Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid Determinants and Effect on Cardiovascular Risk

"Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydrothromboxane B2 concentrations, has been associated with an increased risk of cardiovascular events.  We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether thare are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B2 concentrations that could thereby reduce cardiovascular risk."

"In aspirin-treated patients, urinary concentrations of 11-dehydrothromboxane B2 are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events."

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Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia

"Thromboxane A2 (TXA2) biosynthesis is enhanced in the majority of patients with type lla hypercholesterolemia.  Because simbastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) was previously shown to reduce platelet aggregation and TXB2 production ex vivo, we investigated TXA2 biosynthesis and platelet function in 24 patients with type ll hypercholesterolemia randomized to receive in a double-blind fashion simvastatin (20mg/d) or placebo for 3 months.  The urinary excretion of 11-dehydro-TXb2, largely a reflection of platelet TXA2 production in vivo, was measured by a previously validated radioimmunoassay technique.  Blood lipid levels and urinary 11-dehydo-TXB2 excretion were significantly (p<.001) reduced by simvastatin.  In contrast, placebo-treated patients did not show any statistically signficant changes in either blood lipids or 11-dehydro-TXB2 excretion."

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Statin therapy and inflammation in patients with diabetes treated with high dose aspirin

"Statin and aspirin form the therapeutic cornerstone in patients with coronary artery disease and diabetes.  Little is known about relationship of statins with blood thrombogenicity and inflammation in these patients."

"Statins along with aspirin, confers additional anti-inflammatory and antithrombotic effect in diabetics with CAD. Urinary 11-DHTXB2 may be a useful biomarker for personalizing statin therapy."

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Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions

"The primary established effect of aspirin on hemostasis is to impair platelet aggregation via inhibition of platelet thromboxane A2 synthesis, thus reducing thrombus formation on the surface of the damaged arterial wall."

We review a number of the reported effects of aspirin on 3 basic elements of hemostasis: platelet activation and aggregation, the formation of the fibrin network, and the fibrinolytic process.

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The influence of aspirin dose and glycemic control on platelet inhibition in patients with type 2 diabetes mellitus

"Our baseline results are in line with earlier studies, which have shown an association between glycemic control and urinary 11-DHTXB2 excretion. In addition, improving glycemic control has been shown to lead to a decreased 11-DHTXB2 excretion."

"In the present study, the difference in urinary 11-DHTXB2 excretion was also influenced by C-reactive protein levels, which were different between the study groups and may reflect the influence of the inflammatory state found in diabetes on thromboxane formation."

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Reduced Blood Platelet Sensitivity to Aspirin in Coronary Artery Disease: Are Dyslipidaemia and Inflammatory States Possible factors Predisposing to Sub-optimal Platelet Response to Aspirin?

"Both environmental and genetic factors, including aspirin pharmacokinetics, inflammation, platelet COX-2, use of non-steroid anti-ainflammatory drugs and dyslipidaemia may determine variable platelet response to acetylsalicylic acid.”’ 

"However, CRP level was significantly associated with the extent of platelet refractoriness to acetylsalicylic acid in these patients, which points out that even subclinical inflammatory states may be considered possible candidates for suboptimal acetylsalicylic acid response."

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The Current and Future Landscape of Urinary Thromboxane Testing to Evaluate Atherothrombotic Risk

"Biomarker testing for efficacy of therapy is an accepted way for clinicians to individualize dosing to genetic and/or environmental factors that may be influencing a treatment regimen.  Aspirin is used by nearly 43 million Americans on a regular basis to reduce risks associated with various artherothrombotic diseases.  Despite its widespread use, many clinicians are unaware of the link between suboptimal response to aspirin therapy and increased risk for inferior clinical outcomes in several disease states, and biomarker testing for efficacy of aspirin therapy is not performed as routinely as efficacy testing in other therapeutic areas.  This article reviews the clinical and laboratory aspects of determining whole-body thromboxane production, particularly as it pertains to efficacy assessment of aspirin responsiveness."

"Aspirin use has been shown to cause a dose-dependent reduction in urinary levels of 11-dehydroTxB2."

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Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stoke, or cardiovascular death in patients at high risk for cardiovascular events

"Among aspirin-treated patients at high risk of cardiovascular events, persistent thromboxane generation predicts the risk of the composite outcome of myocardial infarction, stroke, or cardiovascular death, independent of other cardiovascular risk factors."

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Aspirin use and reduced risk of pancreatic cancer

"Few options besides the avoidance of smoking and obesity are available to prevent pancreatic cancer.  The association between aspirin use and risk of pancreatic cancer has been inconsistent across studies.  

"Regular use of aspirin thus appears to reduce risk of pancreatic cancer by almost half."

"People who take aspirin for prevention of other diseases likely also reduce their risk of pancreatic cancer.  Aside from benefits for both cardiovascular disease and certain cancers, long term aspirin use entails some risks of bleeding complications, which necessitates risk-benefit analysis for individual decisions about use."

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Platelets, cyclooxygenases and colon cancer

"A growing body of evidence supports the central role of platelets in early events of tumorigenesis and metastasis.  Activated platelets, in response to tissue damage, induce a proinflammatory program involving the aberrant expression of cyclooxygenase (COX)-2 which leads to increased tissue concentrations of the proinflammatory and protumorigenic prostaglandin E2.  The central role of platelet activation in cancer development is sustained by the analysis of clinical studies with aspiring showing an anti-cancer efficacy by the drug, even at the low doses used for the prevention of atherothrombosis."

"Activated platelets, in response to tissue damage, induce a proinflammatory program involving the aberrant expression of cyclooxygenase (COX)-2.”

“The central role of platelet activation in cancer development is sustained by the analysis of clinical studies with aspirin showing an anticancer efficacy by the drug, even at the low doses used for the prevention of atherothrombosis."

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