Journal of Neuro-Ophthalmology, March 2003, Volume 23, Issue 1

Coagulopathies and Arterial Stroke

Although hypercoagulable states are most often associated with venous thrombosis, arterial thromboses are reported in protein S, protein C, and antithrombin III deficiencies, factor V Leiden and prothrombin gene mutations, hyperhomocysteinemia, dysfibrinogenemia, plasminogen deficiency, sickle cell disease, and antiphospholipid antibody syndrome.

NANOS SYMPOSIUM Coagulopathies and Arterial Stroke MarkL. Moster, MD Abstract: Although hypercoagulable states are most often associated with venous thrombosis, arterial thromboses are reported in protein S, protein C, and antithrombin III defi­ciencies, factor V Leiden and prothrombin gene mutations, hyperhomocysteinemia, dysfibrinogenemia, plasminogen deficiency, sickle cell disease, and antiphospholipid anti­body syndrome. ( JNeuro- Ophthalmol 2003; 23: 63- 71) ost patients presenting with arterial stroke have dia­betes, hypertension, hyperlipidemia, smoking, or valvular heart disease as underlying risk factors. When such risk factors are absent, one should suspect hypercoagulable states as causative. The inherited hypercoagulable syn­dromes primarily affect veins, and only rarely cause arterial thrombosis. The acquired hypercoagulable states, such as the antiphospholipid antibody syndrome, are more com­monly implicated in arterial stroke. The predilection for ve­nous as opposed to arterial stroke may be partly due to the differing mechanisms of thrombosis on the venous and ar­terial sides of the circulation and within various organs ( 1). Stasis is a major predisposing factor in the venous circula­tion, whereas endothelial damage is a more important pre­disposing factor in the arterial circulation. PROTEIN C, PROTEIN S, AND ANTITHROMBIN III ( AT3) DEFICIENCY It has been suggested that deficiencies in protein C, protein S, and antithrombin III are usually not associated with arterial thrombosis ( 4). While this is generally true, arterial stroke may occur. The reported prevalence of pro­tein C, S, and AT3 deficiencies in arterial ischemic stroke ranges up to 23% in various studies ( 5). Protein C deficiency has occasionally been associ­ated with arterial ischemic stroke ( 2- 6). In a series of 50 Department of Neurosensory Sciences, Albert Einstein Medical Cen­ter, Department of Neurology, Thomas Jefferson University, and Division of Neurology, Wills Eye Hospital, Philadelphia, Pennsylvania. Address correspondence to Mark L. Moster, MD, Albert Einstein Medical Center, York and Tabor Roads, Philadelphia, PA 19141, USA; E- mail: mmoster@ aol. com Peer reviewed and modified from an oral presentation at the 28th An­nual Meeting of the North American Neuro- Ophfhalmology Society, Cop­per Mountain, Colorado, February 9- 14, 2002. consecutive stroke patients with a mean age of 65 years, 4% had protein C deficiency, compared with 1% of controls ( 7). In another series of 50 consecutive arterial stroke patients aged less than 45 years ( 8), 3 ( 6%) had protein C deficiency without other risk factors. Only one patient had a history of transient ischemic attack ( TIA) and peripheral venous thrombosis. In another study ( 9) of 60 stroke patients aged less than 45 years, three ( 5%) had protein C deficiency. Ten of 23 children with cerebrovascular occlusion of unknown etiology were found to have low protein C levels ( 10). Two children with stroke occurring at age 17 months and 13 years had protein C deficiency, one with coexisting protein S deficiency ( 11). In a series of 53 patients with known pro­tein C deficiency ( 12), 6 ( 11%) had arterial thromboses, one occurring in infancy. In a Japanese study of 94 patients with protein C deficiency ( 13), 20 ( 21%) had had arterial strokes. These patients had strokes at a younger age than those with­out protein C deficiency ( 57.4 years versus 64.6 years, P = 0.022) ( 13). In contrast, other studies have found no in­crease of protein C even in young stroke patients. In one study ( 14), only one of 329 stroke patients aged between 15 and 45 years had protein C deficiency. Thus, it appears that protein C deficiency is weakly associated with ar­terial stroke. Protein S deficiency has been associated with cere­bral arterial ischemia more often than has protein C defi­ciency. However, conflicting reports limit the reliability of this association ( 3). There are some convincing anecdotes but few adequate studies. Among the anecdotes ( 15), there is one of a 44- year- old woman who had a left temporal in­farct with arterial occlusion by angiography followed 1 month later by deep venous thrombophlebitis of the