Pathogenesis, Diagnosis and Management of Obstetric Antiphospholipid Syndrome: A Comprehensive Review

Abstract

Antiphospholipid syndrome is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity associated with persistent antiphospholipid antibody positivity. Cases fulfilling the Sydney criteria for obstetric morbidity with no previous thrombosis are known as obstetric antiphospholipid syndrome (OAPS). OAPS is the most identified cause of recurrent pregnancy loss and late-pregnancy morbidity related to placental injury. Cases with incomplete clinical or laboratory data are classified as obstetric morbidity APS (OMAPS) and non-criteria OAPS (NC-OAPS), respectively. Inflammatory and thrombotic mechanisms are involved in the pathophysiology of OAPS. Trophoblasts, endothelium, platelets and innate immune cells are key cellular players. Complement activation plays a crucial pathogenic role. Secondary placental thrombosis appears by clot formation in response to tissue factor activation. New risk assessment tools could improve the prediction of obstetric complication recurrences or thromboses. The standard-of-care treatment consists of low-dose aspirin and prophylactic low molecular weight heparin. In refractory cases, the addition of hydroxychloroquine, low-dose prednisone or IVIG improve pregnancy outcomes. Statins and eculizumab are currently being tested for treating selected OAPS women. Finally, we revisited recent insights and concerns about the pathophysiology, diagnosis and management of OAPS.

Keywords: antiphospholipid antibody; diagnosis; management; non-criteria antiphospholipid antibodies; obstetric antiphospholipid syndrome; pathogenesis; review.

Figure 1

Cellular and molecular mechanisms of action of aPL in the pathophysiology of OAPS. aPL affect different cellular processes from blastocyst implantation in the uterus mucosa to trophoblast proliferation and differentiation and, eventually, the impairment of fetal growth due to antiangiogenic and prothrombotic activation. aPL induces inflammation via TLR4/MyD88 (1) in trophoblasts and endothelium and immune cells. Complement component deposition (2) on the endothelium and on trophoblasts drives inflammation and MAC formation, leading to cell death. Trophoblasts apoptosis is also produced when aPT antibodies expose PS on the external trophoblast cellular membrane (3). Inactivation of eNOS and dysfunction in ROS production are observed when the ApoE2 receptor binds to the aβGPI–βGPI complex (4). Trophoblast perturbation also affects decidual NK activity, crucial for embryo implantation (5). aPL in the lumen vessels of placental arteries and veins has pleiotropic actions: induction of leukocyte adhesion (6) on inflamed vasculature that drives neutrophil infiltration (7) inside the decidua and NET formation in response to ROS production (8). These mechanisms altogether enhance thromboinflammation with activation of the coagulation cascade initiated by TF (9). Legend depicts cells and molecules. Image created in BioRender.com (accessed on 13 December 2021).