A perspective on the potential problems with aspirin as an antithrombotic agent: a comparison of studies in an animal model with clinical trials

AbstractAspirin is the most widely prescribed agent to reduce the platelet-mediated contributions to atherosclerosis, coronary thrombosis and restenosis after angioplasty. While aspirin treatment has led to significant reductions in morbidity and mortality in many clinical trials, there are several scenarios in which aspirin may fail to provide a full antithrombotic benefit. The cyclic flow model of experimental coronary thrombosis suggests that elevations of plasma catecholamines, high shear forces acting on the platelets in the stenosed lumen and the presence of multiple, input stimuli can activate platelets through different mechanisms that may lead to thrombosis despite aspirin therapy. Aspirin therapy is limited because it only blocks some of the input stimuli, leaving aspirin-independent pathways through which coronary thrombosis can be precipitated. These include thrombin and thrombogenic arterial wall substrates such as tissue factor. New agents that block the adenosine diphosphate (ADP) receptor, or regulate platelet free cytosolic calcium, such as direct nitric oxide donors, may be more potent overall than aspirin. Agents that block the platelet integrin GPIIb-IIIa receptor inhibit the binding of fibrinogen to platelets regardless of which input stimuli activate the platelet and, thus, as demonstrated in the cyclic flow model, would be much more potent than aspirin as an antithrombotic agent. The cyclic flow model has been useful in predicting which agents are likely to be of benefit in clinical trials

Tocotrienols-induced inhibition of platelet thrombus formation and platelet aggregation in stenosed canine coronary arteries

<p>Abstract</p> <p>Background</p> <p>Dietary supplementation with tocotrienols has been shown to decrease the risk of coronary artery disease. Tocotrienols are plant-derived forms of vitamin E, which have potent anti-inflammatory, antioxidant, anticancer, hypocholesterolemic, and neuroprotective properties. Our objective in this study was to determine the extent to which tocotrienols inhibit platelet aggregation and reduce coronary thrombosis, a major risk factor for stroke in humans. The present study was carried out to determine the comparative effects of α-tocopherol, α-tocotrienol, or tocotrienol rich fraction (TRF; a mixture of α- + γ- + δ-tocotrienols) on <it>in vivo platelet thrombosis </it>and <it>ex vivo </it>platelet aggregation (PA) after intravenous injection in anesthetized dogs, by using a mechanically stenosed circumflex coronary artery model (Folts' cyclic flow model).</p> <p>Results</p> <p>Collagen-induced platelet aggregation (PA) in platelet rich plasma (PRP) was decreased markedly after treatment with α-tocotrienol (59%; <b><it>P </it></b>< 0.001) and TRF (92%; <b><it>P </it></b>< 0.001). α-Tocopherol treatment was less effective, producing only a 22% (<b><it>P </it></b>< 0.05) decrease in PA. Adenosine diphosphate-induced (ADP) PA was also decreased after treatment with α-tocotrienol (34%; <b><it>P </it></b>< 0.05) and TRF (42%; <b><it>P </it></b>< 0.025). These results also indicate that intravenously administered tocotrienols were significantly better than tocopherols in inhibiting cyclic flow reductions (CFRs), a measure of the acute platelet-mediated thrombus formation. Tocotrienols (TRF) given intravenously (10 mg/kg), abolished CFRs after a mean of 68 min (range 22 -130 min), and this abolition of CFRs was sustained throughout the monitoring period (50 - 160 min).</p> <p>Next, pharmacokinetic studies were carried out and tocol levels in canine plasma and platelets were measured. As expected, α-Tocopherol treatment increased levels of total tocopherols in post- vs pre-treatment specimens (57 vs 18 μg/mL in plasma, and 42 vs 10 μg/mL in platelets). However, treatment with α-tocopherol resulted in slightly decreased levels of tocotrienols in post- vs pre-treatment samples (1.4 vs 2.9 μg/mL in plasma and 2.3 vs 2.8 μg/mL in platelets). α-Tocotrienol treatment increased levels of both tocopherols and tocotrienols in post- vs pre-treatment samples (tocopherols, 45 vs 10 μg/mL in plasma and 28 vs 5 μg/mL in platelets; tocotrienols, 2.8 vs 0.9 μg/mL in plasma and 1.28 vs 1.02 μg/mL in platelets). Treatment with tocotrienols (TRF) also increased levels of tocopherols and tocotrienols in post- vs pre-treatment samples (tocopherols, 68 vs 20 μg/mL in plasma and 31.4 vs 7.9 μg/mL in platelets; tocotrienols, 8.6 vs 1.7 μg/mL in plasma and 3.8 vs 3.9 μg/mL in platelets).</p> <p>Conclusions</p> <p>The present results indicate that intravenously administered tocotrienols inhibited acute platelet-mediated thrombus formation, and collagen and ADP-induced platelet aggregation. α-Tocotrienols treatment induced increases in α-tocopherol levels of 4-fold and 6-fold in plasma and platelets, respectively. Interestingly, tocotrienols (TRF) treatment induced a less pronounced increase in the levels of tocotrienols in plasma and platelets, suggesting that intravenously administered tocotrienols may be converted to tocopherols. Tocotrienols, given intravenously, could potentially prevent pathological platelet thrombus formation and thus provide a therapeutic benefit in conditions such as stroke and myocardial infarction.</p

