Dynamic Changes of Fibrin Architecture during Fibrin Formation and Intrinsic Fibrinolysis of Fibrin-rich Clots

Abstract

Clotting and fibrinolysis are initiated simultaneously in vivo, and fibrinolysis usually occurs without any individualized lysis front (intrinsic fibrinolysis). We have developed a novel model to assess whether morphological changes resulting from intrinsic fibrinolysis are similar to those previously reported at the lysis front using externally applied lytic agents. Fibrin assembly and fibrinolysis were followed in real-time by confocal microscopy using gold-labeled fibrinogen molecules. An increase in fiber absorbance (30%, p < 0.01) and a decrease in fiber diameter (60%, p < 0.01) due to the ongoing accumulation and packing of fibrin molecules were the most significant detectable features occurring during fibrin assembly. Similar features with a similar magnitude were observed during fibrin dissolution, but in the reverse order and with a 3-fold increase in duration. Then, lysing fibers were progressively transected laterally, and thinner fibers were cleaved at a 2.5-fold faster rate than thicker fibers (p < 0.001). Frayed lysing fibers were seen to interact progressively with adjoining fibers (agglomeration), leading to a 76 and 88% increase in the network pore diameter (p < 0.05) and fiber diameter (p < 0.01), respectively. At the maximum decrease in fiber absorbance (46%, p < 0.05), the network suddenly collapsed with the release of large fragments that gradually vanished. Morphological changes of fibrin that occur during intrinsic fibrinolysis are similar as those observed next to the lysis front, although they are not restricted spatially to the clot/surrounding milieu interface but are observed through the entire clot.

Plasma Homocysteine Affects Fibrin Clot Permeability and Resistance to Lysis in Human Subjects

“…[27][28][29] The fibrin network configuration rather than fibrin diameter has been reported to have a stronger effect on the fibrinolysis rate. 30 Impaired fibrinolysis in subjects with hyperhomocysteinemia most likely reflects a smaller pore size in fibrin network, as it was shown in patients with diabetes. 11 Values are medians (ranges).…”

Genetic and Environmental Determinants of Fibrin Structure and Function

“…[13][14][15][16][17] Although individually, thin fibers are lysed quicker than thick fibers, it is the fibrin network configuration and the number of fibers per volume of clot that has a bigger impact on the fibrinolysis rate than fiber thickness alone. 18 It is evident that there is considerable variation in the fibrin clot structure of different individuals, suggesting that both genetic and environmental factors have a role in determining the balance between stability and susceptibility of the clot to fibrinolysis.…”

A Model Incorporating Some of the Mechanical and Biochemical Factors Underlying Clot Formation and Dissolution in Flowing Blood

“…Clot dissolution, or at least the changes in the fibrin network, as a result of fibrinolysis has been visualized in experiments. These indicate a gradual process and, after a certain period, a breaking away of larger portions of the network (Collet et al, 2003).…”