JOURIVAL
Or” ADOLESCENT
HEALTH
19%;12:39%4j2
CASE REPORT
Anticoa A Case YAIR
MOLAD,
NACHMAN
M.D.,
EYNAN,
ABIGAIL
AIU.D,
M.D.,
PINKHAS,
M.D.,
AND
MD
A 15-year-old girl with right-sided cerebral infarct in association with lupus anticoagulant is described. The literature on the primary antiphospholipid syndrome its neurological complications is reviewed.
and
RliY WORDS:
Lupus anticoagulant Anti-phospholipid antibodies Systemic lupus erythematosus
P.S.;.. “Ic4a.l
JACK
:..Lma LaII”., C.
Stroke is rare in children and adolescents, and 3-5% of all cerebral infarctions occur in subjects aged IS45 years (1,2). In a series of 144 such patients, more than 40 etiologies of infarction were identified, among which systemic lupus erythematosus (9.X) was found in two patients (2). I”YTetroRsychiatnc manifestations occurred in 20-44% of children with SLE in two recently published series (3,4) and were associated in part with the presence of lupus anticoagulant. Lupus anticoagulant is a procoagulant antibody which reacts with phospholipids and is typically manifested by recurrent venous or arterial thrombosis, habitual abortions, thrombocytopeni3,
From the Department tif Internal Medicine D (Y.M., J.P.!, Rheumatology Unit (Y.M.), and Departmen’ ofNeurosurgery (A.A., N.E.), Beilinson Medical Center, Petah Tiqva,’Suckler School of Medicine, Tel
Aviv University, Israel.
Address Reprint requests to: J. Pinkhas, M.D., Department of Medicine D, Beilinson Medical C&er, Petah Tiqva 49100, Israel.
Manuscript acceptedMarch 26, 1991.
Coombs’ positivity, livedo reticularis, valvular heart disease, leg ulcers, and neurological disturbances (5). The main neurological manifestations associated with lupus anticoagulant include cerebrovascular accidents, transient ischemic attacks (TIAs), amaurosis fugax, migraine, chorea, epilepsy, Guillain-Barre syndrome, and transverse myelopathy (6,‘/). We describe a ISyear-old girl with massive cerebral infarct associated with the primary antiphosRholipid syndrome (lupus anticoagulant without .SLEor oiher known causes). &se Report A IS-year-old girl was admitted to the emergency ward because of headache and clumsiness of her left arm. She was well until 2 weeks earlier when she experienced severe right parietal headache, malaise, 1..___!____ of ki kft arm. The ph;dcal exand ~IUIIISUNXI amination disclosed no abnormality, and routine blood tests were normal except for erythrocyte sedimentation rate (Westergren) 43 mm in the 1st hour. Analgesics were prescribed. She was admitted NJ days later to our hospital because of continuation of her complaints. There was no history of arthritis, rash, photosensitivity, Raynaud phenomenon, renal disease, or deep vein thrombosis. On examination, the temperature was 36.5”C, pulse was 80 per min, and blood pressure was llO/XJ mm Hg. The physical and neurological examination showed only a big SCOtopic deficit on the left lower quadrant of the visual field without ally other neurological deficit or fundi papilledema. A cranial computed tomographic (CT) scan (Figure I) showed a right temporo-parieto-
Q Society for Adolescent Medicine, 1991 Published by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, NY 10010
399 01974070/9w3.!%
400
MOLAD ET AL.
