ltal. J. Neurol. Sci. 13:599-601 1992
The primary antiphospholipid syndrome: case report Severi S.*, Ghezzi M.*, Felici M.** * U.O. di Neurologia e Neurofisiopatologia, Ospedale USL 23, Arezzo ** U.O. di Medicina Interna, Ospedale USL 23, Are:m
Lupus anticoagulant antibodies and anticardiolipin antibodies are acquired circulating immunoglobulins that interact with phospholipids. These factors may exert anticoagulant properties in vitro and so interfere with coagulation tests that use phospholipids. These antibodies are not, however, associated with a hemorrhagic diathesis. Indeed, despite their name and their in vitro anticoagulant properties, they have been associated right from the earliest reports with systemic and cerebral thromboembolic episodes. We report the clinical and instrumental findings in a patient with ischemic stroke and anticoagulant antibodies in the serum.
Key Words: Anticoagulants - - antiphospholipid antibodies - - thrombosis
Introduction Anticoagulant antibodies are acquired circulating immunoglobulins and the principal ones are lupus anticoagulants (LAs) and anticardiolipin antibodies (ACAs) [1]. They are part of a group of antibodies directed against neutral and negative phospholipids and are known as antiphospholipid antibodies [2, 3, 7]. These antibodies, originally identified in subjects with systemic lupus erythematosus (SLE), have since been found in numerous other pathological conditions and even in healthy individuals (2% of the general population). They cross-react with phospholipids in vitro and so have the potential to interfere with coagulation tests that use phospholipids, inducing a lengthening of the whole blood clotting time, prothrombin time and, especially, partial thromboplastin time (PTT). And yet in vivo they do not alter or reduce the activity of the specific coagulation factors [7, 2]. 20%-25% of subjects with antiphospholipid antibodies have thrombophilia with a marked tendency to thromboembolic episodes, both systemic and cerebral [3, 4, 7, 8]. Some authors have proposed Received 2 January 1992 - Accepted 20 May 1992
"primary antiphospholipid syndrome" or "antiphospholipid-antibody syndrome" for cases in which the presence of an ischemic cerebral vascular disorder is associated with the presence of antiphospholipid antibodies, false positive on the VDRL test, lengthening of PTT and platelet deficiency, which categorize the case we now report [1].
Case report A 44 year old woman with no noteworthy history until the age of 30 started 5 pregnancies between the ages of 30 and 35, all ending in miscarriage. In the same period the patient began to have recurrent thrombophlebitis of the lower limbs. At age 37 a change blood chemistry test showed marked platelet deficiency (30 000 ram3), for which the patient was admitted to the internal medicine department and discharged with the diagnosis of platelet deficiency in SLE. The tests done at that time showed no antiplatelet antibodies. After enjoying good health for some years she began at age 44 to have sudden episodes of objective vertigo, diplopia, speech disorders and loss 599
The Batian Journal of Neurological Sciences
TABLE I. Proposed thrombotic mechanisms for lupus anticoagulant antibodies.
Lupus anticoagulant
Anticardiolipin Ab
Anti-DNA Ab
against phospholipids Platelets ~ ~ ' / ~ - - thrombocytopenia - - release of procoagulants
1 Endothelium
- - inhibition of PGI2 formation --inhibition of protein C activation - - r e d u c t i o n of release of plasminogen activator
of strength in the right upper arm, for which she was admitted to the neurology department. Examination revealed: dysarthria, diplopia due to a deficit of cranial nerve VI on the right, anisocoria (L > R), with sparing of the consensual light reflex bilaterally, and a mild rightsided faciobrachiocrural pyramidal syndrome. A C T brainscan done immediately after onset of symptoms was normal. An MRI scan of the brain done a few days later showed in the T2-weighted images numerous hyperintense images between 3 and 10 mm in diameter in the white substance of the left cerebellar hemisphere, in the midbrain near the midline and in the left temporal lobe; other similar but smaller images were present in the two semioval centers. Cerebral angiography (according to Seldinger) revealed nothing pathological in the carotid or vertebral territories. Blood tests showed marked platelet deficiency (50 000/mmS), lengthening of PTT (38") and of the prothrombin time (69%), presence of antinuclear antibodies and native anti-DNA, positive Wassermann reaction (1 : 8) and VDRL ( + + ) but negative TPHA and FFA-ABS. The test for antiphospholipid antibodies was positive for LAs and ACAs. The neurological deficits wore off gradually within a few weeks while the deficit of extraocular movement took several months to clear completely.
