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The human circulatory system does not act simply as an array of inert, lifeless pipes that convey blood between organs; it is an organ itself with functions beyond those of the various compounds and cells that pass through its conduits. One of these functions is the maintenance of its own structural integrity, essential for transmitting blood pressure, ensuring continuity of flow, and minimizing spread of infection. There has evolved a complex hemostatic system that enables on-line monitoring of a large area of endothelial space (approximately 600 m2, or the equivalent of three tennis courts), with rapid, local restoration of breaches as they occur. This system is composed of multifarious actions and interactions among solid-phase vessel wall, cellular platelets, and humoral coagulation factors; Figure 45-1 is a basic schema of the events that follow vessel injury. It is preferable to talk about this system as a whole rather than as a separate “coagulation system” because of the strong interdependence among these three components. An important attribute of hemostasis is the requirement of both “on knobs” and “off knobs,” delicately adjusted, to prevent a response to vessel wall injury from overshooting and resulting in a sealing of both the defect (which is desired) and the vessel lumen itself (which would cause local hypoperfusion). Endogenous anticoagulant systems are shown in Figure 45-2. As with most metabolic systems, the physiological state is optimized by both prohemostatic and antihemostatic reactions occurring simultaneously (i.e., a dynamic system); the net outcome depends on local vessel integrity.

This chapter is concerned with states that predispose to excessive hemostasis (vessel closure) and their neurological effects. By far the commonest mechanism by which vessels close off pathologically is the formation of thrombus, and so such states are commonly referred to as prothrombotic states. A thrombus is a concretion of activated platelets and fibrin, the latter product being the insoluble end product of the coagulation cascade. However, vessel closure may also occur through embolism, progressive thickening of the arterial wall, vasospasm, or cell sludging. Within the neurological system, the most likely outcome of vessel closure is ischemic stroke, but other diseases, such as peripheral nerve ischemia, optic neuropathy, spinal cord infarction, dementia, and parkinsonism, may also be the consequence of ischemic injury to nervous tissue.


In the same way that the physiology of hemostasis is shared among the trio of vessel wall, platelets, and clotting factors, the pathophysiology of excessive hemostasis can be summarized by its own triad. This so-called Virchow’s triad represents three sets of factors, each of which may give rise to vessel closure, thrombosis being a final common pathway in most cases (Fig. 45-3).

A modern-day listing of Virchow’s triad has changed little since its original formulation in 1860:

Figure 45-4 lists the various causes within each of these categories, including states predisposing to thrombosis or vessel closure by other means (e.g., vasospasm). These causes can be remembered by the mnemonic “ADVISE OR HEPARINISE.”

In reality, it is likely that a synergistic interaction of two or three factors contribute to thrombosis. In the arterial circulation, although normal cerebral vessels can withstand a pressure of approximately 1500 mm Hg, the commonest scenario is as follows: An atherosclerotic plaque ruptures or hemorrhages (through a vessel wall defect), thereby inducing local activation of coagulation factors and platelets (hypercoagulability), as well as turbulence with pockets of slow or reversed flow (stasis). In the venous circulation, the initiating event is usually a combination of stasis (e.g., immobility), and a hypercoagulable state (e.g., stress response secondary to recent surgery). In general, vessel wall defects are far more predominant and likely to result in thrombosis in arteries or arterioles, whereas stasis is found in the parts of the circulation in which rate of blood transit is at its lowest: namely, veins. Hypercoagulable states are associated with both arterial and venous thromboses but more commonly result in the latter, possibly because of the prior requirement of local stasis in order for an activated coagulation cascade to result in a significant accumulation of fibrin.

A thrombosis consists of a solid aggregation of platelets and erythrocytes within a fibrin mesh adherent to the vessel wall. Microscopic observation reveals that thrombi within arteries have a higher platelet composition (in relation to fibrin) than do those in veins. Because fibrin tends to adhere to red blood cells, arterial thrombi appear relatively white, whereas venous thromboses, with a higher fibrin content, appear red.


