title: Acquired activated protein C resistance associated with IgG antibodies against beta2-glycoprotein I and prothrombin as a strong risk factor for venous thromboembolism.
abstract: BACKGROUND
  Venous thromboembolic events such as deep vein thrombosis and pulmonary embolism are common manifestations of antiphospholipid syndrome. Our aim was to clarify the roles of anti-phospholipid (aPL) antibodies in the pathogenesis of venous thromboembolism (VTE) in patients with systemic lupus erythematosus (SLE).
  
  
  RESULTS
  We examined anti-cardiolipin/beta2-glycoprotein I (anti-CL/beta2-GPI) antibody concentrations, anti-phosphatidylserine/prothrombin (anti-PS/PT) antibody concentrations, and lupus anticoagulant (LA) activity in 87 patients with SLE (21 with VTE and 66 without thrombosis). Both anti-CL/beta2-GPI and anti-PS/PT antibodies strongly correlated with LA activity. Multivariate logistic analysis confirmed that both anti-CL/beta2-GPI and anti-PS/PT antibodies were significant independent risk factors for VTE (odds ratios = 4.98 and 7.54, respectively; 95% confidence intervals, 1.51-16.4 and 2.30-24.7, respectively). We therefore studied the in vitro effects of IgG fractions containing anti-CL/beta2-GPI or anti-PS/PT antibodies on the anticoagulant activity of activated protein C (APC) and found that purified IgG containing anti-CL/beta2-GPI or anti-PS/PT antibodies significantly hampered the anticoagulant activity of APC. We also studied the ability of IgG fractions to impede the anticoagulant activity of APC before and after complete removal of anti-CL/beta2-GPI or anti-PS/PT antibodies by adsorption. Removal of anti-CL/beta2-GPI or anti-PS/PT antibodies from all positive IgG samples clearly decreased the inhibitory effect of those samples on APC anticoagulant activity.
  
  
  CONCLUSIONS
  Anti-CL/beta2-GPI and anti-PS/PT antibodies independently cause APC resistance, which may contribute to risk of VTE in patients with SLE.
authors.affiliation: Laboratory for Clinical Investigation, Osaka University Hospital, Osaka, Japan. nojima@hp-lab.osaka-u.ac.jp
authors.forename: Junzo
authors.initials: J
authors.lastname: Nojima
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Kuratsune
authors.forename: Etsuji
authors.initials: E
authors.lastname: Suehisa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Iwatani
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kanakura
mesh_terms: D020016:Activated Protein C Resistance / Q000209:etiology / Q000276:immunology*; D000328:Adult; D017152:Antibodies, Antiphospholipid / Q000097:blood*; D016736:Antiphospholipid Syndrome / Q000209:etiology / Q000276:immunology; D002308:Cardiolipins / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D066298:In Vitro Techniques; D008180:Lupus Erythematosus, Systemic / Q000150:complications; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010314:Partial Thromboplastin Time; D010718:Phosphatidylserines / Q000276:immunology; D011486:Protein C / Q000032:analysis; D011516:Prothrombin / Q000276:immunology*; D012307:Risk Factors; D013923:Thromboembolism / Q000209:etiology / Q000276:immunology*; D020246:Venous Thrombosis / Q000209:etiology / Q000276:immunology*; D053482:beta 2-Glycoprotein I
chemical_list: D017152:Antibodies, Antiphospholipid; D002308:Cardiolipins; D006023:Glycoproteins; D007074:Immunoglobulin G; D010718:Phosphatidylserines; D011486:Protein C; D053482:beta 2-Glycoprotein I; D011516:Prothrombin