Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 50, Num. s1, 2002, pp. S21-S29

Neurology India, Vol. 50, (Suppl. 1), Dec, 2002, pp. S21-S29

Pro-thrombotic States in Stroke

D. Nagaraja, R. Christopher*

Departments of Neurology and Neurochemistry*, National Institute of Mental Health and Neurosciences, Bangalore-560 029, India.
Correspondence to : Dr. D. Nagaraja, Professor and Head, Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, India.

Code Number: ni02159

Summary

A large number of prothrombotic states both inherited and acquired, have been linked with ischemic cerebrovascular disease. Inherited deficiencies of the plasma coagulant inhibitory proteins, mainly protein C, protein S, antithrombin III, heparin cofactor-II, and protein Z, defects in the coagulation cascade proteins such as Factor V Leiden and prothrombin gene G20210A mutation, abnormalities of fibrinolysis and hyperhomocystinemia have been associated with stroke. Patients with disorders of the formed blood elements like polycythemia vera, sickle cell anaemia and essential thrombocythemia can also be predisposed to stroke. The most frequently identified acquired states associated with ischemic stroke are the anticardiolipin antibodies and lupus anticoagulants. Screening for occult prothrombotic diathesis is necessary for young patients with stroke of unidentifiable cause, for those with prior venous thrombosis and those with a family history of thrombosis. Knowledge in this area is still incomplete and evolving rapidly.

Key words : Stroke, Thrombophilia, Prothrombotic stroke, Cerebral infarction.

Introduction

A predisposition to thrombotic events is often termed a hypercoagulable state or 'a prothrombotic state'. Hypercoagulable states are a recognized, albeit uncommon etiology of ischemic stroke. In approximately 1% of all patients with ischemic stroke and in up to 4% of young adults with stroke, the major precipitant of brain ischemia is a coagulopathy or a prothrombotic disorder.¹ The contribution of a prothrombotic disorder in children with ischemic stroke has been reported to be 20% to 50% in most studies.^2-4

Thrombosis is central to the major pathophysiological mechanisms of ischemic stroke. Intravascular thrombosis involves a dynamic interplay between the normal blood vessel and certain plasma proteins, platelets, fibrin formation and fibrinolysis. Interaction between the three plasma proteins, protein C, protein S and antithrombin and normal vascular endothelial cells form a particularly important barrier to thrombosis. A defect in any of these natural mechanisms may allow thrombogenesis even when a minimum trigger is present. The familial thrombotic coagulopathies include deficiencies in concentration or function of the natural coagulation inhibitor proteins like protein C, protein S, antithrombin III, heparin cofactor-II, and protein Z, abnormalities of the coagulation cascade proteins including Factor V Leiden, and Prothrombin gene mutation G20210A, hematologic abnormalities like sickle cell disease, and polycythemia vera, hyperhomocystinemia, dysfibrinogenemia and other abnormalities of fibrinolysis. The acquired disorders of hemostasis associated with stroke constitute a larger proportion of the important stroke-related coagulopathies. Antiphospholipid antibodies including the anticardiolipin antibodies and lupus anticoagulants are the most frequently identified acquired states associated with ischemic stroke. Acquired, perhaps transient, abnormalities of platelets, coagulation inhibition, and fibrinolysis may contribute to a prothrombotic state and brain ischemia in synergy with other mechanisms. Recognition of these uncommon conditions has burgeoned during the past two decades and the causes of hypercoagulability and overt thrombosis are becoming clearer with the recent enhanced knowledge of hemostasis and the development and utilization of test systems useful for evaluating patients with thrombotic disorders. It is important to define individuals harboring these defects because this allows appropriate antithrombotic therapy to decrease risks of recurrence and determines the length of time the patient must remain on therapy for secondary prevention. In addition identification of a definable cause for stroke allows testing of family members and could aid in prevention.

Protein C defects

Protein C, a major inhibitor of the procoagulant system, is a vitamin K-dependent, 56,000-dalton protein synthesized in the hepatocyte.⁵ Thrombin activates protein C to its active form, protein Ca, which is a serine protease. Activated protein C exerts its primary inhibitory activity by inactivating clotting factors Va and VIIIa, the two cofactors necessary for thrombin and factor X activation. Protein C inhibitory activity in degrading activated clotting factors is markedly enhanced by protein S. Activated protein C may also promote fibrinolysis by neutralizing plasminogen activator inhibitor-1. Protein C deficiency can exist in two forms. The most common form, type I, is characterized by reduction in both immunologic and biologic function of the protein, whereas, the less common Type II protein C deficiency, is characterized by normal protein C antigen levels but with decreased functional activity. Congenital deficiency of protein C is inherited as an autosomal dominant disorder. Homozygous patients often die of thrombosis in early infancy. Clotting is common in heterozygous individuals whose protein C levels are 30-60% of normal. As many as 75% of the affected individuals have one or more thrombotic events. Acquired protein C deficiency is often seen in patients with acute disseminated coagulation, extensive deep vein thrombosis, severe liver disease, infections, malignancy, adult respiratory distress syndrome and following L-asparaginase therapy.

