Possible Involvement of Chemokine‐induced Platelet Activation in Thrombophilic Diathesis of Antiphospholipid Syndrome

Abstract

Among the heterogeneous antiphospholipid antibodies, many studies suggest that those directed to beta2-glycoprotein I (beta2GPI) are the major pathogenic antibodies in antiphospholipid syndrome (APS). They have been shown to activate the coagulation pathway via several mechanisms, activate platelets via thrombin formation, and suppress fibrinolysis. Additionally, we propose another possible mechanism that involves certain chemokines and results in platelet activation. This hypothesis is based on the observations that anti-beta2GPI antibodies stimulated monocytes to secrete inflammatory cytokines such as IL-1beta and TNF-alpha, which in turn stimulated vascular endothelial cells to express chemokines such as CX3CL1 and CCL5. CX3CL1 increased the ability of normal platelets to adhere to collagen at a high shear rate, while CCL5 induced platelet aggregation. Expression of tissue factor, IL-1beta, and TNF-alpha by monocytes stimulated with anti-beta2GPI antibodies, as well as CX3CL1 and CCL5 by vascular endothelial cells stimulated with IL-1beta or TNF-alpha were all suppressed by the NF-kappaB-specific inhibitor DHMEQ. These results suggest that the NF-kappaB pathway may be a potential therapeutic target relating to both the coagulation pathway and platelet activity.

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

“…In fact, in patients with APS, peripheral blood monocytes express TF (12,14), and higher levels of soluble TF are detected in the plasma than healthy subjects (15). In a previous study, we confirmed that the IgG fraction from patients with SLE who had β2GPI-dependent aPLs induced the expression of TF on monocytes (16). Furthermore, activated monocytes express inflammatory cytokines such as IL-1β and TNFα, which in turn stimulate vascular endothelial cells to express chemokines such as CX3CL1 and CCL5.…”

“…Since CX3CL1 potentially increases the ability of platelets to adhere to collagen (17), and CCL5 potentially induces platelet aggregation (18), these chemokines may also play a pathogenic role in APS. The expression of TF, IL-1β, TNFα, CX3CL1, and CCL5 is dependent upon the NF-κB pathway, and can be inhibited by the NF-κB specific inhibitor (-)-dehydroxymethylepoxiquinomicin (DHMEQ) (16).…”

Targeted therapy in antiphospholipid syndrome

“…In vitro, NF-KB inhibition was associated with a reduction of proinflammatory/prothrombotic biomarkers, including chemokines (CX3CL1 and CCL5) and cytokines (IL-1 and TNFα) [51]. In vitro reduction of expression of TF was also observed when blocking NF-KB [51]. SB 203580 is an inhibitor of p38α and p38β which suppresses downstream activation of MAPKAP kinase-2 and heat shock protein 27.…”

Sequence alignment analysis of proteins involved in platelet-endothelial cell interaction identifies molecular incompatibilities between Homo sapiens and Sus scrofa

“…EC-derived CCL2 (monocyte chemotactic protein-1, MCP-1), CXCL8 (interleukin 8, IL-8), CXCL12, CX3CL1 and CCL5 have been reported as strong activators of platelets and can promote platelet aggregation. [54][55][56] Analysis of these chemokines and other potential candidates showed that most of these proteins share high sequence identity between Homo sapiens and Sus scrofa (see Table 5). Endothelium-derived regulators can also transduce inhibitory signaling to control platelet activation, and these include immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptors, cell surface receptors, or small molecules.…”