Blood Thrombogenicity Research Articles

Inter-relation between Altered Nutritional Status and Clinical Outcomes in Patients with Acute Myocardial Infarction Admitted in a Tertiary Intensive Cardiac Care Unit

Abstract Background: The impact of nutritional status on the early outcome of subjects with acute myocardial infarction (AMI) is still not completely elucidated. This study aimed to assess the correlation between nutritional status, as expressed by the CONUT and PIN scores, and (1) clinical and laboratory characteristics, (2) complication rates, and (3) length of hospitalization, in patients with AMI. Materials and methods: We included 56 consecutive patients with AMI who underwent primary percutaneous intervention and stenting. Evaluation of the nutritional status was comprised in the calculation of the CONUT and PNI scores. The study population was divided into 2 groups according to the calculated CONUT score, as follows: group 1 – CONUT score <3 points (normal to mildly impaired nutritional status) and group 2 – CONUT score ≥3 points (moderate to severe malnutrition). The primary end-point of the study was the rate of in-hospital complications (left ventricular free wall rupture, hemodynamic instability requiring inotropic medication, high-degree atrioventricular block, the need for temporary cardiostimulation, supraventricular and ventricular arrhythmias and in-hospital cardiac arrest). The secondary end-points included the duration of hospitalization and the length of stay in the intensive cardiac care unit. Results: In total, 56 patients (44.64% with STEMI, 55.35% with NSTEMI) with a mean age of 61.96 ± 13.42 years, 58.92% males were included in the study. Group distribution was: group 1 – 76.78% (n = 43), group 2 – 23.21% (n = 23). There were no differences between the two groups regarding age, gender, cardiovascular risk factors, or comorbidities. PNI index in group 1 was 54.4 ± 10.4 and in group 2 41.1 ± 2.8, p <0.0001. Serum albumin was significantly lower in group 1 – 4.1 ± 0.3 vs. group 2 – 3.6 ± 0.3 (p <0.0001), similarly to total cholesterol levels (group 1 – 194.9 ± 41.5 vs. group 2 – 161.2 ± 58.2, p = 0.02). The complete blood cell count showed that group 2 presented lower levels of hematocrit (p = 0.003), hemoglobin (p = 0.002), and lymphocytes (p <0.0001) compared to group 1, but a significantly higher platelet count (p = 0.001), mean platelet volume (p = 0.03), neutrophil/lymphocyte (p <0.0001) and platelet/lymphocyte (p <0.0001) ratios, indicating enhanced blood thrombogenicity and inflammation. Regarding in-hospital complications, group 2 presented a higher rate of hemodynamic instability (group 1 – 11.6% vs. group 2 – 38.4%, p = 0.02). The overall hospitalization period was 7.7 ± 1.4 days in group 1 vs. 10.2 ± 4.8 days in group 2, p = 0.06; while the duration of stay in the intensive cardiac care unit was 2.6 ± 0.5 days in group 1 vs. 4.0 ± 2.5 days in group 2, p = 0.02. Conclusions: This study proved that nutritional deficit in acute myocardial patients who undergo revascularization is associated with an increased rate of in-hospital complications and with a longer observation time in a tertiary intensive cardiac care unit.

Dronedarone exerts anticoagulant and antiplatelet effects independently of its antiarrhythmic actions

Background and aimsDronedarone reduced the rate of stroke and transient ischemic attack in patients with paroxysmal atrial fibrillation (AF) in the ATHENA trial. This cannot be explained by its antiarrhythmic effect alone and may involve alternative mechanisms. This study aimed to investigate any direct effect of dronedarone on blood thrombogenicity, independent of its antiarrhythmic effects. MethodsBlood samples from patients with cardiovascular disease (n = 30) taking no anticoagulant or antiplatelet medication except aspirin were incubated with dronedarone's active metabolite (SR35021A) at 66 ng/ml (am-L) and 119 ng/ml (am-H), i.e., minimum and maximum mean Cmax reported after repeated 400 mg BID dosing. A third aliquot of blood was incubated with vehicle (Control). Antithrombotic effects of dronedarone were assessed using Coagulation Time (CT), Clot Formation Rate (CFR) and Maximum Clot Firmness (MCF) in ThromboElastoMetry and whole blood platelet aggregation in response to ADP, collagen and TRAP. ResultsCompared to Control, mean CT was prolonged by am-L and am-H (164 ± 25 s vs. 180 ± 22 and 182 ± 32 s, respectively, p<0.01 for both). Small but statistically significant reductions were observed in CFR (am-L and am-H) and MCF (am-H). Platelet aggregation induced by ADP and TRAP was also reduced (p<0.05 for both) by am-H. ConclusionsDronedarone exerts direct anticoagulant and antiplatelet effects on human blood in vitro that are independent of its antiarrhythmic actions. This suggests the reductions in ischemic events reported with dronedarone may not be due to amelioration of AF itself. Additional clinical studies are required to further improve understanding of the mechanisms involved.

