Thrombogenic effects of antiphospholipid antibodies are mediated by intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin

Recent studies have shown that antiphospholipid (aPL) enhances expression o f intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion m olecule-1 (VCAM-1), and E-selectin on endothelial cells (ECs) and that thes e effects are correlated with increased adhesion of leukocytes to endotheli um in cremaster muscle in vivo and with thrombosis in a mouse model. Activa tion of ECs by aPL may create a hypercoagulable state that precedes and con tributes to thrombosis in patients with aPL syndrome (APS). This study prop osed to examine whether this in vivo activation of ECs and enhanced thrombo sis by aPL are mediated by ICAM-1, P-selectin, or VCAM-1. The dynamics of t hrombus formation and the number of adhering leukocytes were studied in ICA M-1-deficient (ICAM-1(-/-)) mice or ICAM-1-/P-selectin-deficient (ICAM-1(-/ -)/P-selectin(-/-)) mice treated with affinity-purified aPL antibodies (ap IgG-APS) or with control IgG and compared with wild-type mice treated in a similar fashion. In another set of experiments, the adhesion of leukocytes to cremaster muscle and the dynamics of thrombus formation were studied in CD1 mice treated with aPL or control IgG before and 30 minutes after intrav enous infusion with 100 mug monoclonal antibody anti-VCAM-1. The results in dicate that the enhanced adhesion of leukocytes to endothelium in wild-type mice was significantly reduced in ICAM-1(-/-) and completely abrogated in ICAM-1(-/-)/P-selectin(-/-) mice treated with ap IgG-APS compared with wild -type mice treated with ap IgG-APS (6.9+/-2.3, 0.4+/-0.4 versus 35+/-12, re spectively). More importantly, this correlated with a significant reduction in thrombus size compared with wild-type mice treated with ap IgG-APS (895 +/-259 mum(2), 859+/-243 mum(2) versus 3816+/-672 mum(2), respectively). In fusion of the mice with anti-VCAM-1 antibodies significantly reversed the e nhanced adhesion of leukocytes (14.9+/-3 to 11.3+/-2.1) and thrombus size 3 830+/-1008 mum(2) versus 876+/-548 mum(2)) in mice treated with ap IgG-APS. The data indicate that ICAM-1, P-selectin, and VCAM-1 expression are impor tant in thrombotic complications by aPL antibodies and may provide novel ta rgets for therapy in patients with APS.