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Summary of proposed pathogenic mechanisms in antiphospholipid syndrome

Summary of proposed pathogenic mechanisms in antiphospholipid syndrome
Proposed mechanism In vitro evidence Animal studies Clinical studies
Cellular activation
Endothelial cells aPL activate endothelial cells and induce expression of TF and adhesion molecules[1,2] Blocking E-selectin, P-selectin, VCAM-1, or ICAM-1 protects against aPL-induced venous thrombosis[3,4] High levels of circulating endothelial cell-derived microparticles are present in patients with APS[5]
Monocytes aPL activate monocytes to express TF and proinflammatory cytokines[6-12]   Monocytes from patients with APS express higher levels of TF[13-15]; there are increased monocyte-derived microparticles in patients with APS[16,17]
Neutrophils aPL activate neutrophils to express TF and release NETs[18,19] Deoxyribonuclease or neutrophil depletion reduce aPL-induced venous thrombosis[20,21] The concentration of circulating NETs is increased in patients with APS[19]
Platelets aPL induce platelet activation and adhesion[22,23] Platelet recruitment to activated endothelium is required for thrombus extension in the microcirculation[24] Increased platelet-leukocyte aggregates and platelet-derived microparticles are present in the blood of patients with APS[5,26]
Interactions with coagulation and fibrinolytic systems
Inhibition of natural anticoagulant mechanisms aPL inhibit the activities of protein C and antithrombin[26-31]   Patients with APS have autoantibodies against factor IXa and factor Xa that interfere with their inactivation by antithrombin[32,33]
Inhibition of fibrinolysis aPL inhibit tPA-mediated plasminogen activation and fibrinolysis[34]   Patients with APS have autoantibodies against tPA and plasmin[35,36]
Factor XI aPL enhance the conversion of factor XI to XIa upon treatment with the activators PDI or thioredoxin[37] Factor XIa is required for pathologic thrombus formation; PDI inhibitors attenuate thrombus formation in mice[38] Patients with APS have elevated levels of the free thiol form of factor XI[37]
Disruption of annexin A5 Monoclonal aPL disrupt the annexin A5 shield on phospholipid bilayers in vitro; hydroxychloroquine stabilizes the annexin A5 shield[39,40] Hydroxychloroquine reduces thrombosis in mice[41] Hydroxychloroquine decreases thrombosis in patients with SLE (with or without apL)[42]
Other mechanisms
Complement activation Anti-beta2GPI antibodies induce C5b-9 deposition and complement-mediated cell death[43] aPL-induced thrombosis and fetal loss are attenuated in C3-, C5-, and C6-deficient mice, as well as in the presence of complement inhibitors[44-48] Sera from patients with APS demonstrate higher than normal complement activation in a functional assay; patients with APS have higher levels of circulating C3a, C5b-9, and Bb[49-51]
Trophoblast dysfunction Anti-beta2GPI antibodies interfere with trophoblast proliferation, invasiveness, secretion of HCG, production of angiogenic factors, and syncytialization[52-55]   A lack of well-developed vasculosyncytial membranes in the placenta of aPL-positive patients limits gas and nutrient exchange in the third trimester[56]
mTOR activation In cultured endothelial cells, aPL stimulate mTOR through the PI3K-AKT pathway[57]   In aPL-associated nephropathy, the vascular endothelium displays markers of mTOR activation; sirolimus prevents recurrence of vasculopathy after kidney transplant[57]
aPL: antiphospholipid antibodies; TF: tissue factor; VCAM-1: vascular cell adhesion molecule 1; ICAM-1: intercellular adhesion molecule 1; APS: antiphospholipid syndrome; NETs: neutrophil extracellular traps; tPA: tissue plasminogen activator; PDI: protein disulfide isomerase; SLE: systemic lupus erythematosus; anti-beta2GPI: anti-beta2 glycoprotein I; HCG: human chorionic gonadotrophin; mTOR: mammalian/mechanistic target of rapamycin.
References:
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