Discussion
The patient's clinical history shows that with anticoagulant antibodies in the serum there is high risk of venous and/or arterial thrombosis, both systemic and cerebral [3]. In these situations the majority of the neurological symptoms, as has been suggested by clinical studies and confirmed at necrospy, reflect the presence of thrombotic disease of the medium caliber arteries [3]. 600
~
Plasma - - i n t e r f e r e n c e with antithrombin III --inhibition of prekallikrein (fibrinolysis)
TABLE II. Design of stud)' of hemostasis of
thrombotic episodes without apparent cause. 9 Assay for fibrinogen, plasminogen, alpha-2antiplasmin 9 Assay for coagulation inhibitors 9 antithrombin III 9 protein C 9 protein S
9 Analysis of fibrinolytic activity 9 general tests: thromboelastogram, fibrinolysis 9 specific tests: assay for plasminogen activator and its inhibitors
9 Tests for antiphospholipid antibodies 9 anticardiolipin antibodies (ACAs) 9 lupus anticoagulant antibodies (LAs) from Bernard C., Moerloose P., 1990. Modified)
The precise mechanism of action of antiphospholipid antibodies (Table I) is not yet known but it is clear from the majority of the studies conducted that they have the property of interfering with several reactions of the coagulation system. The most frequent site of inhibition is at the level of the reaction activating prothrombin by prothrombinase or prothrombin activating complex (factor Xa, factor V, calcium and phospholipids). The action of the antibodies seems to be immediate, developing through an interaction with the phospholipid component of the thromboplastin complex, with tissue thromboplastin and with the platelet phospholipids and consequently on thromboplastin formation, both intrinsic and extrinsic [7, 2, 3]. There is a great deal of uncertainty regarding the treatment of patients with cerebral ischemia and LAS and/or ACAs. The doubts center on the use of antiaggregants, anticoagulants, immunosuppressants and plasmapheresis [7, 2, 3]. At the
Severi S.: The primary antiphospholipidsyndrome
moment most authors r e c o m m e n d anticoagulant therapy in all patients presenting anticoagulant antibodies and a history of ischemic episodes, cerebral or systemic, whether or not they have SLE [6, 10]. Treatment with anticoagulants and/ or platelet antiaggregants seems drastically to reduce the frequency of ischemic strokes and retinal thrombosis [5]. On present evidence and on that of the case reported we think that k n o w l e d g e of the physiopathology of these problems would gain from
testing for LAs and A C A s and other factors in hemostasis (Table II) in all subjects with SLE and in subjects with ischemic strokes without apparent risk factors or anyway without pathological conditions likely to favor thromboembolism (emboligenous heart disease, carotid stenosis, complicated atherosclerotic plaques, vasculitis, among others). Greater awareness of the presence of these antibodies in such clinical conditions may contribute in future to more targeted prevention and treatment of cerebral ischemia [7, 9].
Sommario Gli anticorpi anticoagulanti tipo-lupus e gli anticorpi anticardiolipina sono immunoglobuline circolanti acquisite che interagiscono con i fosfolipidi. Questi fattori, in vitro, possono manifestare proprietb anticoagulanti interferendo con i test della coagulazione che utilizzano fosfolipidi. Tali anticorpi non sono tuttavia'associati a diatesi emorragica. Infatti contrariamente al loro nome ed alle loro proprietgl anticoagulanti in vitro, essi fin dalle loro prime descrizioni sono stati correlati ad episodi tromboembolici sistemici e cerebrali. Vengono descritti i reperti clinici e strumentali osservati in una paziente con ictus ischemico e anticorpi anticoagulanti in circolo.