Stroke represents the neurological consequence of a disordered hemostatic system; causes may be logically divided into excessive hemostasis, which results in ischemia, or inadequate hemostasis, which results in hemorrhage. Ischemic strokes, accounting for about 80% of all strokes, result predominantly from arterial occlusion but occasionally result from venous blockage. Most arterial strokes, whether ischemic or hemorrhagic, occur because of lesions affecting the vessel wall component of the hemostatic system. Atherosclerosis results in stenosis of large-vessel arteries, which itself predisposes to development of superimposed thrombosis and resultant vessel occlusion. Diseases of the myocardium result in impaired contractility, which may secondarily cause blood stasis, cardiac thrombus, and eventually embolism into arteries of the brain, spinal cord, or eye (as well as into arteries of other organs). Arterial aneurysms are predisposed to rupture, which overwhelms the hemostatic system’s ability for self repair. Not all strokes are caused by dysfunctional hemostasis: one such example is severe hypotension, such as that caused by cardiac arrhythmia, which results in temporary arrest of blood flow in watershed areas of the brain.

Venous occlusion typically occurs in the venous sinuses located posteriorly within the cranium or in the superior cerebral, ophthalmic, or spinal veins and causes focal ischemia and infarction in the tissue drained by the occluded vein. Because arterial blood continues to enter the infarcted region, capillaries enlarge and eventually rupture, which accounts for the frequent presentation of venous thrombosis as multiple intracerebral hemorrhages. An alternative manifestation is raised intracranial pressure (causing coma or papilledema, for instance) that may be explained by the fact that the cerebral venous sinuses act as the outflow for cerebrospinal fluid drainage.

Thromboembolism represents the commonest cause of ischemic stroke; other pathological processes may also result in vessel closure to produce regional ischemia within the nervous system. Examples of such pathological processes are vasospasm (that in the brain results in migrainous auras), arteriosclerotic lipohyalinosis (commonly caused by hypertension and resulting in isolated “lacunar” strokes or, when diffuse, a subcortical dementia), and vasculitis. Figure 45-5 depicts the varied neurological effects of ischemia secondary to thromboembolism or other processes resulting in vessel closure.



Atherosclerosis describes the pathological appearance of the vessel wall in most cases of strokes and myocardial infarctions. Microscopically, it is characterized by the accumulation of lipid and inflammatory cells within the arterial intima. However, these lesions build up over decades and have relatively inconsequential hemodynamic effects until they encroach on a significant proportion of the vessel lumen. Even when significant stenosis has developed, it is usually insufficient to result in end-organ damage unless a fall in blood pressure across the diseased blood vessel occurs. Hence, the additional factor that appears necessary in the pathogenesis of most clinical syndromes of infarction is the formation of thrombus on a preexisting atherosclerotic plaque. This development probably occurs rapidly, over hours, and is triggered by conformational or biochemical changes within the atherosclerotic lesion and/or by the appearance of prothrombotic substances within the blood. Because any atherosclerotic lesion has the potential of suddenly transforming itself into a substrate for thrombosis, conditions that predispose to atherosclerosis should be regarded as contributing (albeit indirectly) to a prothrombotic state.

Postmortem appearances of arteries from people who died from nonischemic causes have shown that atherosclerotic lesions are virtually universal after middle age, especially in residents of industrialized nations. In fact, the strong geographical dependence of atherosclerosis risk corresponds to recognized environmental factors that may initiate atherogenesis (Fig. 45-6). The most important predisposing state is a high circulating triglyceride (lipid) load, especially during the postprandial period—which for many residents of the industrialized world represents most of the waking day. Because triglyceride-rich particles (very-low-density lipoprotein) continuously exchange their triglycerides with cholesterol found within high-density lipoprotein particles, the level of high-density lipoprotein-cholesterol is inversely correlated with, and an accurate predictor of, atherosclerosis risk. The level of low-density lipoprotein (LDL)-cholesterol is less predictive of atherosclerosis, although a subset of LDL-cholesterol particles formed under high triglyceride conditions, called small, dense LDL-cholesterol,

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