Protein C, Protein S, and Antithrombin III Deficiency

Protein C, protein S, and antithrombin III deficiencies account for 14 to 25 percent of cases of familial thrombotic disease (including systemic thrombosis), although the majority tend to be venous rather than arterial. Hematologic disorders may account for as many as 8 percent of all ischemic strokes. How- ever, the combined prevalence of these disorders is 1 percent or less in the general population. Deficiencies occur in either the amount (quantitative deficiency) or the molecular function (qualitative deficiency) of these coagulant proteins.

Protein C is a vitamin K-dependent factor converted to an active protease by thrombin. Once in active form, it limits coagulation by proteolysis of clotting factors Va and VIIIa. Protein S acts as a cofactor for activated protein C. Antithrombin III acts as a protease inhibitor of clotting factors in the coagulation cascade, except for factors Va and VIIIa, which are regulated by proteins C and S. Combined, these factors help to maintain the delicate balance between vascular hemostasis and fibrinolysis.

The risk of venous thrombosis and thromboembolism in patients with inherited deficiencies of protein C, protein S, and antithrombin III has been recognized widely, although there are fewer data on arterial thrombotic events. A study by Allaart and colleagues showed that by the age of 45 years, half of subjects with heterozygous protein C deficiency had experienced venous thrombosis, and a study by Pabinger and Schneider showed that 80 to 90 percent of subjects with protein C, protein S, or antithrombin III deficiency had some type of thrombotic event (usually venous) by the age of 50 to 60 years. There are many reports of ischemic arterial strokes occurring in the setting of protein C deficiency in the absence of other risk factors. Inherited deficiencies seem to figure more prominently in the pathogenesis of stroke in young adults and children than in the elderly. In a study of 120 young patients with stroke or transient ischemic attack (TIA) and a mean age of 38 years, protein S, protein C, and antithrombin III deficiencies were detected in 20, 3, and 3 patients, respectively. A confirmed coagulation disorder was more common among patients with large-vessel disease. In a retrospective study of 37 children with cryptogenic ischemic stroke, protein C deficiency or protein S deficiency was the only identified risk factor for approximately 5 percent and 14 percent, respectively. In another study of 36 patients younger than 40 years examined at least 3 months after cerebral infarction of undetermined cause, protein S deficiency was found in 5 cases, protein C deficiency in 1, and antithrombin III deficiency in 1. Based on these findings, the authors recommended testing for these inherited deficiencies in every young patient with cryptogenic stroke.

Protein S deficiency has also been reported in a number of cases of cerebral venous sinus thrombosis, but the association of protein C and antithrombin III deficiency with cerebral venous thromboses is less well-established.

When testing for these deficiencies, it is important to recognize that activity levels may be influenced by nongenetic factors. Acute-phase reactants may interfere with both quantitative levels and qualitative function of these anticoagulant proteins. Because low levels of protein C may occur in the setting of acute stroke, any studies with abnormal results should be repeated 3 months after the acute stroke period. Protein S levels may be lowered in chronic or acute illness, such as liver disease, nephrotic syndrome, and disseminated intravascular coagulation (DIC), as well as in the immediate postoperative period. Low levels of protein C and S have also been reported with pregnancy and with the use of vitamin K antagonists taken for oral anticoagulation. The most common causes of secondary protein C and S deficiencies are inflammatory illnesses in which the complement system is activated, leading to increased serum binding of these proteins.

The interactions between antithrombin III and heparin are important to recognize when testing for antithrombin III deficiency. Heparin increases the activity of antithrombin III by approximately 100-fold. Because the anticoagulant effect of heparin is mediated by antithrombin III activity, heparin resistance is a clue to potential antithrombin III deficiency. Antithrombin III levels usually normalize within 48 to 72 hours after cessation of heparin treatment.

