Abstract
Although the mechanisms of action by which aspirin, clopidogrel and dipyridamole inhibit platelets are well characterised, their effects on soluble modulators of thrombosis, inflammation, and endothelial function have yet to assessed systematically. In this investigation aspirin (A), clopidogrel (C), and dipyridamole (D) were administered singly and in combination (A, C, D, AC, AD, CD, ACD) in random order for 2 weeks (without washout) to 11 healthy subjects and 11 patients with previous ischaemic stroke. At the end of each treatment period plasma cyclic guanosine monophosphate (cGMP), monocyte chemoattractant pertide-1 (MCP-1), nitric oxide metabolites (NOx), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWf); and serum C-reactive protein (CRP) and platelet derived growth factor (PDGF); were measured blinded to treatment. Dipyridamole reduced plasma vWf levels (%) in both volunteers, −10.0 (4.95), and patients, −10.11 (4.34) (p < 0.05). Dipyridamole also lowered CRP (mg/l) in patients, −0.96 (0.47), but not volunteers. Clopidogrel reduced PAI-1 (ng/ml) in volunteers, −5.30 (2.20) (p < 0.05), and patients, −3.61 (2.75) (non-significant trend). Aspirin lowered PDGF (ng/ml) in volunteers, −3.46 (1.55), but not patients. Triple antiplatelet therapy was superior to dual and mono therapy in reducing vWf levels. In conclusion, antiplatelet agents have non-platelet-related effects on soluble modulators of thrombosis, inflammation, and endothelial function. In particular, dipyridamole reduces plasma vWf and clopidogrel lowers plasma PAI-1 levels. These effects may explain, in part, their roles in preventing atherothrombogenesis.
Highlights
The three antiplatelet agents, aspirin, clopidogrel and dipyridamole, are widely used for secondary stroke prevention on the basis of results from large trials and systematic reviews.[1, 2] Whilst their antiplatelet actions are well described, their effects on other vascular cells and soluble factors are less well defined.Platelets, leucocytes, and endothelial cells contribute to the pathogenesis of vascular disease[3] through direct cell-cell interactions and the release of atherothrombogenic factors
Endothelial cells release von Willebrand factor, which facilitates platelet and thrombus adhesion to endothelium,[12] and nitric oxide (NO), a potent vasorelaxant, antiplatelet and antileucocyte agent 13 whose effects are mediated by the second messenger cyclic guanosine monophosphate.[14]
The use of triple antiplatelet therapy was not superior to mono or dual therapy with the exception that the combination of all three agents was associated with significantly lower levels of plasma von Willebrand factor (vWf) than dual aspirin and clopidogrel in both volunteers and patients, a finding compatible with the above observation that dipyridamole lowers vWf levels. These studies show that antiplatelet agents may alter soluble markers of vascular function
Summary
The three antiplatelet agents, aspirin, clopidogrel and dipyridamole, are widely used for secondary stroke prevention on the basis of results from large trials and systematic reviews.[1, 2] Whilst their antiplatelet actions are well described, their effects on other vascular cells and soluble factors are less well defined.Platelets, leucocytes, and endothelial cells contribute to the pathogenesis of vascular disease[3] through direct cell-cell interactions and the release of atherothrombogenic factors. The three antiplatelet agents, aspirin, clopidogrel and dipyridamole, are widely used for secondary stroke prevention on the basis of results from large trials and systematic reviews.[1, 2] Whilst their antiplatelet actions are well described, their effects on other vascular cells and soluble factors are less well defined. Platelets release several cytokines including platelet-derived growth factor (PDGF), platelet factor 4 and CD40 ligand, each of which has been linked to the inflammation and coagulation pathways.[4,5,6] monocytes and macrophages generate cytokines including macrophage chemoattractant protein-1 (MCP-1), a chemokine important during atherogenesis,[7] and interleukin-6 (IL-6),[8] a procoagulant and stimulator of hepatic synthesis of C-reactive protein (CRP); CRP amplifies inflammatory and procoagulant responses.[9,10] IL-6 increases endothelial production of the fibrinolytic inhibitor, plasminogen activator inhibitor type 1 (PAI-1).[3, 11] Endothelial cells release von Willebrand factor (vWf), which facilitates platelet and thrombus adhesion to endothelium,[12] and nitric oxide (NO), a potent vasorelaxant, antiplatelet and antileucocyte agent 13 whose effects are mediated by the second messenger cyclic guanosine monophosphate (cGMP).[14]
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