title: A novel mechanism of thrombosis in antiphospholipid antibody syndrome.
abstract: Antiphospholipid antibody syndrome (APS) is an autoimmune thrombophilia mediated by autoantibodies directed against phospholipid-binding plasma proteins, mainly β2 Glycoprotein I (β2GPI)-a plasma apolipoprotein and prothrombin (PT). A subgroup of these antibodies termed "Lupus Anticoagulant" (LA) elongate in vitro the clotting times, this elongation not corrected by adding normal plasma in the detection system. The exact mechanism by which these autoantibodies induce thrombosis is not well understood. Resistance to natural anticoagulants such as protein C, impaired fibrinolysis, activation of endothelial cells to a pro-coagulant phenotype and activation of platelets, are among the mechanisms partially supported by experimental evidence. Artificially dimerized β2GPI binds tightly to platelet membrane activating them. We search for mechanisms of natural dimerization of β2GPI by proteins of the platelet membranes and found that platelet factor 4 (PF4) assembled in homotetramers binds two molecules of β2GPI and this complex is recognized by anti-β2GPI antibodies, the whole complexes being thrombogenic in terms of activating platelets as confirmed by p38MAP kinase phosphorylation and thromboxane B2 production. Of note PF4/heparin complexes are also immunogenic triggering the production of anti-PF4/heparin antibodies which activate also platelets (the so-called "heparin-induced thrombocytopenia and thrombosis syndrome", HITT). The anti-β2GPI antibodies activate platelets by their F(ab)2, while the anti-PF4/heparin by their Fc fragments. Thus PF4 is a common denominator in the pathogenesis of APS and HITT which share also clinical characteristics such as thrombocytopenia and thrombosis.
authors.affiliation: Department of Pathophysiology, Medical School, National University of Athens, 75 Mikras Asias str, 11527 Athens, Greece. pvlah@med.uoa.gr
authors.forename: Panayiotis G
authors.initials: PG
authors.lastname: Vlachoyiannopoulos
authors.forename: John G
authors.initials: JG
authors.lastname: Routsias
mesh_terms: D016736:Antiphospholipid Syndrome / Q000097:blood* / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D005342:Fibrinolysis / Q000276:immunology; D006801:Humans; D046912:Multiprotein Complexes / Q000276:immunology; D015539:Platelet Activation / Q000276:immunology; D010978:Platelet Factor 4 / Q000276:immunology / Q000378:metabolism*; D055503:Protein Multimerization; D013921:Thrombocytopenia; D019851:Thrombophilia; D013927:Thrombosis; D053482:beta 2-Glycoprotein I / Q000276:immunology / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D046912:Multiprotein Complexes; D053482:beta 2-Glycoprotein I; D010978:Platelet Factor 4