Blood Journal
Leading the way in experimental and clinical research in hematology

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

  1. Valerie Proulle1,
  2. Richard A. Furie2,
  3. Glenn Merrill-Skoloff1,
  4. Barbara C. Furie1, and
  5. Bruce Furie1
  1. 1Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; and
  2. 2Division of Rheumatology and Allergy-Clinical Immunology, North Shore-Long Island Jewish Health System, Great Neck NY

Key Points

  • The anti-β2GP1 autoantibody/β2GP1 complex binds to the platelet thrombus, amplifying platelet activation.

  • Platelets are required for enhanced activation of the endothelium and fibrin generation by the anti-β2GP1 autoantibody/β2GP1 complex.

Abstract

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.

  • Submitted February 6, 2014.
  • Accepted April 29, 2014.
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