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The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and/or anti-β2-glycoprotein I antibodies in medium to high titers. The management of thrombosis in patients with APS is a subject of controversy. This set of recommendations is the result of an effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS.

Lupus anticoagulant (LA) antibodies have been shown to be directed to protein-phospholipid complexes. In this study, we report on LA antibodies from patients with the ‘antiphospholipid’ syndrome (APS), that are directed to prothrombin and b2-glycoprotein I, but not to the complexes of these plasma proteins to anionic phospholipids. The anti-prothrombin antibodies studied had different reactivities in two clotting assays: the dilute Russell's viper venom time (dRVVT) and the dilute kaolin clotting time (dKCT). Anti-prothrombin and anti-b2-glycoprotein I (anti-b2GPI) antibodies, affinity-purified from one patient with APS were not cross-reactive and had different effects in the dRVVT and dKCT clotting tests. Polyclonal anti-prothrombin antibodies, affinity-purified on a prothrombin column, from two patients with prothrombin reactivity in their plasma, have affinity constants to prothrombin of 104 and 192 nM. The patient with affinity-purified antibodies to prothrombin and b2GPI, had affinity constants to prothrombin and b2GPI, respectively, of 192 nM and 3030 nM, respectively. LA antibodies are a heterogenous population of antibodies that have different immunological specificities and clotting test reactivities in different patients.

Beta2-glycoprotein I (beta2GPI) is a cofactor for anti-phospholipid (aPL) binding to cardiolipin (CL)-coated plates. Beta2GPI is also able to bind to endothelial cell (EC) membranes as supported by in-vivo as well as by in-vitro studies. The PL-binding site in the fifth domain of the molecule is involved in the adhesion to endothelium. Actually, specific mutations in this molecular portion abolish endothelium binding and a synthetic peptide spanning the sequence Glu274-Cys288 of the CL-binding site displays comparable adhesion to EC monolayers. Heparan sulphate appears to be one of the anionic EC membrane structures with which cationic beta2GPI interacts, as supported by studies with heparitinase-treated EC. Beta2GPI binding to EC might be related to its activity as endothelial growth factor or as a lipid-carrying glycoprotein. Adhesion of beta2GPI to endothelial membranes offers suitable epitopes for circulating aPL that, once bound, can induce cell activation

It has become clear that beta2-glycoprotein I (beta2GPI) is the most common and best-characterised antigenic target for 'antiphospholipid' (aPL) autoantibodies. These antibodies preferentially bind beta2GPI that has been immobilised on anionic phospholipid membranes or certain synthetic surfaces. These surfaces appear to act by increasing antigen density to allow binding of intrinsically low-affinity anti-beta2GPI autoantibodies. Binding of beta2GPI in fluid phase is weak and requires high concentrations of beta2GPI. Our understanding of the pathophysiology of the 'Antiphospholipid' Syndrome (APS) has increased exponentially with the number of studies into the interactions of aPL antibodies and beta2GPI.

‘Antiphospholipid’ (aPL) antibodies are of important clinical significance because of their association with thrombosis both arterial and venous, recurrent foetal loss, specific neurological sequelae like seizures and chorea, cardiac valvular abnormalities and thrombocytopenia.1 Traditionally these autoantibodies have been assayed using phospholipid (PL) dependent tests and are classified as lupus anticoagulants (LA) and anticardiolipin (aCL) antibodies based on the method of detection.2 The antibodies thus, had been thought to bind PLs but it has now become clear that the true antigens are PL-binding proteins. The major protein consistently found as the target antigen for these autoantibodies is β2-glycoprotein I (β2-GPI).3 Other candidate PL-binding proteins have also been investigated including prothrombin, protein C and protein S4 but thus far appear to play less important roles in the binding of these antibodies.

Anticardiolipin antibodies (aCL) purified from patients with autoimmune disease have recently been shown to interact with a phospholipid-binding plasma protein, β2-glycoprotein I (β2-GPI). The aim of this study was to determine whether aCL purified from patients with infection also interact with β2 -GPI. aCL purified from 23 patients with malaria, infectious mononucleosis, tuberculosis, hepatitis A or syphilis did not require the presence of β2-GPI to bind cardiolipin (CL). In contrast, aCL were purified from 11 out of 12 patients with autoimmune disease that bound CL only in the presence of β2-GPI. Thrombotic complications appear to be associated with aCL occurring in autoimmune disease but not with aCL associated with infections. We postulate that this increased risk of thrombosis in the autoimmune group may be due to the presence of aCL that bind CL in association with β2-GPI, a plasma protein with anticoagulant activity.

'Antiphospholipid' (aPL) antibodies are of clinical importance because of their strong association with vascular thrombosis, recurrent pregnancy loss, thrombocytopenia and other clinical manifestations like livedo reticularis, chorea and cardiac valvular disease1. While aPL antibodies have traditionally been thought to be directed against negatively- charged (anionic) phospholipids, current evidence suggests that these autoantibodies recog nise protein-phospholipid complexes or the proteins themselves2-4. A number of candidate proteins have been investigated with the two most extensively researched being β2glycoprotein I and prothrombin.

Antiphospholipid antibodies were originally thought to bind negatively-charged (aniomic) phospholipids. Current evidence suggests that the target antigen is considerably more complex and includes β2-glycoprotein I, a phospholipid-binding plasma protein. Our under standing of the pathophysiology of the antiphospholipid syndrome has increased exponen tially with a number of studies into the interactions of antiphospholipid antibodies and β2-glycoprotein I.

'Antiphospholipid' (aPL) antibodies are a heterogenous group of autoantibodies that are now considered to be directed mainly to plasma proteins or protein-phospholipid complexes 1. Standardisation of assays for anticardiolipin (aCL) antibodies and lupus anti coagulants (LA) have been fraught with difficulty despite numerous attempts to perform this by International Standardisation Workshops and Committees.