Probing antiphospholipid-mediated thrombosis: the interplay between anticardiolipin antibodies and endothelial cells

Abstract

The association of antiphospholipid(aPL) antibodieswith thrombosisin patientswith antiphospholipid syndrome (APS) is well documented in humans and in animal studies. However, the mechanisms by which aPL antibodies induce thrombosis are the subject of much current study. It has been suggested that aPL may activate endothelial cells (ECs), thus creating a hypercoagulablestate that precedes and contributes to thrombosis in patients with APS. Several studies have shown that aPL upregulateECs’ adhesion molecules (CAMs): intercellularcell adhesion molecule-1 (ICAM-1), vascularcell adhesion molecule-1 (VCAM-1) and E-selectin (E-sel) or induce tissue factor (TF) in monocytes in vitro. Similarly, the incubationof EC with antibodiesreactingwith ß₂ glycoproteinI (ß₂ GPI) has been shown to induce EC activation with concomitant upregulation of CAMs, IL-6 production and alteration of prostaglandin metabolism. Our group has shown that aPL-mediated upregulation of adhesion molecules on ECs correlates with an increased adhesion of leukocytes to endothelium in the microcirculationof mouse cremaster muscle, an indicationof EC activation in vivo, and with enhanced thrombosis in vivo. In another series of studies, investigators have shown that upregulation of expression of adhesion molecules by some murine monoclonal anti-β₂ glycoprotein I (anti-β₂ GPI) antibodiescorrelatedwith fetal resorptionin mice invivo. More recently, one studyshowedthat the anti-hypercholesterolaemicdrug fluvastatininhibitedthe aPL-mediatedenhancedadhesionof monocytesto ECs in vitro. Data from our laboratoriesindicate that fluvastatin also reversesthrombus formation and activation of EC induced by aPL in an in vivo mouse model. As additional support for the hypothesis that aPL antibodies activate ECs and may create an hypercoagulablestate in APS patients, two recent studiesindicatedthatlevelsof solubleICAM-1 and VCAM-1 were significantlyincreasedin theplasma of patients with APS and recurrent thrombosis. Furthermore, studies utilizing knockout mice and specific monoclonal anti-VCAM-1 antibodies have demonstrated that expression of ICAM-1, P-selectin, E-selectin and VCAM-1 are important in in vivo aPL-mediated thrombosis and EC activation in mice. Recent data suggests that aPL antibodies also induce expressionof TF not only in monocytesbutin ECs. Hence, the interferenceof aPL with the TF mechanismmay be anotherimportant mechanism by which these antibodies create a hypercoagulablestate and prone patients to thrombosis. Specifically, how aPL alters EC activation state and the molecular and intracellular mechanisms involvedhavenotyetbeen defined.APL may interactwith specific cell surfacereceptors(proteinsand/or lipids) induce signals that have consequences downstream, and that ultimately will result in upregulationof cellsurfaceproteins(i.e., CAMs and TF) and subsequentlyinduceEC activation.In that regard, our group recently showed that aPL-mediated upregulation of adhesion molecules in ECs is precededby activationof the nuclearfactor kappaB (NFkB). Other intracellularmechanisms triggered by aPL are notcompletelyunderstoodand are the subjectof currentinvestigation.In conclusion, studies suggestthat activationof ECs by aPL is an importantmechanismthat may precedethrombusformation in patients with APS. Hence, the interplay between aPL antibodies and ECs is important in the pathogenesisof thrombosis in APS.