PROTHROMBOTIC STATES AND RELATED CONDITIONS

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CHAPTER 45 PROTHROMBOTIC STATES AND RELATED CONDITIONS

Paul Bentley, Pankaj Sharma

THE HEMOSTATIC SYSTEM

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.

Figure 45-1 Hemostatic system showing interdependence among vessel wall, platelets, and coagulation cascade. ADP, adenosine diphosphate; AT-III, antithrombin III; GP, glycoprotein; t-PA, tissue-type plasminogen activator; vWF, von Willebrand factor.

Figure 45-2 Hemostatic system showing endogenous anticoagulation, fibrinolytic, and antiplatelet systems. vWF, von Willebrand factor.

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.

PATHOLOGY OF EXCESSIVE HEMOSTASIS

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).

Figure 45-3 Virchow’s triad superimposed on the hemostatic system: Each main factor may cause vessel closure (principally thrombosis), although the relative contribution each factor provides depends on the part of the circulatory system at which the occluding lesion occurs. FDP, fibrin degradation products; t-PA, tissue-type plasminogen activator; t-PAI, t-PA inhibitor; vWF, von Willebrand factor.

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

1. Vessel wall defect (especially with endothelial disruption).

2. Stasis of blood (including turbulence).

3. Hypercoagulability (or excessive platelet activation).

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.”

Figure 45-4 Pathological causes of Virchow’s triad. COX-2, cyclooxygenase 2; CRP, C-reactive protein; HRT, hormone replacement therapy; OCP, oral contraceptive pill; TB, tuberculosis.

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.

NEUROLOGICAL CONSEQUENCES OF EXCESSIVE HEMOSTASIS

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.

Figure 45-5 Diverse neurological consequences of vessel closure, usually caused by thromboembolism. A, Middle cerebral artery infarction with secondary edema. B, Superior sagittal sinus venous thrombosis with bilateral cerebral infarctions and secondary hemorrhage. C, Bilateral subcortical ischemia (Binswanger’s leukoencephalopathy), resulting from chronic hypertension and causing dementia and gait apraxia. D, Thoracic spinal cord infarction, resulting from embolism from a cardiac source and causing paraparesis, anesthesia of lower limbs, and double incontinence. E, Inferior branch retinal artery occlusion secondary to embolism, causing monocular altitudinal (superior) loss of visual acuity. F, Left abducens nerve palsy resulting from small-vessel infarction of the sixth cranial nerve in a diabetic patient.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(B, From http://www.aic.cuhk.edu.hk/web8/0294_Cerebral_venous_haemorrhagic_infarction.jpg. Copyright © Chanles Gomersall. C, From http://www.kup.at/kup/images/thumbs/336.jpg. E, From The Robert Bendheim Digital Atlas of Ophthalmology, The New York Eye and Ear Infirmary, http://www.nyee.edu/page_deliv.html?page_no=50. F, From http://medicine.ucsd.edu/clinicalmed/eyes-cn6-palsy3.jpg.)

VESSEL WALL DEFECTS

Atherosclerosis

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, are highly atherogenic (after oxidation or glycation).

Figure 45-6 Pathogenesis of atherosclerosis and subsequent plaque destabilization with thrombus formation.

Although diet is the leading global factor in accounting for the distribution of atherosclerosis-related diseases, there are multiple other associations. Some of these factors act through secondary effects on lipid metabolism. Diabetes mellitus results in both a high circulating triglyceride level and glycation of small, dense LDL-cholesterol, both predisposing to premature atherosclerosis. Of interest, most genetic types of hypertriacylglyceridemia are not associated with atherosclerosis, whereas familial hypercholesterolemia (usually caused by a LDL-cholesterol receptor mutation) is strongly associated with premature atherosclerosis; homozygous patients suffer ischemic heart disease or strokes in their 20s. There are other genetic factors for atherosclerosis that may or may not result from interactions with lipid metabolism (Table 45-1). Both lipoprotein(a) and homocysteine levels are risk factors for atherosclerosis that also have strong genetic influences; these factors also have prothrombotic effects as a result of interactions with the coagulation cascade (see later discussion). Certain factors, such as hypertension, smoking, and epinephrine (present with, e.g., “easily stressed” personalities) act as synergistic factors with lipid metabolism for atherogenesis. Exercise and fish oils rich in omega-3 fatty acids (e.g., eicosapentaenoic acid) engender a more favorable lipid profile and correspondingly reduce atherosclerosis.

