The extent of neural tissue dysfunction is not dictated solely by the activation of these mechanisms in neurons. It is now clear that toxic influences are exerted on oligodendroglial cells in white matter during ischemia and on astrocytic cells that support neurons. Moreover, injury to both neurons and astroyctes is augmented by an inflammatory response that activates endothelial cells to express cell adhesion molecules that attract additional inflammatory cells and upregulate levels of inflammatory proteases (e.g., metalloproteases) and cytokines (e.g., interleukins and chemokines). These events are summarized in the review by Lo and coworkers.
Myers and Yamaguchi showed that monkeys infused with glucose before the induction of cardiac arrest suffered more brain damage than did either fasted or saline-infused animals. They suggested that the high cerebral glucose level under anaerobic conditions led to increased glycolysis during the ischemic episode and that the accumulated lactate was neurotoxic. On the basis of such observations, Plum suggested that scrupulous control of the blood glucose might reduce the size of cerebral infarction in diabetic patients. Clinical implementation of this idea remains to be established but there have been correlations between the degree of hyperglycemia and infarct size and progression. Nonetheless, these multiple molecular pathways for neuronal damage provide opportune points for therapeutic intervention.
The process of thrombosis involves changes in a number of anticoagulant factors such as heparin cofactor 2, antithrombin III, protein C, and protein S. Some of these are extrinsic to the blood vessels and hence may result in thrombosis in one or in multiple sites even without prior vascular injury. These are discussed by Furie and Furie. Protein C is a vitamin K-dependent protease that, in combination with its cofactors protein S and antithrombin III, inhibits coagulation. An inherited deficiency of any of these factors may predispose to in situ thrombosis within either the arterial or venous systems and is a cause of otherwise unexplained strokes in young persons. For example, protein C deficiency (heterozygous in one of every 16,000 individuals) is a cause of thrombosis of both veins and arteries; a resistance to activated protein C has also been described (causing venous thrombosis almost exclusively).
Antiphospholipid antibody is yet another cause of vascular occlusion that is apparently not incited by damage to the vessel wall (see later in chapter). The metabolic disturbances in a number of metabolic diseases such as Fabry disease also favor cerebrovascular clotting. Persons with inflammatory bowel diseases (ulcerative colitis, Crohn disease) are known to be prone to thrombotic strokes. Whether inflammation elsewhere in the body predisposes to cerebral vascular occlusions is an open question. Curiously, the hypercoagulable state induced by certain cancers (Trousseau syndrome) does not often produce in situ arterial occlusion but it does lead to thrombotic vegetations on heart valves that precipitate strokes and it predisposes to cerebral venous thrombosis as discussed further on. Hemoglobinopathies such as sickle cell disease are also to be considered as causes of stroke in affected individuals. To this list could be added numerous other hematologic conditions such as thrombocytosis, polycythemia (primary or secondary), hyperviscosity from paraproteinemias, and others.