Effect of high-dose statin therapy on coagulation factors: Lowering of factor XI as a modifier of fibrin clot properties in coronary artery disease.

BACKGROUND: Multiple pleiotropic effects of statins include antithrombotic properties with formation of looser fibrin networks more susceptible to lysis. Recently, rosuvastatin 20 mg/d has been reported to decrease coagulation factors (F) VII, FVIII and FXI in venous thrombosis patients. OBJECTIVES: We investigated how high-dose statin therapy recommended in coronary artery disease (CAD) alters plasma levels of coagulation factors and if such changes might affect fibrin clot properties. METHODS: We studied 130 advanced CAD patients, who initially did not achieve the target low-density lipoprotein cholesterol (LDL-C). Before high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) and 6-12 months after its initiation, FII, FV, FVII, FVIII, FIX, FX, FXI and fibrinogen were assessed. We evaluated the impact of statin-induced alterations to the factors on plasma fibrin clot permeability (Ks) reflecting a fibrin pore size, and clot lysis time (CLT) reflecting fibrinolytic potential. RESULTS: At baseline LDL-C (median 3.2, interquartile range 2.7-3.7 mmol/L) was independently associated solely with FXI (ß = 0.58, P < 0.001). Median LDL-C reduction by 25% (P < 0.001) on high-dose statin treatment was accompanied by lowering of FVII, FVIII, and FXI (for all P < 0.001). On high-dose statin treatment, Ks (R = 0.65, P < 0.001) inversely associated with CRP (ß = -0.41, P < 0.001), LDL-C (ß = -0.26, P = 0.001), and FXI (ß = -0.18, P = 0.016). In turn, CLT (R = 0.45, P < 0.001) was positively associated with LDL-C (ß = 0.19, P = 0.043) and FXI (ß = 0.17, P = 0.049). CONCLUSIONS: High-dose statin therapy in CAD patients decreases FVII, FVIII, and FXI. The statin-induced reduction in FXI may contribute to less prothrombotic fibrin clot phenotype, indicating additional antithrombotic effect of high-dose statins.

Extended treatment with non-vitamin K antagonist oral anticoagulants versus low-molecular-weight heparins in cancer patients following venous thromboembolism. A pilot study.

BACKGROUND: Low-molecular-weight heparins (LMWH) are the drug of choice for treatment of cancer-associated thrombosis (CAT), however non-vitamin K antagonist oral anticoagulants (NOAC) seem to be a reasonable alternative. We investigated the safety and efficacy of NOAC versus LMWH in patients with a history of CAT. METHODS: In a prospective cohort study 128 consecutive patients with active cancer who experienced CAT were enrolled following LMWH treatment for ≥3 months. Symptomatic recurrent venous thromboembolism (VTE), bleeding and death were recorded during follow-up. RESULTS: 65 (50.8%) patients were switched to NOAC and 63 (49.2%) continued with LMWH. During a median follow-up of 17 (interquartile range, 15-21) months, recurrent VTE was observed in 6 (9.2%) patients on NOAC and in 12 (19.0%) on LMWH (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.16-1.16). The rate of major bleeding was 9.2% and 4.8%, respectively (HR 2.00, 95% CI 0.50-8.00). The median time to bleeding was shorter in patients on NOAC (3 [2.25-5.5] months) versus on LMWH (9 [6.5-13.0] months). The mortality rates were similar in both groups (15.4% versus 15.9%, respectively, HR 0.76, 95% CI 0.32-1.84). CONCLUSIONS: In patients following CAT, extended treatment with NOAC, compared with LMWH, appears to be associated with similar effectiveness and safety.

Polyunsaturated omega-3 fatty acids reduce lipoprotein-associated phospholipase A(2) in patients with stable angina.

BACKGROUND AND AIMS: Increased consumption of omega-3 polyunsaturated fatty acids (PUFA) together with lifestyle measures and medications is recommended for the prevention of cardiovascular diseases. However, the exact mechanisms underlying observed benefits are not well defined. To this aim, we evaluated the effects of omega-3 PUFA in stable coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI) on lipoprotein associated phospholipase A2 (Lp-PLA2) mass and activity and their relation to oxidized low-density lipoproteins (oxy-LDL). METHODS AND RESULTS: In a prospective, double-blind, placebo-controlled, randomized study Lp-PLA2, oxy-LDL, myeloperoxidase and interleukin-6 were determined at baseline, 3-5 days and 30 days during administration of omega-3 PUFA 1 g/day (n = 30) or placebo (n = 24). Treatment with omega-3 PUFA resulted in reduction of Lp-PLA2 mass by 10.7%, activity by 9.3 (p = 0.026 for both) and oxy-LDL by 10.9% (p = 0.014) at 30 days, with no change in myeloperoxidase and interleukin-6. Compared with placebo, patients receiving omega-3 PUFA had lower Lp-PLA2 mass by 9.42%, activity by 9.2 (p = 0.041 for both) and oxy-LDL by 12.3% (p = 0.10) after one month, but not at 3-5 days. There were no correlations between Lp-PLA2 and both myeloperoxidase and oxy-LDL throughout the study. The multivariate model showed that only treatment with omega-3 PUFA and baseline myeloperoxidase levels were independent predictors of Lp-PLA2 mass changes at one month (R(2) = 0.37, P = 0.005). CONCLUSIONS: Administration of omega-3 PUFA can decrease Lp-PLA2 in patients with stable angina undergoing PCI. This novel effect may contribute to the benefits derived from omega-3 PUF.

