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Clinical manifestations of the antiphospholipid syndrome
ABSTRACTS
18 SUBCLASSIFICATION OF NON-SPECIFIC CIRCULATING ANTICOAGULANTS. T. Exner, E. Favaloro, Haematology Dept., Westmead Hospital, NSW 2145 a 1 1 n ( - p r . r - i f 1 <- 1-1 I 1-11 1 ;1t 1 n q I n t 1 1 K e, v n 1 1 \ T I,
( D R I V T ) . 1-he f i r : r t ..in:.icoagi11.3nt %as d e t e c t p d i i i l11asm;l froin a n 8 5 y e a r o l d man r ' e q i i i r i n g a k i n q r a f t s
test
~
CLINICAL MANIFESTATIONS OF THE ANTIPHOSPHOLIPID SYNDROME. B. Firkin*, Department Box Hill, VIC, 3128.
of Medicine, B o x Hill Hospital,
There have been an increasing number of reports in the literature relating the association of either lupus anticoagulant (LA) and/or cardiolipin antibodies (CA) with a number of clinical manifestations. There continue$ to be debate as to how significant these relationships are an objective view would be that many of these questions are yet to be resolved. From a clinicians viewooint. there are a number of situations where it
The association of LA/CA with viral infections especially those involving the immune system is quite striking as is the propensity for certain drugs to produce LA without there necessarily being other features of connective tissue illness. High titre LA and/or the CA may be present in patients with systemic lupus erythematosus and is then associated with a higher incidence of thrombotic events. A number of such patients however have no apparent i l l effect. This presentation will analyse and review the current status of this syndrome and its clinical significance.
ANTIBODY POPULATIONS IN THE ANTIPHOSPHOLIPID
SYNDROME
LABORATORY DiAGNOSlS OF LUPUS ANTICOAGULANTS T.Exner. Haematology Department, Westmead Hospital, Westmead. Sydney, NSW, 2145 Recently the significance of a finding of lupus anticoagulant (LA) in a patient has changed. Previously regarded merely a s a laboratory curiosity LA are now recognised a s potential risk factors for thrombosis and in women appear to be responsible for recurrent fetal loss. Though it was initially suggested that LA and anticardiolipin antibodies (aCL) may be identical phospholipid-binding immunoglobulins. more recent studieshave shown the correlation between aCL and LA to b e incomplete. Many patients have raised aCL without LA though the reverse situation is less common. The most sensitive screening tests for LA utilise low concentration of phospholipid for example in the kaolin clotting time, the dilute Russell's viper venom test or the dilute tissue thromboplastin inhibition test. Prolongation of such tests by LA can usually be corrected by the addition of "excess" procoagulant phospholipid Conversely LA are not corrected by mixing with normal plasma A LA test appropriate for a particular purpose should be selected. Thus hospital patients often present with other coagulation complications. e-g. anticoagulants. or liver disease, and the LA defect needs to be carefully distinguished from conditions likely to contribute to Meeding. Thus greater specificity is required for this group whereas sensitivity is the most important consideration for detecting LA in otherwise normal females being investigated e g.for recurrent miscarriages. It is important to carry out LA tests on correctly processed samples particularly avoiding platelet activation which may 'bypass" the LA defect.
CN. Chesterman' and W. Shi. Dept of Haematology, School of Pathology, Universiy of N.S.W., Prince of Wales Hospital, Randwick NSW 2031. Of immunoglobulins directed against self-antigens which arise in autoimmune disorders such as systemic lupus erythematosis (SLE), the antiphospholipid (aPL) antibodies are of major interest to haematologists not only because the lupus anticoagulant (LA) causes an inhibition of Q blood coagulation, but also because the presence of certain aPL antibodies confers a risk of thrombosis. The inhibition of Q phospholipiddependent coagulation (LA) is thought to be due to the binding of LA to procoagulant phospholipid surfaces, thus impeding the clotting process. It is likely that LA interacts with lipid structures formed in the presence of hexagonal phase phosphatidyl-ethanolmineand thus that the antibody is directed against a complex phospholipid epitope. Another class of aPL are those originally described to be directed against negatively charged phospholipids, in particular cardiolipin. We have recently shown that ACL antibodies are usually directed against a complex antigen consisting of negatively charged phospholipid and a plasma protein, p2-glycoprotein-I (&-GPI) (McNeil et al, Proc. Natl. Acad. Sci. 874120,1990). Further, we have found a major degree of antibody heterogeneity even within individual patients so that ACL and LA are separable using physicochemical techniques such as ion exchange chromatography and chromatofocusing. Using such techniques we have enriched Ig fractions for LA and A C A The majority of Ig with LA activity had a PI of 7.3-7.4whereas ACA had a PI of 5-5.3.Using these enriched fractions labelled with '%iodine we have shown that LA binds to platelets in a specific and saturable manner. Binding is dependent on thrombin activation. "I-ACA behaves differently. Like LA-lgG, binding is specific and dependent on thrombin activation but in this case requires the presence of &-GPI. In neither case does LA or ACA have an effect on thrombin-induced release of 5-HT or pthromboglobulin nor do they affect platelet aggregation induced by a number of agonists. This antibody binding may play an aetiological role in thrombocytopenia associated with aPL, but does not explain thrombosis.