lower extremity. Two other family members with the deficiency had deep venous thrombosis. In another report, two unre­lated teenage girls had multiple arterial occlusions. One girl was 16 years old with brainstem infarction associated with right vertebral artery stenosis and posterior cerebral artery occlusion; 18 months later, occlusion of the right vertebral artery developed. The other girl was 17 years old with left hemispheric infarction, multiple arterial stenoses, and left anterior cerebral artery occlusion ( 16). There are reports of a 27- year- old woman with left temporoparietal infarction followed by deep venous thrombosis and pulmonary em­boli ( 17), and of a 6- year- old child with a basal ganglionic Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. J Neuro- Ophthalmol, Vol. 23, No. 1, 2003 63 JNeuro- Ophthalmol, Vol. 23, No. 1, 2003 NANOS SYMPOSIUM stroke ( 18). In a study of 36 consecutive young adults with unexplained cerebral infarction ( 19), five ( 13.8%) had pro­tein S deficiency. In another study of 35 patients ( average age = 46 years) with cerebrovascular disease of unclear cause ( 20), 8 ( 23%) had protein S deficiency. In a subse­quent study of all patients admitted to a stroke unit ( mean age = 59 years) ( 20), 19 of 98 ( 19%) with cerebral infarction had protein S deficiency. Of sixty stroke patients aged less than 45 years, 2 ( 3%) had protein S deficiency ( 9). In a pro­spective assay of hypercoagulable states among 22 of 267 patients with stroke ( 21), 4 ( 27%) had low protein S and arterial thrombosis. There were also family members with protein S deficiency ( 21). A Swedish prospective study of stroke patients younger than age 65 ( 22) found 4 of 66 ( 6%) patients with TIA and stroke had low free levels of protein S. All protein S deficiency patients had elevated anticardio-lipin antibodies ( ACLs). This study suggests an association between ACLs and free protein S deficiency in ischemic stroke patients. Conversely, numerous studies show a less frequent association of stroke and protein S deficiency ( Table 1). In an Iowa cohort, only 1 of 329 stroke patients aged between 15 and 45 years had protein S deficiency ( 14). A Swedish study of 107 patients aged between 18 and 44 years found only one with protein S deficiency ( 23). In a study that mea­sured free protein S in 94 adults with acute cerebral infarct and controls ( 24), a low level of free protein S ( less than 15%) was more common among patients with infarct than among controls ( 11% versus 5%), but the difference was not statistically significant. The authors concluded that de­ficiency of protein S is not a major risk factor for ischemic stroke. Thus, although there is conflicting evidence, pro­tein S deficiency appears to have a mild association with arterial stroke. Antithrombin III ( AT3) deficiency has only rarely been associated with stroke. Anecdotal cases include two TABLE 1. Association of coagulopathies with arterial stroke Association with Coagulopathy arterial stroke Protein C deficiency Protein S deficiency Antithrombin III deficiency Factor V Leiden mutation Prothrombin gene mutation Hyperhomocysteinemia Dysfibrinogenemia Plasminogen deficiency Sickle cell anemia Antiphospholipid antibodies Weak Mild Rare Mild Mild Moderate Rare Rare Common Common sisters, aged 27 and 40, with multiple arterial occlusions and deep venous thrombosis ( 25). In another report ( 26), a patient had recurrent TIAs beginning at age 28. At age 33, he developed branch occlusions of the right anterior cere­bral and right middle cerebral arteries. Plasma heparin co-factor activity was low in the patient and his father. ( Plasma heparin cofactor deficiency is a subtype of AT3 deficiency in which functional abnormality is limited to the heparin binding site of AT3; AT3 antigen is normal but heparin co-factor activity is low.) In a study of 60 stroke patients aged less than 55 years ( 9), 5 ( 8%) had AT3 deficiency; all had suffered carotid artery territory strokes. Two of the patients had acquired AT3 deficiencies; the other three had heterozygous inher­ited deficiencies. In 66 Swedish stroke patients aged less than 65 years ( 22), three ( 5%) had low AT3 levels. In 36 consecutive patients aged less than 40 years who had cere­bral infarcts of undetermined cause, ( 19) only one had AT3 deficiency. In a prospective assay of 22 of 267 stroke pa­tients referred for coagulation studies ( 21), one had isolated AT3 deficiency. Another study found only one of 329 arte­rial stroke patients aged between 15 and 45 years had AT3 deficiency ( 14). Thus, the evidence linking AT3 deficiency with arterial stroke is