Oval housing for the St. Jude Medical bileaflet mechanical heart valve.

The St. Jude Medical bileaflet mechanical heart valve was approved by the Food and Drug Administration in late 1970s. The basic idea for the design of the valve is simply two semicircular flat plates pivoting on hinges. The overall performance of St. Jude Medical valves such as blood flow being central, the leaflets opening completely, and the pressure drop across the valve being trivial is satisfactory. St. Jude Medical valves provide an improved hemodynamics compared to the other mechanical heart valve models; however, their non-physiological hemodynamics which may lead to red blood cells lysis and thrombogenicity still remains a major issue. In this study, we hypothesize that applying ovality to the housing might improve their hemodynamics significantly which is based on the fact that the native annulus is oval by nature. A quick but precise numerical model based on the finite strip method was developed by which the regurgitation flow volume and velocity of the proposed design were assessed in the closing phase. The results are satisfactory and an improved hemodynamics is observed. The proposed design can be considered for further numerical and experimental studies and shows promise and merits further development.

Micro–RNA-126 Reduces the Blood Thrombogenicity in Diabetes Mellitus via Targeting of Tissue Factor

Diabetes mellitus involves vascular inflammatory processes and is a main contributor to cardiovascular mortality. Notably, heightened levels of circulating tissue factor (TF) account for the increased thrombogenicity and put those patients at risk for thromboembolic events. Here, we sought to investigate the role of micro-RNA (miR)-driven TF expression and thrombogenicity in diabetes mellitus. Plasma samples of patients with diabetes mellitus were analyzed for TF protein and activity as well as miR-126 expression before and after optimization of the antidiabetic treatment. We found low miR-126 levels to be associated with markedly increased TF protein and TF-mediated thrombogenicity. Reduced miR-126 expression was accompanied by increased vascular inflammation as evident from the levels of vascular adhesion molecule-1 and fibrinogen, as well as leukocyte counts. With optimization of the antidiabetic treatment miR-126 levels increased and thrombogenicity was reduced. Using a luciferase reporter system, we demonstrated miR-126 to directly bind to the F3-3'-untranslated region, thereby reducing TF expression both on mRNA and on protein levels in human microvascular endothelial cells as well as TF mRNA and activity in monocytes. Circulating miR-126 exhibits antithrombotic properties via regulating post-transcriptional TF expression, thereby impacting the hemostatic balance of the vasculature in diabetes mellitus.

Statin therapy and inflammation in patients with diabetes treated with high dose aspirin

BackgroundStatin and aspirin form the therapeutic cornerstone in patients with coronary artery disease (CAD) and diabetes. Little is known about relationship of statins with blood thrombogenicity and inflammation in these patients. MethodsTwo hundred nine consecutive patients with diabetes and suspected CAD undergoing elective cardiac catheterization were divided in groups based on statin treatment in the Multi-Analyte, Thrombogenic, and Genetic Markers Atherosclerosis study. Urinary 11-dehydrothromboxane B2 (11-dh-TxB2), lipid profile and oxLDL/β2GPI were measured by AspirinWorks™ ELISA assay, vertical density gradient ultracentrifugation and immunoassay respectively. Thrombelastography, and ADP- and collagen-induced light transmittance aggregometry assessed thrombogenicity. CAD was classified as none/minor [<20% diameter stenosis (DS)], moderate (20–75% DS), or severe (>75% DS). ResultsSevere, moderate, and no CAD was observed in 66, 19, and 15% of patients respectively. Patients on statins had significantly lower 11-dh-TxB2, collagen-induced aggregation, total cholesterol, total LDL, LDL3, oxidized-LDL, Apo B100, and ApoB100/A1 ratio (p<0.01 for all). Statin therapy demonstrated a lower proportion of patients with high urinary 11-dh-TxB2 (>1500pg 11-dh-TxB2/mg creatinine) (25 vs. 57%, p=0.01). ConclusionStatins along with aspirin, confers additional anti-inflammatory and antithrombotic effect in diabetics with CAD. Urinary 11-dh-TxB2 may be a useful biomarker for personalizing statin therapy.

