Blood flow controls coagulation onset via the positive feedback of factor VII activation by factor Xa

<p>Abstract</p> <p>Background</p> <p>Blood coagulation is a complex network of biochemical reactions, which is peculiar in that it is time- and space-dependent, and has to function in the presence of rapid flow. Recent experimental reports suggest that flow plays a significant role in its regulation. The objective of this study was to use systems biology techniques to investigate this regulation and to identify mechanisms creating a flow-dependent switch in the coagulation onset.</p> <p>Results</p> <p>Using a detailed mechanism-driven model of tissue factor (TF)-initiated thrombus formation in a two-dimensional channel we demonstrate that blood flow can regulate clotting onset in the model in a threshold-like manner, in agreement with existing experimental evidence. Sensitivity analysis reveals that this is achieved due to a combination of the positive feedback of TF-bound factor VII activation by activated factor X (Xa) and effective removal of factor Xa by flow from the activating patch depriving the feedback of "ignition". The level of this trigger (i.e. coagulation sensitivity to flow) is controlled by the activity of tissue factor pathway inhibitor.</p> <p>Conclusions</p> <p>This mechanism explains the difference between red and white thrombi observed <it>in vivo </it>at different shear rates. It can be speculated that this is a special switch protecting vascular system from uncontrolled formation and spreading of active coagulation factors in vessels with rapidly flowing blood.</p

Новая тормозная энергосберегающая система погрузчика

The paper presents a system which provides an accumulation of kinetic energy of objects with translational and rotary motions in the case of loader hydropump braking (hydropump is connected with drive wheels through transmission). The hydropump injects a working liquid in the hydropneumatic accumulator with subsequent usage of water accumulated energy at starting acceleration.Представлена система, обеспечивающая накопление кинетической энергии поступательно и вращательно движущихся масс при торможении погрузчика посредством гидронасоса (связан через трансмиссию с ведущими колесами), закачивающего рабочую жидкость в гидропневмоаккумулятор с последующим использованием энергии накопленной жидкости при разгоне

New Brake Energy-Saving System of Loader

The paper presents a system which provides an accumulation of kinetic energy of objects with translational and rotary motions in the case of loader hydropump braking (hydropump is connected with drive wheels through transmission). The hydropump injects a working liquid in the hydropneumatic accumulator with subsequent usage of water accumulated energy at starting acceleration

Physiology and pathology of extracellular vesicules

This year marks the 50th anniversary of the first publication about blood plasma microparticles. Initially considered as cell fragments or “platelet dust”, extracellular vesicles currently attracted the attention of biochemists, biophysicists, physicians, pharmacists around the world. They are heterogeneous in structure and derived from many cell types, express different antigen and contain variety of biomolecules that determines wide range of biological activity, including procoagulant, regenerative, immunomodulating, and others. They play an important role in the pathophysiology of different diseases and conditions – from infarction, injuries and pregnancies to the “graft versus host” disease. The vesicles as medicaments and their carriers, as well as the drugs that affect them, are a rapidly developing field of research

Co-ordinated spatial propagation of blood plasma clotting and fibrinolytic fronts

<div><p>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.</p></div

Co-ordinated spatial propagation of blood plasma clotting and fibrinolytic fronts - Fig 1

<p>Pictures of fibrin clot growth in the absence of plasminogen activators (2 (A1), 10 (A2) and 20 (A3) minutes after the clotting onset) and clot growth and lysis in the presence of 30 nmol/L of TPA (2 (B1), 10 (B2) and 20 (B3) minutes after the clotting onset). Yellow rectangle on the panel A1 shows the region of the data collection for processing. The scale bar is 1 mm long. Spatial distribution of fibrin in the absence of plasminogen activators (A4) or in the presence of 30 nmol/L of TPA (B4) shows clot propagation and simultaneous clot growth and dissolution, respectively. Black, red, and blue lines show spatial distribution of light scattering signal (proportional to fibrin concentration) at 2^nd, 10^th,and 20^th minute after initiation of coagulation, respectively. When the signal exceeded the threshold level in any area, we considered that the clot appeared there, and when the level of signal decreased below this threshold, the clot dissolved. Coordinates of these events were designated as fronts of clot growth and lysis. Time course of clot growth front (A5) or clot growth and lysis fronts (B5) allows to calculate the velocities of clot growth or lysis as the average velocity of growth or lysis front propagation within the first 5 minutes after the onset of the process. In order to do that we used its linear approximation within the first 5 minutes after the clotting (lysis) lag time. Clotting (lysis) lag time was calculated as the time when clotting (lysis) front coordinate started to increase.</p

Parameters of clot growth and lysis in the absence and presence of thrombolytics.

<p>Parameters of clot growth and lysis in the absence and presence of thrombolytics.</p

Pictures of fibrin clot growth and lysis in blood plasma 5, 15 and 30 minutes after the start of experiment.

<p>Grey rectangle on the top of each image is an inset with immobilized TF. Fibrin clot is white, while liquid plasma is black/dark grey. (A) PFP from a patient under 0.03 mg/kg/h TPA therapy. (B) Pooled PFP from healthy volunteers supplemented with 14 nmol/L TPA in vitro. (C) PRP from healthy volunteer supplemented with 14 nmol/L TPA in vitro. (D) Pooled PFP from healthy volunteers supplemented with 14 nmol/L TPA in vitro, clotting was initiated with a TF-bearing fibroblasts confluent monolayer. Clot growth and lysis were monitored in plasma, treated as described in Methods section. Individual experiments are shown.</p

Co-ordinated spatial propagation of blood plasma clotting and fibrinolytic fronts - Fig 2

<p>Spatial kinetics of fibrin generation in the absence <b>(A)</b> or in the presence <b>(B)</b> of 50 nmol/L TPA. Spatial fibrin distribution is shown for 10^th (black line), 30^th (blue line) and 60^th (red line) minute of simulation. <b>(C)</b> Time course of clot growth/lysis front during simulation. <b>(D)</b> Scheme of blood coagulation cascade main reactions. Zymogens are shown as blue circles, activated proteins are shown as yellow circles. Inactive cofactors are shown as blue rectangles, activated cofactors are shown as cyan rectangles. Red arrows show activation, black arrows show transition from inactive to active form, and formation of complexes. Green arrows show inhibition. Double arc shows phospholipid surface that is required for complex formation or activation. PgA stands for plasminogen activator; FDP stands for fibrin degradation products.</p