Anti‐protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome

Summary Background Antiphospholipid antibodies may interfere with the anticoagulant activity of activated protein C ( APC ) to induce acquired APC resistance ( APC r). Aims To investigate the frequency and characteristics of APC r by using recombinant human APC (rh APC ) and endogenous protein C activation in antiphospholipid syndrome ( APS ). Methods APC r 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 rh APC and Protac than non‐ APS patients and normal controls (median normalized endogenous thrombin potential inhibition): APS patients with rh APC , 81.3% (95% confidence interval [ CI ] 75.2–88.3%; non‐ APS patients with rh APC , 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 APC r 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. Conclusion Thrombotic APS patients showed greater APC r to both rh APC and activation of endogenous protein C by Protac. High‐avidity anti‐protein C antibodies, associated with greater APC r, 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‐β 2 ‐glycoprotein I antibodies are responsible for APC r.