weak. FACTOR V LEIDEN MUTATION The factor V Leiden mutation ( FVLM), also called " activated protein C ( APC) resistance," is the most com­mon inherited coagulopathy associated with stroke. How­ever, there is conflicting evidence as to whether FVLM is an important risk factor for arterial stroke. In a review of nu­merous studies, APC resistance was found in up to 38% of patients with arterial stroke ( 5). Three pertinent anecdotes have been described ( 27). A woman with multiple venous thromboses beginning at age 29 developed left middle ce­rebral artery occlusion after discontinuing anticoagulation at age 42. A 50- year- old woman without vascular risk fac­tors developed left middle cerebral artery occlusion. Her brother had had venous thromboembolism and myocardial infarction. A third patient was an 8- month- old boy with bi­lateral parietal infarcts in a family with FVLM. A study of 81 patients with TIA or minor arterial stroke ( mean age = 65 years) ( 28) found an FVLM prevalence of 12.3% compared with 4.9% in controls ( odds ratio = 2.75). Numerous studies of younger patients have shown an association between arterial stroke and FVLM. A study of 225 stroke patients aged younger than 45 years ( 29) found no significant association with FVLM, but in a subgroup of 94 patients with " cryptogenic" cerebral ischemia, 15.9% had FVLM compared with 6.4% of controls ( odds ratio = 3.0). In a study of 30 patients with stroke ( 30), 3 had FVLM. One patient was a 39- year- old man with a TIA, another a 26- year- old woman with a posterior cerebral infarct during Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 64 © 2003 Lippincott Williams & Wilkins NANOS SYMPOSIUM JNeuro- Ophthalmol, Vol. 23, No. 1, 2003 the eighth month of pregnancy, and the third a 45- year- old man with a right middle cerebral artery occlusion who had had multiple prior strokes. None of these patients had a his­tory of venous thrombosis. In a study of 206 young people with stroke ( median age = 39 years), FVLM patients had an odds ratio of 2.56; among women, the odds ratio was 3.95. In 95 Italian patients aged less than 45 years who had focal cerebral ischemia ( 31), 4 ( 4.2%) had FVLM compared with 1.6% of controls ( odds ratio = 2.7). Among strokes of un­determined cause, 12% had FVLM compared with only 1.5% among strokes with a known underlying cause ( 31). Another study ( 32) found that among 105 stroke patients with an average age of 39 years, 14.9% had FVLM, com­pared with 4.2% of controls ( odds ratio = 4.03). Among 50 consecutive LIA patients aged between 20 and 45 years, 38% had FVLM ( 33). An Indian study of 37 arterial stroke patients aged between 4 and 42 years found eight patients ( 22%) with APC resistance ( 34). In 30 patients with juve­nile or recurrent stroke, 20% o had APC resistance compared with 2% o of controls ( 35). In 33 Austrian children with isch­emic stroke, 6 ( 18%) had FVLM, exceeding the expected 4.6% ( 36). Of 18 children with arterial thrombosis, includ­ing stroke, seven ( 38%) had FVLM compared with 5.1% of controls ( 37). A study of 30 patients with known FVLM found 16 with stroke, 11 of whom were younger than 50 years of age ( 38). In 166 patients with FVLM, 114 had thrombotic events; presumed arterial stroke or LIA was found in 11 patients, with an average age of 45 years ( 39). Many other studies do not show an association be­tween arterial stroke and FVLM ( 40), including the large prospective Physicians' Health Study ( 41). Lhe Cardiovas­cular Health Study of 5,201 men and women over age 65 found 373 cases of arterial disease including stroke. Lhe odds ratio of FVLM was 0.77 for stroke and 1.33 for LIA, suggesting that FVLM is not a risk factor for arterial throm­bosis in the elderly ( 42). In another study of 236 patients with ischemic stroke, LIA, or myocardial infarction ( 43), an FVLM was seen in 4.5%, not significantly different from healthy blood donors with 2.9%. In 125 consecutive pa­tients with cerebrovascular disease, there was no increased incidence of FVLM ( 44). In 66 patients with stroke without major risk factors, there was 7.5% o APC resistance, with 3 patients showing FVLM ( 4.5%), not significantly different from controls with stroke ( 45). In elderly patients, 2.5% o of 161 patients had FVLM, no different from controls, indi­cating again that FVLM is not a significant risk factor in elderly patients ( 46). In 386 randomly selected cases of acute stroke aged between 65 and 89 years, FVLM was not a risk factor ( 47). Negative studies in younger patients include 23 con­secutive patients younger than age 45, in whom no increase in FVLM was observed ( 48). A case- control