Title: Antithrombotic properties of atorvastatin in healthy subjects and venous thromboembolism patients


Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, affects 1-3 per 1000 persons per year. The pathogenesis of VTE is multifactorial and not fully understood. Recently VTE patients have been shown to display unfavorably altered fibrin clots as compared to healthy individuals. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (statins) not only reduce cholesterol biosynthesis, but also attenuate blood coagulation including favorable alteration of fibrin clots properties, as seen in coronary artery disease patients and in low cardiovascular risk subjects. Rosuvastatin has been reported to reduce the risk of VTE within a 2-year period. It is unknown whether statin-related alteration of fibrin properties occurs in VTE patients. The aim of the study was to evaluate atorvastatin induced alterations of fibrin clots in VTE patients and in disease control group matched for cardiovascular risk factors. 25 volunteers without VTE (control group) and 28 VTE patients were enrolled to the open-label intervention study. Inclusion criteria for control group were low cardiovascular risk (SCORE <5%) and - for VTE patients - documented venous thrombosis within previous 30 months with over 1 month anticoagulation withdrawal prior to the enrollment. Exclusion criteria from control group was a history of any thrombosis, and for VTE patients a history of arterial thrombosis. Angina, acute thrombosis, diabetes, haemorrhagic diathesis, autoimmune diseases, hypo- or hyperthyroidism, acute inflammation, medication usage (beside antihypertensive drugs) and severe comorbidities were the exclusion criteria for both groups. Study participants received atorvastatin (Sortis, Pfizer) 40 mg/day for 3 days. Fasting blood was collected before intake of the first dose and after 3 days of atorvastatin administration. Lipid profiles, high-sensitivity C-reactive protein (CRP), other serum routine parameters, fibrinogen concentrations, D-dimers, prothrombin fragment 1.2 (F1.2), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), lipoprotein(a) [Lp(a)] and total homocysteine (tHcy) were determined. ; Plasma fibrin clot properties were expressed as permeation coefficient (Ks), turbidity measurements of fibrin polymerization [lag phase, maximum absorbance (Δ Abs)], plasma clot lysis assays in presence of recombinant tissue-type plasminogen activator (rtPA) with (t50%) or without (CLT) exogenous thrombin and D-dimer levels [maximum concentration (D-D max) and rate of increase (D-D rate)] in a fibrin clot perfusion model. The location of venous thrombosis in VTE patients was analyzed. Screening for thrombophilia and residual venous thrombosis (RVT) detection were also performed. Two groups did not differ with respect to demographic data and arterial hypertension, however overweight was more common in VTE patients. There were no differences in laboratory data between the groups at the baseline, except for higher CRP (1.66 [interquartile range 0.74-2.22] mg/l vs 0.84 [0.54-1.12] mg/l, p= 0.03), glucose (5.66 ±0.36 mM vs. 5.44 ±0.36 mM, p= 0.03) and t-PA levels (14.05 [11.05-17.35] ng/ml vs 10.80 [10.10-13.70] ng/ml, p= 0.015) in VTE patients. Plasma fibrin clot variables prior to atorvastatin administration significantly differed between two groups. VTE patients displayed 9% faster protofibril formation and 14.2% thicker fibrin fiber formation, together with 27.4% lower clot permeability and 25% lysability compared to control group (p for all <0.0001). The presence of RVT in the lower extremity deep veins (n=9) led to faster protofibril (lag phase 41.2 ±2.5 s vs 44.5 ±2.8 s, p= 0.005) and thicker fibrin fiber (Δ Abs 0.9 ±0.04 vs 0.8 ±0.06, p= 0.005) formation together with lower clot permeability (Ks 6.0 ±0.9 *10-9 cm2 vs 7.2 ±1.4 *10-9 cm2, p= 0.03) and lysability (t50% 10.6 [9.5 – 11.3] min vs 9.9 [7.5 – 10.3] min, p= 0.03). In control group atorvastatin decreased total (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels (p for all <0.05), while CRP level remained unchanged. A reduction in CLT (by 11%, p= 0.003) was noted; other fibrin parameters were unaltered. Atorvastatin in VTE patients resulted in TC, LDL-C reduction (p for all < 0.0001), no change in CRP concentration and a decrease in tHcy (by 31.6%, p= 0.006), PAI-1 (by 19.4%, p= 0.009), Lp(a) (by 7.2%, p= 0.0006) levels. VTE patients following atorvastatin administration had an increase in Ks (by 23.2%, p< 0.0001), lag phase (by 4.5%, p= 0.04), D-D rate (by 10.3%, p< 0.0001) and decrease in Δ Abs (by 4.5%, p= 0.002), t50% (by 19.9%, p< 0.0001) and CLT (by 13.7%, p= 0.0004). Atorvastatin-induced reduction of Δ Abs was more pronounced in patients with RVT as compared to patients without RVT (0.10 ±0.07 vs 0.01 ±0.07, p= 0.005), while CLT reduction was seen only in patients without RVT. D-D rate increase following atorvastatin was higher in unprovoked (n=10) than provoked VTE (0.012 mg/l/min ±0.01 vs 0.005 mg/l/min ±0.006, p= 0.044, respectively). Patients with proximal venous thrombosis (n=17), contrary to distal thrombosis patients, displayed Δ Abs reduction following atorvastatin administration (p= 0,01). Thrombophilia (n=14) did not alter fibrin clot properties either before or after statin administration. The improvement of fibrin clot structure/function in VTE patients after atorvastatin was unrelated to TC or tHcy, t-PA, PAI-1, F1.2, Lp(a) changes. ; In conclusion, the present study confirms that fibrin clots in VTE patients are less permeable, more compact and resistant to lysis compared with controls without VTE. A 3-day administration of atorvastatin (40 mg/d) alters favorably fibrin clot properties, however more explicitly in VTE patients than in controls, in whom only lysis is accelerated. Atorvastatin-induced improvement in fibrin clot permeability and susceptibility to lysis is independent to any changes in lipid profile. The presence of RVT modulates fibrin clot properties and its alteration following statin use. The current study demonstrates that even a 3-day course of atorvastatin alters favorably fibrin clot structure/function, which might reflect additional antithrombotic properties of statins in VTE patients.

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2 - studia doktoranckie

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choroby układu krążenia ; farmakologia

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Uniwersytet Jagielloński. Collegium Medicum. Wydział Lekarski.


Anetta Undas

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Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

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Oct 22, 2019

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ZB-117071 Oct 22, 2019


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