On the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies.

Abstract

Phosphatidylethanolamine (PE) is an important membrane component for supporting activated protein C anticoagulant activity but has little influence on prothrombin activation. This difference constitutes a potential mechanism for selective inhibition of the protein C anticoagulant pathway by lupus anticoagulants and/or antiphospholipid antibodies. In this study, we demonstrate that the presence of PE augments lupus anticoagulant activity. In the plasma of some patients with lupus anticoagulants, activated protein C anticoagulant activity is more potently inhibited than prothrombin activation. As a result, in the presence of activated protein C and PE, these patient plasmas clot faster than normal plasma. Patients with minimal lupus anticoagulant activity are identified whose plasma potently inhibits activated protein C anticoagulant activity. This process is also PE dependent. In three patient plasmas, these phenomena are shown to be due to immunoglobulins. The PE requirement in the expression of activated protein C anticoagulant activity and the PE dependence of some antiphospholipid antibodies provide a mechanistic basis for the selective inhibition of the protein C pathway. Inhibition of activated protein C function may be a common mechanism contributing to increased thrombotic risk in certain patients with antiphospholipid antibodies. (J. Clin. Invest. 1995. 95:309-316.)

Lipid Oxidation Enhances the Function of Activated Protein C

“…Our previous studies indicated the importance of PE and polyunsaturation in the expression of APC activity (6,8,49). The studies reported here indicate yet another feature that distinguishes procoagulant from anticoagulant phospholipid surfaces.…”

“…The Effect of Patient Immunoglobulin on APC ActivityPreviously we showed that plasma or immunoglobulin derived from at least a subset of lupus patients could inhibit APC function selectively in a PE-dependent manner (37,49). Screening of IgG from several patients with thrombosis and APA or lupus anticoagulant indicated the anticoagulant activity of APC was inhibited more effectively on oxidized phospholipid than on nonoxidized phospholipid (data not shown).…”

A thrombin–cross‐reactive anticardiolipin antibody binds to and inhibits the anticoagulant function of activated protein C

“…The PLs 1,2-dilinoleoylsn-glycero-3-phosphatidylethanolamine (PE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (PS), and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (phosphatidylcholine) were purchased from Avanti Polar Lipids (Alabasta, AL). The PL liposomes were prepared by ultrasonication of a 1 mg/ml mixture of 40% PE, 20% PS, and 40% phosphatidylcholine in TBS (15).…”

“…Subsequently, the effects of APC-reactive mAb on APC activity in terms of plasma coagulation were examined according to the method described by Smirnov et al (15), with minor modifications. Experiments were conducted using TBS containing 0.1% gelatin in microtiter plates at 25°C.…”

“…For example, it was suggested that antibodies against ␤ 2 GPI and/or its complexes with cardiolipin (CL) interact with endothelial cells (ECs) and monocytes and induce a tissue factor (TF)-dependent procoagulant state (7)(8)(9)(10). On the other hand, antibodies against PC, protein S, or PLs in complexes with either PC or activated PC (APC) and protein S may inhibit activation of PC and/or function of APC (6,(11)(12)(13)(14)(15). Since APC proteolytically inactivates the activated factors V and VIII (denoted as Va and VIIIa, respectively), the reduced activation of PC and/or reduced APC function may lead to a procoagulant effect and thrombotic events.…”