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. To investigate the impact of flow and intrathrombus forces on the stability of homogeneous and heterogeneous platelet thrombi in a wide range of thrombus geometries, critical interplatelet forces, vessel diameters, and hydrodynamic conditions, we took advantage of the recently developed in silico models. To perform analysis of thrombus stability/embolization in arterioles, we used our previously developed particle-based 2D model with a single-platelet resolution. Its results and predictions were further extended to a 3D case and the large spatial scales of arteries using novel particle-based and continuum 3D models. We found a robust quantitative parameter, termed force balance ratio, which quantifies the balance between destabilizing hydrodynamic and stabilizing interplatelet forces. This parameter predicts whether a homogeneous thrombus (or the shell of a heterogeneous thrombus) with a particular value of critical interplatelet forces will embolize under given hydrodynamic conditions. Our simulations also predict that, for a given magnitude of critical interplatelet forces, the longer thrombi are more stable than the shorter ones. Furthermore, the aggregates formed on top of the severe stenosis are more stable than thrombi formed at moderate stenosis. Taken together, our results give new insights into the interplay between critical interplatelet forces, local hydrodynamics, and overall thrombus stability against the flow.

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. Ligand binding to platelet receptor glycoprotein (GP) VI stimulates intracellular ROS generation consisting of a spleen tyrosine kinase-independent production involving NOX activation and a following spleen tyrosine kinase-dependent generation. In addition to GPVI, stimulation of platelet thrombin receptors (protease-activated receptors [PARs]) can also trigger NOX-derived ROS production. Our recent study found that mitochondria-derived ROS production can be induced by engagement of thrombin receptors but not by GPVI, indicating that mitochondria are another source of PAR-dependent ROS generation apart from NOX. However, mitochondria are not involved in GPVI-dependent ROS generation. Once generated, the intracellular ROS are also involved in modulating platelet function and thrombus formation; therefore, the site-specific targeting of ROS production or clearance of excess ROS within platelets is a potential intervention and treatment option for thrombotic events. In this review, we will summarize the signaling pathways involving regulation of platelet ROS production and their role in platelet function and thrombosis, with a focus on GPVI- and PAR-dependent platelet responses.