Treatment decisions in patients with any of the inherited deficiencies should be made on an individual basis because there are inadequate prospective studies to guide therapy. Some authors recommend that any patient with protein C, protein S, or antithrombin III deficiency should be considered for lifelong anticoagulation following a thrombosis; others recommend treatment only during periods of heightened thrombotic risk (e.g., bed rest, pregnancy, and postoperative periods). Antithrombin III deficiency has the highest risk of recurrence of thrombotic events, and any patient with an inherited deficiency should be advised of the risks of thrombosis with oral contraceptive use, prolonged bed rest, and pregnancy. Warfarin- induced skin necrosis may occur in individuals with protein C deficiency.

Activated Protein C Resistance and Factor V Leiden Deficiency

Activated protein C resistance has been described in a number of patients with venous thromboembolic events, and some authors recognize it as the single most common cause of hereditary thrombophilia. At a site of blood vessel or endothelial injury, thrombin activates platelets, leading to aggregation. Fibrinogen is converted to fibrin, which binds the aggregated platelets to form a platelet plug. In addition to its procoagulant effects, thrombin plays an anticoagulant role in a feedback mechanism by binding to thrombomodulin. Once bound to thrombomodulin, thrombin loses its procoagulant activity and then activates protein C, which—in turn—acts with protein S to inactivate factors Va and VIIIa, thereby preventing further clotting ( Fig. 11-1 ). Activated protein C also inhibits tissue plasminogen activator inhibitor to stimulate fibrinolysis.

The protein C anticoagulant pathway. Thrombin converts factor VIII and factor V to their activated forms, factor VIIIa and factor Va. A complex of thrombin with the endothelial cell receptor thrombomodulin activates protein C (APC). APC inactivates factor VIIIa and factor Va on the platelet surface, and this reaction is accelerated by APC cofactor and free protein S.

(From Bauer KA: Hypercoagulability: a new cofactor in the protein C anticoagulant pathway. N Engl J Med 330:567, 1994, with permission. © 1994, Massachusetts Medical Society. All rights reserved.)

Although there are many genetic and environmental factors that contribute to activated protein C resistance, a genetic defect in factor V is the most commonly described, accounting for 85 to 95 percent of cases in some series. Dysfunctional factor V, referred to as factor V Leiden, is caused by a G-to-A mutation in the factor V gene. This amino acid substitution renders factor V resistant to protein C–induced enzymatic cleavage, thereby negating the anticoagulant properties of activated protein C. In vitro studies show that factor V Leiden is inactivated by activated protein C 10 times more slowly than normal factor V.

The prevalence of the factor V Leiden mutation was found to be 4.4 percent among European subjects, although only 4 percent of these were homozygous for the mutation. A study of the 15,000 men in the Physician’s Health Study showed a carrier rate of approximately 6 percent. There appears to be an uneven geographic distribution of the factor V Leiden mutation, which occurs more rarely in Japanese, Asian, and Middle Eastern populations than in Europeans. However, it is estimated that only 6 percent of those with the genetic defect will actually develop venous thrombosis over a 30-year period.

Activated protein C resistance is more of a risk for venous than arterial thrombotic events, including stroke. The presence of the factor V Leiden mutation has been associated with a nearly fivefold increased risk of ischemic stroke in children. Women who smoke and have the factor V mutation had an almost ninefold increased risk of stroke. In a population-based study of 826 men, the risk of carotid stenosis increased linearly with a decreased response to activated protein C. This association applied to those with and without the factor V Leiden mutation, suggesting that there are also hormonal and environmental factors that contribute to activated protein C resistance.

A study of the role of activated protein C resistance in 40 patients with cerebral venous thrombosis showed that 15 percent had an underlying thrombophilia of protein C deficiency, protein S deficiency, or activated protein C resistance. In most of these cases, other risk factors for venous thrombosis were also present, suggesting that thrombophilia may make individuals more susceptible to thrombogenic environmental or physiologic factors. A study of 321 women with the factor V Leiden mutation showed a 50-fold increased risk of venous thrombosis in heterozygotes taking oral contraceptives and a greater than 100-fold increased risk in homozygotes using oral contraceptives. Other small series have shown that between 20 and 25 percent of patients with cerebral venous thrombosis carry the factor V Leiden mutation.