JOURNAL OF ADOLESCENT HEALTH Vol. 12, Nti. 5
F&we 1. Cranial computed tomography demonstmting .?n infirct in the temporo-parieto-occipital right lobe (A) without enhancementafter intravenous injection of contrast fffaterid @A
occipital hypodense lesion with no enhancement after intravenous injection of contrast material. There was no displacement or enlargement of the ventricles, and the sulci appeared normal. Magnetic resonance imaging (MRI) of the brain (Figure 2) showed a defined area of low intensity signal on T1 weighted spin echo and high intensity signal on T2 spin echo in the right parietal lobe, without signs of edema or mass effect. Doppler ultrasonography of the carotid arteries was normal and echocardiography demonstrated normal size and contractibility of the heart with no evidence of valvular abnormality or mural thrombi. The hematocrit was 36.2%; hemoglobin, 11.7 .g/dL; white cell count, 6,200/mm3; and platelet count, 124,000/mm3. Blood electrolytes, creatinine, aild liver enzymes were within normal limits. The prothrombin time (PT) was 88% (normal,
70-lOO%), partial thromboplastin time {MT) was 66.8-72.7 set (normal, less than 30 set), and fibrinogen 297-343 mg/dL. Urina$sis was normal. Antinuclear antibody (ANA) was positive (1:80), while anti-dsDNA, Coombs’ test, and the Venereal Disease Research Laboratory (VDRL) test were negative. The kaolin clotting time was prolonged and was not corrected by 1:l mixture of patient’s plasma and normal plasma (8). Anticardiolipin antibody studies were not performed because the assay was not failable at the time. The diagnosis of primary antiphospholipid syndrome with a right temporo-paneto-occipital brain infarct was made and warfarin anticoagulant treatment was started. CJI? month later, the paticfit,..was asymptomatic, and on brain CT scan the hypodense lesion was smaller.
July 1991
Discussion This 15-year-old girl with cerebral infarct demonstrates one of the most common and ominous complications attributed to the presence of ihe lupus anticoagulants (LAC) or the antiphospholipid antibodies (APA). Our patient met the criteria for the diagnosis of the primary antiphospholipid syndrome (6) but not for SLE (9). Cerebrovascular accident (CVA) owing to LAC in such a young ado81escent patient is very rare and not reported in the English literature (l-4,7,10-16). The existence of LAC should be suspected when prolonged partial thcomboplastin time, and/or false-positive VDRL test are detected in a patient with any of the following: recurrent venous or arterial t.hrombosis, recurrant fetal loss, mild thromboq topenia, Coombs’ positivity, livedo reticularis, valvdar heart disease, and chronic leg ulcers (6). The incidence of CVA in
CEREBRAL INFARCT AND LkJPUS /Xi’ICQAGULANT
401
patients with LAP L appears to be approximately 25% (16), commonly in the form of multiple cerebral infarctions. Other neurological manifestabons associated with LAC i Iclude TIAs, amaurosis fugax, migraine, chorea, epilepsy, Guillain-Barre syndrome, transverse myelopathy, pseudomultiple sclerosis, and progressive dementia (6). These procoaguhtion antibodies can be manifested as a primary disorder or in association with a varieg of conditions including SLE, rheumatoid arthritis, Sjiigren syndrome, progressive systemic sclerosis, idiopathic thrombocytopenic purpura, malignancies, infections (especially viral), or drug-induced conditions (6). Contrary to the serological features of SLE, patients with the primary antiphosphoiipid SYIIdrome show low titers of ANA, or are _4NP,negative, and some may have anti-mitochondrizd antibodies (h& type), or cryoplobuiins (63. The XItiphospholipid antibodies react with the anionL:
Figure 2. Brain magnetic resonance irnagiug showiilg a deFned area of low intensity on Tz spin echo (B) in the right parietal lobe, without edema or mass effect,
signs! OH T; zoeighted spin echo (A) and Kg!, mtemity
signa,
402
MOLAD ET AL.
phospholipids found in cell membranes (17), probably with the phosphodiester-linked phosphate groups (18). Specifically, these antibodies bind to cardiolipin, phosphatidylcholine, phosphatidic acid, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine. Currently, they can be detected by the VDRL test (which detects cardidipin and is false-positive for syphilis), coagulation studies such as the activated PIT, or more sensitive assays like the kaolin clot&>ime and Russell viper venom time, and the anticardiolipin antibodies assay using either the enzyme-linked i_mmtmosorbent assay (ELBA) ‘ora radioimmunoassay @IA). The VDRL is positive in only 2S% of the patients with antiphospholipid antibodies, and these tests detect overlapping populations of antibodies (17). The ELISA test is more sensitive than the lupus anticoagulant assays, although the latter are more specific (19). The anticardiolipin ELISA detects the IgC and IgM isotypes, and some studies have found that raised IgG antlphospholipid antibody levels are more closely associated with thrombosis, fetal loss, and thrombcytopenia than raised IgM (17). The ‘way by which these antibodies can cause the associated clinical manifestations is not fully understood. However, thrombosis (not vasculitis) has been found in autopsies (10). These antibodies bind to phospholipids that act in the formation of the prothrombinasecomplex, which involves the assembly of factors Xa, Va, calcium ions, and inionic phospholipid on the surface of platelets, to convert prothrombin to thrombin. Similarly, factors IXa, VIIIc, caldum ions, and phospholipids act to convert factor X tcrXa. This explains why the PTT is prolonged in spite of the p&ant nature of these antibodies. The mechanisms accounting for the formation of thrombosis in&de reduced prostacyclin production by the endothelial cells and inhibition of thrombomodulin, protein C, prekallikrein, or antlthrombin III activity (17). Accordingly, :vhen these patients become symptomatic they should be anticoagulated with warfti anCr low dose aspirin in order to lower the risk of thrombotic events. Whether corticosteroids and/or immunosuppressive therapy have any potential benefit in this disorder remains to be determined. In conclusion, this case demonstrates the possible accurrenw of stroke as a manifestation of the primary antiphospholipid syndrome in juveniles and the importance Of its diagnosis to specific treatment ancI prognosis.
