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Abstract
Fibrinolysis is a cascade of proteolytic reactions occurring in blood and soft tissues, which functions to disintegrate fibrin clots when they are no more needed. In order to elucidate its regulation in space and time, fibrinolysis was investigated using an in vitro reaction-diffusion experimental model of blood clot formation and dissolution. Clotting was activated by a surface with immobilized tissue factor in a thin layer of recalcified blood plasma supplemented with tissue plasminogen activator (TPA), urokinase plasminogen activator or streptokinase. Formation and dissolution of fibrin clot was monitored by videomicroscopy. Computer systems biology model of clot formation and lysis was developed for data analysis and experimental planning. Fibrin clot front propagated in space from tissue factor, followed by a front of clot dissolution propagating from the same source. Velocity of lysis front propagation linearly depended on the velocity clotting front propagation (correlation r2 = 0.91). Computer model revealed that fibrin formation was indeed the rate-limiting step in the fibrinolysis front propagation. The phenomenon of two fronts which switched the state of blood plasma from liquid to solid and then back to liquid did not depend on the fibrinolysis activator. Interestingly, TPA at high concentrations began to increase lysis onset time and to decrease lysis propagation velocity, presumably due to plasminogen depletion. Spatially non-uniform lysis occurred simultaneously with clot formation and detached the clot from the procoagulant surface. These patterns of spatial fibrinolysis provide insights into its regulation and might explain clinical phenomena associated with thrombolytic therapy.
Highlights
Blood coagulation and fibrinolysis are two interconnected networks of proteolytic reactions that control formation and dissolution of fibrin clots, respectively[1]
Ex vivo spatial clot growth in the platelet free plasma (PFP) from the patient under fibrinolytic therapy with recombinant tissue plasminogen activator (TPA) (Actilyse, Boehringer Ingelheim, Germany) was accompanied by a simultaneous clot lysis: the front of lysis propagation appeared on the clotting activation surface and followed clot growth (S2 Video, Fig 3A)
In order to investigate whether this phenomenon would persist under more physiological conditions, we performed these experiments in platelet-rich plasma (PRP, 300,000 platelets/μl) and found the very same pattern of spatial clot lysis (S4 Video, Fig 3C)
Summary
Blood coagulation and fibrinolysis are two interconnected networks of proteolytic reactions that control formation and dissolution of fibrin clots, respectively[1]. Both these networks are organized as cascades with numerous positive and negative feedback loops[2,3]. Coagulation is triggered by tissue factor (TF), a transmembrane glycoprotein expressed at the sites of vascular injury. Science for Medicine); by Grant of President of Russian Federation MK-9245.2016.4 to AMS and MD-229.2017.4 to MAP. Theoretical modelling was supported by grant from Russian Science Foundation 16-14-00-224 to FIA (sections Computational model of fibrin clot growth and lysis and Computer simulation of spatial clot growth and lysis; Figures 6 and 7). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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