Diabetes Mellitus, Hypercholesterolemia, and Hypertension but Not Vascular Disease Per Se Are Associated With Persistent Platelet Activation In Vivo

Abstract

Background Previous studies relating increased thromboxane (TX) biosynthesis to cardiovascular risk factors do not answer the question whether platelet activation is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of metabolic and hemodynamic disturbances on platelet biochemistry and function. Methods and Results We examined 64 patients with large-vessel peripheral arterial disease and 64 age- and sex-matched control subjects. TXA 2 biosynthesis was investigated in relation to cardiovascular risk factors by repeated measurements of the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB 2 , by radioimmunoassay. Urinary 11-dehydro-TXB 2 was significantly ( P =.0001) higher in patients with peripheral arterial disease (57±26 ng/h) than in control subjects (26±7 ng/h). Seventy percent of patients had metabolite excretion >2 SD above the normal mean. However, 11-dehydro-TXB 2 excretion was enhanced only in association with cardiovascular risk factors. Multivariate analysis showed that diabetes, hypercholesterolemia, and hypertension were independently related to 11-dehydro-TXB 2 excretion. During a median follow-up of 48 months, 8 patients experienced major vascular events. These patients had significantly ( P =.001) higher 11-dehydro-TXB 2 excretion at baseline than patients who remained event free. Conclusions The occurrence of large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA 2 biosynthesis appears to reflect the influence of coexisting disorders such as diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. Enhanced TXA 2 biosynthesis may represent a common link between such diverse risk factors and the thrombotic complications of peripheral arterial disease.