Biophysical Mechanisms Mediating Fibrin Fiber Lysis

Abstract

The formation and dissolution of blood clots is both a biochemical and a biomechanical process. While much of the chemistry has been worked out for both processes, the influence of biophysical properties is less well understood. This review considers the impact of several structural and mechanical parameters on lytic rates of fibrin fibers. The influences of fiber and network architecture, fiber strain, FXIIIa cross-linking, and particle transport phenomena will be assessed. The importance of the mechanical aspects of fibrinolysis is emphasized, and future research avenues are discussed.

Figure 1

The fibrin molecule and polymerization into fibers. (a) Crystallography-based fibrin molecule: the fibrin molecule structure shown was created using crystal structure 3GHG [9], combined with discrete molecular dynamics methods to fill in amino acids α17–26, α201–610, and β15–57 [15], which were missing in the crystal structure. The α chain is shown in green, β chain in red, and γ chain in blue; disulfide bonds are emphasized as yellow spheres. The αC region was built from homology modeling and molecular dynamics methods as described in [15]. Fibrin degradation fragments D and E are highlighted. Fragment X is formed from plasmin cleavage of the αC region. (b) Cartoon fibrin molecule: upon thrombin cleavage of FpA and FpB, knob A and knob B are exposed to bind the respective hole a and hole b. Cartoon model highlights these interactions and draws structural correlations between the crystal structure and the cartoon (c) Polymerization model for a protofibril: during polymerization, a half-staggered protofibril is formed as the knobs in the central region of one molecule bind to the holes in the distal region of two opposite molecules. Knob B has been implicated in the lateral aggregation of protofibrils and could potentially bind to holes in adjacent protofibrils (not shown).

Figure 2

Fibrin fiber structure and mechanical stretching. (a) Cartoon model of the fibrin molecule showing fibrinolytic binding and cleavage sites. Relative positions of plasmin cleavage sites, and tPA, plasmin(ogen), and α2AP binding sites are color coded. Mechanical stretching alters each site, as seen below. (b) A structural model for the fibrin fiber, consisting of protofibrils (c) linked together by unstructured αC regions. Knob-hole interactions are not shown and the β- and γ-nodules have been simplified to one structure in (b–f) for clarity. The protofibrils align to give a 23 nm banding pattern as seen in electron microscopy images, although the interactions mediating this alignment are unclear. The red dashes between adjacent molecules indicate the site of γ-γ FXIII cross-linking. (d–f) Cartoon models depicting extension of the fiber arising from stretching of the coiled coil region (d), γ-nodule (e), and the αC regions between protofibrils (f), respectively.

Figure 3

Interaction network of the biophysical determinants of fibrinolysis rates. A diagram highlighting the influence of FXIIIa, network architecture, platelets, and fluid flow on lytic rates. The diagram is simplified and does not include many of the interactions discussed in the paper but is meant to emphasize some of the major impacts. Black arrows show an influence of one property on a downstream property. The end result is either faster or slower network fibrinolytic rates. The red arrow indicates that cross-linked fibrin fibers have reduced extensibility and thus reduced fiber stretching. “Fibrinolytic activation/increased binding” and similarly worded effects are meant to indicate that a fibrinolytic enzyme such as plasmin is activated and/or has increased binding affinity or avidity.