Address reprint requests to: Dr Sauro Severi U.O. Neurologia - Ospedale U S L 23 Via della Fonte Veneziana, 17 52100 - Arezzo
References [1] ASHERSON R.A., G1L A., VAZQUER J.-J., CHAN 0., BAGULEY E., HUGHES G.R.V.: Cerebrovascular disease and antiphospholipid antibodies in systemic lupus er3,thematosus, lupus-like disease, and the primary antiphospholipid syndrome. Am. J. Med. 86:391-399, 1989. [2] BERNARD C., MOERLOOSE P.: Anticorps anticardiolipins et thromboses. M~d. et Hyg. 48:166-169, 1990. [3] BRILEY D.P., COULL B.M., GOODNIGHT S.H. JR.: Neurological diseases associated with antiphospholipid antibodies. Ann. Neurol. 25:221-227, 1989. [4] COVLL B.M., GOODNEGHTS.H.: Antiphospholipid antibodies, prethrombotic states, and stroke. Stroke 2l:1370-1374, 1990. [5] D1GREK.B., DURCANF.J., BRANCH D.W., JACOB-
[6] [7]
[8] [9] [10]
SON D.M., VARNER M.W., BARINGER J.R.: Amaurosis fugax associated with antiphospholipid antibodies. Ann. Neurol. 25:228-232, 1989. FUTRELL N., MILLIKAN C.: Frequency, etiology, and prevention of stroke in patients with systemic lupus ervthematosus. Stroke 20:583-591, 1989. HART I~.G., KANTER M.C.: Hematologic disorders and ischemic stroke. A selective review. Stroke 21:111 l-1121, 1990. INZELBERGR., KORCZYN A.D.: Lupus anticoagulant and late onset seizures. Acta Neurol. Scand. 79:114-118, 1989. KUSHNER M., SIMONIAN N.: Lupus anticoagulants, anticardiolipin antibodies, and cerebral ischemia. Stroke 20:225-229, 1989. THE ANTIPHOSPHOLIPID ANTIBODIES 1N STROKE STUDY GROUp: Clinical and laborator)' findings in patients with antiphospholipid antibodies and cerebral ischemia. Stroke 21 : 1268-1273, 1990.
601
The primary antiphospholipid syndrome: case report Severi S.*, Ghezzi M.*, Felici M.** * U.O. di Neurologia e Neurofisiopatologia, Ospedale USL 23, Arezzo ** U.O. di Medicina Interna, Ospedale USL 23, Are:m
Lupus anticoagulant antibodies and anticardiolipin antibodies are acquired circulating immunoglobulins that interact with phospholipids. These factors may exert anticoagulant properties in vitro and so interfere with coagulation tests that use phospholipids. These antibodies are not, however, associated with a hemorrhagic diathesis. Indeed, despite their name and their in vitro anticoagulant properties, they have been associated right from the earliest reports with systemic and cerebral thromboembolic episodes. We report the clinical and instrumental findings in a patient with ischemic stroke and anticoagulant antibodies in the serum.
Key Words: Anticoagulants - - antiphospholipid antibodies - - thrombosis
Introduction Anticoagulant antibodies are acquired circulating immunoglobulins and the principal ones are lupus anticoagulants (LAs) and anticardiolipin antibodies (ACAs) [1]. They are part of a group of antibodies directed against neutral and negative phospholipids and are known as antiphospholipid antibodies [2, 3, 7]. These antibodies, originally identified in subjects with systemic lupus erythematosus (SLE), have since been found in numerous other pathological conditions and even in healthy individuals (2% of the general population). They cross-react with phospholipids in vitro and so have the potential to interfere with coagulation tests that use phospholipids, inducing a lengthening of the whole blood clotting time, prothrombin time and, especially, partial thromboplastin time (PTT). And yet in vivo they do not alter or reduce the activity of the specific coagulation factors [7, 2]. 20%-25% of subjects with antiphospholipid antibodies have thrombophilia with a marked tendency to thromboembolic episodes, both systemic and cerebral [3, 4, 7, 8]. Some authors have proposed Received 2 January 1992 - Accepted 20 May 1992
"primary antiphospholipid syndrome" or "antiphospholipid-antibody syndrome" for cases in which the presence of an ischemic cerebral vascular disorder is associated with the presence of antiphospholipid antibodies, false positive on the VDRL test, lengthening of PTT and platelet deficiency, which categorize the case we now report [1].
