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 not clear. To investigate it, we examined the effect of monoclonal anticardiolipin (aCL) antibodies and beta2-glycoprotein I (beta2-GPI), which is required for formation of the aCL epitopes, on activated protein C (APC) and on fibrinolytic activity. First, APC activities were measured in the presence and absence of beta2-GPI or gamma M immunoglobulin (IgM) monoclonal aCLs (EY1C8 and EY2C9), or both, established from peripheral blood lymphocytes obtained from a patient with aCL. beta2-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 beta2-GPI. The remaining tissue plasminogen activator (t-PA) of the sample consisting of beta2-GPI, two-chain recombinant t-PA, and plasminogen activator inhibitor (PAI)-1 was measured by a chromogenic assay using the synthetic substrate S-2251, Glu-plasminogen, and soluble fibrin monomer. beta2-GPI protected t-PA activity from inhibition by PAI-1. However, monoclonal aCLs (EY1C8 and EY2C9) inhibited the effect of beta2-GPI on fibrinolytic activity; that is, monoclonal aCLs inhibited fibrinolytic activity by elevating PAI-1 activity. Thrombosis in patients with aCL can be explained in part by both the inhibition of APC anticoagulant activity and the impairment of fibrinolytic activity by aCL.
Ieko
M
M
Department of Internal Medicine, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Toubetsu, Japan.
Sawada
K I
KI
Koike
T
T
Notoya
A
A
Mukai
M
M
Kohno
M
M
Wada
N
N
Itoh
T
T
Yoshioka
N
N
D017153:Antibodies, Anticardiolipin / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology; D016736:Antiphospholipid Syndrome / Q000150:complications* / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D011486:Protein C / Q000187:drug effects; D013927:Thrombosis / Q000209:etiology* / Q000378:metabolism*; D053482:beta 2-Glycoprotein I
D017153:Antibodies, Anticardiolipin; D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D006023:Glycoproteins; D011486:Protein C; D053482:beta 2-Glycoprotein I