Arterial strokes, cerebral venous thrombosis, hemispheric transient ischemic attacks, and amaurosis fugax have all been described in patients with hereditary protein C deficiency. In a study of 50 consecutive patients younger than 45 years who had non-hemorrhagic stroke, decreased protein C activity and antigens were found in 3 patients.⁶ The cerebral angiograms of these patients showed segmental occlusion of intracranial arteries. Anzola and colleagues⁷ found abnormally low levels of protein C in 14% of 43 consecutive patients admitted with acute stroke. These patients with protein C deficiency had a significantly lower initial score on the Barthel and Canadian neurological scales, a higher prevalence of emboligenic cardiac diseases, and a higher mortality at six months. They suggested that low levels of protein C in the acute stroke reflect massive activation of the coagulation factors and were predictive of an adverse outcome. The Atherosclerosis Risk in Communities Study showed that reduced levels of protein C were associated with cerebral infarction identified by MRI.⁸

Protein S defects

Protein S, a vitamin K-dependent glycoprotein of molecular weight 70,000 Daltons serves as a cofactor for protein C-induced inactivation of the clotting factors, factor Va and VIIIa. Protein S also serves as a cofactor for protein C enhancement of fibrinolysis. Roughly 60% of protein S is bound to a C4b binding protein, and only free protein S has anticoagulant properties. Congenital protein S deficiency is inherited as an autosomal dominant trait and homozygotes often die in utero or in early infancy. Heterozygotes have a strong tendency to develop thrombosis. Decreases in protein S levels are also seen in patients receiving warfarin therapy, in severe liver disease and during pregnancy.

Congenital protein-S deficiency was first reported in 1984 by three independent groups.⁹ Both venous and arterial occlusive events associated with stroke are well described in protein S deficiency. Green and coworkers¹⁰ found 8 of 22 patients with brain infarction to have protein S deficiency. Sacco and coworkers¹¹ reported that roughly 23% of young patients admitted to hospital with stroke of unknown etiology had low free protein S levels. In a study by Schafer and von Felton, 13 of 33 patients with brain infarctions of unknown cause were found to have protein S deficiencies.¹² In contrast, other investigators have not found many young patients with stroke to have protein S deficiency.^13,3 Although the panoply of studies indicate that protein S deficiency may contribute more often to enigmatic stroke than abnormalities of other natural anticoagulant proteins, the accuracy of this view must be ascertained by better population studies.

Antithrombin deficiency

Antithrombin (AT) is a serine protease inhibitor, which serves to inhibit thrombin and factor Xa, and, to a lesser extent, factors IXa, XIa, XIIa and factor VIIa/tissue factor. The physiologic range of AT in normal human blood is quite narrow; the usual plasma concentration is about 150ug/ml. Only moderate decreases of AT are often associated with thrombosis and thromboembolism. Although, generally AT deficiency is associated with venous thrombotic events including dural sinus thrombosis in the central nervous system, cases of arterial thrombotic occlusion including stroke have also been reported. Ueyama and colleagues¹⁴ first reported a 31-year old woman with middle cerebral artery branch occlusion and brain infarction. Other cases of cerebral arterial thrombosis associated with AT deficiency have also been reported.¹⁵ In all these cases the patients were young and the large cerebral or precerebral arteries were involved. These reports indicate that adults with homozygous AT deficiency are at increased risk for ischemic cerebrovascular disease although many studies have not found AT deficiency in ischemic stroke.¹⁶ Haapanienni and coworkers¹⁷ showed that AT level in patients with mild to moderate ischemic stroke on admission showed significant correlation with stroke severity and disability at 3 months.