Case report A 44 year old woman with no noteworthy history until the age of 30 started 5 pregnancies between the ages of 30 and 35, all ending in miscarriage. In the same period the patient began to have recurrent thrombophlebitis of the lower limbs. At age 37 a change blood chemistry test showed marked platelet deficiency (30 000 ram3), for which the patient was admitted to the internal medicine department and discharged with the diagnosis of platelet deficiency in SLE. The tests done at that time showed no antiplatelet antibodies. After enjoying good health for some years she began at age 44 to have sudden episodes of objective vertigo, diplopia, speech disorders and loss 599
The Batian Journal of Neurological Sciences
TABLE I. Proposed thrombotic mechanisms for lupus anticoagulant antibodies.
Lupus anticoagulant
Anticardiolipin Ab
Anti-DNA Ab
against phospholipids Platelets ~ ~ ' / ~ - - thrombocytopenia - - release of procoagulants
1 Endothelium
- - inhibition of PGI2 formation --inhibition of protein C activation - - r e d u c t i o n of release of plasminogen activator
of strength in the right upper arm, for which she was admitted to the neurology department. Examination revealed: dysarthria, diplopia due to a deficit of cranial nerve VI on the right, anisocoria (L > R), with sparing of the consensual light reflex bilaterally, and a mild rightsided faciobrachiocrural pyramidal syndrome. A C T brainscan done immediately after onset of symptoms was normal. An MRI scan of the brain done a few days later showed in the T2-weighted images numerous hyperintense images between 3 and 10 mm in diameter in the white substance of the left cerebellar hemisphere, in the midbrain near the midline and in the left temporal lobe; other similar but smaller images were present in the two semioval centers. Cerebral angiography (according to Seldinger) revealed nothing pathological in the carotid or vertebral territories. Blood tests showed marked platelet deficiency (50 000/mmS), lengthening of PTT (38") and of the prothrombin time (69%), presence of antinuclear antibodies and native anti-DNA, positive Wassermann reaction (1 : 8) and VDRL ( + + ) but negative TPHA and FFA-ABS. The test for antiphospholipid antibodies was positive for LAs and ACAs. The neurological deficits wore off gradually within a few weeks while the deficit of extraocular movement took several months to clear completely.
Discussion
The patient's clinical history shows that with anticoagulant antibodies in the serum there is high risk of venous and/or arterial thrombosis, both systemic and cerebral [3]. In these situations the majority of the neurological symptoms, as has been suggested by clinical studies and confirmed at necrospy, reflect the presence of thrombotic disease of the medium caliber arteries [3]. 600
~
Plasma - - i n t e r f e r e n c e with antithrombin III --inhibition of prekallikrein (fibrinolysis)
TABLE II. Design of stud)' of hemostasis of
thrombotic episodes without apparent cause. 9 Assay for fibrinogen, plasminogen, alpha-2antiplasmin 9 Assay for coagulation inhibitors 9 antithrombin III 9 protein C 9 protein S
9 Analysis of fibrinolytic activity 9 general tests: thromboelastogram, fibrinolysis 9 specific tests: assay for plasminogen activator and its inhibitors
9 Tests for antiphospholipid antibodies 9 anticardiolipin antibodies (ACAs) 9 lupus anticoagulant antibodies (LAs) from Bernard C., Moerloose P., 1990. Modified)
The precise mechanism of action of antiphospholipid antibodies (Table I) is not yet known but it is clear from the majority of the studies conducted that they have the property of interfering with several reactions of the coagulation system. The most frequent site of inhibition is at the level of the reaction activating prothrombin by prothrombinase or prothrombin activating complex (factor Xa, factor V, calcium and phospholipids). The action of the antibodies seems to be immediate, developing through an interaction with the phospholipid component of the thromboplastin complex, with tissue thromboplastin and with the platelet phospholipids and consequently on thromboplastin formation, both intrinsic and extrinsic [7, 2, 3]. There is a great deal of uncertainty regarding the treatment of patients with cerebral ischemia and LAS and/or ACAs. The doubts center on the use of antiaggregants, anticoagulants, immunosuppressants and plasmapheresis [7, 2, 3]. At the
Severi S.: The primary antiphospholipidsyndrome
moment most authors r e c o m m e n d anticoagulant therapy in all patients presenting anticoagulant antibodies and a history of ischemic episodes, cerebral or systemic, whether or not they have SLE [6, 10]. Treatment with anticoagulants and/ or platelet antiaggregants seems drastically to reduce the frequency of ischemic strokes and retinal thrombosis [5]. On present evidence and on that of the case reported we think that k n o w l e d g e of the physiopathology of these problems would gain from
testing for LAs and A C A s and other factors in hemostasis (Table II) in all subjects with SLE and in subjects with ischemic strokes without apparent risk factors or anyway without pathological conditions likely to favor thromboembolism (emboligenous heart disease, carotid stenosis, complicated atherosclerotic plaques, vasculitis, among others). Greater awareness of the presence of these antibodies in such clinical conditions may contribute in future to more targeted prevention and treatment of cerebral ischemia [7, 9].
