Personalization of a computational systems biology model of blood platelet calcium signaling.

Anuclear blood cells, platelets, are the basis for the formation of blood clots in human vessels. While antiplatelet therapy is most often used after ischemic events, there is a need for its personalization due to the limited effectiveness and risks of bleeding. Previously, we developed a series of computational models to describe intracellular platelet signaling and a set of experimental methods to characterize the platelets of a given patient.

Kinetic analysis of prothrombinase assembly and substrate delivery mechanisms.

Prothrombinase complex, composed of coagulation factors Xa (FXa) and Va (FVa) is a major enzyme of the blood coagulation network that produces thrombin via activation of its inactive precursor prothrombin (FII) on the surface of phospholipid membranes. However, pathways and mechanisms of prothrombinase formation and substrate delivery are still discussed. Here we designed a novel mathematical model that considered different potential pathways of FXa or FII binding (from the membrane or from solution) and analyzed the kinetics of thrombin formation in the presence of a wide range of reactants concentrations.

Dissecting thrombus-directed chemotaxis and random movement in neutrophil near-thrombus motion in flow chambers.

Background: Thromboinflammation is caused by mutual activation of platelets and neutrophils. The site of thromboinflammation is determined by chemoattracting agents release by endothelium, immune cells, and platelets. Impaired neutrophil chemotaxis contributes to the pathogenesis of Shwachman-Diamond syndrome (SDS).

Rapid HPLC method reveals dynamic shifts in coenzyme Q redox state.

Ubiquinol or coenzyme Q (CoQ) is a lipid-soluble electron carrier in the respiratory chain and an electron acceptor for various enzymes in metabolic pathways that intersect at this cofactor hub in the mitochondrial inner membrane. The reduced form of CoQ is an antioxidant, which protects against lipid peroxidation. In this study, we have optimized a UV-detected HPLC method for CoQ analysis from biological materials, which involves a rapid single-step extraction into n-propanol followed by direct sample injection onto a column.

Redox regulation of platelet function and thrombosis.

Platelets are well-known players in several cardiovascular diseases such as atherosclerosis and venous thrombosis. There is increasing evidence demonstrating that reactive oxygen species (ROS) are generated within activated platelets. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a major source of ROS generation in platelets.

Force balance ratio is a robust predictor of arterial thrombus stability.

Thrombus formation on a damaged vessel wall can lead to the formation of a stable occlusive/subocclusive clot or unstable embolizing thrombus. Both outcomes can cause significant health damage. The mechanisms that regulate maximum thrombus size, its stability, and embolization in both micro- and macrocirculation are poorly understood.

A growth chamber for chronic exposure of mammalian cells to HS.

HS is a redox-active signaling molecule that exerts an array of cellular and physiological effects. While intracellular HS concentrations are estimated to be in the low nanomolar range, intestinal luminal concentrations can be significantly higher due to microbial metabolism. Studies assessing HS effects are typically conducted with a bolus treatment with sulfide salts or slow releasing sulfide donors, which are limited by the volatility of HS, and by potential off-target effects of the donor molecules.

Different modeling approaches in the simulation of extrinsic coagulation factor X activation: Limitations and areas of applicability.

Proteolytic reactions on the phospholipid membrane surface, so-called "membrane-dependent" reactions, play central role in the process of blood clotting. One particularly important example is FX activation by the extrinsic tenase (VIIa/TF). Here we constructed three mathematical models of FX activation by VIIa/TF: (A) a homogeneous "well-mixed" model, (B) a two-compartment "well-mixed" model, (C) a heterogeneous model with diffusion, to investigate the impact and importance of inclusion of each complexity level.

Significance of two transmembrane ion gradients for human erythrocyte volume stabilization.

Functional effectiveness of erythrocytes depends on their high deformability that allows them to pass through narrow tissue capillaries. The erythrocytes can deform easily due to discoid shape provided by the stabilization of an optimal cell volume at a given cell surface area. We used mathematical simulation to study the role of transport Na/K-ATPase and transmembrane Na+ and K+ gradients in human erythrocyte volume stabilization at non-selective increase in cell membrane permeability to cations.

[Peculiarities of blood coagulation disorders in patients with COVID-19].

Aim: To study the relationship of hemostatic disorders with inflammation and estimate their role in the course and outcomes of COVID-19.

Materials And Methods: We examined 215 consecutive patients with moderate and severe forms of acute COVID-19. The patients were on anticoagulants and immunosuppressive drugs.

Procoagulant Activity in Amniotic Fluid Is Associated with Fetal-Derived Extracellular Vesicles.

Procoagulant activity in amniotic fluid (AF) is positively correlated with phosphatidylserine (PS) and tissue factor (TF)-expressing(+) extracellular vesicles (EVs). However, it is unknown if pathological fetal conditions may affect the composition, phenotype, and procoagulant potency of EVs in AF. We sought to evaluate EV-dependent procoagulant activity in AF from pregnant people with fetuses with or without diagnosed chromosomal mutations.

IL-6 Gene Expression as a Marker of Pathological State in Psoriasis and Psoriatic Arthritis.