Acquired deficiency of antithrombin has also been reported to produce a prothrombotic state related to brain infarction. Although extensive epidemiological studies have not yet been performed, acquired anticoagulant protein deficiencies usually are associated with stroke in special clinical settings. Reduced levels of antithrombin have been found in perioperative settings, in women who are pregnant or taking oral contraceptives, and patients with malignancies, hepatic failure or nephrotic syndrome. Acute fluctuations of anticoagulant protein levels can also follow plasmapharesis and hemodialysis. When stroke is encountered in patients with any of these conditions, careful evaluation may uncover one of these prothrombotic states.

Heparin Cofactor II defects

Heparin cofactor II (HC-II) is a thrombin inhibiting glycoprotein with a molecular weight of 64,000 Daltons. The inhibitory activity of HC-II is accelerated by heparin, including heparins with low antithrombin affinity, dermatan sulfate, and other sulfated polysaccharides. HC-II is not capable of significant inhibition of factors Xa XIa, IXa, or plasmin, and in addition to thrombin inhibition, HC-II inhibits chymotrypsin. HC-II deficiency appears to be inherited as an autosomal dominant trait, with heterozygous individuals having about 50% of normal HC-II levels. The first case of congenital HC-II deficiency was reported in a 42-year-old woman with left middle cerebral artery thrombosis and an HC-II level of 50% of normal.¹⁸ Two of 4 additional family members had suffered thrombotic events and were also found to have low HC-II levels. Some studies have shown low HC-II activity in asymptomatic individuals and families, and because of this finding it appears that the clinical manifestations of hereditary HC-II deficiency can span from arterial or venous thrombosis to asymptomatic states.^19,20

Protein Z

Protein Z is a vitamin K-dependent plasma glycoprotein synthesized by the liver.²¹ Although protein Z seems to assist hemostasis by binding thrombin and promoting its association with phospholipid vesicles, it also downregulates coagulation by forming a complex with the plasma protein Z-dependent protease inhibitor, which inhibits activated factor Xa on phospholipid surfaces.²² Vasse and coworkers²³ have reported a high frequency of protein Z deficiency among 169 patients with ischemic stroke (about 20%) as well as in the general population (about 5%). These frequencies suggest a moderate ischemic risk associated with protein Z deficiency. In contrast, Wuilleman and colleagues²⁴ noted no higher prevalence of protein Z deficiency in 157 patients with a history of ischemic stroke compared to healthy controls. Clearly, these results must be confirmed and further studies are required to define the role of protein Z deficiency in ischemic cerebrovascular disease.

Factor V Leiden

The normal Factor V, a clotting factor, is activated by thrombin to produce Factor Va which has procoagulant effects. Activated protein C normally proteolytically degrades Factor Va. Recently resistance to activated protein C (APC) has been reported as the most frequently identifiable risk factor for thrombosis. Resistance to APC is an abnormally low anticoagulant response to APC and is most often due to a point mutation in the coagulation factor V gene (G-A mutation at nucleotide 1691) called the Leiden mutation. This causes replacement of amino acid residue arginine 506 by glutamine, the exact site where APC normally cleaves and inactivates the Va procoagulant. The Leiden mutation in factor V gene blocks the degradation of factor Va by activated protein C. This tilts the homeostasis to the prothrombotic side by virtue of the excess of factor Va.

Although the Factor V Leiden (FVL) is known to increase the risk of venous thrombosis including cerebral venous thrombosis, its association with strokes is a matter of continued debate. Some studies have shown a significantly increased prevalence of this hypercoagulable syndrome in stroke in young adults,^25,26 children²⁷ and neonates²⁸ whereas other studies have failed to find any difference.^29,30 Szolnoki and coworkers³¹ have showed that FVL was not a risk factor for ischemic stroke as a whole but was significantly more common in patients with large infarcts. Although the FVL on its own may not confer a significant risk for arterial thrombosis, it may do so in conjunction with other abnormalities such as hyperhomocysteinemia.³²

Another genetic component of the factor V gene that contributes to activated protein C resistance both in the presence and absence of FV 1691 G-A has been reported. This highly conserved FV gene haplotype was marked as R2 polymorphism, anA to G alteration at position 4070 in exon 13 that predicts His 1299 Arg substitution. In a case-control study of young Turkish patients with ischemic infarct, Akar et al³³ have reported that 20.8% of the 48 patients were found to carry the FV 1299 His mutation, one being homozygous. One patient who had a combination of FV1691 G-A and protein C deficiency also carried FV4070A mutation.

