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Sneddon's syndrome and antiphospholipid antibodies
THROMBOSIS RESEARCH 69; 555-560, 1993 0049-3848/93 $6.00 + .OOPrinted in the USA. Copyright (c) 1993 Pergamon Press Ltd. All rights reserved.
BRIEFCOMMUNICATION SNEDDON'S SYNDROME AND ANTIPHOSPHOLIPID
ANTIBODIES
Piedad Villa*, Ricardo Yayd **, Fernando Ferrando*, Just0 Aznar*, Amparo EstellBs***, Juana Vall&s***, Ma Teresa Santos***. * Departments of Clinical Pathology, ** Neurology and *** Research Center. Hospital La Fe. Valencia, Spain. (Received 9.9.1992; accepted in revisedform7.12.1992by EditorE. Angles-Cano) (Received by ExecutiveEditorialOffice 1.2.1993)
The antiphospholipid antibodies (APA) represent a wide group includes which anticardiolipine antibodies of autoantibodies, (ACA) and lupus anticoagulant antibodies (LA). APA are associated with various clinical pathologies and are recognized markers for spontaneous abortions and an increased risk of thrombosis (l-3), Systematic laboratory assays to detect intrauterine deaths (4,5). in many APA (6) have revealed the presence of these antibodies clinical pathologies and led to a definition of a new syndrome, the anticardiolipin (7) or antiphospholipid syndrome (8). Increased LA and ACA levels have been found in some patients syndrome, which with Sneddon's is characterized by a (9-13) and multiple cerebrovaslivedo reticularis diffuse idiopathic cular lesions of an ischaemic nature (14). Kalashnikova et al (15) and found positive ACA in recently reviewed 39 Sneddon patients However, Rautenberg 57 % of them, while 60 % showed positive LA. (16) reported positive ACA findings only in one of five et al patients studied, and ACA was not present in a group of Sneddon patients reported by Burton (17). In another Sneddon case the authors found no positive ACA (18,19). Since, as these reports between ACA and Sneddon's syndrome still show, the association remains unclear, we have evaluated ACA as well as other haemostatic tests in a group of Sneddon patients.
MATERIAL AND METHODS Subiects. Seven patients (4 males and 3 females) with Sneddon's syndrome whose mean age was 47 years (range from 32 to 63 years) were studied. Clinically all of them showed constant livedo reticularis, repeated ischaemic cerebrovascular episodes and signs of peripherical vascular insufficiency. The hypertension displayed by Key words: Sneddon syndrome, antiphospholipid antibodies, anticardiolipin antibodies, lupus anticoagulant, lupus erythematosus. 555
556
ANTIPHOSPHOLIPID
ANTIBODIES
Vol. 69, No. 6
three subjects responded easily to treatment. Nuclear magnetic resonance (NMR) proved to be the test of choice to diagnose these patients, who showed many lacunar infarcts in vessels of the posterior fossa which were not observed in brain computerized tomography (CT). Moreover, widespread lacunar infarcts were seen in the anterior, median cerebral arteries, bilaand posterior teral and asymmetrical lacunes in basal ganglions, cortical atrophy, and in three patients a remarkable reduction of the corpus callosum. In all the patients the occurrence of systemic lupus erythomatous (SLE) was ruled out since no clinical SLE symptoms, LE cells, anti DNA antibodies or false VDRL were found. The control group included 7 healthy subjects matched with the patients. Methods. Diluted APTT (dAPTT), Russell viper venom time (RWT) (20), plasma clot time in platelet rich plasma (PCT) (21) and kaolin clotting time (KCT) (22) were used to detect LA. The ACA were measured by an ELISA method (23) (normal range was O-9 Anticardiolipin ELISA Units (AEU) for IgG and O-8 AEU for IgM). B-TG levels were measured by RIA (Amersham International) (24). t-PA antigen and PAI- activity were measured as previously described (25). PGIz was determined by RIA as 6-keto-PGFla (Amersham International). followins a method Platelet activity was evaluated developed in our laboratory (26,27). RESULTS LA and ACA were found in only one of the seven Sneddon patients studied (Table 1). Hemostasic tests (Table 2) showed increased levels of B-TG, t-PA antigen and PAI activity as well slightly but not as decreased PGFI a values. Platelet activity was . significantly increasea. TABLE Coagulation
1
tests for the APA diagnosis ACA
~APTT
RVVT
PCT
KCT
IgG
IgM
Sneddon 1st to 6th x patients SD
104.2 19.3
28.9 0.7
128 11
85.3 13.8
1
1
Sneddon 7th patient
135
35.0
168
131.5
49
15
116.1 11
27.4 1.8
127.7 9.0
91.6 13.6
1
1
CG n=7
X SD
dAPTT, RVVT, PCT and KCT are expressed in seconds. ACA as AEU. CG = control group. 1st to 6th Sneddon patients were LA (evaluaThe 7th pated by dAPTT, RWT,PCT and KCT) and ACA negative. tient was LA and ACA positive.