JOURNAL OF ADOLESCENT HEALTH Vol. 12, No. 5
References 1. Hart RG, Sherman DG, Miller VT, et al. Diagnosis and management of ischemic stroke. II. Selected controversies. Curr Probl Cardio! 1983;7:43-53. 2. Ha&in&i V. The young stroke. In: Hachinski V, Novis _m, eds. Acute Stroke, Philadelphia: FA Davis, 1985: 141-6& 3. Glidden RS,,Mantzouranis EC, Bore1Y. Lupus erythematosus in childhood: Clinical manifestations and improved survival in fifty-five patients. Clin Immunol lmmunopathol 1.983;29:196-210. 4. YancozyCL, Doughty RA, Athreya BH. Central nervous systell &olvement in chlldho~d systemic lupus erythematosus. Arthritis Rheum 1981;24(11):1389-95. 5. Hughes GRV, Harris EN, Gilaravi AE. The anticardiolipin syndrome (Editorial). J Rheumatol 19116;13(3):486-9. 6. Asherson RA, Khamashta MA, Ordi-Ras J, et al. The primary rntiphospholipid syndrome: Major clinical and serological features. Medicine (Baltimore) 1989;68(6):366-74. 7. Levine SR, Welch ICMA. The spectrum of neurol+c disease associated with antiphospholipid antibodies: Lupus anticoagulants and anticardiolipin antibodies. .Arch Neuroi 1987;54:876-83. 8. Bosner E, Pausner d, Lugky A, et al. Detection and qoantitative evaluation of Iup;ls circulating anticoagulant activity. Thromb Haemost 19H7;5~(2):i& 7. 9. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of system& lupus erythematosus. Arthritis Rheum 1952;25(11):1271-7. IO. Briley DP, Coull RM, Goodnight SH, Jr. Neurological di~ase associated with antiphospholipid antibodies. Aun Nemo1 1989;25221-7. 11. Mueh JR, Herbst KD, Rapaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 1980;92:1569. 12. Boey ML, Colaco CB, Gharavi AE, et al. Thrombosis in systemic lupus erythematosus: Striking association with the presence-of circulating lupus anti-&&ant. Br Mcd J [Clin Res] I983;287~1021-3. 13. Hart RG. Miter VT, Coull BM, et al. Cerebral infarction associated with lupus anticoagulants-preliminary report. Stroke 1984;15(1):114-8. Ia. Fisher M, McGehee W. Cerebral infarct, TIA and lupus inhibitor. Neurology 1986;36%34-7. 15. Alarcon-Fegovia D, Sanchez-&z cro J. Primary antiphospholipid syndrome. J Rheumatoll989;16:482-8. B 16. Asherson RA, Khamashta MA, Gil A, et al. Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus-like disease, and the primary antiphosphulipid syndrome. Am J Me%1198~&35?1-~. 17. Mackworth-Young C. Antiphospdolipid antibodies: More than just a disease marker? Immur?ol Today 1990;11(2):60-5. 18. Levine SR, Welch KMA. Antiphospholipid antibodies. Ann Neurol1989;26:386-9. 19. Derksen RI-I, Hasselaar P, Blokzijl L, et al. Coagulation screen is more specific than the anticardiolloin antibodv ELISA in defining a thrombotic subset of Iup& patients. Ann Rheum Dis i986;4?:364-7i.
