Atorvastatin reduces thrombin generation and expression of tissue factor, P-selectin and GPIIIa on platelet-derived microparticles in patients with peripheral arterial occlusive disease

Abstract

We investigated the effects of statin treatment on platelet-derived microparticles (PMPs) and thrombin generation in atherothrombotic disease. Nineteen patients with peripheral arterial occlusive disease were randomised to eight weeks of treatment with atorvastatin or placebo in a cross-over fashion. Expression of GPIIIa (CD61), P-selectin (CD62P), tissue factor (TF, CD142) and phosphatidylserine (PS; annexin-V or lactadherin binding) was assessed on PMPs. Thrombin generation in vivo was assessed by measurement of prothrombin fragment 1+2 in plasma (F1+2) and ex vivo by using the calibrated automated thrombogram (CAT). During atorvastatin treatment, expression of TF, P-selectin and GPIIIa was significantly reduced vs. placebo (p<0.001 for all). No effect on annexin-V or lactadherin binding was seen. Thrombin generation was significantly reduced during atorvastatin as assessed by both the CAT assay (p<0.001) and by measurements of F1+2 (p<0.01). Subsequent in vitro experiments showed that when TF on microparticles (MPs) was blocked by antibodies, the initiation of thrombin generation was slightly but significantly delayed. Blocking PS on MPs using annexin-V or lactadherin resulted in almost complete inhibition of thrombin generation. In conclusion, atorvastatin reduces thrombin generation and expression of TF, GPIIIa and P-selectin on PMPs in patients with peripheral vascular disease. Microparticle-bound TF slightly enhances initiation of thrombin generation whereas negatively charged surfaces provided by MPs or lipoproteins could reinforce thrombin generation. Statins may inhibit initiation of thrombin generation partly through a microparticle dependent mechanism but the main effect is probably through reduction of lipoprotein levels.

Platelet microparticles inhibit IL-17 production by regulatory T cells through P-selectin

“…Like their parental cells, PMPs are involved in hemostasis, maintenance of vascular health, and immunity. 3,6,21,23,29,30,42 Here, we report that PMPs have the capacity to prevent the differentiation of Tregs into IL-17-and IFN-g-producing cells, even in the presence of proinflammatory cytokines. The mechanism of action consists of rapid and selective P-selectin-dependent binding of PMPs to a specialized CCR6…”

“…52,53 These megakaryocyte-derived microparticles are abundant in healthy individuals, 3 whereas PMPs, identified by the expression of platelet activation markers P-selectin and/or CD63, are only observed during disease. 29,42 This implies that although megakaryocyte-derived microparticles have a more systemic function, PMPs may act locally at sites of platelet activation and that each has its own distinct role in homeostasis.…”

Microparticles as Biomarkers of Vascular Dysfunction in Metabolic Syndrome and its Individual Components

“…Furthermore, in patients with peripheral arterial occlusive disease, atorvastatin treatment reduced the expression of tissue factor, GPIIIa and P-selectin in platelet-derived microparticles thus inhibiting initiation of thrombin generation [79].…”

Randomized Study of the Effects of Statin on Inflammatory and Prothrombotic States in Obese Adolescents

“…ETP is increased in obese children as young as six years of age [40] and hemostatic alterations can normalize after weight loss due to successful lifestyle intervention [41]. Patients with peripheral arterial occlusive disease treated for 8 weeks with atorvastatin showed a significant reduction of thrombin generation [42]. The mechanisms by which statins reduce thrombosis risk are unclear, but a recent review by researchers at the National Institutes of Health (NIH) confirmed that the anti-thrombotic effects of statins are likely related to their anti-inflammatory properties [43].…”