Internal lysis of contracted clots is accelerated by fiber alignment and bundling

Background: Clot contraction is the volume shrinkage of a blood clot due to action of platelet-driven contractile forces. It is known that clot contraction accelerates internal fibrinolysis (the physiological degradation of the fibrin network) but restricts external fibrinolysis (the exogenous delivery of thrombolytic agents) in whole blood. We previously showed that external fibrinolysis is limited in contracted clots due to the densified fibrin network in the periphery, but the mechanism of acceleration of internal lysis is unknown. Methods: A comprehensive array of wet-lab experiments at the micro- and macroscopic levels, as well as computational modeling, were used to systematically disentangle the dominating mechanism leading to faster fibrinolysis of contracted clots during internal fibrinolysis. Scanning electron and confocal microscopy were used to visualize clots made with platelet-rich plasma and platelet-poor plasma to study the fibrin network structure. Platelet-driven tension was mimicked by applying uniaxial tensile strain both in large clots and individual fibers. Results: Clot contraction results in fibrin network structural changes; notably, a dense periphery and heterogeneous core. Internal lysis of clots made with platelet-rich plasma that contract normally was faster than all other clots tested. Tension delays lysis of individual fibers but speeds up lysis when fibers bundle with a high percent strain. Conclusion: Apparent thickening of fibers due to fibrin bundling as a result of platelet-driven fibrin rearrangement and alignment, rather than platelet-driven tension on fibers, drives the acceleration of internal fibrinolysis of contracted clots.