The putative mechanism of thrombosis in antiphospholipid syndrome: Impairment of the protein C and the fibrinolytic systems by monoclonal anticardiolipin antibodies

The mechanism of thrombosis in patients with antiphospholipid syndrome is n ot clear. To investigate it, we examined the effect of monoclonal anticardi olipin (aCL) antibodies and beta(2)-glycoprotein I (beta(2)-GPI), which is required for formation of the aCL epitopes, on activated protein C (APC) an d on fibrinolytic activity. First, APC activities were measured in the pres ence and absence of beta(2)-GPI or gamma M immunoglobulin (IgM) monoclonal aCLs (EY1C8 and EY2C9), or both, established from peripheral blood lymphocy tes obtained from a patient with aCL, beta(2)-GPI exhibited a procoagulant activity by inhibiting APC activity as well as an anticoagulant activity by inhibiting thrombin generation. Any further inhibition of APC activity was caused by monoclonal aCL, and then only in the presence of beta(2)-GPI, Th e remaining tissue plasminogen activator (t-PA) of the sample consisting of beta(2)-GPI, two-chain recombinant t-PA, and plasminogen activator inhibit or (PAI)-1 was measured by a chromogenic assay using the synthetic substrat e S-2251, Glu-plasminogen, and soluble fibrin monomer, beta(2)-GPI protecte d t-PA activity from inhibition by PAI-1, However, monoclonal aCLs (EY1C8 a nd EY2C9) inhibited the effect of beta(2)-GPI on fibrinolytic activity; tha t is, monoclonal aCLs inhibited fibrinolytic activity by elevating PAI-1 ac tivity. Thrombosis in patients with aCL can be explained in part by both th e inhibition of APC anticoagulant activity and the impairment of fibrinolyt ic activity by aCL.