Exploring the thrombus niche: lessons learned and potential therapeutic opportunities

ABSTRACT: Thrombus structure and composition are the main determinants of the severity, course, and outcomes of thrombosis. Detailed thrombus morphology has become available due to mechanical thrombectomy, which allows for the extraction of fresh thrombi from patients, followed by scanning electron microscopy. The major structural elements of a thrombus are platelets, erythrocytes, and fibrin, each playing a critical role in the determination of biological and physical properties of thrombi, such as permeability, stiffness, and lytic and mechanical stability. The minor components include neutrophils, monocytes, von Willebrand factor, cellular microvesicles, plasma proteins, cholesterol crystals, and other structures. Platelets are responsible for the contraction (retraction) of thrombi, which results in compaction with very little free space, low permeability, and high stiffness. Because of clot contraction, erythrocytes, which are prevalent in all types of thrombi, undergo compressive deformation to polyhedral (polyhedrocytes) and polyhedral-like cells, altogether comprising pressure-deformed cells (piezocytes). Fibrin is the structural and mechanical scaffold of thrombi that changes in time and space both quantitatively and qualitatively during their formation. Fibrin is an equilibrium polymer that can adapt to forced deformations by reorientation at the microscopic level and unfolding at the molecular level. The relative volume fractions of thrombus components, along with their functional and structural forms, vary substantially, providing a basis for the diverse pathogenic mechanisms and clinical manifestations of thrombosis. Modulating any of these components leads to prospective therapeutic approaches. This review summarizes recent research describing the quantitative and qualitative morphologic characteristics of arterial and venous thrombi, which provide a basis for new therapeutic opportunities in thrombosis.