Virchow's triad: the vascular basis of cerebral injury

Abstract

Both the large arteries and microvascular beds of the central nervous system respond to injury by initiating processes compatible with Virchow's triad: alterations in the microvascular permeability barrier, reduction in flow with the target bed, and/or thrombosis of brain-supplying arteries and of the microvasculature. This is particularly true during focal cerebral ischemia. The temporal and topographical coincidence of neuron injury and microvessel response during focal ischemia has suggested that neuron-microvessel interactions could be bidirectional. The neurovascular unit offers a conceptual and structural framework with which to examine events within the microvasculature and their impact on neuron integrity, with the participation of the intervening astrocytes, matrix, and other supportive cells (eg, pericytes and oligodendroglia). Activation of the endothelium and of coagulation, capture of leukocytes, and increased microvessel permeability lead to the focal "no-reflow" phenomenon. Decreased shear stress is a component of the evolving ischemia. Strategies that inhibit the interactions within the microvasculature have been shown to prevent no-reflow and improve neurological outcome. It is, therefore, possible that addressing the processes of Virchow's triad in the setting of focal ischemia could promote neurovascular function.

Figure 1

Cerebral capillary. Astrocytes and endothelial cells comprise capillaries throughout the brain. These cells are separated by the matrix proteins of the basal lamina. Embedded in the matrix are pericytes.

Figure 2

The neurovascular unit. A simplified depiction of the relationship between neuron and axon location and a supply microvessel. The astrocyte end-feet form the abluminal portion of capillaries and small microvessels via their attachment to the basal lamina matrix, and astrocyte arborizations contact neurons.

Figure 3

Schematic diagram of the effect of ischemia on microvessel permeability and integrity. (A) Normal cerebral microvessel. Endothelial cells and astrocyte end-feet bound to basal lamina by integrin and dystroglycan adhesion receptors. Blood-brain barrier intact. (B) Breakdown of the blood-brain barrier. (C) Leukocyte adhesion by receptors on endothelium and granulocytes. Increased permeability caused by granule release. (D) Breakdown of basal lamina with loss of astrocyte and endothelial cell contacts. Permeability to erythrocytes and other blood borne cells. Reprinted with permission from del Zoppo et al.