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] |
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