Patient specific approach to analysis of shear-induced platelet activation in haemodialysis arteriovenous fistula.

Shear-induced platelet activation (SIPAct) is an important mechanism of thrombosis initiation under high blood flow. This mechanism relies on the interaction of platelets with the von Willebrand factor (VWF) capable of unfolding under high shear stress. High shear stress occurs in the arteriovenous fistula (AVF) commonly used for haemodialysis. A novel patient-specific approach for the modelling of SIPAct in the AVF was proposed. This enabled us to estimate the SIPAct level via computational fluid dynamics. The suggested approach was applied for the SIPAct analysis in AVF geometries reconstructed from medical images. The approach facilitates the determination of the SIPAct level dependence on both biomechanical (AVF flow rate) and biochemical factors (VWF multimer size). It was found that the dependence of the SIPAct level on the AVF flow rate can be approximated by a power law. The critical flow rate was a decreasing function of the VWF multimer size. Moreover, the critical AVF flow rate highly depended on patient-specific factors, e.g., the vessel geometry. This indicates that the approach may be adopted to elucidate patient-specific thrombosis risk factors in haemodialysis patients.

Dynamic Effects in Nucleation of Receptor Clusters.

Nucleation theory has been widely applied for the interpretation of critical phenomena in nonequilibrium systems. Ligand-induced receptor clustering is a critical step of cellular activation. Receptor clusters on the cell surface are treated from the nucleation theory point of view. The authors propose that the redistribution of energy over the degrees of freedom is crucial for forming each new bond in the growing cluster. The expression for a kinetic barrier for new bond formation in a cluster was obtained. The shape of critical receptor clusters seems to be very important for the clustering on the cell surface. The von Neumann entropy of the graph of bonds is used to determine the influence of the cluster shape on the kinetic barrier. Numerical studies were carried out to assess the dependence of the barrier on the size of the cluster. The asymptotic expression, reflecting the conditions necessary for the formation of receptor clusters, was obtained. Several dynamic effects were found. A slight increase of the ligand mass has been shown to significantly accelerate the nucleation of receptor clusters. The possible meaning of the obtained results for medical applications is discussed.

Platelet activation via dynamic conformational changes of von Willebrand factor under shear.

Shear-induced conformational changes of von Willebrand factor (VWF) play an important role in platelet activation. A novel approach describing VWF unfolding on the platelet surface under dynamic shear stress is proposed. Cumulative effect of dynamic shear on platelet activation via conformational changes of VWF is analysed. The critical condition of shear-induced platelet activation is formulated. The explicit expression for the threshold value of cumulative shear stress as a function of VWF multimer size is derived. The results open novel prospects for pharmacological regulation of shear-induced platelet activation through control of VWF multimers size distribution.

Control of fibrinolytic drug injection via real-time ultrasonic monitoring of blood coagulation.

In the present study, we investigated the capabilities of a novel ultrasonic approach for real-time control of fibrinolysis under flow conditions. Ultrasonic monitoring was performed in a specially designed experimental in vitro system. Fibrinolytic agents were automatically injected at ultrasonically determined stages of the blood clotting. The following clots dissolution in the system was investigated by means of ultrasonic monitoring. It was shown, that clots resistance to fibrinolysis significantly increases during the first 5 minutes since the formation of primary micro-clots. The efficiency of clot lysis strongly depends on the concentration of the fibrinolytic agent as well as the delay of its injection moment. The ultrasonic method was able to detect the coagulation at early stages, when timely pharmacological intervention can still prevent the formation of macroscopic clots in the experimental system. This result serves as evidence that ultrasonic methods may provide new opportunities for real-time monitoring and the early pharmacological correction of thrombotic complications in clinical practice.

On the chemotherapeutic agents localization in tissue by means of snake venoms.

The efficiency of anti-tumour drug strongly depends on its dose. Higher drug doses and exposure times usually result in better treatment. It is why the implementation of high-dose treatment is always attractive. However, most of the drug delivery techniques meet essential limitations. In isolated regional perfusion a tumour can be exposed to high-dose therapeutic influence but the target organ may be isolated from the rest of circulatory system only for a relatively short period of time. During systemic injection of anti-tumour agents dose limitations are dictated by side toxicity danger. Viperidae venoms are known to cause local stagnation of blood flow and blood-tissue exchange processes in the place of snakebite. In present paper we suggest to use Viperidae snake venoms in addition to anti-tumour drugs for regional anti-cancer therapy. We suppose that Viperidae venoms will assist in drug localization. We state that their usage will help in high-dosage therapy implementation.

Mathematical Modeling of Intravascular Blood Coagulation under Wall Shear Stress.

Increased shear stress such as observed at local stenosis may cause drastic changes in the permeability of the vessel wall to procoagulants and thus initiate intravascular blood coagulation. In this paper we suggest a mathematical model to investigate how shear stress-induced permeability influences the thrombogenic potential of atherosclerotic plaques. Numerical analysis of the model reveals the existence of two hydrodynamic thresholds for activation of blood coagulation in the system and unveils typical scenarios of thrombus formation. The dependence of blood coagulation development on the intensity of blood flow, as well as on geometrical parameters of atherosclerotic plaque is described. Relevant parametric diagrams are drawn. The results suggest a previously unrecognized role of relatively small plaques (resulting in less than 50% of the lumen area reduction) in atherothrombosis and have important implications for the existing stenting guidelines.

Spatial aspects of blood coagulation: two decades of research on the self-sustained traveling wave of thrombin.

In a number of experimental studies, it has been demonstrated that the forefront of blood coagulation can propagate in the manner of a signal relay. These data strongly support the concept that the formation of a blood clot is governed by a self-sustained traveling wave of thrombin. The present review critically appraises the experimental data obtained in recent decades concerning the self-sustained spatial propagation of thrombin. Open questions regarding the experimental detection of the self-sustained propagation of thrombin are discussed.

Instabilities in fibrinolytic regulatory system. Theoretical analysis of blow-up phenomena.

The network of fibrinolytic regulatory reactions is analyzed by means of a bipartite graph technique. Basic kinetic models relevant to the graphs describing the fibrinolytic regulatory system (FRS) with several degrees of resolution are derived. These models enable us to describe the phenomenon of threshold activation of fibrinolytic processes. The activation is accompanied by plasmin and urokinase blow-up generation. The areas in parametric space corresponding to threshold activation of FRS are established. It is shown that blow-up generation of plasmin may be caused by a supercritical perturbation of the values of dynamical variables (the active enzyme concentrations) as well as by the change of system parameters. An expression for the threshold activation value is suggested. Possible medical applications of the obtained results are discussed.

Acoustic determination of early stages of intravascular blood coagulation.

The blood coagulation system (BCS) is a complex biological system playing a principal role in the maintenance of haemostasis. Insufficient activity of the BCS may lead to bleeding and blood loss (e.g. in the case of haemophilia). On the other hand, excessive activity may cause intravascular blood coagulation, thromboses and embolization. Most of the methods currently used for BCS monitoring suffer from the major disadvantage of being invasive. The purpose of the present work is to demonstrate the feasibility of using ultrasonic methods for non-invasive registration of the early stages of blood coagulation processes in intensive flows. With this purpose, a special experimental set-up was designed, facilitating the simultaneous detection of optical and acoustic signals during the clotting process. It was shown that (i) as microemboli appear in the flow during the early stage of blood coagulation, the intensity of the Doppler signal increases twofold, and (ii) microemboli formation in the early stages of blood clotting always reveals itself through an acoustic contrast. Both of these effects are well defined, so we hope that they may be used for non-invasive BCS monitoring in clinical practice.