Hypercoagulable State in Patients With Antiphospholipid Syndrome Is Related to High Induced Tissue Factor Expression on Monocytes and to Low Free Protein S

Abstract

Antiphospholipid antibodies (aPLs) are associated with thrombosis, but the mechanisms of this thrombotic tendency are unknown. We studied 56 patients 612 with systemic lupus erythematosus [SLE] and aPLs and previous thrombosis, 12 with SLE and aPLs but no thrombosis, 15 with SLE without aPLs or thrombosis, 11 with primary antiphospholipid syndrome with thrombosis, and 6 asymptomatic subjects with aPLs) to investigate the ability of aPLs to induce tissue factor (TF) expression on human normal monocytes. A double direct immunofluorescence technique (anti-CD14 and anti-TF) was used, and procoagulant activity in viable and disrupted cells was measured after plasma incubation for 6 hours at 37 degrees C with normal mononuclear cells. Hemostasis regulatory proteins, prothrombin fragment 1 + 2, and thrombin-antithrombin III complex levels were determined. Increased TF expression and procoagulant activity were observed using plasma samples from SLE patients with aPLs and thrombosis (P < .01) and from primary antiphospholipid syndrome patients (P < .01) but not from patients with SLE and aPLs but no thrombosis, patients with SLE without aPLs, or asymptomatic patients with aPLs. Purified aPL immunoglobulins from one primary antiphospholipid syndrome and two SLE patients added to normal plasma showed a significant increase in both TF expression and procoagulant activity (P < .05) compared with purified aPL from two SLE patients without thrombosis. The addition of nonspecific IgG from three SLE patients without aPLs and from three control subjects did not increase TF expression. Low free protein S was seen in eight patients. Increased TF expression and low free protein S correlated with thrombosis (P < .01) and with higher prothrombin fragment 1 + 2 and thrombin-antithrombin III values (P < .01). These observations may contribute to a further understanding of the thrombotic risk in aPL patients.

Antiphospholipid Antibodies From Antiphospholipid Syndrome Patients Activate Endothelial Cells In Vitro and In Vivo

“…11 Simantov et al 22 recently showed that on adhesion of monocytes to ECs, adhesion molecule expression is enhanced in ECs and monocytes produce tissue factor. In our in vivo experiments, we have not eliminated the possibility that aPL may directly bind to monocytes via the Fc receptor and induce direct procoagulant activity in monocytes.…”

“…Investigators speculate that a prothrombotic state may be induced by aPL antibodies activating platelets 8 -10 or endothelial cells (ECs) or by inhibition of protein C activation. [11][12][13][14][15][16][17][18][19][20][21] aPL antibodies may bind phospholipids or ␤ 2 -glycoprotein 1 (␤ 2 GP1) in the membranes of ECs or platelets, resulting in their activation. 8 -10,16,22 EC activation by aPL antibodies has been demonstrated in vitro in several ways, including enhanced adhesion molecule expression and monocyte adherence 22,23 ; however, no in vivo studies have shown such activation.…”

Thrombosis in primary antiphospholipid syndrome. A pivotal role for monocyte tissue factor expression

“…Kornberg and colleagues (32) induced a potent PCA activity resembling TF using human aCL MAb which previously induced APS. Reverter et al (33) described an increase of TF expression on healthy donor monocytes when incubated with plasma from antiphospholipid-positive SLE patients with thrombosis.…”

Molecular Pathogenesis of the Antiphospholipid Syndrome

“…98 In one study, the ability of IgG to stimulate monocyte tissue factor expression was associated with the presence of decreased free protein S and increased prethrombotic markers. 99,100 Another means by which aPL antibodies may increase tissue factor activity and resultant Xa generation is via antibody-mediated inhibition of tissue factor pathway inhibitor activity. 101,102 Interference With the Components of the Protein C Pathway…”