doi: 10.1161/01.ATV.0000190697.74465.ab
© 2005 American Heart Association, Inc.
Letters to the Editor |
Early Anticoagulant Effect of Atorvastatin
Divisione IV Clinica Medica (P.P., F.V.), Dipartimento di Medicina Sperimentale e Patologia (B.B., L.L.), Università di Roma "La Sapienza", Departimento di Medicina Interna (V.S.), Univerisità di Roma "Tor Vegata"
To the Editor,
Undas et al1 reported the effect of short term treatment of 14 hypercholesterolemic patients with 40 mg/d simvastatin, showing that this statin can reduce thrombin generation independently of its lipid lowering effect; they also claim that "the anticoagulant effect of any statin within first days of its administration have not been reported." However, the findings by Undas and colleagues confirm what we have already demonstrated in 30 hypercholesterolemic patients randomly allocated to 3 days treatment with diet or 10 mg/d atorvastatin.2 Thus, although patients allocated to only diet did not show any change of the prothrombin fragment F1+2, a marker of thrombin generation, patients treated with statin had significant decrease of thrombin generation suggesting that statins may have an early anticoagulant effect. At least 2 mechanisms may account for this finding. One mechanism could be dependent on statin-induced downregulation of CD40L, a protein of the tumor-necrosis factor family that enhances the expression of tissue factor (TF) and the rate of thrombin generation.3 Another mechanism might involve a direct interference of the drug with other intracellular signaling responsible for TF expression. This suggestion is supported by a previous study demonstrating that statin inhibits in vitro the expression of TF and the generation of thrombin4 with a mechanism likely involving the activation of the nuclear factor NF-
B, which has a key role in cellular expression of TF.5 As reactive oxidant species (ROS) are implicated in the activation of NF-B, it is possible that the down regulation of TF could be dependent on an antioxidant effect of statin. To explore whether statin has an inhibitory effect on the cellular formation of ROS we performed in vitro experiments in monocytes taken from 3 patients (2 male, 1 female, age 45±3 years) with hypercholesterolemia; monocytes were incubated with scalar concentrations of atorvastatin and stimulated as described in the Figure; ROS formation was measured by flow cytometry as previously described.6 The study showed that statin has an antioxidant effect as the monocyte formation of ROS was dose-dependently inhibited by atorvastatin (see Figure), suggesting that atorvastatin could interfere with cellular pathway implicated in the ROS formation. Accordingly with this hypothesis, statins have been shown to inhibit the activation of NADPH oxidase enzyme, which has a key role in the cellular formation of superoxide anion,7 but the mechanism has not been fully clarified and deserves further investigation. Therefore the findings by Undas et al reinforce our data showing that statins have an early anticoagulant effect likely in virtue of a direct interference with mechanisms involved in the expression of TF; these findings may help to explain recent data indicating that statins are of clinical usefulness in patients with acute coronary syndrome.
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References
1. Undas A, Celinska-Lowenhoff M, Brummel-Ziedins KE, Brozek J, Szczeklik A, Mann KG. Simvastatin given for 3 days can inhibit thrombin generation and activation of factor V and enhance factor Va inactivation in hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2005; 25: 1524–1525.
2. Sanguigni V, Pignatelli P, Lenti L, Ferro D, Bellia A, Carnevale R, Tesauro M, Sorge R, Lauro R, Violi F. Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients. Circulation. 2005; 111: 412–419.
3. Cipollone F, Mezzetti A, Porreca E, Di Febbo C, Nutini M, Fazia M, Falco A, Cuccurullo F, Davi G. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation. 2002; 106: 399–402.
4. Ferro D, Basili S, Alessandri C, Cara D, Violi F. Inhibition of tissue-factor-mediated thrombin generation by simvastatin. Atherosclerosis. 2000; 146: 111–116.