There is a limited amount of data concerning the exact risk of cerebral venous thrombosis and venous infarction with the factor V Leiden mutation, and this risk cannot confidently be extrapolated from the data on peripheral venous disease.

Testing for activated protein C resistance and the factor V Leiden mutation following stroke should be performed in young patients without other risk factors, those with a personal or family history of thrombotic or venous occlusive disease, and patients with venous infarctions. Laboratory testing for activated protein C resistance measures the activated partial thromboplastin time in the presence and absence of activated protein C. Because anticoagulants may increase the activated partial thromboplastin time, tests should be performed only after the cessation of heparin and oral anticoagulants. If activated protein C resistance is discovered, it is appropriate then to test for the factor V Leiden mutation. Initial testing for the mutation is preferable in some instances because the results are not affected by anticoagulant use or treatment.

It is common to treat stroke patients with activated protein C resistance with anticoagulation. However, the decision to treat with oral anticoagulation, rather than antiplatelet therapy, is not based on prospective trials. No studies have established an adequate treatment regimen or optimal length of therapy. Some investigators advocate lifelong treatment and others opt for a short course of anticoagulants (3 to 6 months) followed by conversion to antiplatelet medications.

Antiphospholipid Antibodies: Lupus Anticoagulant and Anticardiolipin Antibodies

The lupus anticoagulant and anticardiolipin antibodies fall under the category of antiphospholipid antibodies, and both are recognized as markers for an increased risk of thrombosis, spontaneous abortion, cerebral ischemia, and vascular dementia. The presence of anticardiolipin antibodies in association with thrombotic events has been recognized increasingly in patients without evidence of connective tissue disease and is referred to as primary anti-phospholipid antibody syndrome (APS).

Thrombotic episodes affecting virtually every organ in the body have been reported in persons with antiphospholipid antibodies, and this association has been particularly well demonstrated for stroke and TIA ( Fig. 11-2 ). In one study, it was found that antiphospholipid antibodies were present in 46 percent of young patients with stroke, and antiphospholipid antibodies may be a contributing factor in approximately 10 percent of all cerebrovascular events. The presence of either the lupus anticoagulant or anticardiolipin antibodies in patients with systemic lupus erythematosus (SLE) doubles the risk of thrombotic events. Increased stroke risk correlates with high anticardiolipin immunoglobulin G (IgG) titers; IgM titers appear to be less predictive.

Angiography showing a middle cerebral artery occlusion ( arrow ) in a young woman with anticardiolipin antibodies, the lupus anticoagulant, and myxomatous mitral valve thickening.

(From Coull BM, Levine SR, Brey RL: The role of antiphospholipid antibodies in stroke. Neurol Clin 10:130, 1992, with permission.)

Studies have failed to show a clear association between antiphospholipid antibodies and recurrent vascular events of many types. In one large study of stroke patients regardless of age or sex, an increased risk of subsequent vascular occlusive events was not found, although the follow-up period was relatively short (2 years). Other studies have demonstrated an association between stroke and antiphospholipid antibodies mainly in young women, suggesting that these individuals may be at increased risk of stroke and its recurrence.

The pathophysiologic process of antiphospholipid antibody–associated thrombosis remains speculative ( Fig. 11-3 ). The lupus anticoagulant inhibits prostacyclin, which acts as a vasodilator and inhibitor of platelet aggregation, and this may be responsible. Other possible mechanisms include an interference with the activation of protein C. Because platelet membranes as well as endothelial cells are rich in phospholipids, antiphospholipid antibodies may bind to or damage these membranes, increasing the risk of thrombogenesis. Antiphospholipid antibodies have also been associated with an increased incidence of Libman–Sacks endocarditis and other left-sided cardiac valvular abnormalities that are associated with an increased stroke risk.

Proposed mechanism of antiphospholipid antibody-induced thrombosis. Antiphospholipid antibodies in a complex with β ₂ -glycoprotein-1 bind to platelet or endothelial membrane phospholipids, thereby causing platelet activation and endothelial damage. The ensuing platelet adhesion, aggregation, and impairment of endothelial anticoagulant function promote coagulation activation, vasospasm, and thrombosis. EDRF, endothelium-derived relaxing factor; PGI ₂ , prostacylin.