ANTIPHOSPHOLIPID
Vol. 69, No. 6
557
ANTIBODIES
TABLE 2 Haemostatic
PTG ng/ml
tests
6-keto-PGFla ng/ml
t-PA ng/ml
PAIU/ml
Platelet reactivity (%)
Sneddon 1st 6th X patients SD
66.8*
0.19**
6.9**
84
47.4
0.007
2.9
4.5
15
Sneddon 7th patient
393.0
0.14
19.5
5.5
51
29.4 9.9
0.48 0.18
9.8 3.9
0.8 1.0
62 24
CG
X SD
13.1*
* pco.01; ** p
DISCUSSION The incidence of positive APA in patients with Sneddon's syndrome has not been clearly established. This could be due to the difficulty in standardizing the techniques used but is more probably the result of the selection of the patients studied. with livedo reticularis may also have SLE or show the Patients cerebrovascular lesions which characterize Sneddon's syndrome. In with livedo reticularis associated with SLE, APA incipatients dence is about 77 %, but in SLE patients without livedo reticularis it is only about 15 % (28). In patients whose livedo reticularis is associated with cerebrovascular lesions (Sneddon's syndrome), but in whom associated SLE has been ruled out, the incidence of APA has been reported to be 60 % (15), 20 % (16) or complete absence (17). The variations of APA incidence in Sneddon's syndrome reported in the literature may result from the association of SLE or any other autoimmune disease with Sneddon's syndrome in the patients studied. Although the mechanism which causes thrombosis in APA patients is not clear, it has been suggested (29) that it could be related to the alteration of platelet phospholipids, the inhibition in the production of prostacyclin or pre-kallikrein or to alterations of the anticoagulant activity of thrombomodulin. The fact that our patient with positive LA and ACA showed sharply increased circulating B-TG, low platelet reactivity, higher t-PA and PAI- release and lower levels of circulating 6-keto-PGFla, suggests that antiphospholipid antibodies may have activated platelets and vascular endothelium, which could facilitate the development of thrombotic episodes. Thus, the incidence of APA in Sneddon's syndrome and the relationship between positive levels of these antibodies and thrombotic episodes or the severity of the clinical
558
ANTlPHOSPHOtlPlD
ANTIBODIES
Vol. 69, No. 6
symptoms remain unclear. REFERENCES 1.
HARRIS, E.N. Annotation: Haematol. 74, l-9, 1990.
2.
LECHNER, K., PABINGER-FASCHING, I. Lupus anticoagulant and thrombosis: A study of 25 cases and review of the literature. Haemostasis. 15, 254-262, 1985.
3.
BLATT, P.M., MARTIN, S.E. The lupus anticoagulant. Path01 Lab Med. 111, 113, 1987.
4.
BRANCH, D.W., SCOTT, J.R., KOUCHENOUR, N.K., HERSHGOLD, E. Obstetric complications associated with the lupus anticoagulant. N Engl J Med. 313, 1322-1326, 1985.