5. Hilgendorff A, Muth H, Parviz B, Staubitz A, Haberbosch W, Tillmanns H, Holschermann H. Statins differ in their ability to block NF-kappaB activation in human blood monocytes. Int J Clin Pharmacol Ther. 2003; 41: 397–401.[Medline] [Order article via Infotrieve]
6. Robinson JP, Bruner LH, Bassoe CF, Hudson JL, Ward PA, Phan SH. Measurement of intracellular fluorescence of human monocytes relative to oxidative metabolism. J Leukoc Biol. 1988; 43: 304–310.[Abstract]
7. Pignatelli P, Sanguigni V, Lenti L, Ferro D, Finocchi A, Rossi P, Violi F. gp91phox-dependent expression of platelet CD40 ligand. Circulation. 2004; 110 (10): 1326–9.
8. Boyum A. Isolation of mononuclear and granulocytes from human blood. Scand J Clin Lab Invest. 1968; (Suppl. 97): 77.
In Response:
Department of Medicine, Jagiellonian University School of Medicine, Krakow, Poland
Department of Biochemistry, University of Vermont, Burlington
We recently reviewed the growing body of evidence which indicates that statins produce anticoagulant effects in vivo through incompletely understood mechanisms.1 Suppression of thrombin formation after statin administration for a few days has been shown independently by Sanguigni et al2 and by us.3 Our report was submitted for publication before the publication of Sanguigni et al. A larger randomized double-blind study by Undas et al4 showing early anticoagulant and antiplatelet effects of simvastatin versus fenofibrate has also been published.
It should be stressed that our findings show a rapid decrease in thrombin generation by statins using an in vivo challenge to the physiological coagulation system. These studies show that thrombin-mediated reactions toward its physiological substrates such as fibrinogen and factor V are significantly depressed to an extent similar to that observed after 3 months of simvastatin therapy. Conversely, the protein C-thrombomodulin–thrombin dynamic anticoagulant pathway is enhanced leading to increased factor Va inactivation by activated protein C (APC). Thus simvastatin has a dual role of depression of the procoagulant processes and enhancement of an anticoagulant reaction.3,5 In addition, our novel intriguing observation, not reported by Sanguigni et al, has been the association between a reduction in C-reactive protein levels in response to simvastatin and decrease in thrombin generation.
We agree with the prevailing view that the most likely mechanism of the thrombin-lowering action of statins represents suppressed TF expression but potentially also enhanced thrombomodulin expression/function. We cannot exclude indirect mechanisms, including involvement of the CD40 ligand pathway. Nevertheless, in 14 subjects analyzed in our report, soluble CD40 ligand levels were also determined and their values were significantly reduced by 
20%. However, there was no association with the magnitude of a decrease in soluble CD40 ligand levels and that of changes in thrombin formation or other coagulant reactions studied. Undoubtedly, a role of sCD40 ligand in statin-induced reduction in thrombin generation deserves further elucidation. Likewise, a relative contribution of the antioxidant properties of statins to the overall antithrombotic potential of this class of drugs, determined not only in vitro, but also in vivo, remains to be established.
Acknowledgments
This work was supported by Program Project Grant #P01 HL46703 from the National Institutes of Health.
References
1. Undas A, Brummel-Ziedkins KE, Mann KE. Statins and blood coagulation. Arterioscler Thromb Vasc Biol. 2005; 25: 287–294.
2. Sanguigni V, Pignatelli P, Lenti L, Ferro D, Bellia A, Carnevale R, Tesauro M, Sorge R, Lauro R, Violi F. Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients. Circulation. 2005; 111: 412–419.
3. Undas A, Celinska-Lowenhoff M, Brummel-Ziedkins KE, Brozek J, Szczeklik A, Mann KG. Simvastatin given for 3 days can inhibit thrombin generation and activation of factor V and enhance factor Va inactivation in hypercholesterolemic subjects. Arterioscler Thromb Vasc Biol. 2005; 25: 1524–1525.
4. Undas A, Celinska-Lowenhoff M, Domagala TB, Iwaniec T, Dropinski J, Lowenhoff T, Szczeklik A. Early antithrombotic and anti-inflammatory effects of simvastatin versus fenofibrate in patients with hypercholesterolemia. Thromb Haemost. 2005; 94: 193–199.[Medline] [Order article via Infotrieve]
5. Undas A, Brummel KE, Musial J, Mann KG, Szczeklik A. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation. 2001; 103: 2248–2253.
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