Or” ADOLESCENT
HEALTH
19%;12:39%4j2
CASE REPORT
Anticoa A Case YAIR
MOLAD,
NACHMAN
M.D.,
EYNAN,
ABIGAIL
AIU.D,
M.D.,
PINKHAS,
M.D.,
AND
MD
A 15-year-old girl with right-sided cerebral infarct in association with lupus anticoagulant is described. The literature on the primary antiphospholipid syndrome its neurological complications is reviewed.
and
RliY WORDS:
Lupus anticoagulant Anti-phospholipid antibodies Systemic lupus erythematosus
P.S.;.. “Ic4a.l
JACK
:..Lma LaII”., C.
Stroke is rare in children and adolescents, and 3-5% of all cerebral infarctions occur in subjects aged IS45 years (1,2). In a series of 144 such patients, more than 40 etiologies of infarction were identified, among which systemic lupus erythematosus (9.X) was found in two patients (2). I”YTetroRsychiatnc manifestations occurred in 20-44% of children with SLE in two recently published series (3,4) and were associated in part with the presence of lupus anticoagulant. Lupus anticoagulant is a procoagulant antibody which reacts with phospholipids and is typically manifested by recurrent venous or arterial thrombosis, habitual abortions, thrombocytopeni3,
From the Department tif Internal Medicine D (Y.M., J.P.!, Rheumatology Unit (Y.M.), and Departmen’ ofNeurosurgery (A.A., N.E.), Beilinson Medical Center, Petah Tiqva,’Suckler School of Medicine, Tel
Aviv University, Israel.
Address Reprint requests to: J. Pinkhas, M.D., Department of Medicine D, Beilinson Medical C&er, Petah Tiqva 49100, Israel.
Manuscript acceptedMarch 26, 1991.
Coombs’ positivity, livedo reticularis, valvular heart disease, leg ulcers, and neurological disturbances (5). The main neurological manifestations associated with lupus anticoagulant include cerebrovascular accidents, transient ischemic attacks (TIAs), amaurosis fugax, migraine, chorea, epilepsy, Guillain-Barre syndrome, and transverse myelopathy (6,‘/). We describe a ISyear-old girl with massive cerebral infarct associated with the primary antiphosRholipid syndrome (lupus anticoagulant without .SLEor oiher known causes). &se Report A IS-year-old girl was admitted to the emergency ward because of headache and clumsiness of her left arm. She was well until 2 weeks earlier when she experienced severe right parietal headache, malaise, 1..___!____ of ki kft arm. The ph;dcal exand ~IUIIISUNXI amination disclosed no abnormality, and routine blood tests were normal except for erythrocyte sedimentation rate (Westergren) 43 mm in the 1st hour. Analgesics were prescribed. She was admitted NJ days later to our hospital because of continuation of her complaints. There was no history of arthritis, rash, photosensitivity, Raynaud phenomenon, renal disease, or deep vein thrombosis. On examination, the temperature was 36.5”C, pulse was 80 per min, and blood pressure was llO/XJ mm Hg. The physical and neurological examination showed only a big SCOtopic deficit on the left lower quadrant of the visual field without ally other neurological deficit or fundi papilledema. A cranial computed tomographic (CT) scan (Figure I) showed a right temporo-parieto-
Q Society for Adolescent Medicine, 1991 Published by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, NY 10010
399 01974070/9w3.!%
400
MOLAD ET AL.
