Pathogenic role of antiphospholipid antibodies

Abstract

The antiphospholipid antibody syndrome (APS) is characterized by recurrent arterial and venous thrombosis and/or pregnancy in association with antiphospholipid (aPL) antibodies. The pathogenic mechanisms in APS that lead to in vivo injury are incompletely understood. Recent evidence suggests that APL antibodies alter regulation of haemostasis and induce activation of complement. We will discuss the current knowledge on how aPL antibodies trigger increased inflammation and enhanced thrombotic tendency, and thereby lead to tissue damage.

Figure 1. Proposed mechanism for the pathogenic effects of aPL antibodies on fetal injury

Based on the results of our mouse studies, we proposed a mechanism for pregnancy complications associated with aPL antibodies: aPL antibodies preferentially targeted at decidua and placenta activate complement via the classical pathway (Fc- and C4-dependent), leading to the generation of potent anaphylatoxins (C3a and C5a) and mediators of effector cell activation, including TF and TNF-α. Recruitment of inflammatory cells accelerates local alternative pathway activation and creates a proinflammatory amplification loop that enhances C3 activation and deposition, generates additional C3a and C5a, and results in further influx of inflammatory cells into the placenta and increased generation of TF, oxidants, TNF-α, and anti-angiogenic factor sVEGFR-1. Depending on the extent of damage, either death in utero or fetal growth restriction ensues. Adapted from Girardi et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 2003;112(11):1644-54. With kind permission from the American Society for Clinical Investigation.