18 SUBCLASSIFICATION OF NON-SPECIFIC CIRCULATING ANTICOAGULANTS. T. Exner, E. Favaloro, Haematology Dept., Westmead Hospital, NSW 2145 a 1 1 n ( - p r . r - i f 1 <- 1-1 I 1-11 1 ;1t 1 n q I n t 1 1 K e, v n 1 1 \ T I,
( D R I V T ) . 1-he f i r : r t ..in:.icoagi11.3nt %as d e t e c t p d i i i l11asm;l froin a n 8 5 y e a r o l d man r ' e q i i i r i n g a k i n q r a f t s
test
~
CLINICAL MANIFESTATIONS OF THE ANTIPHOSPHOLIPID SYNDROME. B. Firkin*, Department Box Hill, VIC, 3128.
of Medicine, B o x Hill Hospital,
There have been an increasing number of reports in the literature relating the association of either lupus anticoagulant (LA) and/or cardiolipin antibodies (CA) with a number of clinical manifestations. There continue$ to be debate as to how significant these relationships are an objective view would be that many of these questions are yet to be resolved. From a clinicians viewooint. there are a number of situations where it
The association of LA/CA with viral infections especially those involving the immune system is quite striking as is the propensity for certain drugs to produce LA without there necessarily being other features of connective tissue illness. High titre LA and/or the CA may be present in patients with systemic lupus erythematosus and is then associated with a higher incidence of thrombotic events. A number of such patients however have no apparent i l l effect. This presentation will analyse and review the current status of this syndrome and its clinical significance.
ANTIBODY POPULATIONS IN THE ANTIPHOSPHOLIPID
SYNDROME
LABORATORY DiAGNOSlS OF LUPUS ANTICOAGULANTS T.Exner. Haematology Department, Westmead Hospital, Westmead. Sydney, NSW, 2145 Recently the significance of a finding of lupus anticoagulant (LA) in a patient has changed. Previously regarded merely a s a laboratory curiosity LA are now recognised a s potential risk factors for thrombosis and in women appear to be responsible for recurrent fetal loss. Though it was initially suggested that LA and anticardiolipin antibodies (aCL) may be identical phospholipid-binding immunoglobulins. more recent studieshave shown the correlation between aCL and LA to b e incomplete. Many patients have raised aCL without LA though the reverse situation is less common. The most sensitive screening tests for LA utilise low concentration of phospholipid for example in the kaolin clotting time, the dilute Russell's viper venom test or the dilute tissue thromboplastin inhibition test. Prolongation of such tests by LA can usually be corrected by the addition of "excess" procoagulant phospholipid Conversely LA are not corrected by mixing with normal plasma A LA test appropriate for a particular purpose should be selected. Thus hospital patients often present with other coagulation complications. e-g. anticoagulants. or liver disease, and the LA defect needs to be carefully distinguished from conditions likely to contribute to Meeding. Thus greater specificity is required for this group whereas sensitivity is the most important consideration for detecting LA in otherwise normal females being investigated e g.for recurrent miscarriages. It is important to carry out LA tests on correctly processed samples particularly avoiding platelet activation which may 'bypass" the LA defect.
CN. Chesterman' and W. Shi. Dept of Haematology, School of Pathology, Universiy of N.S.W., Prince of Wales Hospital, Randwick NSW 2031. Of immunoglobulins directed against self-antigens which arise in autoimmune disorders such as systemic lupus erythematosis (SLE), the antiphospholipid (aPL) antibodies are of major interest to haematologists not only because the lupus anticoagulant (LA) causes an inhibition of Q blood coagulation, but also because the presence of certain aPL antibodies confers a risk of thrombosis. The inhibition of Q phospholipiddependent coagulation (LA) is thought to be due to the binding of LA to procoagulant phospholipid surfaces, thus impeding the clotting process. It is likely that LA interacts with lipid structures formed in the presence of hexagonal phase phosphatidyl-ethanolmineand thus that the antibody is directed against a complex phospholipid epitope. Another class of aPL are those originally described to be directed against negatively charged phospholipids, in particular cardiolipin. We have recently shown that ACL antibodies are usually directed against a complex antigen consisting of negatively charged phospholipid and a plasma protein, p2-glycoprotein-I (&-GPI) (McNeil et al, Proc. Natl. Acad. Sci. 874120,1990). Further, we have found a major degree of antibody heterogeneity even within individual patients so that ACL and LA are separable using physicochemical techniques such as ion exchange chromatography and chromatofocusing. Using such techniques we have enriched Ig fractions for LA and A C A The majority of Ig with LA activity had a PI of 7.3-7.4whereas ACA had a PI of 5-5.3.Using these enriched fractions labelled with '%iodine we have shown that LA binds to platelets in a specific and saturable manner. Binding is dependent on thrombin activation. "I-ACA behaves differently. Like LA-lgG, binding is specific and dependent on thrombin activation but in this case requires the presence of &-GPI. In neither case does LA or ACA have an effect on thrombin-induced release of 5-HT or pthromboglobulin nor do they affect platelet aggregation induced by a number of agonists. This antibody binding may play an aetiological role in thrombocytopenia associated with aPL, but does not explain thrombosis.