Anticardiolipin Antibodies Block the Inhibition by β2-Glycoprotein I of the Factor Xa Generating Activity of Platelets

Abstract

SummaryAntiphospholipid antibodies, defined either by lupus anticoagulant (LA) activity or positive anticardiolipin immunoabsorbent assay (ACA) are associated with a predisposition to thromboses, recurrent fetal loss or thrombocytopenia. The mechanisms for these predispositions remain undefined. We have enriched immunoglobulin fractions from two patient plasmas to obtain antibodies with LA activity but no ACA, or conversely, with ACA positivity but no LA, in order to investigate in vitro characteristics which might explain a thrombotic propensity. β2-glycoprotein I (β2-GPI), the plasma cofactor required for ACA binding to negatively charged phospholipid, has previously been shown to inhibit prothrombinase generation in the presence of activated platelets (8). We now report that β2-GPI, at physiological concentrations, inhibits the generation of factor Xa in the presence of activated gel-filtered platelets. Further, ACA interferes with this inhibition, resulting in protracted, unopposed factor Xa generation. This interference with β2-GPI, a natural anticoagulant component of plasma, is potentially prothrombotic. LA immunoglobulins behave differently and inhibit factor Xa generation in a manner similar to β2-GPI. These findings provide the basis for a previously unsuspected mechanism for thrombosis in patients with aPL.

Antiphospholipid antibody: functional specificity for inhibition of prothrombin activation by the prothrombinase complex

“…One sample, designated S, was anti-cardiolipin negative and demonstrated only weak binding of the phospholipid-dependent coagulation reaction. It is possible that sample S may inhibit another phospholipid-dependent coagulation reaction such as activation of factor X (Shi et al, 1993). These findings suggest the existence of at least two populations of antibodies in these series, the larger group inhibits phospholipiddependent prothrombin-thrombin conversion, and a small number may be directed at prothrombin alone.…”

A monoclonal IgG anticardiolipin antibody from a patient with the antiphospholipid syndrome is thrombogenic in mice.

“…Based on a KCT assay, the mAbs did not possess any LAC activity. Hence, the mAbs described in this report have features similar to at least one subset of polyclonal APA from patients with the APS, in that they are specific for some negatively charged phospholipids, exhibit enhanced binding activity in the presence of sera, and lack LAC or prothrombinase inhibitory activity (11,(43)(44)(45)(46).…”

Nicked 2-glycoprotein I: a marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis

“…This cleavage is generated by factor Xa or by plasmin, with plasmin being more effective. 6 A large number of reports have detailed the in vitro properties of ␤ 2 -GPI as a natural anticoagulant/procoagulant regulator by inhibiting phospholipid-dependent reactions, such as prothrombinase and tenase activity on platelets or phospholipid vesicles, 7,8 factor XII activation, 9 and anticoagulant activity of activated protein C. 10,11 Apart from specific hemostatic functions, ␤ 2 -GPI activates lipoprotein lipase, 12 lowers the triglyceride level, 13 binds to oxidized low-density lipoprotein to prevent the progression of atherosclerosis, 14 and binds to nonself particles or apoptotic bodies to allow their clearance. [15][16][17] Little attention has been given to the functions of the nicked form of ␤ 2 -GPI because its phospholipidbinding activity was thought to exert the physiologic or pathologic functions of ␤ 2 -GPI.…”