Abstract 13988: Novel Quantitative Assessment of Whole Blood Thrombogenicity in Patients Treated With Anticoagulants Undergoing Radiofrequency Catheter Ablation for Atrial Fibrillation

Introduction: Non-vitamin K antagonist oral anticoagulants (NOACs) are equivalent to warfarin in preventing thromboembolism in patients with atrial fibrillation (AF). Recently, Total Thrombus-formation Analysis System (T-TAS) was developed as an easy-to-use system for quantitative analysis of thrombus formation using microchips with thrombogenic surfaces (collagen, PL chip; collagen plus tissue factor, AR chip). Hypothesis: We evaluated the efficacy and safety of NOACs using the T-TAS in AF patients undergoing radiofrequency catheter ablation (RFCA). Methods: After exclusion of 19 from 121 consecutive patients undergoing RFCA for AF, the remaining 102 patients were divided into two groups; AF patients treated with warfarin (n=28), and NOACs (n=74). Blood samples obtained on the day (anticoagulant-free point), 3 days and 1 month after RFCA were used in T-TAS to compute the thrombus formation area under the curve (AUC) (PL24-AUC10, AUC for PL chip; AR10-AUC30, for AR chip). Results and Conclusion: The AR10-AUC30 and PL24-AUC10 levels were identical between the warfarin and NOACs groups on the day of RFCA (1708.5±162.1 vs 1757.5±138.0 in AR10-AUC30, p=0.13 and 389.1±95.5 vs 391.7±76.0 in PL24-AUC10, p=0.94, respectively). AR10-AUC30, but not PL24-AUC10 levels, was significantly lower in warfarin and NOACs groups at 3 days and 1 month after RFCA. Multiple logistic regression analysis identified AR10-AUC30 levels on the day of RFCA as a significant predictor of bleeding events in the period of three months after RFCA [odds ratio (OR) 20.6; 95% confidence interval (95%CI): 2.46 to 172.6; p=0.005]. Receiver-operating characteristic analysis showed that AR10-AUC30 levels on the day of RFCA significantly predicted bleeding events [AUC 0.849 (95%CI: 0.719-0.979; p&lt;0.001)]. The cut-off levels of AR10-AUC30 were 1647.6 for identification of bleeding events within three months after RFCA. These results suggested that AR10-AUC30 level determined by T-TAS is a potentially useful marker for assessment of the efficacy and safety of anti-coagulant therapy including warfarin and NOACs, in AF patients undergoing RFCA.

A novel quantitative assessment of whole blood thrombogenicity in patients treated with a non-vitamin K oral anticoagulant

Non-vitamin K oral anticoagulants(NOAC) negate complex patient management issues, such as frequent blood sampling, diet restriction, and drug interactions, that had to be dealt with during the warfarinonly era. However, there is no definite tool tomonitor the anticoagulant effects of NOACs, although some patients suffer from bleeding complications related to exceedingly high blood concentrations of NOACs. [1, 2] Routine tests, such as prothrombin time-international normalized ratio (PT-INR) and activated partial thromboplastin time (APTT), can be problematic formonitoring the anticoagulant effects of all NOACs because each individual NOAC has a different characteristic chemical structure and different pharmacokinetic profile (e.g., plasma half-life and tissue penetration rate) [3]. Recently, the Total Thrombus-formation Analysis System (T-TASTM) [4,5], a microchip-based flow chamber system capable of evaluating whole blood thrombogenicity, was developed as an easy-to-use system for quantitative analysis of thrombus formation (Fig. 1A,B). In the present study, we sought to examine whether the T-TASTM was useful for the quantitative analysis of thrombogenicity in patients treated with the NOAC edoxaban (Fig. 1C, D). We recruited 20 consecutive patients (male: n = 8 [40%] and female: n=12 [60%], average age: 75.2±8.7 years)whowere scheduled

Targeting blood thrombogenicity precipitates atherothrombotic events in a mouse model of plaque destabilization.

