4Antiphospholipid syndrome
Introduction
Although antiphospholipid syndrome (APS) is often considered a relatively new disorder, its origin dates to the early 20th century with the identification of Wasserman's antibody, which binds the phospholipid cardiolipin and was used to detect the presence of Treponema pallidum [1]. The antibody was subsequently identified in patients who did not have syphilis, giving rise to the term biologic false-positive serologic test for syphilis (BFP-STS). In the 1950s, the BFP-STS was associated with an inhibitor of coagulation termed the lupus anticoagulant (LA), so called because early case reports linked it with hemorrhage in patients with systemic lupus erythematosus (SLE) [2]. The presence of LA was subsequently associated with both thrombosis and pregnancy loss, but the intricacies of performing the LA assay (a functional clotting assay requiring fresh plasma) limited research efforts. In 1983, more easily performed and standardized ELISA tests became available that detected anticardiolipin antibody (aCL) and many reports followed describing a wide variety of clinical manifestations associated with anticardiolipin, now termed APS, including the identification of patients with APS alone (primary APS, or PAPS) and patients with acute multisystem thrombosis (catastrophic APS (CAPS)). In the 1990s, it became clear that antiphospholipid antibodies (aPL) bind primarily to the circulating plasma protein β2-glycoprotein I (β2GPI) when it is bound to phospholipid, rather than to phospholipid directly. The anti-β2GPI antibody ELISA now provides an additional test to detect the presence of aPL [1]. Understanding the role of β2GPI and other phospholipid-binding proteins has led to greater clarity regarding the multiple mechanisms involved in the characteristic manifestations of this syndrome, including cellular activation, complement activation, and both prothrombotic and antifibrinolytic effects. This multiplicity of mechanisms highlights both the spectrum of aPL-related manifestations (not all of which are the result of thrombosis) as well as the rationale for suggested future therapies (not all of which are anticoagulants).
Binding of aPL to β2GPI on cellular surfaces activates endothelial cells, monocytes, and platelets leading to proinflammatory and prothrombotic phenotypes and complement activation, with the net result leading to thrombosis and potential interference with trophoblast and decidual cells. Recent studies also suggest the involvement of neutrophils with tissue factor (TF) expression and the release of neutrophil extracellular traps (NETosis), as well as the upregulation of the mechanistic target of rapamycin (mTOR) complex on endothelial cells, which may contribute to aPL-related vasculopathy. Hemostatic reactions include both prothrombotic effects such as acquired protein C resistance and the inhibition of TF pathway inhibitor and fibrinolytic changes, such as the inhibition of tissue plasminogen inhibitor activity [3]. As a result of the ever-increasing understanding of a complex interplay of thrombosis, inflammation, and vasculopathy, new therapies may emerge to better treat a broad spectrum of APS manifestations including cardiac and renal disease. Currently, anticoagulation with warfarin remains the mainstay of therapy for thrombosis, and combination therapy with aspirin and heparin the standard treatment for obstetric complications.
Section snippets
Diagnosis of antiphospholipid syndrome
Given the tremendous surge in both basic and clinical aPL and APS research over the last thirty years, as well as the clear association of the syndrome with clinically available antibody tests, it seems it should be simple to diagnose APS. It is not always the case, however, because of the wide variation in both laboratory findings and clinical manifestations; as a result, both overdiagnosis and underdiagnosis still occur. The relatively high frequency of low titer aPL (low titers are much less
Treatment of antiphospholipid syndrome
Treatment of the most common clinical manifestations of APS, such as venous thrombosis or fetal loss, is straightforward and supported by randomized clinical studies. However, many clinical situations remain where therapy must be based on weaker clinical data or even on expert opinion. Treatment categories may be separated into primary thromboprophylaxis, secondary thromboprophylaxis, the treatment of CAPS, pregnancy prophylaxis, and the treatment of non-criteria manifestations. Treatment
Summary
APS continues to be a cause of significant morbidity and mortality among rheumatology patients. While progress has been made in treating the classic complications of thrombosis and pregnancy loss, better treatments are needed. Recurrent thromboses occur even on warfarin, and maintaining a therapeutic INR is challenging especially in the setting of a strong LA. The mortality associated with the best identified therapy for CAPS is still almost 30%, and the success of standard pregnancy therapy
Funding
No funding for this publication.
Declaration of Competing Interest
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