Fibrinolysis at the Fluid-Solid Interface of Thrombi

Abstract

Thrombolysis is conventionally regarded as dissolution of the fibrin matrix of thrombi by plasmin, a protease generated by plasminogen activators from its inactive precursor, plasminogen. Typically plasminogen activation occurs on the surface of the clot, where fibrin behaves as a cofactor in this process, and plasmin also initiates its proteolytic action at the fluid-solid interface. Although the basic reactions of the plasminogen/plasmin system in fluid phase are well characterized in terms of classical enzymology, they cannot explain completely the interfacial fibrinolytic events. Recently new methods have been introduced for quantitative evaluation of plasminogen activation on gel-phase fibrin and heterogenous-phase proteolysis, an overview of the new methodology is presented. Following formation of an interfacial lytic zone, fibrin dissolution proceeds through propagation of this zone to the core of the clot, which depends on diffusion and permeation phenomena affected by the composition of thrombi. Phospholipids (originating from platelets) form a diffusion barrier to the thrombolytic agents and also bind some of them; structural cellular proteins (namely myosin) interact with the fibrin fibers masking their cofactor and plasmin-cleavage sites. The contribution of these recent findings to our understanding of the limitations of current thrombolytic therapy is discussed. Finally, attention is focused on the termination of thrombus-associated proteolytic action in an environment abundant in proteinase inhibitors. Thus, combining together the interfacial events in the initiation, progress and termination of thrombolysis, a concept for modeling the thrombus as a temporary fibrinolytic compartment is presented.

The interplay between tissue plasminogen activator domains and fibrin structures in the regulation of fibrinolysis: kinetic and microscopic studies

“…Fibrinolysis and clot structure Fibrinolysis may be considered as a 2-step process, 27 and the work presented here shows the value of approaching plasminogen activation and the whole process of fibrinolysis as distinct yet overlapping processes. We observe that the behavior of fibrin as a template for the stimulation of plasminogen activation is independent of the effectiveness of fibrin as a substrate for plasmin.…”

“…Inevitably, fibrin and clot structure/function relationships are more complicated in vivo than suggested here as clots will include numerous proteins and cells and other constituents, which can affect structure and hence lysis rates. 27 Recent work has also identified polyphosphate released from platelets 41,42 and red blood cells 43 as important regulators of fibrin fiber thickness, clot structure, and mechanical properties. Further work is required to identify all the factors that regulate clot structure, fibrin binding, plasminogen activation, and fibrin lysis.…”

Effects of Extracellular DNA on Plasminogen Activation and Fibrinolysis

“…The role of the structure of fibrin in fibrinolysis is incompletely understood, and the degradation of a pure fibrin network depends on its structure and thickness (86,87). The entrapment of DNA could further stabilize the fibrin meshwork and affect both Plg activation and subsequent fibrinolysis.…”

Applications of Monte Carlo Methods in Biology, Medicine and Other Fields of Science

“…The dissolution of intravascular thrombi is performed through the hydrolytic degradation of their fibrin matrix catalyzed by the serine protease plasmin (Kolev et al, 2005). Arterial thrombi enclose millimolar concentrations of phospholipids (Varadi et al, 2004) and free fatty acids (Rabai et al, 2007).…”