TABLE 45-1 Genetic Causes of Thrombophilia

Genetic Causes of Atherosclerosis

Familial hyperlipidemias

Familial hypercholesterolemia: LDL receptor mutation

Familial combined hyperlipidemia

Familial dysbetalipoproteinemia (hypertriacylglyceridemia)

Hyperhomocysteinemia: MTHFR: C667T mutation

Lipoprotein(a) elevation

Hyperfibrinogenemia

Dysfibrinogenemia (β-chain variants)

Although the influences of lipid and glucose metabolism on atheroma formation are well established, the contributions played by the immune system on both atherogenesis and plaque destabilization are becoming increasingly appreciated. Inflammation is triggered at the first sign of vessel wall injury and results in upregulation of cell-adhesion molecules, release of chemotaxins and reactive oxygen species, and facilitation of lipid influx and storage. Eventually, the fibrinous cap and endothelial lining of an atherosclerotic plaque becomes degraded by proteolytic enzymes derived from the inflammatory infiltrate, and at this point, rapid thrombus development is triggered. The effects of local inflammation within the vessel wall can often be observed through levels of circulating inflammatory markers. Hence, levels of C-reactive protein, an acute-phase reactant, and of CD3 provide indexes of the risk of ischemic heart disease or stroke. In addition to mirroring the inflammatory turnover within atherosclerotic lesions, these proteins act together to accelerate atheroma formation. Of interest, statins have been found to have anti-inflammatory effects, including reduction of C-reactive protein levels, and these effects have been associated with reduction of stroke or myocardial infarction risk, independent of the effect that these drugs have through lowering cholesterol.

Arteriosclerosis

Arteriosclerosis is the progressive replacement of smooth muscle cells with proteinaceous material (predominantly collagen) within the media of small arteries and arterioles (40 to 400 μm in diameter). The microscopic appearance is of concentric layers of a hyaline substance in the same location where smooth muscle normally occurs. The most strongly associated risk factors are hypertension and diabetes. As the process continues, the lumen constricts, which results in progressive tissue hypoperfusion. The latter is exacerbated during periods of hypotension, because the loss of smooth muscle prevents vasodilation. In certain cases, especially with accelerated hypertension, the same vessels develop a more disorganized process, which results in patchy fibrinoid accumulation, necrosis, and foam cell formation. When this accumulation is rapid, the end result may be acute small-vessel or lacunar infarction. From a therapeutic point of view, this knowledge is important, because it explains why anticoagulation and thrombolysis have no effect on stroke from this cause.

Dissection

Large arteries may be injured by an externally applied stretch or twist to cause, first, an endothelial breach and, subsequently, an elongating, longitudinal split between intima and media that is driven by the shearing forces within the arterial lumen. As blood enters the wall defect, the intimal aspect is forced into the lumen to create stenosis, with resultant turbulence and stasis. Together with the original endothelial breach, these conditions are ripe for thrombus formation within the true lumen. The initiating event for such dissections may be an apparently trivial movement, such as lifting or looking up, but the history is one classically of the patient’s suffering at the hands of overenthusiastic hairdressers or osteopaths.

Vasculitis

Inflammation centered on the vessel wall results in progressive luminal narrowing as a result of cellular infiltration and deposition of proteins, including fibrin. At the same time, inflammatory cell and cytokine interactions with platelets and coagulation factors favor a prothrombotic state. There are multiple causes of this lesion type, ranging from primary endogenous “vasculitides” to exogenous factors such as infections (e.g., herpes zoster or tuberculosis), toxins, and radiotherapy. An important example with neurological consequences is giant cell arteritis, a large-artery vasculitis in elderly people that results in headache, ischemic optic neuropathy, and stroke. In younger patients, the large or medium-sized vessel vasculitides Takayasu’s arteritis, polyarteritis nodosa, or Churg-Strauss syndrome should be considered, especially in patients with recurrent ischemic events, renal dysfunction, rash, or constitutional symptoms such as fever, myalgia, and testicular pain.

Spasm

The commonest neurological result of vasospasm—indeed one of the commonest neurological conditions—is migraine. More specifically, intracranial arterial spasm results in focal cerebral or brainstem ischemia that correlates with the migrainous “aura” phase in which affected patients complain of a focal sensory disturbance, typically a visual scotoma or flickering jagged lines. A rare but well-recognized complication of the migrainous aura is progression of the ischemia to infarction, typically in a small-vessel territory.

STASIS

Wherever the circulation becomes sluggish, activated clotting factors may accumulate to reach a concentration that surpasses a critical threshold, potentiating formation of an expanding fibrin core and, ultimately, thrombus. The most common predisposing circumstance is prolonged immobility, when thrombosis tends to form in the deep leg veins and usually when an additional hypercoagulability risk factor, such as infection or genetic status, prevails. The usual clinical consequences of this are local pressure effects in the leg and, more devastatingly, pulmonary embolism. However, in patients with a right-to-left cardiopulmonary shunt, a dislodged venous thrombus may course into the arterial circulation to cause, among other outcomes, cerebral embolism. This “paradoxical embolism” occurs most commonly in patients with either congenital cyanotic heart disease or a pulmonary arteriovenous malformation (e.g., as part of hereditary hemorrhagic telangiectasia), but in rare cases, it occurs in patients with a patent foramen ovale (present in up to 25% of the population) during, for example, inadvertent performance of the Valsalva maneuver.