5.
LOCKSHIN, M.D., DRUZIN, M.L., GOEI, S. et al. Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med. 313, 152-156, 1985.
6.
BARNA, L.K., TRIPLETT, D.A. A report on the first internaClin tional workshop for lupus anticoagulant identification. Exp Rheumatol. 9, 557-567, 1991.
7.
HUGHES, G.R.V., HARRIS, E.N., GHARAVI, D.E.. The anticardiolipin syndrome. J Rheumatol. 13, 486-489, 1986.
8.
ASHERSON, R.A. A primary antiphospholipid matol. 15, 1742-1746, 1988.
9.
JONAS, J., KOLBLE, K., WijLCHER, H.E., KALDEN, J.R. Central retinal artery occlusion in Sneddon's disease associated with antiphospholipid antibodies. Am J Ophthalmol. 102, 37-40, 1986.
10.
MONTALBAN, J., ORDI, J., BARQUINERO, J., VILARDELL, M. Sneddon'ssyndrome and antiardiolipin antibodies. Stroke. 19,785786, 1988.
11.
GRATTAN, C.E.H., BURTON, J.L., BOON, A.P. Sneddon's syndrome and cerebral thrombosis) with livedo (livedo reticularis vasculitis and anticardiolipin antibodies. Br J Dermatol.120, 441-447, 1989.
12.
LEVINE, S.R., DEEGAN, M.J., FUTRELL, N., WELCH, K.M.A. Cerebrovascular and neurologic disease associated with antiphospholipid antibodies: 48 cases. Neurology. 40, 1181-1189, 1990.
13.
VARGAS, J.A., YEBRA, M., PASCUAL, M.L., DEZ, A. Antiphospholipid antibodies and Am J Med. 87, 597, 1989.
Antiphospholipid
antibodies.
syndrome?
Br J
Arch
J Rheu-
MANZANO, L., DURANSneddon's syndrome.
Vol. 69, No. 6
ANTIPHOSPHOLIPID
ANTIBODIES
559
and
livedo reticu-
14.
Cerebro-vascular lesions SNEDDON, I.B. laris. Br J Dermatol. 77, 180-185, 1965.
15.
KALASHNIKOVA, L.A., NASONOV, E.L., KUSHEKBAEVA, A.E., GRACHEin Sneddon's syndrome. VA, L.A. Antiocardiolipin antibodies Neurology. 40, 464-467, 1990.
16.
RAUTENBERG, W., HENNERICI, M., AULICH, A., HGLZKE, E., LAKOand Sneddon's syndrome. MEL, H.G.Immunosuppresive therapy Lancent. 2, 629-630, 1988.
17.
BURTON, J.L. Livedo reticularis, porcelain-white scars, cerebral thrombosis. Lancet. 4, 1263-1264, 1988.
18.
COSNES, A., PERROUD, A.M., MATHIEU, A, GOURDAIN, C., TOURINE, R. Livedo reticularis et accidents vasculaires cerebraux. Ann Dermatol Venerol. 113, 137-141, 1986.
19.
MARTINEZ, B., PEREZ, A., GONZALEZ, M., VILLAVERDE, F.J., BERMEJO, F. Sneddon's syndrome with negative antiphospholipid antibodies. Stroke. 21, 1510-1511, 1990.
20.
THIAGARAJAN, P., PENGO, V. and SHAPIRO, S.S. The use of the dilute Russell Viper Venom Time for the diagnosis of lupus anticoagulants. Blood. 68, 869-874, 1986.
21.
GASTINEAU, D.A, KAZMIER, F.J, NICHOLS, W.L. and BOWIE, EJW. Lupus anticoagulant: An analysis of the clinical and laboratory features of 219 cases. Am J Hematol. 19, 265-275, 1985.
22.
EXNER, T., RICKARD, K.A., KRONENBERG, H. A sensitive demonstrating lupus anticoagulant and its behavioural terns. Br J Haematol. 40, 143-151, 1978.
