The antiphospholipid syndrome as a disorder initiated by inflammation: implications for the therapy of pregnant patients

Abstract

Arterial thrombosis, venous thrombosis and morbidity during pregnancy, or a combination of these events, are clinical outcomes associated with antiphospholipid antibodies produced by patients with antiphospholipid syndrome (APS). Our understanding of the etiology and pathogenesis of the syndrome is limited, but it has generally been considered a thrombophilic disease and treatment has focused on anticoagulation. Agents such as aspirin and heparin, administered alone or in combination, are empirical treatments that are used in the management of obstetric patients with APS. Clinical features, such as heart valve abnormalities, thrombocytopenia and livedo reticularis, suggest multiple pathogenic mechanisms and provide other therapeutic targets. Findings from research in animal models of APS challenge the dogma that this syndrome is a noninflammatory, thrombotic disease and provide evidence that activation of complement is crucial for complications in pregnancy. These studies, in addition to evidence of inflammatory-mediated tissue damage in placentae of patients with APS, suggest that therapy should also be directed towards preventing inflammation. This Review describes the potential mechanisms of tissue injury by antiphospholipid antibodies, the management of pregnant patients with APS and how heparin therapy might inhibit the pathogenic mediators of disease.

Profiling the Enzymatic Properties and Inhibition of Human Complement Factor B

“…Recent studies using knock-out mice and a specific antibody have demonstrated important contributions from factor B to a number of inflammatory disorders (10,11), such as airway hyper-responsiveness (12), lupus nephritis (34), and antiphospholipid syndrome (26,35), and have provided insights to the role of factor B in complement activation via the alternative pathway. The new data from those studies suggest that factor B may be a potential therapeutic target in its own right.…”

Tracing the molecular pathogenesis of antiphospholipid syndrome

“…Infusion of aPLs isolated from human patients into pregnant mice is sufficient to reproduce fetal loss and fetal growth restriction. A remarkable series of genetic and pharmacologic intervention studies in this mouse model has led to a detailed understanding of the pathogenesis underlying aPLinduced fetal loss (1,4,5). Clinically, the most relevant antigen recognized by aPLs is β2-glycoprotein I (β2GPI), a plasma protein with poorly characterized functions.…”

Pregnancy and Catastrophic Antiphospholipid Syndrome

“…Annexin V appears to play a thrombomodulatory role in the placental circulation where it is necessary for maintenance of placental integrity. Some patients with APS have evidence for antibodies that specifically recognize annexin V and increased levels of these antibodies has also been reported in patients with thrombosis [7].…”