Resistance to annexin A5 anticoagulant activity: a thrombogenic mechanism for the antiphospholipid syndrome

Abstract

The phospholipid binding protein, annexin A5 (AnxA5), has potent anticoagulant properties that result from its forming 2-dimensional crystals over phospholipids, blocking the availability of the phospholipids for critical coagulation enzyme reactions. This article reviews the evidence that antiphospholipid antibodies can disrupt this anticoagulant shield and unmask thrombogenic anionic phospholipids, which may thereby contribute to thrombosis in patients with the antiphospholipid syndrome (APS). This mechanism for thrombosis in APS can be monitored with coagulation assays for resistance to anticoagulant activity of AnxA5.

Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug

“…4 AnxA5, which had been isolated from tissues as a vascular anticoagulant protein 5 and as a placental anticoagulant protein, 6 exhibits high affinity for anionic phospholipids. 5,6 Its potent anticoagulant properties result from its forming 2-dimensional crystals over phospholipid bilayers, 7 thereby shielding them from availability for critical coagulation enzyme reactions.…”

Protein Interactions on Phospholipid Bilayer, Studied by AFM Under Physiological Conditions

“…Results are achieved by using the AFM probes functionalized with antigen or antibody molecules (Hinterdorfer et al, 1996;Allen et al, 1997); c.) to measure the effects of antibody-antigen interactions. AFM played very important role in visually presenting the possible pathophysiology in autoimmune diseases called antiphospholipid syndrome (Rand et al, 2008;Irman et al, 2010Irman et al, , 2011Žager et al, 2011), as presented in the next section (Section 5) of the Chapter. As such, AFM could also be used in the evaluation of the biological drugs activity.…”

“…Many pathologic mechanisms of antiphospholipid antibodies associated with the antiphospholipid syndrome have been suggested so far. One of the possible mechanisms was 1998 presented by Rand et al: antiphospholipid antibodies interfere with a formation of ANX A5 crystalline shield over blood vessels and therefore diminish the proteins anticoagulant protective role (Rand et al, 1998(Rand et al, , 2008.…”

“…Anti-ǐ 2 -GPI of different isotypes, directed toward different epitopes of the antigen molecule and of different avidity, have been associated with various clinical manifestations (Shoenfeld 2003): thrombosis and pregnancy complications in patients with antiphospholipid syndrome (de Laat et al, 2006a(de Laat et al, , 2006b(de Laat et al, , 2007Rand et al, 2008;Čučnik et al, 2004b;Ioanou et al, 2007) described in patients with systemic lupus erythematosus (Čučnik et al, 2004b), in infectious diseases (Arvieux et al, 2002) and childhood atopic dermatitis , in patients with stroke and acute coronary syndrome (Bizzaro et al, 2010). Disruption of ANX A5 protective crystalline structure by complexes of ǐ 2 -GPI and anti-ǐ 2 -GPI on phospholipid surfaces presents one of their possible pathological mechanisms of action.…”

Clinical Reasoning: A young woman with progressive headache and pancytopenia

“…When annexin-V is reduced around phospholipids in the cell membranes of vascular endothelial cells, thrombosis may occur. 7,8 If this mechanism is independent of the activity of factor Xa and platelets in the coagulation pathway, it may imply a persistent risk of thrombosis in APS despite both anticoagulation and thrombocytopenia.…”