study of young women aged between 18 and 44 years in Washington state found only one of 406 patients with FVLM ( 49). Of 35 chil­dren with stroke, two had FVLM ( odds ratio = 2.5), but the difference did not reach significance ( 50). In 67 children with arterial stroke, 12% were found to have FVLM com­pared with 5.2% of controls, which was not significant. However, larger numbers of patients might have confirmed an association ( 5). One study looked at the clinical course of LIA and stroke patients with FVLM compared with LIA and stroke patients without FVLM. There were no differ­ences with regard to age at time of the first event or other vascular events. Recurrences were seen in 38% o of both groups. There were no significant differences in other risk factors for stroke ( 51). Although some of these studies show an association between arterial stroke and FVLM, they are limited by ob­solete assays, selected patient populations, or use of the modified activated APC without PCR confirmation. Were these limitations to be taken into account the cumulative prevalence rate of 7%> for FVLM would have resulted, in an odds ratio of 1.6 for having the FVLM and stroke at all ages and 3.1 for arterial stroke occurring before age 50 ( 5). Therefore, it appears that FVLM is only mildly associated with stroke. PROTHROMBIN GENE MUTATION The G20210A mutation in the prothrombin ( factor II) gene is the second most common hereditary cause of ve­nous thrombosis ( 6). Its association with arterial stroke re­mains controversial. In 71 Brazilian patients with arterial disease, including stroke, 5.7% o had the prothrombin muta­tion compared with 0.7% o in the control group ( 52). In 72 patients aged less than 50 years, there were 9.7% o heterozy-gotes and 2.7% o homozygotes for the prothrombin mutation with only 2.5% o heterozygotes in controls. The odds ratio for ischemic stroke associated with the prothrombin mutation was 5.1 ( 53). In contrast to the above studies, other investigations have not shown an association between stroke and the pro­thrombin mutation. The Physicians' Health Study prospec­tively evaluated 4,916 men for myocardial infarction, stroke, or venous thrombosis; an odds ratio of 1.05 was found ( 54). In 195 patients with coronary or cerebrovascu­lar disease, there was a mutation prevalence of only 4% ( 55). In 104 patients with cerebral infarct, there was no as­sociation with the prothrombin mutation. In the same study, 7.3% of patients with deep venous thrombosis were positive ( 56). Of 125 French stroke patients aged less than 45 years, 3.7% of controls and 6.4% o of patients had the prothrombin mutation, a statistically insignificant difference. In the eight patients with the mutation, there were other abnormalities, including protein C, protein S, cardiac embolism, and arte­rial dissection. The authors suggest that this mutation pre­cipitates ischemia in patients who are young and have other Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 65 JNeuro- Ophthalmol, Vol. 23, No. 1, 2003 NANOS SYMPOSIUM abnormalities but not in an unselected population ( 57). Among 50 children with stroke, there was no increased odds ratio for the prothrombin mutation ( 50). A review of 13 studies found a cumulative prothrombin mutation preva­lence of 4.5% at all ages ( odds ratio = 1.4) and 5.7% among those aged less than 50 years ( odds ratio = 1.9). ( 5). In sum­mary, prothrombin gene mutation is only mildly associated with arterial stroke. HYPERHOMOCYSTEINEMIA Numerous mechanisms for homocysteinemia-induced ischemia have been proposed ( 1,58- 61). These in­clude an increase in adhesiveness of platelets, activation of the coagulation cascade, conversion of LDL cholesterol into proatherogenic forms, and endothelial damage with in­creased tissue factor expression. The most severe manifes­tations of elevated homocysteine occur in congenital ho-mocystinuria, with homocysteine concentrations of up to 400 Limol/ 1 ( 62). Patients present with premature athero­sclerosis, thromboembolism, mental retardation, seizures, psychiatric disorders, skeletal deformities ( Marfanoid hab­itus), and dislocated lenses. They tend to have myocardial infarctions and ischemic strokes in young adulthood and decreased life expectancy ( 60,63). Evidence from over 20 case- control studies, includ­ing more than 2,000 individuals, has validated the relation­ship between elevated homocysteine and accelerated ath­erosclerosis ( 62). Patients with increased homocysteine have more severe carotid artery disease than those with nor­mal levels ( 64). Elevated homocysteine increases the odds of carotid intimal thickening more