Microvascular thrombosis: experimental and clinical implications

Abstract

A significant amount of clinical and research interest in thrombosis is focused on large vessels (eg, stroke, myocardial infarction, deep venous thrombosis, etc.); however, thrombosis is often present in the microcirculation in a variety of significant human diseases, such as disseminated intravascular coagulation, thrombotic microangiopathy, sickle cell disease, and others. Further, microvascular thrombosis has recently been demonstrated in patients with COVID-19, and has been proposed to mediate the pathogenesis of organ injury in this disease. In many of these conditions, microvascular thrombosis is accompanied by inflammation, an association referred to as thromboinflammation. In this review, we discuss endogenous regulatory mechanisms that prevent thrombosis in the microcirculation, experimental approaches to induce microvascular thrombi, and clinical conditions associated with microvascular thrombosis. A greater understanding of the links between inflammation and thrombosis in the microcirculation is anticipated to provide optimal therapeutic targets for patients with diseases accompanied by microvascular thrombosis.

Fig 1

Examples of striking differences between arterioles and venules in vivo. (A) Silver-stained microvessels of rat mesentery outlining endothelial cell borders (arrows) showing long spindle-shaped cells in arterioles (Art.) and polygonal cells in venules (Ven.). Adherent leukocytes (arrowheads) are evident only on venules. (B) Immunofluorescence of mouse cremaster microvessels demonstrating vascular smooth muscle limited to the arteriole (stained with alpha smooth muscle alpha actin, green) and considerably greater von Willebrand factor expression (stained red) in the venule. Bar = 30 μm. From reference, with permission.

Fig 2

Schematic of experimental models of microvascular thrombosis induced by focal stimulation of individual microvessels, adapted from a schematic from reference.

Fig 3

Three-dimensional ultrastructure of a photochemical injury-induced thrombus in a mouse cremaster venule (45 μm in diameter) by serial block-face scanning electron microscopy. (A) Longitudinal section demonstrates cellular heterogeneity within the thrombus; the dimensions of the bounding box are 43 × 43 × 107 μm. (B) Cross section of the distal end of the thrombus shows loosely packed, discoid (unactivated) platelets. (C) Cross-section of the center of the thrombus shows densely packed platelets with evidence of significant degranulation. (D) Cross-section of the proximal end of the thrombus shows platelet (Plt)-endothelial cell (EC) adhesion, leukocytes (WBC) and erythrocytes (RBC). Scale bar = 5 μm. Images courtesy of Drs. Alan Burns and Samuel Hanlon, University of Houston College of Optometry.

Fig 4

Schematic of inter-related pathways that contribute to the clinical conditions associated with microvascular thrombosis discussed in this review; please see the body of the manuscript for details of each condition. The pathways depicted in red circles are traditionally viewed in the context of inflammation, while those depicted in blue circles are traditionally viewed in the context of coagulation/thrombosis.