Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS.
Antiphospholipid syndrome (APS) is defined by thrombosis, fetal loss, and the presence of antiphospholipid antibodies, including anti-β2-glycoprotein-1 autoantibodies (anti-β2GP1) that have a direct role in the pathogenesis of thrombosis in vivo. The cellular targets of the anti-β2GP1 autoantibody/β2GP1 complex in vivo were studied using a laser-induced thrombosis model of APS in a live mouse and human anti-β2GP1 autoantibodies affinity-purified from APS patients. Cell binding of fluorescently labeled β2GP1 and anti-β2GP1 autoantibodies revealed their colocalization on the platelet thrombus but not the endothelium. Anti-β2GP1 autoantibodies enhanced platelet activation, monitored by calcium mobilization, and endothelial activation, monitored by intercellular adhesion molecule-1 expression. When eptifibatide was infused to block platelet thrombus formation, enhanced fibrin generation and endothelial cell activation were eliminated. Thus, the anti-β2GP1 autoantibody/β2GP1 complex binds to the thrombus, enhancing platelet activation, and platelet secretion leads to enhanced endothelium activation and fibrin generation. These results lead to a paradigm shift away from the concept that binding of the anti-β2GP1 autoantibody/β2GP1 complex activates both endothelial cells and platelets toward one in which activation of platelets in response to anti-β2GP1 autoantibody/β2GP1 complex binding leads to subsequent enhanced endothelium activation and fibrin generation.
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; and.
Valerie
V
Proulle
Division of Rheumatology and Allergy-Clinical Immunology, North Shore-Long Island Jewish Health System, Great Neck NY.
Richard A
RA
Furie
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; and.
Glenn
G
Merrill-Skoloff
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; and.
Barbara C
BC
Furie
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; and.
Bruce
B
Furie
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000097:blood*; D016736:Antiphospholipid Syndrome / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001792:Blood Platelets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004727:Endothelium / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015539:Platelet Activation; D013927:Thrombosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053482:beta 2-Glycoprotein I / Q000276:immunology / Q000378:metabolism*
D017152:Antibodies, Antiphospholipid; D001323:Autoantibodies; C090509:Icam1 protein, mouse; D053482:beta 2-Glycoprotein I; D018799:Intercellular Adhesion Molecule-1; D005337:Fibrin; D005340:Fibrinogen