Anti-β2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies interfere with cleavage of factor V(a) by activated protein C

Background: The acquired thrombotic risk factor known as lupus anticoagulant (LA) interferes with laboratory clotting assays and can be caused by autoantibodies against & beta;2-glycoprotein I (& beta;2GPI) and prothrombin. LA is associated with activated protein C (APC) resistance, which might contribute to thrombotic risk in patients with antiphospholipid syndrome. How antibodies against & beta;2GPI and prothrombin cause APC resistance is currently unclear.Objectives: To investigate how anti-& beta;2GPI and antiphosphatidylserine/prothrombin (PS/PT) antibodies induce APC resistance.Methods: The effects of anti-& beta;2GPI and anti-PS/PT antibodies on APC resistance were studied in plasma (of patients with antiphospholipid syndrome) and with purified coagulation factors and antibodies.Results: APC resistance was observed in LA-positive patients with anti-& beta;2GPI or antiPS/PT antibodies and in normal plasma spiked with monoclonal anti-& beta;2GPI or anti-PS/ PT antibodies with LA activity. Analysis of factor (F)V cleavage patterns after APC incubation indicated that anti-& beta;2GPI antibodies attenuated APC-mediated FV cleavage at R506 and R306. APC-mediated cleavage at R506 is required for FV cofactor activity during inactivation of FVIIIa. Assays with purified coagulation factors confirmed that anti-& beta;2GPI antibodies interfered with the cofactor function of FV during FVIIIa inactivation but not with FVa inactivation. Anti-PS/PT antibodies attenuated APC-mediated FVa and FVIIIa inactivation. Analysis of FV(a) cleavage patterns after APC incubation indicated that anti-PS/PT antibodies interfere with APC-mediated cleavage of FV at positions R506 and R306.Conclusion: Anti-& beta;2GPI antibodies with LA activity contribute to a procoagulant state by causing APC resistance via interference with the cofactor function of FV during FVIIIa inactivation. LA-causing anti-PS/PT antibodies interfere with the anticoagulant function of APC by preventing FV(a) cleavage.