than three- fold ( 59). A British Regional Heart study ( 65) demonstrated a powerful independent relationship between non- fasting homocys­teine level and stroke incidence. At a homocysteine concen­tration greater than 15.4 umol/ 1, the odds ratio rises to 4.7. In an Irish study ( 66), 42% of 38 stroke patients had el­evated homocysteine. A Swedish study ( 67) found that dur­ing acute stroke, homocysteine levels were lower than in controls, but 1 to 2 years after stroke, they were higher. A meta- analysis of 27 studies, including 11 concerned with cerebrovascular disease, ( 68) concluded that elevated ho­mocysteine is an independent risk factor for stroke with an odds ratio of 2.5. It is an independent risk factor similar to smoking and lipids, particularly among patients who have high blood pressure ( 69). It has been suggested that patients may become as familiar with their homocysteine levels as with their lipid levels and blood pressure ( 63). With regard to the methylenetetrahydrofolate ( MTHFR) reductase mutation, a cause of elevated ho­mocysteine, numerous studies do not support an increased stroke risk. Among 37 children with stroke, the odds ratio for MTHFR was a nonsignificant 1.7, but the study may have been too small to show an effect ( 49). In 72 stroke patients aged younger than 50 years, there was no preva­lence difference for MTHFR ( 70). Another study of patients with TIA or minor stroke also found no difference in MTHFR between controls and stroke patients ( 28). Clinical trials using folic acid, B12, and pyridoxine to prevent myocardial infarction and stroke have begun ( 63,71- 72). Specific recommendations regarding treatment of patients without vascular disease are not yet available. In the interim, use of folic acid and B vitamins may be consid­ered for patients with elevated homocysteine levels ( 73). Based on this evidence, homocysteine appears to be an in­dependent risk factor moderately associated with stroke. DYSFIBRINOGENEMIA Dysfibrinogenemia is a rare cause of arterial throm­bosis, including stroke, in children and young adults ( 4,74). For instance, a brother and sister aged 21 and 26 had throm­botic episodes in the carotid and abdominal aortic distribu­tion. An asymptomatic relative also had dysfibrinogenemia ( 75). A dysfibrinogenemic man who suffered two throm­botic strokes before age 30 has been reported ( 76). PLASMINOGEN DEFICIENCY Plasminogen deficiency, a rare autosomal recessive disorder, may cause deep venous thrombosis ( 4). A case of arterial stroke with apparent autosomal dominant inheri­tance has also been reported ( 77). There is also a case report of arterial stroke in a woman taking oral contraceptives who also had plasminogen deficiency and FVLM ( 78). SICKLE CELL ANEMIA Stroke is common in patients with sickle cell anemia, occurring in 11% of patients by age 20 ( 79), with infarction mainly in the internal carotid and middle cerebral arteries. Patients at risk for stroke may be determined by screening with transcranial Doppler ultrasonography, which is recom­mended at 6- month intervals ( 73). Those at elevated risk should be considered for blood transfusion therapy, which can prevent strokes in children with sickle cell anemia ( 73,80), although such transfusions carry other risks. ANTIPHOSPHOLIPID ANTIBODIES Antiphospholipid antibodies ( APL) antibodies are found in numerous clinical settings ( 81- 87). Patients with systemic lupus erythematosus ( SLE) present with clinical thrombosis associated with lupus anticoagulant ( LA) and/ or other anticardiolipin antibodies ( ACLs). In the pri­mary antiphospholipid antibody syndrome ( PAPS), throm­bosis occurs in the absence of collagen vascular disease. A third setting involves elderly patients with atherosclerosis who may have APLs as an epiphenomenon. A fourth setting is infectious diseases ( syphilis, viral, malaria, parasitic, Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 66 © 2003 Lippincott Williams & Wilkins NANOS SYMPOSIUM JNeuro- Ophthalmol, Vol. 23, No. 1, 2003 HIV) or medication exposure ( neuroleptics, quinidine, procainamide) ( 81). PAPS represents a clinical syndrome including thromboembolic disease, arterial occlusions, spontaneous abortions, and thrombocytopenia, together with laboratory evidence of ACL or LA ( 3). In one series of 70 patients, 31 had arterial thrombosis, including myocardial infarction, LI A, multi- infarct dementia, or strokes. Lhere is also a risk of chorea gravidarum with PAPS ( 3,88). Catastrophic anti- phospholipid syndrome is a rare ac­celerated form of PAPS involving widespread thrombi in the kidney, lung, heart, gastrointestinal system, and