JOURNAL OF ADOLESCENT HEALTH Vol. 12, Nti. 5
F&we 1. Cranial computed tomography demonstmting .?n infirct in the temporo-parieto-occipital right lobe (A) without enhancementafter intravenous injection of contrast fffaterid @A
occipital hypodense lesion with no enhancement after intravenous injection of contrast material. There was no displacement or enlargement of the ventricles, and the sulci appeared normal. Magnetic resonance imaging (MRI) of the brain (Figure 2) showed a defined area of low intensity signal on T1 weighted spin echo and high intensity signal on T2 spin echo in the right parietal lobe, without signs of edema or mass effect. Doppler ultrasonography of the carotid arteries was normal and echocardiography demonstrated normal size and contractibility of the heart with no evidence of valvular abnormality or mural thrombi. The hematocrit was 36.2%; hemoglobin, 11.7 .g/dL; white cell count, 6,200/mm3; and platelet count, 124,000/mm3. Blood electrolytes, creatinine, aild liver enzymes were within normal limits. The prothrombin time (PT) was 88% (normal,
70-lOO%), partial thromboplastin time {MT) was 66.8-72.7 set (normal, less than 30 set), and fibrinogen 297-343 mg/dL. Urina$sis was normal. Antinuclear antibody (ANA) was positive (1:80), while anti-dsDNA, Coombs’ test, and the Venereal Disease Research Laboratory (VDRL) test were negative. The kaolin clotting time was prolonged and was not corrected by 1:l mixture of patient’s plasma and normal plasma (8). Anticardiolipin antibody studies were not performed because the assay was not failable at the time. The diagnosis of primary antiphospholipid syndrome with a right temporo-paneto-occipital brain infarct was made and warfarin anticoagulant treatment was started. CJI? month later, the paticfit,..was asymptomatic, and on brain CT scan the hypodense lesion was smaller.
July 1991
Discussion This 15-year-old girl with cerebral infarct demonstrates one of the most common and ominous complications attributed to the presence of ihe lupus anticoagulants (LAC) or the antiphospholipid antibodies (APA). Our patient met the criteria for the diagnosis of the primary antiphospholipid syndrome (6) but not for SLE (9). Cerebrovascular accident (CVA) owing to LAC in such a young ado81escent patient is very rare and not reported in the English literature (l-4,7,10-16). The existence of LAC should be suspected when prolonged partial thcomboplastin time, and/or false-positive VDRL test are detected in a patient with any of the following: recurrent venous or arterial t.hrombosis, recurrant fetal loss, mild thromboq topenia, Coombs’ positivity, livedo reticularis, valvdar heart disease, and chronic leg ulcers (6). The incidence of CVA in
CEREBRAL INFARCT AND LkJPUS /Xi’ICQAGULANT
401
patients with LAP L appears to be approximately 25% (16), commonly in the form of multiple cerebral infarctions. Other neurological manifestabons associated with LAC i Iclude TIAs, amaurosis fugax, migraine, chorea, epilepsy, Guillain-Barre syndrome, transverse myelopathy, pseudomultiple sclerosis, and progressive dementia (6). These procoaguhtion antibodies can be manifested as a primary disorder or in association with a varieg of conditions including SLE, rheumatoid arthritis, Sjiigren syndrome, progressive systemic sclerosis, idiopathic thrombocytopenic purpura, malignancies, infections (especially viral), or drug-induced conditions (6). Contrary to the serological features of SLE, patients with the primary antiphosphoiipid SYIIdrome show low titers of ANA, or are _4NP,negative, and some may have anti-mitochondrizd antibodies (h& type), or cryoplobuiins (63. The XItiphospholipid antibodies react with the anionL:
Figure 2. Brain magnetic resonance irnagiug showiilg a deFned area of low intensity on Tz spin echo (B) in the right parietal lobe, without edema or mass effect,
signs! OH T; zoeighted spin echo (A) and Kg!, mtemity
signa,
402
MOLAD ET AL.
phospholipids found in cell membranes (17), probably with the phosphodiester-linked phosphate groups (18). Specifically, these antibodies bind to cardiolipin, phosphatidylcholine, phosphatidic acid, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine. Currently, they can be detected by the VDRL test (which detects cardidipin and is false-positive for syphilis), coagulation studies such as the activated PIT, or more sensitive assays like the kaolin clot&>ime and Russell viper venom time, and the anticardiolipin antibodies assay using either the enzyme-linked i_mmtmosorbent assay (ELBA) ‘ora radioimmunoassay @IA). The VDRL is positive in only 2S% of the patients with antiphospholipid antibodies, and these tests detect overlapping populations of antibodies (17). The ELISA test is more sensitive than the lupus anticoagulant assays, although the latter are more specific (19). The anticardiolipin ELISA detects the IgC and IgM isotypes, and some studies have found that raised IgG antlphospholipid antibody levels are more closely associated with thrombosis, fetal loss, and thrombcytopenia than raised IgM (17). The ‘way by which these antibodies can cause the associated clinical manifestations is not fully understood. However, thrombosis (not vasculitis) has been found in autopsies (10). These antibodies bind to phospholipids that act in the formation of the prothrombinasecomplex, which involves the assembly of factors Xa, Va, calcium ions, and inionic phospholipid on the surface of platelets, to convert prothrombin to thrombin. Similarly, factors IXa, VIIIc, caldum ions, and phospholipids act to convert factor X tcrXa. This explains why the PTT is prolonged in spite of the p&ant nature of these antibodies. The mechanisms accounting for the formation of thrombosis in&de reduced prostacyclin production by the endothelial cells and inhibition of thrombomodulin, protein C, prekallikrein, or antlthrombin III activity (17). Accordingly, :vhen these patients become symptomatic they should be anticoagulated with warfti anCr low dose aspirin in order to lower the risk of thrombotic events. Whether corticosteroids and/or immunosuppressive therapy have any potential benefit in this disorder remains to be determined. In conclusion, this case demonstrates the possible accurrenw of stroke as a manifestation of the primary antiphospholipid syndrome in juveniles and the importance Of its diagnosis to specific treatment ancI prognosis.