Prothrombin gene G20210A

Prothrombin is the precursor to thrombin in the coagulation cascade. A single mutation in the 3'untranslated region of the prothrombin gene was reported resulting in a G-to-A substitution. The mutation leads to an increased amount of circulating thrombin. The exact mechanism by which the prothrombin gene mutation results in a thrombophilic state is unclear. It is thought that the increased amount of circulating prothrombin provides a springboard upon which the clotting cascade can get started. The prothrombin gene mutation is seen more commonly in the Caucasian population. About 1-2% of the general population is heterozygous for this mutation. The prothrombin gene mutation is relatively uncommon in the native populations of India, Korea, Africa and North America. In contrast, in Spain rates of 6% have been reported. The association between ischemic stroke and prothrombin gene G20210A has been debated. The prevalence of this mutation in ischemic stroke patients has varied from 1% to 12%.³⁴ Majority of case-control studies show no association between prothrombin gene G20210A and ischemic stroke. In a large cohort of US men, the G20210A prothrombin gene variant was not associated with increased risk of myocardial infarction or stroke.²⁹ No association has also been found with an increased risk of ischemic stroke in children.³ However, a few studies have found a significant association with ischemic stroke in highly selected patients.^35,36

Activated clotting factors

Clotting factors which normally circulate in a nonactivated or zymogen form may be converted to an activated state by certain stimuli, increasing the possibility of thrombosis. These stimuli include surgical procedures, tissue necrosis due to infarction, malignancy, infections or inflammatory reactions with the release of thrombogenic cytokines such as interleukin 1 or tumor necrosis factor. A few studies suggest that high concentrations of fibrinogen, and excess concentrations of factor V, Factor VIII and factor VII may all be risk factors for ischaemic cerebrovascular disease, but their exact roles remain unknown.³⁷

Fibrinolytic defects

The fibrinolytic mechanisms provide a check on unopposed thrombus formation. Plasmin, cleaved from the zymogen, plasminogen, by tissue plasminogen activator is able to digest fibrin to soluble fibrin-degradation products. In common with the coagulation system, interplay between activators and inhibitors modulate the fibrinolytic process. Inherited abnormalities of fibrinolysis, which have been linked to thrombosis, include dysfibrinogenemia, plasminogen deficiency, plasminogen activator deficiency, and factor XII/prekallikrein deficiencies. Over 200 cases of hereditary dysfibrinogenemia have been described, where genetic mutations produce fibrinogen molecules that form clots that resist fibrinolysis. In families with these mutations, the risk of venous and arterial thrombotic events including stroke appears to be enhanced.³⁸

Hereditary plasminogen deficiency is transmitted as an autosomal dominant trait. The absence form (Type I) and the dysfunctional form (type II) have been described, and the dysfunctional form is more common.^39,40 Plasminogen-deficient patients begin to experience thrombotic events in their late teenage years. The most common manifestations are DVT and pulmonary embolisation. Arterial thrombotic and thromboembolic events are not prominent. Although plasminogen deficiency has been reported in a patients with ischemic stroke² available studies still do not permit definitive statements to be made on the association of plasminogen deficiency with a thrombotic risk.

Inherited deficiencies of tissue plasminogen activator (tPA) have been linked to venous thrombosis, including CVT, and defective release has been reported in stroke patients.⁴¹ Congenital increase in PAI-1 has also been reported but appears uncommon, although acquired increases occur commonly, especially in premature coronary artery disease.⁴² Olah and coworkers⁴³ in their study of 53 young patients with cerebral ischemia, found impaired fibrinolysis and elevation of PAI-1 in 23 patients upon admission.

Although cases of stroke have been reported in patients with hereditary deficiencies in factor XII or prekallikrein, it is controversial whether these deficiencies cause prothrombotic states.⁴⁴

Disorders of formed blood elements

Polycythemia vera is a primary myeloproliferative stem cell disorder causing panhyperplasia of erythrocyte, leukocyte, and megakaryocyte cell line in the bone marrow. Thrombotic occlusion of larger cerebral arteries complicates polycythemia vera in 10- 20% of patients. Thrombotic risk correlates with hematocrit elevation, age, and phlebotomy frequency. The incidence of stroke and TIA in phlebotomytreated patients with polycythemic vera has been reported to be 4-5% per year. Ischemic stroke is less frequently associated with secondary polycythemia than with polycythemia vera. The relative contribution of the elevated hematocrit to stroke in the presence of other cerebrovascular risk factors has been difficult to define.