brain, leading to multi- organ failure and death in more than 50% of cases. Lhrombocytopenia and hemolytic anemia occur in 25%, and there may be elevated fibrin split products without other evidence of disseminated intravascular coagulation ( 81). The prevalence of APLs in the normal population varies. Many studies report a 2 to 7% range ( 81), but it ap­pears to increase with age, up to 51.6% among patients aged between 67 and 95 years ( 90). Among patients with APLs, 20% present with stroke. Extracranial venous thrombosis is most common, but cerebrovascular disease accounts for more morbidity. Lhere are large and small arterial occlu­sions in the anterior or posterior circulations, as well as la­cunar infarcts and venous occlusions ( 59,63). Lhe high fre­quency of stroke may reflect selective vulnerability of brain vasculature ( 81). APL patients tend to have an exception­ally high stroke recurrence rate ( 88), often with similar manifestations. That is, patients presenting with deep ve­nous thrombosis tend to have recurrent deep venous throm­bosis; those who present with arterial stroke are likely to have recurrent arterial stroke ( 91). Although there is much evidence for association of APL with arterial stroke, many problems exist in interpret­ing the reported studies, including lack of standardization of laboratory tests or criteria for a positive result ( 5). Because titers may fluctuate, repeat studies for confirmation are im­portant but are not routinely reported ( 5). Lhe stroke risk is greatest with IgG APL greater than 40 GPL units; it may not be significant with lower levels. IgM carries an intermedi­ate risk and IgA a minimal risk of stroke ( 89,92- 94). Strokes may be preceded by migraine- like episodes, amaurosis fugax, or other LIAs ( 84,95). However, the inci­dence of stroke in patients with migraine and APL is low ( 96). With recurrent strokes, multi- infarct dementia may occur ( 81,97). In case- controlled studies, APLs are an inde­pendent risk factor for stroke and are present in 7 to 10% in an unselected stroke population ( 95,98- 99). One study found 9.7% of stroke patients had ACL compared with 4.3% in controls ( 98). In another study with an average age of 58 years, 8.2% had IgG ACL compared with 1.6% of controls ( 94). The association of stroke with APLs is stron­ger in adults younger than 50 years of age ( 95,100) and per­haps in children ( 81). A Lexas study of stroke and LIA pa­tients younger than 50 years of age ( 100) found 46% with APL but in only 8% of controls. In a Canadian study of younger patients, ( 101) 3 of 51 with stroke or LIA had LA. In a Polish study of 49 patients below age 50 with first stroke or LIA ( with liberal definition of positive titer), 32% were positive, but only 6% had IgG greater than 20 GPL ( 102). An Italian study of 55 stroke or LIA patients between age 15 and 44 ( 103) found 18% with LA or ACL. Among patients followed for an average of 35 months, recurrent thrombosis was seen in 40% of APL patients and in only 4% of non- APL patients ( 103). In a study of 60 stroke patients younger than age 40 years, ( 104) 23% had low to medium positive titers compared with 3% of controls, which were all low positive. Lwo children with APL and stroke also had decreased protein C or protein S ( 105). In contrast to these positive studies, the Physician Health Study ( 106) found no association between APLs and arterial stroke, but the study was performed on plasma fro­zen for almost 8 years. A Canadian study ( 107) found that 12% of stroke patients had APL compared with 10% of con­trols, but the study had a high number of false positives because of loose criteria in the control population. Lhe au­thors also included low titers ( less than 20 GPL) as positive. A negative Scottish study ( 108) had many limitations, in­cluding an elderly population and inclusion of elevated IGA as a positive APL, which carries little risk. However, if one excludes IGA, then 23% of patients and 15% of controls had high titers. If one included only IgG, the ACLs were significantly greater in the patient population ( 108). Although there is wide variability in the reported prevalence of APL in stroke patients of all ages, many con­trolled studies of ACL or LA have found a significant asso­ciation ( 5). There is a well- established association between APL and stroke in patients with PAPS and in SLE-associated APL, but unselected patients likely have an as­sociation as well ( 88). A multiethnic case control study ( 109) recently showed a similar ACL increase in whites, blacks, and Hispanics with stroke. The cumulative odds ra­tio for ACL is 5.8 below age 50 