network and the fiber levels reveal aspects o f the physical process of clot lysis. Furthermore, these results provide a clear explanation for the hypofibrinolysis related to a defective fibrin ar chitecture as described in venous thromboembolism and in premature coronary artery disease.