Antiphospholipid Antibody-Induced Pregnancy Loss and Thrombosis

Abstract

Antiphospholipid (aPL) antibodies are a family of autoantibodies that exhibit a broad range of target specificities and affinities, all recognizing various combinations of phospholipids, phospholipid binding proteins, or both. The first aPL antibody, a complement fixing antibody that reacted with extracts from bovine hearts, was detected in patients with syphilis in 1906 [1]. The relevant antigen was later identified as cardiolipin, a mitochondrial phospholipid [2]. The presence of aPL antibodies in serum has been associated with arterial and venous thrombosis and recurrent pregnancy loss [3–7], but the pathogenic mechanisms mediating these events are unknown. Several hypotheses have been proposed to explain the cellular and molecular mechanisms by which aPL antibodies induce thrombosis and fetal loss. There are reports that aPL antibodies activate endothelial cells, monocytes, and platelets [8–10]. In vivo and in vitro studies have shown that exposure to aPL antibodies induces activation of endothelial cells and a prothrombotic phenotype, as assessed by upregulation of the expression of adhesion molecules, secretion of cytokines, and the metabolism of prostacyclins [8, 10, 11]. aPL antibodies recognize β2-glycoprotein I bound to resting endothelial cells, although the basis for the interaction of β2-glycoprotein I with viable endothelial cells remains unclear [12, 13]. As β2-glycoprotein I is considered a natural anticoagulant [14], some authors propose that aPL antibodies interfere with or modulate the function of phospholipid binding proteins involved in the regulation of coagulation, activate platelets, or induce monocytes to express tissue factor [9]. That endothelial cell, monocyte, and platelet activation are associated with aPL antibodies and thrombophilia, and that these cell phenotypes may also occur as a consequence of complement activation products, suggested a role for complement activation in aPL antibody–induced tissue damage.