Pathogenesis of antiphospholipid antibodies: impairment of fibrinolysis and monocyte activation via the p38 mitogen-activated protein kinase pathway

Abstract

Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis or pregnancy morbidity associated with antiphospholipid antibodies (aPL). Impaired fibrinolysis is a contributing factor for the development of thrombosis, and the effect of aPL in the fibrinolytic system has been investigated. Impaired release of tPA and enhanced release of PAI-1 after endothel activation is reported in patients with APS. Elevated Lipoprotein (a) levels have been found in APS, which results in inhibition of fibrinolytic activity. Phospholipid-bound β 2 -glycoprotein I (β 2 GPI) is a major autoantigen for aPLs. β2GPI exerts both anti-coagulant and pro-coagulant properties mainly by interacting with other phospholipid-binding proteins such as coagulation factors and protein C. Dramatic increase in the affinity of β 2 GPI to the cell surface is induced by binding of pathogenic anti-β 2 GPI antibodies, which may modify the physiological function of β 2 GPI and may affect the coagulation/fibrinolysis balance on the cell surface.Using chromogenic assays for measuring fibrinolytic activity, we demonstrated that addition of monoclonal anticardiolipin antibody (aCL) decreases the activity of extrinsic/intrinsic fibrinolysis. Significantly lower activity of intrinsic fibrinolysis was also demonstrated in the euglobulin fractions from APS patients.Endothelial cells and monocytes are activated by aPLs in vitro, resulting in production of tissue factor (TF), a major initiator of the coagulation system. Recently, aPLs are reported to induce thrombocytes to produce thromboxane. The importance of apoE receptor 2 on platelets for the binding of artificially-dimerized β 2 GPI was suggested. By investigating aPL-inducible genes in peripheral blood mononuclear cells, we found that mitogen-activated protein kinase (MAPK) pathway was up-regulated. Using monocyte cell line, phosphorylation of p38 MAPK, NF-κB 3 translocation to the nuclear fraction, and up-regulated TF mRNA expression were demonstrated after treatment with monoclonal aCL. These phenomena were observed only in the presence of β 2 GPI. Moreover, a specific p38 MAPK inihibitor SB203580 decreased aCL/β 2 GPI-induced TF mRNA expression.

Increase in plasma thrombin-activatable fibrinolysis inhibitor may not contribute to thrombotic tendency in antiphospholipid syndrome because of inhibitory potential of antiphospholipid antibodies toward TAFI activation

“…There is increasing evidence that aPL play a role in the hyper-coagulable state of APS patients, as these antibodies are able to inhibit anticoagulant activity, such as the protein C-protein S system via phospholipid-binding proteins [34,35,36], and fibrinolytic function [37,38,39]. aPL activate endothelial cells by recognizing the complex of phospholipid-binding proteins and phospholipids on the cell surface, and induce procoagulant substances such as tissue factor [40,41].…”

Innate immune response gene expression profiles characterize primary antiphospholipid syndrome

“…[1][2][3][4] These autoantibodies are not only markers of APS, but also believed to play pathogenic roles in the development of symptoms in patients with APS. [1][2][3][4] APS was first fully described in the context of connective tissue autoimmune diseases, most usually systemic lupus erythematosus (SLE), although it was soon recognized that the condition can exist as an isolated, primary condition ('primary' APS, PAPS). 5,6 Furthermore, patients with PAPS may subsequently develop SLE, implying a strong relationship between both conditions.…”

“…[1][2][3][4] Thus, it is important to uncover the underlying pathways that are relevant to this condition, since they are likely to be a contributing factor for a significant proportion of patients with a variety of vascular conditions. However, the pathogenic mechanism of aPL-induced thrombosis is not fully understood.…”

The NF-κB specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome

“…aPLs are known to induce TF expression on monocytes and vascular endothelial cells via the MAP kinase pathways, notably the p38 MAP kinase and MEK-1/ERK pathways (11,12,21). However, an MEK-1/ERK inhibitor PD98059 suppressed TF expression (12,13) but did not suppress NF-κB (12), and the critical transcription factor underlying aPL-induced TF expression had not yet been fully determined.…”