Omega-3 polyunsaturated fatty acids increase plasma adiponectin to leptin ratio in stable coronary artery disease.

BACKGROUND: Growing evidence suggests a cardioprotective role of omega-3 polyunsaturated fatty acids (PUFA). However, the exact mechanisms underlying the effects of omega-3 PUFA in humans have not yet been fully clarified. PURPOSE: We sought to evaluate omega-3 PUFA-mediated effects on adipokines in patients with stable coronary artery disease (CAD) undergoing elective percutaneous coronary intervention (PCI). METHODS: We conducted a prospective, double-blind, placebo-controlled, randomized study, in which adiponectin, leptin and resistin were determined at baseline, 3-5 days and 30 days during administration of omega-3 PUFA 1 g/day (n=20) or placebo (n=28). RESULTS: As compared to controls administration of omega-3 PUFA resulted in increase of adiponectin by 13.4% (P<0.0001), reduction of leptin by 22% (P<0.0001) and increase of adiponectin to leptin (A/L) ratio by 45.5% (P<0.0001) at 30 days, but not at 3-5 days. Compared with placebo adiponectin was 12.7% higher (P=0.0042), leptin was 16.7% lower (P<0.0001) and A/L ratio was 33.3% higher (P<0.0001) in the omega-3 PUFA group at 30 days. Resistin decreased similarly in both groups after 1 month, without intergroup differences (P=0.32). The multivariate model showed that the independent predictors of changes in adiponectin at 1 month (P<0.001) were: omega-3 PUFA treatment, baseline platelet count, total cholesterol and those in leptin (P<0.0001) were: omega-3 PUFA treatment and waist circumference. Independent predictors of A/L ratio changes (P<0.0001) were: assigned treatment, current smoking and hyperlipidemia. CONCLUSIONS: In high risk stable coronary patients after PCI omega-3 PUFA supplementation improves adipokine profile in circulating blood. This might be a novel, favourable mechanism of omega-3 PUFA action.

Platelet activation and microvascular injury in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Dual antiplatelet therapy reduces the risk of thrombotic complications after primary percutaneous coronary intervention (PCI). AIM: To assess whether inhibition of platelet function attenuates microvascular damage in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We studied 83 STEMI patients treated with primary PCI. Platelet aggregation was measured on admission (ADM) and 4 days later (D4) by light transmission aggregometry after stimulation with 0.5 mM of arachidonic acid and after stimulation with 5 and 20 µM of adenosine diphosphate (ADP) on treatment with dual antiplatelet therapy with aspirin and clopidogrel. Platelet-neutrophil aggregate (PNA) and platelet-monocyte aggregate (PMA) were analysed by flow cytometry. Contrast-enhanced magnetic resonance imaging was performed 2-4 days after STEMI to detect the area of perfusion defect at rest and to determine the size of microvascular obstruction. Microvascular obstruction was expressed as a percentage of infarct area. RESULTS: Perfusion defect at rest was found in 56 (67.5%) patients whereas microvascular obstruction in 63 (75.9%) patients. Patients with perfusion defect at rest had on admission a significantly higher level of both PMA (7.0 vs. 4.5%, p = 0.004) and PNA (4.1 vs. 2.2%, p = 0.016), however there were no significant differences at D4. Platelet aggregation after stimulation with 5 µM of ADP on ADM was correlated (r = 0.37, p = 0.004) with microvascular obstruction area. Moreover, the higher the concentration of PMA(ADM) (r = 0.31, p = 0.016), PNA(ADM) (r = 0.34, p = 0.006) and PM(AD4) (r = 0.35, p = 0.005) the larger the size of microvascular obstruction. Infarct size (ß = 0.43, 95% CI 0.19 to 0.67, p 〈 0.0001), TIMI < 3 after PCI (ß = -0.27, 95% CI -1.90 to -0.11, p = 0.015) and PMA(D4) (ß = 0.21, 95% CI 0.13 to 1.86, p = 0.032) independently influenced the size of microvascular obstruction (R2 = 0.60, p 〈 0.0001). CONCLUSIONS: Excessive platelet activation during reperfusion in STEMI patients despite dual antiplatelet therapy is associated with greater microvascular impairment.