(From Coull BM, Clark WM: Abnormalities of hemostasis in ischemic stroke. Med Clin North Am 77:86, 1993; modified from Eisenberg GM: Antiphospholipid syndrome: the reality and implications. Hosp Pract 27:121, 1992, with permission.)

The presence of antiphospholipid antibodies has been found in up to 58 percent of patients with SLE. Antiphospholipid antibodies have also been found in patients with a host of other connective tissue diseases, including Sjögren syndrome, Behçet syndrome, mixed connective tissue disease, rheumatoid arthritis, and autoimmune thrombocytopenic purpura. Systemic infections, especially syphilis, Lyme disease, and viral infections, may also cause an elevation of antiphospholipid antibodies, but their presence in these conditions usually has little or no association with thrombotic events.

The diagnosis of APS involves both clinical and laboratory criteria. Individuals younger than 55 years with one or more thrombotic events without known vascular risk factors should be screened for the presence of these antibodies. Associated clinical signs include the presence of left-sided cardiac valvular lesions, spontaneous abortions, livedo reticularis, migraine headaches, and a prolonged activated partial thromboplastin time or a positive Venereal Disease Research Laboratory (VDRL) test result. Because the lupus anticoagulant and anticardiolipin antibodies are probably different immunoglobulins, patients should be tested for both; they may occur independently, and it is unclear which antibody is more predictive of thrombosis. In patients with the lupus anticoagulant, the activated partial thromboplastin time is prolonged in 80 percent of cases, and mixing studies show that this prolongation is not correctable by the addition of normal sera and is thus not a consequence of a factor deficiency. One large study failed to find any difference in recurrent events with aspirin or warfarin treatment in patients with antiphospholipid antibodies and initial ischemic stroke. Therefore, at present, antiplatelet agents are generally recommended in this setting, and efforts should be made to identify and treat other stroke risk factors. In patients with antiphospholipid antibodies and recurrent strokes or in those with APS and stroke, anticoagulants are often recommended. Previously it was thought that higher levels of anticoagulation were necessary in these patients, but the recent literature indicates that a goal INR of 2.0 to 3.0 is effective. Cortico-steroids are of no benefit in these patients.

Homocysteine

Homocysteine is an intermediate in the metabolism of the amino acid methionine. An elevated level of plasma total homocysteine increases the risk of all-cause vascular disease and is an independent risk factor for stroke. Hyperhomocysteinemia can be caused by an error in metabolism of sulfur-containing amino acids, nutritional deficiencies of folate, vitamin B ₁₂ , or vitamin B ₆ , or a genetic defect in the methylenetetrahydrofolate reductase ( MTHFR ) gene. It is unclear whether elevated blood levels of homocysteine have a causative role in the pathogenesis of vascular disease or are merely a secondary effect of an underlying causal process.

A number of vascular and hematologic abnormalities are associated with elevated serum homocysteine levels. Mild hyperhomocysteinemia increases carotid artery wall thickness and plaque formation, and smooth muscle cells cultured in the presence of homocysteine show increases in both cell density and collagen production, perhaps leading to prothrombotic effects. Other reported pathophysiologic changes include endothelial cell injury, increased platelet aggregation, and abnormalities of the clotting cascade by activation of factors V, X, and XII.

Several studies have documented the association between hyperhomocysteinemia and cerebrovascular disease. Yoo and colleagues performed a case-control study of 78 men with ischemic stroke and 140 control subjects and found an odds ratio of 1.7 (adjusted for total cholesterol, hypertension, smoking, age, and diabetes) for stroke in patients with the highest 5 percent of homocysteine levels. In a substudy of the Framingham Study, 1,947 elderly participants were followed prospectively and nonfasting homocysteine levels were measured. After the investigators adjusted for other risk factors, the relative risk of stroke associated with nonfasting homocysteine levels of 14.24 to 219.84 µmol/L compared with levels of 4.13 to 9.25 µmol/L was 1.82. The Rotterdam Study examined the relationship between elevated homocysteine levels in the elderly and the risk of stroke and myocardial infarction and found an increased risk of 6 to 7 percent for every 1 µmol/L increase in total plasma homocysteine. In a case-control study of 80 young patients with stroke between the ages of 18 and 44 years, a 4.8-fold increased risk of ischemic stroke was found in those with postmethionine load elevations in plasma homocysteine levels. A number of other studies have also shown this association in younger patients.