23.
LOIZOU, s., McCREA, J.D., RUGDE, A.C., REYNOLDS, R., BOYLE, C.C., HARRIS, E.N. Measurement of anticardiolipin antibodies by an enzymelinked immunosorbent assay (ELISA) standardization and guantitation of results. Clin Exp Immunol. 62, 738745, 1985.
24.
SANTOS, M.T., VALLES, J., AZNAR, J., VILLA, P. Platelet P-TG release"in vitro" induced by mechanical and chemical stimulus. Correlation with the aggregation curve parameters. Stand J Haematol. 29, 368-372, 1982.
25.
AZNAR, J., GILABERT, J., ESTELLES, A., ESPANA, F. Fibrinolytic activity and protein C in pre-eclampsia. Throm Haemost.55, 314-317, 1986.
26.
PEREZ-REQUEJO, J.L., AZNAR, J. SANTOS, M.T., VALLES, J. Early platelet collagen interaction in whole blood and their modifications by Aspirin and Dipyridamole evaluated by a new method (BASIC-wave). Thromb Haemost. 54, 799-803, 1985.
and
test pat-
560
ANTIPHOSPHOLIPID
ANTIBODIES
Vol. 69, No. 6
27.
SANTOS, M.T., VALLES, J., MARCUS, A.J., SAFIER, L.B., BROEKMAN, M.J., ISLAM, N., ULLMAN, H.L., EIROA, M.A., AZNAR, J. Enhancement of platelet reactivity and modulation of eicosanoid production by intact erythrocytes. A new approach to platelet activation and recruitment. Erythrocytes modulate platelet reactivity and eicosanoid production. J Clin Invest. 87, 571-580, 1991.
28.
ENGLERT, H.J., LOIZOU, S., DERUE, G.G.M., WALPORT, M.J. HUGHES, G.R.V. Clinical and immunologic features of livedo reticularis in lupus: A case-control study. Am J Med. 87,408-410, 1989.
29.
antibody BINGLEY, P.J., HOFFBRAND, B.I. Antiphospholipid syndrome: A review. J R Sot Med. 80, 445-448, 1987.
BRIEFCOMMUNICATION SNEDDON'S SYNDROME AND ANTIPHOSPHOLIPID
ANTIBODIES
Piedad Villa*, Ricardo Yayd **, Fernando Ferrando*, Just0 Aznar*, Amparo EstellBs***, Juana Vall&s***, Ma Teresa Santos***. * Departments of Clinical Pathology, ** Neurology and *** Research Center. Hospital La Fe. Valencia, Spain. (Received 9.9.1992; accepted in revisedform7.12.1992by EditorE. Angles-Cano) (Received by ExecutiveEditorialOffice 1.2.1993)
The antiphospholipid antibodies (APA) represent a wide group includes which anticardiolipine antibodies of autoantibodies, (ACA) and lupus anticoagulant antibodies (LA). APA are associated with various clinical pathologies and are recognized markers for spontaneous abortions and an increased risk of thrombosis (l-3), Systematic laboratory assays to detect intrauterine deaths (4,5). in many APA (6) have revealed the presence of these antibodies clinical pathologies and led to a definition of a new syndrome, the anticardiolipin (7) or antiphospholipid syndrome (8). Increased LA and ACA levels have been found in some patients syndrome, which with Sneddon's is characterized by a (9-13) and multiple cerebrovaslivedo reticularis diffuse idiopathic cular lesions of an ischaemic nature (14). Kalashnikova et al (15) and found positive ACA in recently reviewed 39 Sneddon patients However, Rautenberg 57 % of them, while 60 % showed positive LA. (16) reported positive ACA findings only in one of five et al patients studied, and ACA was not present in a group of Sneddon patients reported by Burton (17). In another Sneddon case the authors found no positive ACA (18,19). Since, as these reports between ACA and Sneddon's syndrome still show, the association remains unclear, we have evaluated ACA as well as other haemostatic tests in a group of Sneddon patients.