Polyunsaturated omega-3 fatty acids improve responsiveness to clopidogrel after percutaneous coronary intervention in patients with cytochrome P450 2C19 loss-of-function polymorphism.

BACKGROUND: Antiplatelet properties of omega-3 polyunsaturated fatty acids (PUFA) have been demonstrated in patients with coronary artery disease (CAD). It is unknown whether omega-3 PUFA can enhance platelet inhibition on standard aspirin and clopidogrel treatment in the setting of CYP2C19 loss-of-function polymorphism. AIM: To investigate whether omega-3 PUFA are able to modify platelet responsiveness to clopidogrel therapy in patients with CYP2C19 loss-of-function polymorphism undergoing percutaneous coronary intervention (PCI). METHODS: 63 patients with stable CAD undergoing PCI (48 males, mean age 63.2 ± 9.6 years) were enrolled into an investigator- initiated, prospective, single-centre, double-blind, placebo-controlled, randomised study. Patients on standard dual antiplatelet therapy (aspirin 75 mg daily and clopidogrel 600 mg loading dose followed by 75 mg daily) were assigned to receive the addition of 1 g of omega-3 ethyl esters (n = 33) or placebo (n = 30) for 1 month. Platelet function was measured serially by light transmittance aggregometry in response to 5 and 20 µmol/L ADP at baseline, 12 h, 3-5 days and 30 days after randomisation. CYP2C19*2 was genotyped at baseline. RESULTS: No significant differences were found in baseline variables, including the frequency of CYP2C19 genetic variants. At least one loss-of-function variant of CYP2C19*2 was found in 19 (30.2%) patients. In patients with CYP2C19*1/*2 and *2/*2 variants, maximal platelet aggregation induced by 5 and 20 µmol/L ADP was reduced by 21.4% (p = 0.006) and 14.3% (p = 0.041), respectively, after 1 month of treatment with omega-3 PUFA as compared to placebo. The beneficial effect of omega-3 PUFA was demonstrated in carriers of CYP2C19 loss-of-function polymorphism, whereas no differences in platelet aggregation between the omega-3 PUFA and placebo groups were found in patients with the 1*/1* variant. CONCLUSIONS: The addition of omega-3 ethyl esters significantly potentiates platelet response to clopidogrel after PCI mostly in patients with CYP2C19 loss-of-function polymorphism.

Reduced thrombin formation and altered fibrin clot properties induced by polyunsaturated omega-3 fatty acids on top of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (OMEGA-PCI clot).

OBJECTIVE: The goal of this study was to investigate whether omega-3 polyunsaturated fatty acids (n-3 PUFA) are able to alter plasma fibrin clot properties and reduce thrombin formation in stable coronary artery disease patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: In an investigator-initiated, prospective, double-blind, placebo-controlled, randomized study, patients undergoing PCI who received standard pharmacotherapy were assigned to the treatment with 1 g/day n-3 PUFA (n = 30) or placebo (n = 24) for 1 month. Plasma fibrin clot permeability (K(s)); lysis time (t(50%)); prothrombin fragment 1.2; and peak thrombin generation from automated thrombogram, 8-isoprostaglandin F(2α) (8-iso-PGF(2α), an oxidative stress marker), and C-reactive protein were determined at baseline, 3 to 5 days after randomization, and 30 days after randomization. At baseline, both treatment groups did not differ significantly. A 1-month treatment with n-3 PUFA compared with placebo was associated with 15.3% higher K(s), indicating larger pores in the fibrin network (P = 0.0005); 14.3% shorter t(50%), indicating increased susceptibility to fibrinolysis (P<0.0001); 33.8% lower prothrombin fragment 1.2 (P = 0.0013); 13.4% lower peak thrombin generation (P = 0.04); and 13.1% lower 8-iso-PGF(2α) (P = 0.009). Treatment with n-3 PUFA had no effect on fibrinogen and C-reactive protein. After 1 month of treatment, fibrinogen (r = -0.53, P<0.0001), treatment assignment (r = 0.29, P = 0.006) and 8-iso-PGF(2α) (r = -0.27, P = 0.015) were independently associated with clot permeability (P<0.0001, R(2) = 0.66). CONCLUSIONS: Adding n-3 PUFA to standard therapy in stable patients undergoing PCI significantly decreases thrombin formation and oxidative stress and favorably alters fibrin clot properties. These findings indicate novel antithrombotic effects induced by n-3 PUFA in humans.