Although supplementation with folate, pyridoxine (vitamin B ₆ ), or cobalamin (vitamin B ₁₂ ) can reduce homocysteine levels, it is unclear whether these supplements lower the risk of subsequent vascular events. A recent Cochrane review evaluated 12 randomized trials of homocyteine-lowering interventions and found no significant effect on stroke or death from any cause. Therefore, at present, we do not perform routine screening of serum homocysteine levels in stroke patients and do not recommend lowering elevated homocysteine levels with folic acid and B vitamins.

Lipoprotein (a)

Lipoprotein (a) is a low-density lipoprotein (LDL)–like molecule that has been linked to both coronary artery and cerebrovascular disease. Levels are partially genetically determined and do not appear to be correlated with age, sex, blood pressure, smoking habits, or levels of total cholesterol or triglycerides. A number of medical conditions have been associated with elevated lipoprotein (a) levels, particularly diabetes with poor glycemic control and renal impairment. Reduced levels of lipoprotein (a) have been reported also in women taking hormone replacement therapy, although oral contraceptives seem to have little effect on levels.

The lipoprotein (a) molecule is composed of two components: apolipoprotein B and apolipoprotein A, or apoA. The apoA portion shares significant structural homology with plasminogen, and it has been postulated that lipoprotein (a) may compete for plasminogen-binding sites on fibrin and endothelial cells, thereby inhibiting endogenous fibrinolysis. Lipoprotein (a) accumulation has been demonstrated histopathologically in coronary atherosclerotic lesions in humans, and modification of lipoprotein (a) by sulfated polysaccharides leads to cholesterol deposition in mouse macrophages, similar to the atherogenic process caused by high levels of LDL cholesterol. Because of its fibrin-binding activity, lipoprotein (a) may help deliver cholesterol to developing thrombi or areas of endothelial injury. However, despite these observations, it still remains unclear whether elevated lipoprotein (a) levels actually contribute to atherosclerotic plaque formation or merely reflect the presence of atherosclerotic disease.

Numerous studies have linked high serum lipoprotein (a) levels to cerebrovascular disease and stroke. Even after controlling for other risk factors, lipoprotein (a) levels higher than 30 mg/dl are an independent risk factor for ischemic stroke, even in normocholesterolemic and normolipidemic patients.

Some studies show a reduction in lipoprotein (a) levels when diets are enriched with palm oil and polyunsaturated fatty acids. Alcohol consumption has also been associated with lower serum lipoprotein (a) levels, as has the use of low-dose (81 mg) aspirin. A study by Guyton and colleagues showed a 36 percent reduction in elevated lipoprotein (a) levels in individuals taking a mean nightly dose of 2,000 mg extended-release niacin. None of these therapies has been associated convincingly with reducing subsequent vascular events. Despite the similarity of lipoprotein (a) to other cholesterol constituents of the blood, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, bile acid sequestrants, and fibric acid derivatives seem to have little effect on lipoprotein (a) concentrations. Other risk factors such as dyslipidemia, diabetes, and obesity may enhance the atherothrombotic risk attributable to lipoprotein (a). Therefore, treatable risk factors should be tightly controlled in patients with elevated lipoprotein (a).

Screening for elevated lipoprotein (a) levels can be considered for patients younger than 55 years who experience a stroke, those with a personal or family history of premature cardiovascular disease, and patients with stroke who lack other conventional risk factors.