The expression of the IL-6 gene in mononuclear blood cells of 45 patients with psoriatic arthritis and 31 patients with plaque psoriasis was studied for possible differential diagnosis of the pathologies. The expression level of IL-6 in psoriatic arthritis and psoriasis surpassed that in healthy controls by 192 and 147 times, respectively. Significant differences in the gene expression were revealed between the patients with psoriatic arthritis and mild psoriasis.

Beyond Hemostasis: Platelet Innate Immune Interactions and Thromboinflammation.

There is accumulating evidence that platelets play roles beyond their traditional functions in thrombosis and hemostasis, e.g., in inflammatory processes, infection and cancer, and that they interact, stimulate and regulate cells of the innate immune system such as neutrophils, monocytes and macrophages.

Analysis of microvascular thrombus mechanobiology with a novel particle-based model.

Platelet accumulation at the site of a vascular injury is regulated by soluble platelet agonists, which induce various types of platelet responses, including integrin activation and granule secretion. The interplay between local biochemical cues, mechanical interactions between platelets and macroscopic thrombus dynamics is poorly understood. Here we describe a novel computational model of microvascular clot formation for the detailed analysis of thrombus mechanics.

Occurrence of Calcium Oscillations in Human Spermatozoa Is Based on Spatial Signaling Enzymes Distribution.

In human spermatozoa, calcium dynamics control most of fertilization events. Progesterone, present in the female reproductive system, can trigger several types of calcium responses, such as low-frequency oscillations. Here we aimed to identify the mechanisms of progesterone-induced calcium signaling in human spermatozoa.

Remote Health Monitoring During and After the COVID-19 Pandemic.

High importance of the remote health monitoring (RHM) especially during and after the pandemic is accentuated in this article. It is displayed that by this way it is possible to revealing automatically situations "suspicious" from the COVID-19 illness view point for some concrete patients and also to keep up with possible complications after the illness. Another great opportunity of the RHM is connected with investigation of the vaccines.

Asymmetrical Forces Dictate the Distribution and Morphology of Platelets in Blood Clots.

Primary hemostasis consists in the activation of platelets, which spread on the exposed extracellular matrix at the injured vessel surface. Secondary hemostasis, the coagulation cascade, generates a fibrin clot in which activated platelets and other blood cells get trapped. Active platelet-dependent clot retraction reduces the clot volume by extruding the serum.

Modeling Thrombus Shell: Linking Adhesion Receptor Properties and Macroscopic Dynamics.

Damage to arterial vessel walls leads to the formation of platelet aggregate, which acts as a physical obstacle for bleeding. An arterial thrombus is heterogeneous; it has a dense inner part (core) and an unstable outer part (shell). The thrombus shell is very dynamic, being composed of loosely connected discoid platelets.

Accelerated Spatial Fibrin Growth and Impaired Contraction of Blood Clots in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease associated with thrombotic complications. To elucidate pathogenic mechanisms, hemostatic disorders in RA were correlated with other laboratory and clinical manifestations. Hemostasis was assessed using relatively new complementary tests, the spatial growth of a plasma clot (Thrombodynamics assay), and contraction of whole blood clots.

Programmed Cell Death and Functional Activity of Platelets in Case of Oncohematologic Diseases.

Programmed cell death of non-nucleated blood cells - platelets - could be associated with pathophysiology of oncologic and oncohematologic diseases. It contributes to both bleedings (caused by the thrombocytopenia, which is induced by elimination of the platelets) and thrombosis (caused by the processes of blood coagulation on the surface of phosphatidylserine exposing platelets). Here we characterized functional responses of platelets from the patients with various oncological disorders undergoing chemotherapy and compared them to the platelets from the healthy donors and platelets pre-incubated with apoptosis inducer ABT-737.

Microvesicle Formation Induced by Oxidative Stress in Human Erythrocytes.

Extracellular vesicles (EVs) released by different cell types play an important role in many physiological and pathophysiological processes. In physiological conditions, red blood cell (RBC)-derived EVs compose 4-8% of all circulating EVs, and oxidative stress (OS) as a consequence of different pathophysiological conditions significantly increases the amount of circulated RBC-derived EVs. However, the mechanisms of EV formation are not yet fully defined.

Effects of bacterial lipopolysaccharides on platelet function: inhibition of weak platelet activation.

Platelets are anucleate blood cells with reported roles in hemostasis and immune responses, which possess a functional receptor for bacterial lipopolysaccharides (LPSs), the well-known inducers of inflammation. However, LPSs effects on platelets are contradictory. Here we aim to investigate mechanisms of platelet functioning in the presence of LPS and to find the cause of the discrepancy in the previously published data.

Redistribution of TPA Fluxes in the Presence of PAI-1 Regulates Spatial Thrombolysis.

The fibrin clot is gelatinous matter formed upon injury to stop blood loss and is later destroyed by fibrinolysis, an enzymatic cascade with feedback. Pharmacological fibrinolysis stimulation is also used to destroy pathological, life-threatening clots and thrombi (thrombolysis). The regulation of the nonlinear spatially nonuniform fibrinolytic process in thrombolysis is not currently well understood.