Inhibition of Thrombin Generation by Aspirin Is Blunted in Hypercholesterolemia

Abstract

Recent evidence indicates that aspirin inhibits thrombin generation in clotting blood. We noticed that this effect was less pronounced in patients with hypercholesterolemia. The aim of the study was to prove this observation. The effects of aspirin on thrombin generation were evaluated in (1) 46 healthy volunteers, 2 hours after ingestion of a single, 500-mg dose and (2) 28 survivors of myocardial infarction who took 300 mg aspirin/d for 2 weeks. In both populations, two well-matched subgroups were distinguished, using a serum cholesterol level of 6.2 mmol/L (240 mg/dL) and an LDL cholesterol level of 4.0 mmol/L (155 mg/dL) as borderline. Thrombin generation was monitored ex vivo in blood emerging from a skin microvasculature injury and additionally, in a single-dose study in vitro in recalcified plasma. Aspirin depressed thrombin generation in the group of subjects with serum cholesterol < 6.2 mmol/L and LDL cholesterol < 4.0 mmol/L but not in the group with high blood cholesterol levels. Inhibitory effects of aspirin were more pronounced after the 2-week treatment than after a single dose. There was a significant correlation between total serum cholesterol or LDL cholesterol and total amount of thrombin generated after aspirin treatment. In subjects with high blood cholesterol levels, thrombin generation was not affected by aspirin. Blunting of aspirin action in hypercholesterolemia might be explained by (1) alterations in platelet lipid-protein matrix that render their membrane proteins less accessible for acetylation by aspirin and (2) changes in composition and structure of plasma lipoproteins that diminish the chance of aspirin to interact with prothrombin.

Blood coagulation at the site of microvascular injury: effects of low-dose aspirin

“…Previous studies on blood coagulation at sites of hemostatic plug formation, however, have been limited to measurements of FPA, TAT, or F1.2 by commercially available ELISAs. [18][19][20] In the present study, we have extended these observations to the determination of the kinetics of prothrombin, FV, and FXIII activation as well as Fbg consumption and inactivation of FVa using quantitative immunochemical techniques.…”

“…Previous studies on blood coagulation at sites of hemostatic plug formation, however, have been limited to measurements of FPA, TAT, or F1.2 by commercially available ELISAs. [18][19][20] In the present study, we have extended these observations to the determination of the kinetics of prothrombin, FV, and FXIII activation as well as Fbg consumption and inactivation of FVa using quantitative immunochemical techniques.The principal conclusions from our analyses, performed in bleeding-time blood, are the following: (1) Prothrombin is rapidly and almost completely removed at 3 to 4 minutes of bleeding.(2) Thrombin B chain and prethrombin 2 appear at 60 to 120 seconds of bleeding and are produced in similar amounts. Their maximum concentrations reach approximately 35 to 40 nM at the end of bleeding.…”

“…Previous studies undertaken to quantitate thrombin generation in bleeding-time blood focused on the measurement of FPA, thrombin-antithrombin III complexes (TAT), and prothrombin fragment 1.2 (F1.2) concentrations. [17][18][19][20] We wondered whether the model of microvascular injury could also be used to monitor other coagulant reactions that regulate thrombin formation, or are catalyzed by this enzyme (ie, activation of FV and FXIII or inactivation of FVa).…”

“…12,23,24 Using the model of microvascular injury, it has been demonstrated that aspirin at a dose from 30 to 500 mg down-regulates thrombin formation in healthy subjects 15,25 and patients with CAD. 19,26 The purpose of the present study is to describe major coagulant events during blood clotting at the site of microvascular injury and to evaluate the effect of low-dose aspirin on the activation of prothrombin, FV, FXIII, and Fbg, and inactivation of FVa by APC. …”

Pl A2 Polymorphism of β 3 Integrins Is Associated With Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury

“…2 Evaluation of blood clotting in blood emerging from skin bleeding-time wounds seems to be a useful approach when alterations in ␤ 3 integrin function or thrombin generation are suspected. 3,4 A common polymorphism of GP IIIa, HPA-1, is characterized by a thymidine to cytosine transition at nucleotide 1565, which results in Leu33 to Pro substitution, which defines the Pl A1 (HPA-1a) and Pl A2 (HPA-1b) alleles, respectively. 5 The Pl A2 allele is present in 20% to 30% of the European population.…”