Several hemoglobin variants that cause sickling of erythrocytes mainly sickle cell anaemia (HbSS), sickle cell trait (HbSA), and sickle C (HbSC) disease have been associated with cerebrovascular symptoms. Cerebral ischemia occurs in approximately 15% of patients homozygous for HbSS and the mean age for ischemic stroke in such patients is approximately 10 years. In young adults hemorrhagic strokes are more frequent. Although the frequency of stroke in patients with HbSA has been reported to be the same as in the general population, several case reports of otherwise unexplained stroke in young patients with HbSA suggest a causal relationship.⁴⁵

Thrombocytosis associated with primary myeloproliferative disorders may be complicated by thrombosis. Ischemic stroke is frequent in essential thrombocythemia in which there is an elevated platelet count with qualitative platelet dysfunction.

Thrombocytosis due to secondary causes including postsplenectomy thrombocytosis are not usually associated with thrombosis unless other risk factors are present although there are anecdotal case reports of secondary thrombocytosis due to iron deficiency.⁴⁶

Paroxysmal nocturnal hemoglobinuria, a rare disorder caused by the expansion of a clone of red cells that has acquired a somatic mutation of erythrocyte membrane proteins, thereby producing increased sensitivity to lysis by complement, is an occasional cause of stroke. This disorder usually presents in early adulthood with nocturnal episodes of hemolysis accompanied sometimes by episodes of venous thrombosis. The complement lysis sensitivity test is useful in identifying this disorder.

Hyperhomocysteinemia

As early as in 1975, McCully and Wilson⁴⁷ put forward their theory that defective metabolism of homocysteine can cause atherosclerosis and premature vascular disease. In the last few years dozens of studies have shown conclusively that patients with the various forms of atheromatous disease have in common elevated plasma homocysteine compared to matched controls. Homocysteine is a sulfhydryl-containing amino acid that is derived from the demethylation of dietary methionine. The level of plasma homocysteine is rigorously controlled and kept within a normal range in normal subjects, either by its degradation via cystathionine to cysteine and pyruvate or by its remethylation to methionine. Elevated plasma homocysteine or hyperhomocystinemia, can result from an inherited deficiency of enzymes involved in the metabolism of homocysteine, cystathionine b- synthase (CBS) or methylene tetrahydrofolate reductase (MTHFR) or from a deficiency of cofactor for these enzymes.

A rare genetic cause of severe hyperhomocysteinemia associated with homocystinuria is a homozygous deficiency of CBS. At least 60 mutations of the CBS gene have been described of which 1278T and G307S appear to be most common. The most common enzyme defect associated with moderate hyperhomocystinemia is a point mutation (C-T substitution at nucleotide 677 (C677T) in the coding region of the gene for MTHFR which is associated with the termolabile variant that has reduce activity. About 10-13% of the white population are homozygous for this mutation and, in the presence of a suboptimal folate intake, will have a moderately raised total homocysteine (tHcy). A less common polymorphism in the methionine synthase gene (D919G), a A-G transition at base pair 2756, is significantly associated with homocysteine concentration, and the DD genotype contributes to a moderate increase in homocysteine levels. Deficiency of vitamin B12, an essential cofactor for methionine synthase, vitamin B6 an essential cofactor for CBS, and folate deficiency causes hyperhomocysteinemia. Other acquired causes include hypothyroidism, renal failure, and chronic ingestion of drugs such as phenytoin.

Many studies have demonstrated that even mildly increased plasma homocysteine can be a significant risk factor for stroke.^48,49 A prospective populationbased cohort study of 1947 individuals who had not previously had a stroke, followed up for a median period of 9.9 years concluded that nonfasting tHcy levels is an independent risk factor for incident stroke among elderly people of mean age 70±7 years.⁵⁰ Another case-control study of young adults with firstever ischemic stroke found that baseline fasting and postmethionine load of tHcy were similar among cases and controls.⁵¹ However, the increase in tHcy after methionine was significantly higher among cases. Moderate hyperhomocysteinemia has been reported to be risk factor for ischemic stroke for children.⁵² Raised tHcy concentrations are also associated with carotid atherosclerosis as measured by ultrasound evidence of an increase in carotid artery wall thickness,⁵³ or carotid plaque area⁵⁴ and ischemic stroke caused by large artery disease.⁵⁵ In a study of 1041 subjects, Selhub et al⁵⁶ showed that the risk of carotid stenosis was increased in subjects with homocysteine concentrations >11 mmol/L, the odds ratio for having stenosis of >25% in at least one of the two carotid arteries being about twice as high for subjects with homocysteine concentration >14.4 mmol/L, than those with homocysteine < 9.1mmol/L. Some studies suggest that persons who are heterozygous for cystathionine b-synthase deficiency are at increased risk for the development of premature atherosclerosis and stroke.⁵⁷ Clarke and coworkers⁴⁸ found plasma homocysteine levels to be inversely related to red cell folate and serum B12 levels. An inadequate folic acid intake was found to be associated with increased plasma homocysteine concentrations in subjects with thickening of the carotid artery wall.⁵⁷