Sickle Cell Anemia

Hematological disorders are estimated to be the causative factor for up to 8 percent of all ischemic strokes and are particularly important in the etiology of stroke in young patients. Sickle cell anemia, in addition to causing a host of peripheral complications such as sickle cell crises, has been linked to cerebrovascular events. Strokes occur in 8 to 17 percent of patients with sickle cell anemia, although cerebral ischemic events usually do not occur in the context of a sickle cell crisis.

Approximately 15 percent of homozygotes (designated HbSS) experience a cerebral ischemic event during their lifetime. There are conflicting data as to whether individuals with sickle cell trait (heterozygotes, HbSA) and those with sickle C disease are at increased risk of stroke. The estimated prevalence of stroke is 1.5 to 2.0 percent in blacks with HbSA, which is essentially the same as the incidence in the overall black population. However, the risk of stroke in those with sickle C disease (HbSC) has been reported as high as 2 to 5 percent, which suggests a higher risk of stroke in these patients. In HbSS patients, the average age of stroke onset is relatively young, with a mean age of 7 to 9 years. Approximately 8 percent of all children with sickle cell anemia experience a cerebrovascular event by the age of 15. The actual risk of stroke may be significantly higher, however, because up to 24 percent of patients with HbSS have silent infarcts on neuroimaging, with no apparent clinical manifestations.

Most strokes in patients with sickle cell disease are ischemic, although older individuals are also at increased risk of hemorrhagic cerebral events. Thrombosis of large arteries is common although venous sinus thrombosis also occurs. Some evidence indicates that individuals with particularly severe sickle cell disease, characterized by a high number of crises and complications, are more prone to cerebrovascular events, possibly because of higher blood viscosity and greater endothelial damage.

The pathophysiologic process of stroke in patients with sickle cell anemia (discussed in Chapter 25 ) is still under investigation. It was initially believed that the lowered solubility of deoxygenated hemoglobin S resulted in aggregation and sickling in small vessels, but increasing evidence suggests large-vessel stenosis as the primary etiology of cerebrovascular events. In one study, cerebral angiograms performed in seven patients with sickle cell anemia and stroke revealed partial or complete occlusion of the internal carotid artery in six, with concurrent vertebral and large intracranial artery stenosis in others. Similarly, angiographic evidence of large-vessel arterial disease was found in 10 of 12 patients and 23 of 30 patients in two other studies.

The vascular damage, when examined histologically, consists of segmental thickening due to intimal proliferation of fibroblasts and smooth muscle cells. Once these vascular changes occur, vessel occlusion likely results from in situ thrombus formation or embolization. Given that HbSS erythrocytes are abnormally adherent to the vascular endothelium, this cascade of events could lead to vessel thrombosis, occlusion, and subsequent stroke.

Arterial narrowing and occlusion may also lead to a pattern like that of moyamoya syndrome on conventional angiography. Contrast agents used during angiography may enhance intravascular sickling, so angiography should be performed with caution, but is probably safe if the hemoglobin S level is less than 20 percent.

Conventional imaging studies such as computed tomography (CT) and MRI typically show infarcts in a watershed or border zone distribution, consistent with the large-vessel involvement of the disease. Transcranial Doppler (TCD) ultrasonography is a useful diagnostic imaging tool because increased middle cerebral artery flow velocities indicate the presence of underlying arteriopathy and increased stroke risk in patients with sickle cell disease. The risk of stroke during childhood in those with sickle cell disease is 1 percent per year, but patients with TCD evidence of high cerebral blood-flow velocities (>200 cm per second) have a stroke rate in excess of 10 percent per year. A study using transcranial Doppler imaging in 190 children with sickle cell disease showed that in those with Doppler imaging evidence of vessel stenosis, 26 percent went on to sustain cerebrovascular events, compared with 0.6 percent of patients without evidence of stenosis.

