Antiphospholipid syndrome: multiple mechanisms.

Abstract

It is 20 years since the use of a radioimmunoassay enabled an association to be described between antibodies to the anionic phospholipid cardiolipin and a set of clinical features [1]. These features, which included thrombosis – both venous and arterial – and recurrent foetal loss, subsequently became known as the antiphospholipid syndrome (APS) [2–4]. They had previously been shown to be associated with positive Venereal Disease Reference laboratory (VDRL) and lupus anticoagulant (LA) tests, both of which detect antiphospholipid antibodies [5–8]. However, the radioimmunoassay, and the enzyme-linked assays (ELISA) derived from it [9], are considerably more sensitive, and their use enabled the clinical syndrome to be clearly defined. Many additional clinical features have been described, such as neurological disorders, migraine, livedo reticularis and thrombocytopenia [10–12]. Some of these remain controversial, and may be features of associated connective tissue diseases such as systemic lupus erythematosus (SLE), with which APS frequently coexists. They are not all directly related to thrombosis. APS can occur as an isolated, primary condition [13–15]. It has emerged as the most common cause of acquired thrombophilia, and is a major cause of pregnancy morbidity. Because thrombosis in APS can occur at almost any site, it is a condition that is seen in almost all medical specialities. Central to our understanding of antiphospholipid syndrome has been the demonstration that the autoantibodies in the condition probably play a direct role in pathogenesis. Strong evidence for this has come from murine models. Passive transfer of antiphospholipid antibodies (aPL) to normal mice can generally [16–19], though not always [20], produce features resembling human APS, notably impairment of foetal development. Similar results have been obtained by immunizing mice with aPL [21]. In a murine model of venous injury the addition of aPL results in increased local clot formation [22]. Another critical discovery was that antibodies to phospholipid appear to represent part of a large family of autoantibodies, many of which recognize phospholipid-binding plasma proteins either alone, or in combination with phospholipid. The first of these proteins to be recognized was beta-2-glycoprotein I (β2GPI) [23,24]. This molecule has number of physiological functions, which include a regulatory role within coagulation pathways. Prothrombin is another important protein recognized by sera of patients with APS. Others include annexin V, high and low molecular weight kininogens, protein C and protein S (see Table 1). Table 1 Antigen specificities of antibodies that have been detected in the serum of patients with antiphospholipid syndrome.