Stasis of venous circulation may also cause neurological disease through the formation of intracranial venous thrombosis, most often within the superior sagittal or transverse sinuses. Factors that tend to encourage intracranial venous stasis are hypovolemia (e.g., from prolonged vomiting), raised central venous pressure (e.g., from heart failure), obesity, and pregnancy. Intracranial venous thrombosis may also be triggered by vessel wall defects that secondarily result in turbulence and stasis effects, such as tumor compression or indwelling catheter within the jugular vein or superior vena cava, causing back-propagation of thrombosis; bacterial or fungal infection of a bony sinus or orbit; or traction of sinuses after lumbar puncture (rarely associated with thrombosis). Neoplastic and infective processes are also associated with hypercoagulability (see later discussion).

Stasis may also be caused by hyperviscosity as a result of increase in circulating cell numbers, reduced cell deformability, or increased plasma proteins. Because some of these conditions also encourage coagulation, they are discussed as follows.

HYPERCOAGULABILITY

Hereditary

Many of the recognized genetic causes of hypercoagulability (and ischemic stroke) can be appreciated by reference to the endogenous coagulation and anticoagulation pathways (see Fig. 45-3 and Table 45-1). Hence, one of the most common abnormalities, factor V Leiden mutation, can be explained as an insensitivity of factor V to deactivation by protein C, which leads to deregulation of the production of thrombin. Mutations of endogenous anticoagulant/coagulant proteins are associated most strongly with venous thrombosis, although certain mutations (mainly factor V Leiden and prothrombin mutations and protein S deficiency) are also associated with arterial thrombosis, including stroke. The odds ratio associated with these conditions is approximately 10 for development of venous thrombosis and less than 3 for development of an arterial thrombosis. Whether a particular mutation results in an ischemic event depends on whether other prothrombotic or vascular risk factors coexist. Factor V Leiden and prothrombin mutations occur in approximately 10% and 5% of the population, respectively. Most affected people are heterozygous for the mutations although the relative risk for thrombosis is much greater in people with homozygous mutations. Deficiencies of protein C, protein S, and antithrombin III occur in fewer than 1% of the population for each. Most of these mutations are autosomal dominant, except for plasminogen deficiency, which is autosomal recessive.

Screening of children or young adults who present with arterial stroke has revealed that fewer than 25% have a recognized inherited prothrombotic state. Measurements of baseline coagulation and anticoagulation factor activity are often depressed for several weeks after an ischemic event (because of peripheral factor consumption), which necessitates delay in measurements of functional components of the thrombophilia screen. Genetic mutation analyses are, however, time independent. Also, measurements from functional assays of certain coagulation components (e.g., protein C) increase with age, which necessitates use of appropriate normal ranges. Protein S deficiency may also be acquired (e.g., because of infection or antiphospholipid syndrome). When a known prothrombotic mutation is identified, genetic counseling can be offered and family members tested. Although anticoagulation or antiplatelet drugs are not recommended for asymptomatic carriers or homozygotes, such information may influence future care in the event of illness.

Both hyperhomocysteinemia and elevated lipoprotein(a) levels are strong risk factors for ischemic stroke in either arterial or venous circulations, which indicates that these conditions incur risks of both atherosclerosis and hypercoagulability. The main determinant of the population’s distribution of homocysteine levels lies with the methylene-tetrahydrofolate reductase (MTHFR) genotype: high levels are predicted by the TT genotype and low levels by the CC wild-type (abbreviations refer to a single nucleic acid polymorphism within the gene). A high homocysteine level may be exacerbated by deficiencies of folate or vitamin B₁₂, both of which are required for the metabolism of homocysteine (Fig. 45-7). Homocysteine interacts with all three components of the hemostatic system: increasing platelet adhesiveness, activating coagulation factors, and resulting in endothelial disruption; it is also involved in the conversion of LDL-cholesterol into proatherogenic forms. Hyperhomocysteinemia may be treated with supplemental folic acid and vitamins B₁₂ and B₆, although there is insufficient evidence at present to support this form of treatment routinely for prophylaxis against arterial events. Lipoprotein(a) is a cholesterol-rich lipoprotein that also has close homology with plasminogen, the latter fact helping explain its influence on coagulation.