914-68 SDZ GPI 562, an Oral Peptidomimetic Inhibitor of the Platelet GpIIbIIIaAbolishes Epinephrine and Shear Induced Cyclic Flow Reductions in Stenosed Monkey Carotid Arteries

Aspirin (ASA) is the only oral agent approved as an anti platelet agent (AA) to prevent platelet mediated thrombosis (PMT) myocardial infarction, strokes and reocclusion after thrombolysis or angioplasty. However, animal and human platelets inhibited with ASA can be reactivated to produce PMT with elevated plasma epinephrine levels or increased shear stress. In 7 anesthetized monkeys (M), mechanical carotid artery stenosis (MCAS) 70% diameter reduction with intimal damage was produced and blood flow measured (EMF probe). Cyclic flow reductions (CFR's) occurred due to acute PMT followed by embolization to the brain, ASA, 5mg/kg IV, abolished the CFR's in all M but they returned with Epinephrine (E), 0,2μ/kg given IV, or increase in MCAS to 85%, due to shear induced aggregation. In 8 M with 70% MCAS, after 30 minutes of CFR's, 1–2mg/kg of the drug SDZ GPl562 was given by stomach tube. Eighty-five±22 min after SDZ GPI 562, the CFR's were abolished in all 8M. Template bleeding time increased from a control of 2.3±1.0 min to 4.1±1.2 min (p&lt;0.05) Ex vivo whole blood platelet aggregation (collagen stimulus) decreased by 76±8% (p&lt;0,0001) and by 83±10% (p&lt;0.0001) to ADP after SDZ GPI 562, The CFR's due to periodic acute PMT were not renewed by E, 0.2 μ/kg/min given IV for 20 minutes and/or by increased stenosis from 70% to 85% diameter reduction which increases shear from 144±15 Pa to 266±22 Pa (p&lt;0.005). CFR's due to acute PMT have been observed in patient coronary arteries at the time of angioplasty inspire of pretreatment with aspirin and heparin but could be abolished with c7E3, a monoclonal antibody inhibitor of the platelet Gpllbilia which is available only for IV use. SDZ GPI 562 is likely to be a superior AA because it is available in oral or IV form, it blocks the final step in platelet activation by blocking the platelet GpIIbIIIa, thus protecting against platelet activation by elevated E and shear stress produced by very severe stenosis. It is also likely to be more effective than ASA for reducing the platelet contribution to atherosclerosis preventing coronary thrombosis and fatal or non fatal myocardial infarction and early and late PMT after angioplasty or atherectomy procedures