Once a diagnosis of stroke has been made, immediate therapy to prevent further episodes of brain ischemia should be instituted because the recurrence rate may be as high as 67 percent, usually within the first 12 to 24 months after the initial event. The mainstay of preventive therapy is lowering of the percentage of hemoglobin S in the blood, most effectively carried out by exchange transfusion therapy, which effectively lowers the percentage of red blood cells that can sickle. Most authors recommend maintaining the hemoglobin S level at less than 30 percent by performing exchanges every 3 to 4 weeks. In 1995, the National Heart, Lung, and Blood Institute conducted a multicenter, randomized, controlled study that was stopped prematurely when a 90 percent stroke reduction was noted in patients treated with exchange transfusions. The Stroke Prevention in Sickle Cell Anemia (STOP) study showed that the risk of stroke could be reduced from 10 percent per year to less than 1 percent per year with routine exchange transfusion therapy guided by TCD velocities. The optimal duration of therapy is unclear. A prospective, randomized trial that investigated the effect of stopping exchange transfusions once TCD velocities had normalized was ended prematurely because 14 of the 41 patients who had stopped monthly exchange transfusions re-developed high-risk velocities and 2 had strokes (compared with no strokes in the arm with continued exchange transfusions). Based on these data, it appears that exchange transfusions may be required indefinitely, although such an extensive treatment regimen should be weighed against the risks of iron overload, transfusion reactions, and donor-borne transmission of infectious diseases. Guidelines on primary prevention of ischemic stroke from the American Heart Association and American Stroke Association recommend that children with sickle cell disease be screened with TCD beginning at 2 years of age.

Systemic Lupus Erythematosus

SLE predisposes affected individuals to a host of neurologic disorders, including strokes, seizures, chorea, dementia, psychosis, neuropathy, and myelopathy, as discussed in Chapter 50 . In one study, 63 of 91 patients with SLE had central or peripheral neurologic dysfunction, with cerebrovascular events being the third most common manifestation, following seizures and delirium.

Stroke occurs in 3 to 20 percent of patients with SLE. These ischemic events typically involve younger patients, with a mean age at the time of stroke of 42 years. Elderly patients with SLE also are at high risk, perhaps due to the presence of other vascular risk factors which may act synergistically with SLE.

Although most infarcts in SLE are ischemic, intracerebral hemorrhage has been reported, usually in the setting of concurrent thrombocytopenia. Subarachnoid hemorrhage in SLE is also well documented, although many published studies are from Japan, where there is an overall increased risk of hemorrhagic stroke presumably due to genetic factors. The most frequent mechanism for ischemic cerebrovascular events appears to be either cardiogenic embolus or an antibody-mediated hypercoagulable state. In one autopsy study, cardiac valvular disease was discovered in nearly half of the patients, with Libman–Sacks endocarditis being the most frequent valvular lesion. These valvular lesions are often associated with the presence of antiphospholipid antibodies. Therefore, echocardiography and laboratory testing for antiphospholipid antibodies should be performed in any patient with SLE and an unexplained stroke or TIA.

The incidence of an inflammatory cerebral vasculitis in SLE has been extremely low or zero in autopsy studies, making this an unlikely cause of stroke in patients with lupus. Fibrin-platelet occlusion of intracranial arterioles may occur, and a noninflammatory vasculopathy secondary to vessel-wall hyalinization and endothelial proliferation has been the most common cerebrovascular abnormality in other autopsy studies. These lesions appear to correlate with the scattered punctate periventricular and white matter hyperintensities seen on MRI in patients with SLE. The cause of the vasculopathy in SLE is unclear, although postulated mechanisms include endothelial damage by antineuronal antibodies or immune complex deposition. Other pathologic findings include isolated large-vessel stenosis, arterial dissection, and fibromuscular dysplasia.

Although prospective studies of stroke treatment or prevention strategies in SLE are lacking, the occurrence of multiple infarcts in some patients (up to 64% of patients with SLE and stroke in one study ), as well as a high recurrence rate approaching 50 percent, underscores the need for thorough evaluation and secondary prevention. In one study, patients with SLE and stroke were compared with patients with SLE without cerebrovascular events. Concurrent cardiac valvular disease, coagulopathy, previous TIA or stroke, and age older than 60 years were all more common in the group with stroke.

