Mechanism of antiphospholipid antibody-mediated thrombosis in antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the occurrence of thrombotic or obstetrical events in patients with persistent antiphospholipid antibodies (aPL). Thrombotic events, the primary pathological hallmarks and clinical manifestations, are among the leading causes of mortality in APS. Our understanding of the mechanism underlying APS-related thrombosis has significantly advanced in recent years. The presence of aPL, particularly anti-β2-glycoprotein I (anti-β2GPI) antibodies, is a major driver of thrombosis. The proposed pathophysiological mechanisms of aPL-mediated pro-thrombotic events can be broadly categorized into three types: disruption of anticoagulant reactions and fibrinolysis, interference with coagulation cascade cells, and complement activation. A triggering 'second hit' is typically necessary to initiate thrombosis. The development of animal models of APS has further refined our understanding of the role of aPL in thrombosis. In this review, we focused on the role of β2GPI-dependent aPL in thrombosis of thrombotic APS.

Keywords: antiphospholipid antibody; antiphospholipid syndrome; thrombotic event; two hit model; β2-glycoprotein I.

Figure 1

β2GPI-dependent aPL effects on cells in thrombotic antiphospholipid syndrome. β2GPI-dependent aPL activates monocytes (A), endothelial cells (B), neutrophils (C), and platelets (D) through various signaling pathways, thereby regulating downstream cellular activities and contributing to thrombosis in APS. aPL, antiphospholipid antibody;β2GPI, β2-glycoprotein I; ApoER2, apolipoprotein E receptor 2; TLR, toll-like receptor; MyD88, myeloid differentiation primary response gene 88; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa B; AKT, protein kinase B; TF, tissue factor; TNFα, tumor necrosis factor-alpha; LBPA, lysobisphosphatidic acid; EPCR, endothelial protein C receptor; LRP6, LDL receptor-related protein 6; PAR1, protease-activated receptor 1;eNOS, endothelial nitric oxide synthase; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; ROS, reactive oxygen species; NETs, neutrophil extracellular traps; KLF, krüppel-like factor 2; PSGL-1, P-selectin glycoprotein ligand 1; IRAK, interleukin-1 receptor-associated kinase; MAC-1, macrophage-1 antigen; CEACAM1, carcinoembryonic antigen related cell adhesion molecule 1; PF4, platelet factor 4; GPIIbIIIα, glycoprotein IIIbIIIα.

Figure 2

Schematic diagram of two-hit model in antiphospholipid syndrome. The presence of aPL (first hit) and the activation of the coagulation system, complement, monocytes, endothelial cells, neutrophils, and platelets increase the risk of thrombosis. Clotting occurs in the presence of additional procoagulant condition (second hit).