and 2.5 at all ages. For LA it is 2.1 in patients less than 50 years of age and 2.9 at all ages ( 8). There is also an association of APLs with heart disease and an increase in ACLs with increasing stroke risk factors, such as age, atrial fibrillation, valvular disease and congestive heart failure ( 90,110- 112). Therefore, ACL IgG titers may be a risk factor for atherosclerosis in general rather than a specific causal factor for stroke ( 5). A recent observation is that antibodies that react to oxidized low den­sity lipoproteins ( LDLs) can cross react with cardiolipin. Lherefore, in elderly patients with stroke, these measured Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 67 JNeuro- Ophthalmol, Vol. 23, No. 1, 2003 NANOS SYMPOSIUM antibodies may be a manifestation of underlying atheroscle­rosis and not a true APL syndrome ( 59). Valvular heart dis­ease is a contributing factor in many patients with APL. Mitral and aortic valvular emboli may contribute to multi­focal cerebral ischemia ( 5). IN SLE, 40 to 60% of patients have valvular lesions, which are more frequent with APLs. Valvular lesions are also seen in 30 to 60% of patients with PAPS. Valvular thickening may be accompanied by veg­etations ( 5) and occasionally overt thrombi ( 5,81,113). Sneddon syndrome presents with stroke in associa­tion with livedo reticularis, sometimes together with mi­graine. Some patients have APLs ( 105,114), which may worsen the prognosis ( 115). Although dementia in patients with APL may be at­tributed to multiple infarcts, subtle cognitive deficits may be associated with APL alone, even without ischemic mag­netic resonance imaging ( MRI) changes. Lhese patients may perform poorly on learning, memory, and visual por­tions of neuropsychologic tests ( 116). Mechanisms other than ischemia may also account for migraine, chorea, and transverse myelopathy ( 86). In one case with " lupoid scle­rosis," APL might have been binding to myelin ( 117). In summary, antiphospholipid antibodies have a moderate as­sociation with arterial stroke. THE COAGULATION EVALUATION OF THE STROKE PATIENT The decision to evaluate stroke patients for hyperco­agulable states should depend on the expectation of a posi­tive yield of the tests and on whether positive results would change the intended therapy. A study investigating the ap­propriateness of coagulation tests on an academic stroke service found that 29% of those tested were not likely to have their management affected by the result ( 118). Hypercoagulability studies should be ordered when one or more of the following criteria are met: ( 1) few risk factors for arteriosclerosis; ( 2) recurrent thromboses; ( 3) a strong family history of thrombosis; or ( 4) a young age at the time of thrombosis. Under these circumstances, one might consider obtaining tests for all the known hyperco­agulable states ( 5). However, there are certain features that should guide testing toward specific entities. For example, clinical fea­tures that suggest a workup for APLs are idiopathic throm­bocytopenia, multiple miscarriages, thrombosis on both the arterial and venous side, livedo reticularis, early age of thrombosis, noninfectious endocarditis, or a history consis­tent with lupus or collagen vascular disease. When testing for APLs, it is useful to wait 6 weeks after the stroke and when there is no evidence of active infection or inflamma­tion, as falsely elevated and falsely depressed APL levels have been seen with acute thrombosis. Testing for APC resistance from FVLM or prothrom­bin gene mutation should be considered in patients with ce­rebral arterial or venous thrombosis without any precipitat­ing factors, thrombosis during pregnancy, or a positive fam­ily history. The tests should be done 2 months after stroke, and the patient should have had heparin treatment stopped for at least a day, and warfarin stopped for at least 2 weeks, as thrombosis and anticoagulation affect these assays. Features that should prompt testing for protein S, pro­tein C, and antithrombin III deficiencies include venous or arterial thrombosis occurring in patients aged below 45 years, recurrent thrombosis without precipitating factors, thrombosis in unusual locations, a positive family history of thrombosis, thrombosis during pregnancy, warfarin-induced skin necrosis ( protein S, protein C) or resistance to heparin ( AT3 deficiency). These tests should also be per­formed 2 months after the stroke and after the patient has been taken off warfarin for at least 2 weeks. The tests should be repeated for confirmation, and family members should be tested. 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