The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis

Abstract

Annexin A5 (AnxA5) binds to phospholipid bilayers, forming two-dimensional crystals that block the phospholipids from availability for coagulation enzyme reactions. Antiphospholipid (aPL) antibodies cause gaps in the ordered crystallization of AnxA5 which expose phospholipids and thereby accelerate blood coagulation reactions. The aPL antibody-mediated disruption of AnxA5 crystallization has been confirmed on artificial phospholipid bilayers and on cell membranes including endothelial cells, placental trophoblasts and platelets. Recently, we reported that hydroxychloroquine, a synthetic antimalarial drug, can reverse this antibody-mediated process through two mechanisms: (1) by inhibiting the formation of aPL IgG-beta2glycoprotein I complexes; and (2) by promoting the formation of a second layer of AnxA5 crystal 'patches' over areas where the immune complexes had disrupted AnxA5 crystallization. In another translational application, we have developed a mechanistic assay that reports resistance to AnxA5 anticoagulant activity in plasmas of patients with aPL antibodies. AnxA5 resistance may identify a subset of aPL syndrome patients for whom this is a mechanism for pregnancy losses and thrombosis. The elucidation of aPL-mediated mechanisms for thrombosis and pregnancy complications may open new paths towards addressing this disorder with targeted treatments and mechanistic assays.

Antiphospholipid Syndrome: Changing Knowledge During the Time – The ”Four P” Pattern

“…The pathophysiology of  2 -glycoprotein I was discussed by Matsuura (Matsuura E, et al 2010), the role of the receptor LRP8 by de Groot (de ) and involvement of protein C pathway by Urbanus (Urbanus RT, de Last B;2010). The annexin A5-mediated mechanism in pregnancy losses and thrombosis was clarified by Rand (Rand JH, et al 2010). These are the most important but definitely not all publications concerning antiphospholipid antibodies pathophysiology at this congress.…”

The Pathophysiology of Antiphospholipid Syndrome

“…Antiphospholipid (aPL) antibodies cause gaps in the ordered crystallization of annexin A5, which expose phospholipids and thereby accelerate blood coagulation reactions. The reduction of annexinA5 levels on vascular cells may therefore be an important mechanisms leading to thrombosis and pregnancy loss in APS [67]. An ex vivostudy demonstratedthat plasmas with anti-ß2-GPI-dependent LAC that recognize domain I displayed significantly increased annexinA5 resistance.…”

Adverse Pregnancy Outcome in Antiphospholipid Antibodies Syndrome: Pathogenic Mechanisms and Clinical Management

“…The main target antigens reported in patients with APS include beta-2-glycoprotein-1 ( 2GPI), prothrombin and annexin V (Galli et al, 2003). Other putative antigens are thrombin, protein C, protein S, thrombomodulin, tissue plasminogen activator, kininogens (high or low molecular), prekallikrein, factor VII/VIIa, factor XI, factor XII, complement component C4, heparan sulfate proteoglycan, heparin, oxidised low-density lipoproteins (Galli et al, 2003;Rand et al, 2010). The main autoantigens are attracted to negatively charged phospholipids exposed on the outer side of cell membranes in great amounts only under special circumstances such as damage or apoptosis (e.g.…”