CLINICAL STUDIES
Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia
Andrzej Szczeklik, MD, PhDa,
Jacek Musia , MD, PhDa,
Anetta Undas, MDa,
Piotr Gajewski, MDa,
Pawe Góra, PhDa,
Jakub Swad ba, MDa and
Miosz Jankowski, MDa
a Departments of Medicine and Physics, School of Medicine, Jagiellonian University, Cracow, Poland
Manuscript received May 13, 1998;
revised manuscript received November 4, 1998,
accepted January 5, 1999.
Reprint requests and correspondence: Prof. Andrzej Szczeklik, Jagiellonian University, School of Medicine, Department of Medicine, 8 Skawinska Street, 31-066 Cracow, Poland
mmszczek{at}cyf-kr.edu.pl
OBJECTIVES
To assess the effects of aspirin compared with simvastatin on thrombin generation in hypercholesterolemic men, and to establish whether the reduction of elevated blood cholesterol by simvastatin would affect the action of aspirin on thrombin formation.
BACKGROUND
Aspirin inhibits thrombin formation, but its performance is blunted in hypercholesterolemia. By virtue of altering lipid profile, statins could be expected to influence thrombin generation.
METHODS
Thirty-three men, aged 34 to 61 years, with minimal or no clinical symptoms, serum total cholesterol >6.5 mmol/liter and serum triglycerides <4.6 mmol/liter, completed the study consisting of three treatment phases. First, they received 300 mg of aspirin daily for two weeks (phase I), which was then replaced by simvastatin at the average dose of 24 mg/d for three months (phase II). In phase III, aspirin, 300 mg/day, was added for two weeks to simvastatin, the dose of which remained unchanged. Thrombin generation was assessed: 1) in vivo, by measuring levels of fibrinopeptide A (FPA) and prothrombin fragment 1+2 (F1+2) in venous blood; and 2) ex vivo, by monitoring the rates of increase of FPA and F1+2 in blood emerging from standardized skin incisions of a forearm. A mathematical model was used to describe the kinetics of thrombin formation at the site of microvascular injury.
RESULTS
Two-week treatment with aspirin had no effect on thrombin markers in vivo, while ex vivo it depressed the total amount of thrombin formed, though not the reaction rate. After simvastatin treatment, serum cholesterol decreased by 31% and LDL cholesterol by 42%, while thrombin generation became markedly depressed. In venous blood, FPA was significantly reduced. Concomitantly, the initial thrombin concentration and total amount of thrombin generated decreased significantly. Addition of aspirin to simvastatin (phase III) had no further effect on any of these parameters.
CONCLUSIONS
In men with hypercholesterolemia, lowering serum cholesterol level by a three-month simvastatin treatment is accompanied by a marked reduction of thrombin generation both at basal conditions in venous blood and after activation of hemostasis by microvascular injury. Once blood cholesterol became reduced, adding aspirin to simvastatin did not enhance dampening of thrombin formation.
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Abbreviations and Acronyms
| | ALT | = alanine aminotransferase | | AP | = alkaline phosphatase | | AST | = aspartate aminotransferase | | CK | = creatine phosphokinase | | F1+2 | = prothrombin fragments 1+2 | | FPA | = fibrinopeptide A | | HDL | = high-density lipoprotein | | LDL | = low-density lipoprotein | | TAT | = thrombin-antithrombin III complexes |
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