title: Anti-protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome.
abstract: BACKGROUND
  Antiphospholipid antibodies may interfere with the anticoagulant activity of activated protein C (APC) to induce acquired APC resistance (APCr).
  
  
  OBJECTIVE
  To investigate the frequency and characteristics of APCr by using recombinant human APC (rhAPC) and endogenous protein C activation in antiphospholipid syndrome (APS).
  
  
  METHODS
  APCr was assessed in APS and non-APS venous thromboembolism (VTE) patients on warfarin and normal controls with rhAPC or Protac by thrombin generation. IgG anti-protein C and anti-protein S antibodies and avidity were assessed by ELISA.
  
  
  RESULTS
  APS patients showed greater resistance to both rhAPC and Protac than non-APS patients and normal controls (median normalized endogenous thrombin potential inhibition): APS patients with rhAPC, 81.3% (95% confidence interval [CI] 75.2-88.3%; non-APS patients with rhAPC, 97.7% (95% CI 93.6-101.8%; APS patients with Protac, 66.0% (95% CI 59.5-72.6%); and non-APS patients with Protac, 80.7 (95% CI 74.2-87.2%). APS patients also had a higher frequency and higher levels of anti-protein C antibodies, with 60% (15/25) high-avidity antibodies. High-avidity anti-protein C antibodies were associated with greater APCr and with a severe thrombotic phenotype (defined as the development of recurrent VTE while patients were receiving therapeutic anticoagulation or both venous and arterial thrombosis). Twelve of 15 (80%) patients with high-avidity anti-protein C antibodies were classified as APS category I.
  
  
  CONCLUSIONS
  Thrombotic APS patients showed greater APCr to both rhAPC and activation of endogenous protein C by Protac. High-avidity anti-protein C antibodies, associated with greater APCr, may provide a marker for a severe thrombotic phenotype in APS. However, in patients with category I APS, it remains to be established whether anti-protein C or anti-β2 -glycoprotein I antibodies are responsible for APCr.
authors.affiliation: Haemostasis Research Unit, Department of Haematology, University College London, London, UK.
authors.forename: D R J
authors.initials: DR
authors.lastname: Arachchillage
authors.forename: M
authors.initials: M
authors.lastname: Efthymiou
authors.forename: I J
authors.initials: IJ
authors.lastname: Mackie
authors.forename: A S
authors.initials: AS
authors.lastname: Lawrie
authors.forename: S J
authors.initials: SJ
authors.lastname: Machin
authors.forename: H
authors.initials: H
authors.lastname: Cohen
mesh_terms: D020016:Activated Protein C Resistance / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology*; D000328:Adult; D000368:Aged; D017152:Antibodies, Antiphospholipid / Q000097:blood*; D000925:Anticoagulants / Q000627:therapeutic use; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D001780:Blood Coagulation Tests; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000627:therapeutic use; D010641:Phenotype; D011486:Protein C / Q000276:immunology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012720:Severity of Illness Index; D054556:Venous Thromboembolism / Q000097:blood / Q000175:diagnosis / Q000276:immunology* / Q000517:prevention & control; D014859:Warfarin / Q000627:therapeutic use
chemical_list: D017152:Antibodies, Antiphospholipid; D000925:Anticoagulants; D015415:Biomarkers; D005343:Fibrinolytic Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011486:Protein C; D011994:Recombinant Proteins; C049647:snake venom protein C activator; D014859:Warfarin
keywords: Protac; activated protein C resistance; antibodies; antiphospholipid syndrome; protein C; venous thromboembolism