The use of anticoagulants may reduce the risk of stroke recurrence in patients with SLE. Oral anticoagulation may be warranted in patients with SLE who have concurrent risk factors of cardiac valvular lesions or APS, although standard secondary prevention still involves antiplatelet medications. Given the absence of inflammatory vascular lesions in patients with SLE who have strokes, corticosteroids probably have no role, although most authors recommend their use in the setting of systemic vasculitis and high anticardiolipin antibody titers.

Cryoglobulins

Cryoglobulins are serum proteins with temperature-dependent insolubility, precipitating below 37°C. These proteins may occur in association with a number of autoimmune disorders, including SLE. Among connective tissue disorders, SLE, rheumatoid arthritis, and Sjögren syndrome are the diseases most frequently associated with the presence of cryoglobulins (8 to 48%). Most of the clinical manifestations of cryoglobulinemia are attributed to the precipitation of cryoglobulins in small vessels leading to arterial and venous occlusion. Both peripheral (most commonly neuropathy) and CNS involvement occur in cryo- globulinemia. Imaging studies of the brain in select patients with cryoglobulinemia show multiple small hyperintensities compatible with ischemic lesions. The association of stroke with cryoglobulinemia may relate to hyperviscosity, cold agglutinization of erythrocytes, or defective clotting and platelet functions. Stroke may result when blood vessels in the nervous system are injured by mixed cryoglobulin deposition that causes an immune complex–mediated vasculitis. In support of this possibility, Serena and co-workers found evidence of vasculitis in the vasa nervorum of small vessels in the brain of a patient with vascular dementia secondary to cryoglobulinemia.

Plasmapheresis has been effective in some patients with neurologic complications, presumably through lowering of cryoglobulinemia and therefore improvement of the microcirculation. Beneficial results may be obtained in some cases by minimizing cold exposure. Immunosuppressive agents have had limited success, as have cytotoxic agents, and controlled clinical trials are needed before any definitive treatment recommendations can be made.

Stroke and Malignancy

CNS lesions are present on postmortem examination in approximately 30 percent of patients with cancer. Although the most common manifestation is metastatic disease to the brain, hemorrhagic and ischemic infarcts make up a substantial percentage of these lesions. Approximately 50 percent of those with evidence of cerebrovascular disease are symptomatic, although a diffuse encephalopathy, rather than focal neurologic deficits, is the most common presenting symptom.

The results of one study suggest that, at least in elderly patients with cancer, conventional stroke risk factors account for most ischemic events. Other studies clearly implicate malignancy-specific causes of stroke. There is a high incidence of embolic strokes in cancer patients, due either to malignancy-related hypercoagulable states or to cardioembolism. Four etiologic categories of cerebrovascular events have been described in patients with cancer: direct tumor effects, coagulation disorders, infections, and complications of therapeutic or diagnostic procedures. The cause of cerebrovascular events in patients with cancer often correlates with the type of primary tumor, the extent of metastases or disseminated malignancy, and the type of cancer therapy administered.

Nonbacterial Thrombotic Endocarditis

A case of “thromboendocarditis” was first described by Ziegler in 1888, when fibrin deposits were found at autopsy on cardiac valves in a patient with cancer. Since then, the terms marantic and cachectic endocarditis have been used to describe the same clinical entity. Although nonbacterial thrombotic endocarditis (NBTE) may represent a continuum with intravascular coagulation and malignancy-induced DIC, this clinical entity warrants separate consideration because it plays a prominent role in the pathogenesis of cerebrovascular disease and stroke. Although the prevalence of NBTE is relatively low in patients with cancer (approximately 1%), it is a leading cause of stroke in these patients.

Pathologically, NBTE consists of platelet-fibrin vegetations that develop on the cardiac valves, with the aortic and mitral valves ( Fig. 11-4 ) being the most common sites of involvement. These friable vegetations frequently embolize, causing infarction in brain, lung, kidney, and cardiac tissue. Symptoms of brain ischemia may occur concurrently with pulmonary embolism, myocardial infarction, or peripheral emboli, and the presence of these clinical events in multiple locations increases the probability of a cardiac embolic source.

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