No abstract

To elucidate the bleeding tendency that follows the administration of ticlopidine, we investigated the skin bleeding time and some ex vivo functions of platelets obtained from eight healthy volunteers before and 1 wk after daily administration of 500 mg of ticlopidine. We found the following: ticlopidine significantly (P < 0.001) prolonged the skin bleeding time and impaired the binding of radiolabeled fibrinogen and von Willebrand Factor, the clot retraction and the aggregation of platelets in response to ADP, epinephrine, thrombin, ionophore A23187, collagen, or arachidonic acid. In contrast, the administration of this drug did not affect intraplatelet levels of cAMP, agglutination and binding of von Willebrand Factor in response to ristocetin, shape change in response to ADP, collagen, thrombin, or arachidonic acid, or binding of prostaglandin El to resting platelets. Secretion of ATP in response to ADP or epinephrine was completely inhibited, whereas secretion as well as thromboxane synthesis in response to high concentrations of collagen, arachidonic acid, calcium ionophore A23187, or thrombin was unaffected. Studies with monoclonal antibodies showed that the glycoprotein IIb-IIIa complex (the putative receptor for fibrinogen and von Willebrand Factor on the surface of platelets exposed to naturally occurring aggregating agents) was quantitatively unaffected by ticlopidine. This observation was further confirmed by densitometric scannings of Periodic Acid-Schiff-stained gels of platelet suspensions. The onset, as well as the cessation of the inhibitory effect of ticlopidine on platelets was very slow, and reached a maximum after a 3-5-d administration. In addition, ticlopidine appeared to be a much more potent inhibitor when administered to subjects than when added in vitro to platelets. Finally, abnormalities comparable to those found in volunteers taking ticlopidine were observed when platelets from untreated subjects were incubated in the plasma of ticlopidine-treated subjects.We conclude that ticlopidine induces a thrombasthenic state in normal platelets without affecting the glycoprotein IlbIIIa complex quantitatively. Furthermore, our data suggest that one or more active metabolites rather than the native drug Portions of this work were presented at a symposium ("Ticlopidine: Quo vadis?") in Montpellier, France, 1983, and were published in abstract form in the proceedings of that symposium.Address reprint requests to Dr. Di Minno.

The finding suggests that hyperfibrinogenemia may be considered a component of the metabolic syndrome. This may also explain the increased cardiovascular risk associated with hyperinsulinemia/insulin resistance.

In NIDDM patients with hypertriglyceridemia, moderate amounts of fish oil induce a long-term significant reduction in plasma triglycerides, VLDL triglycerides, and NEFA and a significant enrichment in the erythrocyte phospholipid content of long-chain omega-3 fatty acids, without deteriorating blood glucose control. However, this amount of omega-3 fatty acids was unable to improve insulin sensitivity in this group of patients.

The aim of this study was to evaluate exogenous and endogenous lipoprotein responses to a standard fat-rich meal in type 2 diabetic patients with optimal fasting triglyceridemia and optimal blood glucose control. Seven type 2 diabetic patients and five nondiabetic controls (age, 49 +/- 7 and 48 +/- 4 yr; body mass index, 28.3 +/- 3.6 and 25.1 +/- 3.6 kg/m(2); mean +/- SD) were given, after at least 12 h of fasting, a standard fat-rich meal. Before and over the 6 h after the meal, serial blood samples were taken for determination of glucose, insulin, lipids, lipoproteins, apolipoprotein B-48 (apo B-48), apo B-100, free fatty acids, and lipoprotein lipase activity. The main abnormality in the postprandial lipid response of diabetic patients involved large very low density lipoproteins. In these particles, apo B-48, apo B-100, cholesterol, and triglyceride incremental areas were, in fact, significantly higher in diabetics compared with controls [7.08 +/- 2.65 vs. 1.17 +/- 0.88 mg/liter.h, 65.5 +/- 11.5 vs. 12.4 +/- 1.77 mg/liter.h, 29.7 +/- 3.9 vs. 13.1 +/- 3.1 mg/dl.h (0.77 +/- 0.10 vs. 0.34 +/- 0.08 mmol/liter.h), 170 +/- 31 vs. 94 +/- 22 mg/dl.h (1.93 +/- 0.35 vs. 1.06 +/- 0.25 mmol/liter.h)] (all P < 0.05; mean +/- SEM). Postprandial preheparin lipoprotein lipase plasma activity was, if anything, higher in diabetic patients. In conclusion, even with fasting normotriglyceridemia and optimal blood glucose control, type 2 diabetic patients are characterized, in the postprandial period, by a significant increase in large very low density lipoproteins of both endogenous and exogenous origins.