MATERIAL AND METHODS Subiects. Seven patients (4 males and 3 females) with Sneddon's syndrome whose mean age was 47 years (range from 32 to 63 years) were studied. Clinically all of them showed constant livedo reticularis, repeated ischaemic cerebrovascular episodes and signs of peripherical vascular insufficiency. The hypertension displayed by Key words: Sneddon syndrome, antiphospholipid antibodies, anticardiolipin antibodies, lupus anticoagulant, lupus erythematosus. 555
556
ANTIPHOSPHOLIPID
ANTIBODIES
Vol. 69, No. 6
three subjects responded easily to treatment. Nuclear magnetic resonance (NMR) proved to be the test of choice to diagnose these patients, who showed many lacunar infarcts in vessels of the posterior fossa which were not observed in brain computerized tomography (CT). Moreover, widespread lacunar infarcts were seen in the anterior, median cerebral arteries, bilaand posterior teral and asymmetrical lacunes in basal ganglions, cortical atrophy, and in three patients a remarkable reduction of the corpus callosum. In all the patients the occurrence of systemic lupus erythomatous (SLE) was ruled out since no clinical SLE symptoms, LE cells, anti DNA antibodies or false VDRL were found. The control group included 7 healthy subjects matched with the patients. Methods. Diluted APTT (dAPTT), Russell viper venom time (RWT) (20), plasma clot time in platelet rich plasma (PCT) (21) and kaolin clotting time (KCT) (22) were used to detect LA. The ACA were measured by an ELISA method (23) (normal range was O-9 Anticardiolipin ELISA Units (AEU) for IgG and O-8 AEU for IgM). B-TG levels were measured by RIA (Amersham International) (24). t-PA antigen and PAI- activity were measured as previously described (25). PGIz was determined by RIA as 6-keto-PGFla (Amersham International). followins a method Platelet activity was evaluated developed in our laboratory (26,27). RESULTS LA and ACA were found in only one of the seven Sneddon patients studied (Table 1). Hemostasic tests (Table 2) showed increased levels of B-TG, t-PA antigen and PAI activity as well slightly but not as decreased PGFI a values. Platelet activity was . significantly increasea. TABLE Coagulation
1
tests for the APA diagnosis ACA
~APTT
RVVT
PCT
KCT
IgG
IgM
Sneddon 1st to 6th x patients SD
104.2 19.3
28.9 0.7
128 11
85.3 13.8
1
1
Sneddon 7th patient
135
35.0
168
131.5
49
15
116.1 11
27.4 1.8
127.7 9.0
91.6 13.6
1
1
CG n=7
X SD
dAPTT, RVVT, PCT and KCT are expressed in seconds. ACA as AEU. CG = control group. 1st to 6th Sneddon patients were LA (evaluaThe 7th pated by dAPTT, RWT,PCT and KCT) and ACA negative. tient was LA and ACA positive.
