Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and P‐selectin expression in a human ex vivo in vitro model

Abstract

Formation of platelet-leukocyte aggregates (PLA) through the CD62 ligand is an important mechanism by which leukocytes contribute to thrombosis and inflammation. We investigated the formation of PLA in human subjects after stimulation with thrombin receptor activating peptide and adenosine diphosphate (ADP) after treatment with clopidogrel and after in vitro application of the platelet glycoprotein IIb/IIIa complex antagonist abciximab. Expression of CD62 was significantly reduced 30% to 50% with clopidogrel, depending on the type and concentration of the inducer, but addition of abciximab led to a significant approximately 30% increase in CD62 expression when platelets were stimulated by ADP. Formation of PLA decreased significantly with clopidogrel to 55% to 75% of the baseline value, whereas addition of abciximab caused a significant increase in PLA in ADP-stimulated samples before but not after administration of clopidogrel. The increase in formation of PLA after in vitro addition of abciximab was not paralleled by a decrease in platelet microaggregates and is therefore presumed not caused by enhanced availability of platelets. To our knowledge, this is the first report showing that clopidogrel reduces formation of PLA. The findings also suggest intersection between an "outside-in" signal generated by abciximab and stimulation of platelet P2T(12) purinergic receptors that augments degranulation and increases formation of PLA but is inhibited by clopidogrel.

Role of the P2Y12 Receptor in the Modulation of Murine Dendritic Cell Function by ADP

“…However, this anti-inflammatory action is likely to be an indirect effect involving inhibition of platelets that are known to play a key role in vascular inflammation through the expression and release of several proinflammatory mediators (CD40L and P-selectin) (36)(37)(38). But our results suggest that the P2Y 12 receptor also may directly modulate the immune responses by stimulating Ag endocytosis and presentation by DCs.…”

Anti-inflammatory Renoprotective Effect of Clopidogrel and Irbesartan in Chronic Renal Injury

“…12 Platelet activation also plays an important role in thrombosis and arteriosclerosis. 8,13,14 Some studies showed that platelet activation is closely related to inflammation, and platelet activation can induce or increase inflammation in vivo. 3,[15][16][17][18] Inhibition of the platelet activation contributes to the repression of the inflammation.…”

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…Indeed, clopidogrel withdrawal results in the re-emergence of inflammation in patients with diabetes and coronary artery disease (Angiolillo et al, 2006). Clopidogrel significantly reduces platelet-associated inflammatory markers in renal transplant patients with no clinical signs of atherosclerosis (Graff et al, 2005) and patients with stable coronary artery disease, for example P-selectin and CD40L release, platelet-leukocyte complexes and MMP9 release (Klinkhardt et al, 2002;Azar et al, 2006). This increased inflammatory activity of platelets in renal transplant patients may account for the high cardiovascular mortality rate as a result of the development of atherosclerotic lesions in such patients.…”

“…While this outcome may be the result of partial agonism at sub-therapeutic concentrations (Cox et al, 2000), leading to 'platelet escape' and thrombus formation, a pro-inflammatory profile of GPIIb/IIIa antagonists is apparent. In vitro studies reveal that both monoclonal antibodies and non-peptide inhibitors increase platelet P-selectin expression and plateletleukocyte complexes (Caron et al, 2002;Klinkhardt et al, 2002), as well as the release of CD40L and tissue factor (Zhao et al, 2003) and may explain the negative clinical effects of GPIIb/IIIa antagonists. These studies also demonstrate that pathways leading to platelet aggregation are distinct to pathways leading to platelet activation of P-selectin expression and CD40L release.…”