JOURNAL OF ADOLESCENT HEALTH Vol. 12, No. 5
References 1. Hart RG, Sherman DG, Miller VT, et al. Diagnosis and management of ischemic stroke. II. Selected controversies. Curr Probl Cardio! 1983;7:43-53. 2. Ha&in&i V. The young stroke. In: Hachinski V, Novis _m, eds. Acute Stroke, Philadelphia: FA Davis, 1985: 141-6& 3. Glidden RS,,Mantzouranis EC, Bore1Y. Lupus erythematosus in childhood: Clinical manifestations and improved survival in fifty-five patients. Clin Immunol lmmunopathol 1.983;29:196-210. 4. YancozyCL, Doughty RA, Athreya BH. Central nervous systell &olvement in chlldho~d systemic lupus erythematosus. Arthritis Rheum 1981;24(11):1389-95. 5. Hughes GRV, Harris EN, Gilaravi AE. The anticardiolipin syndrome (Editorial). J Rheumatol 19116;13(3):486-9. 6. Asherson RA, Khamashta MA, Ordi-Ras J, et al. The primary rntiphospholipid syndrome: Major clinical and serological features. Medicine (Baltimore) 1989;68(6):366-74. 7. Levine SR, Welch ICMA. The spectrum of neurol+c disease associated with antiphospholipid antibodies: Lupus anticoagulants and anticardiolipin antibodies. .Arch Neuroi 1987;54:876-83. 8. Bosner E, Pausner d, Lugky A, et al. Detection and qoantitative evaluation of Iup;ls circulating anticoagulant activity. Thromb Haemost 19H7;5~(2):i& 7. 9. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of system& lupus erythematosus. Arthritis Rheum 1952;25(11):1271-7. IO. Briley DP, Coull RM, Goodnight SH, Jr. Neurological di~ase associated with antiphospholipid antibodies. Aun Nemo1 1989;25221-7. 11. Mueh JR, Herbst KD, Rapaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 1980;92:1569. 12. Boey ML, Colaco CB, Gharavi AE, et al. Thrombosis in systemic lupus erythematosus: Striking association with the presence-of circulating lupus anti-&&ant. Br Mcd J [Clin Res] I983;287~1021-3. 13. Hart RG. Miter VT, Coull BM, et al. Cerebral infarction associated with lupus anticoagulants-preliminary report. Stroke 1984;15(1):114-8. Ia. Fisher M, McGehee W. Cerebral infarct, TIA and lupus inhibitor. Neurology 1986;36%34-7. 15. Alarcon-Fegovia D, Sanchez-&z cro J. Primary antiphospholipid syndrome. J Rheumatoll989;16:482-8. B 16. Asherson RA, Khamashta MA, Gil A, et al. Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus-like disease, and the primary antiphosphulipid syndrome. Am J Me%1198~&35?1-~. 17. Mackworth-Young C. Antiphospdolipid antibodies: More than just a disease marker? Immur?ol Today 1990;11(2):60-5. 18. Levine SR, Welch KMA. Antiphospholipid antibodies. Ann Neurol1989;26:386-9. 19. Derksen RI-I, Hasselaar P, Blokzijl L, et al. Coagulation screen is more specific than the anticardiolloin antibodv ELISA in defining a thrombotic subset of Iup& patients. Ann Rheum Dis i986;4?:364-7i.