Sommario Gli anticorpi anticoagulanti tipo-lupus e gli anticorpi anticardiolipina sono immunoglobuline circolanti acquisite che interagiscono con i fosfolipidi. Questi fattori, in vitro, possono manifestare proprietb anticoagulanti interferendo con i test della coagulazione che utilizzano fosfolipidi. Tali anticorpi non sono tuttavia'associati a diatesi emorragica. Infatti contrariamente al loro nome ed alle loro proprietgl anticoagulanti in vitro, essi fin dalle loro prime descrizioni sono stati correlati ad episodi tromboembolici sistemici e cerebrali. Vengono descritti i reperti clinici e strumentali osservati in una paziente con ictus ischemico e anticorpi anticoagulanti in circolo.
Address reprint requests to: Dr Sauro Severi U.O. Neurologia - Ospedale U S L 23 Via della Fonte Veneziana, 17 52100 - Arezzo
References [1] ASHERSON R.A., G1L A., VAZQUER J.-J., CHAN 0., BAGULEY E., HUGHES G.R.V.: Cerebrovascular disease and antiphospholipid antibodies in systemic lupus er3,thematosus, lupus-like disease, and the primary antiphospholipid syndrome. Am. J. Med. 86:391-399, 1989. [2] BERNARD C., MOERLOOSE P.: Anticorps anticardiolipins et thromboses. M~d. et Hyg. 48:166-169, 1990. [3] BRILEY D.P., COULL B.M., GOODNIGHT S.H. JR.: Neurological diseases associated with antiphospholipid antibodies. Ann. Neurol. 25:221-227, 1989. [4] COVLL B.M., GOODNEGHTS.H.: Antiphospholipid antibodies, prethrombotic states, and stroke. Stroke 2l:1370-1374, 1990. [5] D1GREK.B., DURCANF.J., BRANCH D.W., JACOB-
[6] [7]
[8] [9] [10]
SON D.M., VARNER M.W., BARINGER J.R.: Amaurosis fugax associated with antiphospholipid antibodies. Ann. Neurol. 25:228-232, 1989. FUTRELL N., MILLIKAN C.: Frequency, etiology, and prevention of stroke in patients with systemic lupus ervthematosus. Stroke 20:583-591, 1989. HART I~.G., KANTER M.C.: Hematologic disorders and ischemic stroke. A selective review. Stroke 21:111 l-1121, 1990. INZELBERGR., KORCZYN A.D.: Lupus anticoagulant and late onset seizures. Acta Neurol. Scand. 79:114-118, 1989. KUSHNER M., SIMONIAN N.: Lupus anticoagulants, anticardiolipin antibodies, and cerebral ischemia. Stroke 20:225-229, 1989. THE ANTIPHOSPHOLIPID ANTIBODIES 1N STROKE STUDY GROUp: Clinical and laborator)' findings in patients with antiphospholipid antibodies and cerebral ischemia. Stroke 21 : 1268-1273, 1990.
601