ANTIPHOSPHOLIPID
Vol. 69, No. 6
557
ANTIBODIES
TABLE 2 Haemostatic
PTG ng/ml
tests
6-keto-PGFla ng/ml
t-PA ng/ml
PAIU/ml
Platelet reactivity (%)
Sneddon 1st 6th X patients SD
66.8*
0.19**
6.9**
84
47.4
0.007
2.9
4.5
15
Sneddon 7th patient
393.0
0.14
19.5
5.5
51
29.4 9.9
0.48 0.18
9.8 3.9
0.8 1.0
62 24
CG
X SD
13.1*
* pco.01; ** p
DISCUSSION The incidence of positive APA in patients with Sneddon's syndrome has not been clearly established. This could be due to the difficulty in standardizing the techniques used but is more probably the result of the selection of the patients studied. with livedo reticularis may also have SLE or show the Patients cerebrovascular lesions which characterize Sneddon's syndrome. In with livedo reticularis associated with SLE, APA incipatients dence is about 77 %, but in SLE patients without livedo reticularis it is only about 15 % (28). In patients whose livedo reticularis is associated with cerebrovascular lesions (Sneddon's syndrome), but in whom associated SLE has been ruled out, the incidence of APA has been reported to be 60 % (15), 20 % (16) or complete absence (17). The variations of APA incidence in Sneddon's syndrome reported in the literature may result from the association of SLE or any other autoimmune disease with Sneddon's syndrome in the patients studied. Although the mechanism which causes thrombosis in APA patients is not clear, it has been suggested (29) that it could be related to the alteration of platelet phospholipids, the inhibition in the production of prostacyclin or pre-kallikrein or to alterations of the anticoagulant activity of thrombomodulin. The fact that our patient with positive LA and ACA showed sharply increased circulating B-TG, low platelet reactivity, higher t-PA and PAI- release and lower levels of circulating 6-keto-PGFla, suggests that antiphospholipid antibodies may have activated platelets and vascular endothelium, which could facilitate the development of thrombotic episodes. Thus, the incidence of APA in Sneddon's syndrome and the relationship between positive levels of these antibodies and thrombotic episodes or the severity of the clinical
558
ANTlPHOSPHOtlPlD
ANTIBODIES
Vol. 69, No. 6
symptoms remain unclear. REFERENCES 1.
HARRIS, E.N. Annotation: Haematol. 74, l-9, 1990.
2.
LECHNER, K., PABINGER-FASCHING, I. Lupus anticoagulant and thrombosis: A study of 25 cases and review of the literature. Haemostasis. 15, 254-262, 1985.
3.
BLATT, P.M., MARTIN, S.E. The lupus anticoagulant. Path01 Lab Med. 111, 113, 1987.
4.
BRANCH, D.W., SCOTT, J.R., KOUCHENOUR, N.K., HERSHGOLD, E. Obstetric complications associated with the lupus anticoagulant. N Engl J Med. 313, 1322-1326, 1985.
5.
LOCKSHIN, M.D., DRUZIN, M.L., GOEI, S. et al. Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med. 313, 152-156, 1985.
6.
BARNA, L.K., TRIPLETT, D.A. A report on the first internaClin tional workshop for lupus anticoagulant identification. Exp Rheumatol. 9, 557-567, 1991.
7.
HUGHES, G.R.V., HARRIS, E.N., GHARAVI, D.E.. The anticardiolipin syndrome. J Rheumatol. 13, 486-489, 1986.
8.
ASHERSON, R.A. A primary antiphospholipid matol. 15, 1742-1746, 1988.
9.
JONAS, J., KOLBLE, K., WijLCHER, H.E., KALDEN, J.R. Central retinal artery occlusion in Sneddon's disease associated with antiphospholipid antibodies. Am J Ophthalmol. 102, 37-40, 1986.
10.
MONTALBAN, J., ORDI, J., BARQUINERO, J., VILARDELL, M. Sneddon'ssyndrome and antiardiolipin antibodies. Stroke. 19,785786, 1988.
11.
GRATTAN, C.E.H., BURTON, J.L., BOON, A.P. Sneddon's syndrome and cerebral thrombosis) with livedo (livedo reticularis vasculitis and anticardiolipin antibodies. Br J Dermatol.120, 441-447, 1989.
12.
LEVINE, S.R., DEEGAN, M.J., FUTRELL, N., WELCH, K.M.A. Cerebrovascular and neurologic disease associated with antiphospholipid antibodies: 48 cases. Neurology. 40, 1181-1189, 1990.
13.
VARGAS, J.A., YEBRA, M., PASCUAL, M.L., DEZ, A. Antiphospholipid antibodies and Am J Med. 87, 597, 1989.
Antiphospholipid
antibodies.
syndrome?
Br J
Arch
J Rheu-
MANZANO, L., DURANSneddon's syndrome.
Vol. 69, No. 6
ANTIPHOSPHOLIPID
ANTIBODIES
559
and
livedo reticu-
14.
Cerebro-vascular lesions SNEDDON, I.B. laris. Br J Dermatol. 77, 180-185, 1965.