It is generally held that homocysteinemia promotes thrombosis by adversely affecting the functions of the vascular endothelium that maintain the blood's fluidity. Homocysteine may inhibit the protein C anticoagulant pathway, interfere with heparin sulfate proteoglycans that modulate antithrombin III activity, inhibit tissue plasminogen activator receptor function, decrease endothelial ADPase activity and enhance the fibrin binding and tissue factor stimulating activity of lipoprotein(a). Other proposed mechanisms include mitogenic effects on vascular smooth muscle and cytotoxic effects on the endothelium. Establishing the presence of hyper-homocysteinemia may well be worthwhile, since many abnormalities of methionine metabolism respond to treatment with dietary supplements of folic acid, pyridoxine, or vitamin B12.

Antiphospholipid antibodies

The antiphospholipid antibody syndrome is now recognized as one of the most important acquired causes of hypercoagulability.⁵⁸ The antiphospholipid antibodies (aPL) are a heterogeneous family of autoimmune and alloimmune immunoglobulins that recognize phospholipid-protein complexes in in-vitro laboratory test systems. Until recently, these antibodies were thought to have specificity for anionic or neutral phospholipids. APL includes not only anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) but also more recently recognized subtypes of antiphospholipid antibodies (antibodies to phosphotidylserine, phosphatidyl ethanolamine, phsophatidylinositol, phosphatidylcholine and antiannexin- V). ACL are assayed by an enzyme-linked immuno-sorbent assay using cardiolipin as the antigen. LA is identified by functional coagulation assays that reveal prolongation of the phospholipiddependent coagulation steps in the absence of coagulation factor deficiency.

The prevalence of aPL in stroke have varied greatly. Nencini and co-workers (1992)⁵⁹ found aCL as shown by ELISA in only 4% of 55 young adults with ischemic stroke, whereas Hess and coworkers⁶⁰ found 46% prevalence in young adults with cerebral ischemia. Briley and colleagues found that in 80 subjects with aPL, 25(31%) had neurologic symptoms caused by cerebral ischemia.⁶¹ In this study the patients with neurologic dysfunction were young, with an average age of 42 years. In one of the largest case-control studies by the APASS (1993), aCLs were present in 9.7% of 255 first ischemic stroke patients and in 4.3% of control subjects.⁶² Based on these reports aPL has been suggested to be an important factor in approximately 10% of all strokes and probably may be present more frequently in young patients with stroke especially in subjects with unexplained recurrent stroke. In contrast, the Physicians' Health Study reported no significant association between aCL and ischemic stroke in men.⁶³ In a study from India, the aCL as measured by ELISA using cardiolipin as the antigen, was present in 23% of young patients with ischemic stroke.⁶⁴ Prior TIA, ischemic retinopathy, and asymptomatic infection were reported to be more frequent in the aCL-positive group. Another study of the clinicoinvestigative profile of 12 young, antiphospholipid antibody-positive stroke patients showed pretreatment recurrences, multiple smaller infarcts on CT and a good prognosis. In a systematic review of available studies on aPL in ischemic stroke patients, Bushnell and Goldstein have reported that the cumulative pretest probabilities of the prevalence of LA in ischemic stroke was 3% (8% for those < 50 years) and aCL 12% (21% for those aged < 50 years).³⁴

Conclusion

It is well established that many inherited and acquired factors cause thrombotic diseases. More complete laboratory screening of patients with ischemic cerebrovascular disease for currently identified prothrombotic states will probably increase the percentage of strokes attributed to disorders of hemostasis. However, specific tests to exclude many of the uncommon disorders are expensive and not widely available. Therefore, special, step-wise screening for occult prothrombotic entities in stroke patients is recommended for selected young patients with stroke of uncertain cause, for those with prior venous thrombosis, or a family history of unusual thrombosis, and for those with no other explanation for recurrent stroke. The importance of finding these defects has significant implication for therapy of the individual patient and for institution of family studies to identify and possibly treat others at risk. As the knowledge of hemostasis increases, more hereditary and acquired defects may be associated with an enhanced risk of thrombosis and ischemic stroke.

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