Effect of diet and treatment with statins on platelet-dependent thrombin generation in hypercholesterolemic subjects.
OBJECTIVE
Platelets are strictly involved in arterial thrombosis and their hyperactivity has been shown in hypercholesterolemia. It has been reported that drugs affecting cholesterol metabolism (statins) decrease cardiovascular events by lowering lipid levels or by means of non-lipidic actions such as the direct inhibition of platelet function. The aim of this study was to detect the effect on platelet-dependent thrombin generation (PDTG) of a reduction in cholesterol obtained by means of a lipid-lowering diet or treatment with statins.


RESULTS
We compared PDTG (T0) in 144 hypercholesterolemic subjects (94 males and 50 females of child-bearing age, mean age 48.2 +/- 13.8, plasma total cholesterol 6.93 +/- 0.64, high density lipoprotein cholesterol 1.25 +/- 0.14, triglycerides 1.15 +/- 0.19 mmol/L) and 70 normolipidemic controls (37 males and 33 females, mean age 43.1 +/- 12.6. After six weeks on an appropriate diet, the patients were randomised to receive different statin therapies if there was no reduction in their lipid profile and/or PDTG (T1). They were re-evaluated six weeks later, and the drug doses were maintained or increased on the basis of the variables (T2). A final evaluation was made after a further six weeks (T3). All of the data were evaluated using ANOVA and Spearman's correlation coefficent. The results showed increased PDTG in hypercholesterolemic subjects (418.2 +/- 29.2 mIU/mL, p < 0.001 vs controls). Diet alone did not reduce PDTG (380.2 +/- 28.5 mIU/mL, p = 0.226 vs controls). At T2, simvastatin and atorvastatin significantly decreased PDTG (P < 0.001 vs T0-1) and low-density lipoprotein cholesterol (LDL-C). No correlation was found between the two variables in the simvastatin group (r = 0.16). Cerivastatin reduced PDTG without significantly decreasing LDL-C (p < 0.001 and p = 0.476, r = 0.14). Pravastatin and fluvastatin significantly reduced thrombin generation only at T3 (40 mg/day); pravastatin was also associated with a decrease in LDL-C (p < 0.01, r = 0.66).


CONCLUSIONS
Our results confirm an increased PDTG in patients with type IIa hyperlipoproteinemia, which is not reduced by diet. Statins at different doses significantly decrease PDTG but do not correlate with a reduction in LDL-C.
Puccetti
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Institute of Medical Semeiotics, Centro per lo Studio delle Malattie Dismetaboliche e della Aterosclerosi, University of Siena, Siena, Italy. puccetti@unisi.it
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D000328:Adult; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000069059:Atorvastatin; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000178:diet therapy / Q000188:drug therapy / Q000628:therapy*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D017035:Pravastatin / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000096:biosynthesis*; D016896:Treatment Outcome
D000924:Anticholesteremic Agents; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D007211:Indoles; D011725:Pyridines; D011758:Pyrroles; D000077340:Fluvastatin; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin; C086276:cerivastatin; D013917:Thrombin; D017035:Pravastatin