15.
KALASHNIKOVA, L.A., NASONOV, E.L., KUSHEKBAEVA, A.E., GRACHEin Sneddon's syndrome. VA, L.A. Antiocardiolipin antibodies Neurology. 40, 464-467, 1990.
16.
RAUTENBERG, W., HENNERICI, M., AULICH, A., HGLZKE, E., LAKOand Sneddon's syndrome. MEL, H.G.Immunosuppresive therapy Lancent. 2, 629-630, 1988.
17.
BURTON, J.L. Livedo reticularis, porcelain-white scars, cerebral thrombosis. Lancet. 4, 1263-1264, 1988.
18.
COSNES, A., PERROUD, A.M., MATHIEU, A, GOURDAIN, C., TOURINE, R. Livedo reticularis et accidents vasculaires cerebraux. Ann Dermatol Venerol. 113, 137-141, 1986.
19.
MARTINEZ, B., PEREZ, A., GONZALEZ, M., VILLAVERDE, F.J., BERMEJO, F. Sneddon's syndrome with negative antiphospholipid antibodies. Stroke. 21, 1510-1511, 1990.
20.
THIAGARAJAN, P., PENGO, V. and SHAPIRO, S.S. The use of the dilute Russell Viper Venom Time for the diagnosis of lupus anticoagulants. Blood. 68, 869-874, 1986.
21.
GASTINEAU, D.A, KAZMIER, F.J, NICHOLS, W.L. and BOWIE, EJW. Lupus anticoagulant: An analysis of the clinical and laboratory features of 219 cases. Am J Hematol. 19, 265-275, 1985.
22.
EXNER, T., RICKARD, K.A., KRONENBERG, H. A sensitive demonstrating lupus anticoagulant and its behavioural terns. Br J Haematol. 40, 143-151, 1978.
23.
LOIZOU, s., McCREA, J.D., RUGDE, A.C., REYNOLDS, R., BOYLE, C.C., HARRIS, E.N. Measurement of anticardiolipin antibodies by an enzymelinked immunosorbent assay (ELISA) standardization and guantitation of results. Clin Exp Immunol. 62, 738745, 1985.
24.
SANTOS, M.T., VALLES, J., AZNAR, J., VILLA, P. Platelet P-TG release"in vitro" induced by mechanical and chemical stimulus. Correlation with the aggregation curve parameters. Stand J Haematol. 29, 368-372, 1982.
25.
AZNAR, J., GILABERT, J., ESTELLES, A., ESPANA, F. Fibrinolytic activity and protein C in pre-eclampsia. Throm Haemost.55, 314-317, 1986.
26.
PEREZ-REQUEJO, J.L., AZNAR, J. SANTOS, M.T., VALLES, J. Early platelet collagen interaction in whole blood and their modifications by Aspirin and Dipyridamole evaluated by a new method (BASIC-wave). Thromb Haemost. 54, 799-803, 1985.
and
test pat-
560
ANTIPHOSPHOLIPID
ANTIBODIES
Vol. 69, No. 6
27.
SANTOS, M.T., VALLES, J., MARCUS, A.J., SAFIER, L.B., BROEKMAN, M.J., ISLAM, N., ULLMAN, H.L., EIROA, M.A., AZNAR, J. Enhancement of platelet reactivity and modulation of eicosanoid production by intact erythrocytes. A new approach to platelet activation and recruitment. Erythrocytes modulate platelet reactivity and eicosanoid production. J Clin Invest. 87, 571-580, 1991.
28.
ENGLERT, H.J., LOIZOU, S., DERUE, G.G.M., WALPORT, M.J. HUGHES, G.R.V. Clinical and immunologic features of livedo reticularis in lupus: A case-control study. Am J Med. 87,408-410, 1989.
29.
antibody BINGLEY, P.J., HOFFBRAND, B.I. Antiphospholipid syndrome: A review. J R Sot Med. 80, 445-448, 1987.