Although some features of plaque instability can be observed in genetically modified mouse models, atherothrombosis induction in mice has been attested to be difficult. We sought to test the hypothesis that alterations in blood thrombogenicity might have an essential role in the development of atherothrombosis in ApoE−/− mice. In a mouse model of plaque destabilization established in our laboratory, we targeted blood thrombogenicity by systemically overexpressing murine prothrombin via adenovirus-mediated gene transfer. Systemic overexpression of prothrombin increased blood thrombogenicity, and remarkably, precipitated atherothrombotic events in 70% of the animals. The affected plaques displayed features of culprit lesions as seen in human coronary arteries, including fibrous cap disruption, luminal thrombosis, and plaque hemorrhage. Treatment with aspirin and clopidogrel substantially reduced the incidence of atherothrombosis in this model. Mechanistically, increased inflammation, apoptosis and upregulation of metalloproteinases contributed to the development of plaque destabilization and atherothrombosis. As conclusions, targeting blood thrombogenicity in mice can faithfully reproduce the process of atherothrombosis as occurring in human coronary vessels. Our results suggest that blood-plaque interactions are critical in the development of atherothrombosis in mice, substantiating the argument that changes in blood coagulation status may have a determinant role in the onset of acute coronary syndrome.

How do we prevent the vulnerable atherosclerotic plaque from rupturing? Insights from in vivo assessments of plaque, vascular remodeling, and local endothelial shear stress.

Coronary atherosclerosis progresses both as slow, gradual enlargement of focal plaque and also as a more dynamic process with periodic abrupt changes in plaque geometry, size, and morphology. Systemic vasculoprotective therapies such as statins, angiotensin-converting enzyme inhibitors, and antiplatelet agents are the cornerstone of prevention of plaque rupture and new adverse clinical outcomes, but such systemic therapies are insufficient to prevent the majority of new cardiac events. Invasive imaging methods have been able to identify both the anatomic features of high-risk plaque and the ongoing pathobiological stimuli responsible for progressive plaque inflammation and instability and may provide sufficient information to formulate preventive local mechanical strategies (eg, preemptive percutaneous coronary interventions) to avert cardiac events. Local endothelial shear stress (ESS) triggers vascular phenomena that synergistically exacerbate atherosclerosis toward an unstable phenotype. Specifically, low ESS augments lipid uptake and catabolism, induces plaque inflammation and oxidation, downregulates the production, upregulates the degradation of extracellular matrix, and increases cellular apoptosis ultimately leading to thin-cap fibroatheromas and/or endothelial erosions. Increases in blood thrombogenicity that result from either high or low ESS also contribute to plaque destabilization. An understanding of the actively evolving vascular phenomena, as well as the development of in vivo imaging methodologies to identify the presence and severity of the different processes, may enable early identification of a coronary plaque destined to acquire a high-risk state and allow for highly selective, focal preventive interventions to avert the adverse natural history of that particular plaque. In this review, we focus on the role of ESS in the pathobiologic processes responsible for plaque destabilization, leading either to accelerated plaque growth or to acute coronary events, and emphasize the potential to utilize in vivo risk stratification of individual coronary plaques to optimize prevention strategies to preclude new cardiac events.

Number of coronary risk factors is associated with blood thrombogenicity

Number of coronary risk factors is associated with blood thrombogenicity

Statin therapy and thromboxane generation in patients with coronary artery disease treated with high-dose aspirin

Aspirin and statin therapy are mainstay treatments in patients with coronary artery disease (CAD). The relation between statin therapy, <i>in vivo</i> thromboxane (Tx) generation; a marker of inflammation, and blood thrombogenicity has never been explored. Urinary 11-dehydro (dh) TxB₂ was determined in patients with suspected CAD on 325 mg daily aspirin therapy prior to undergoing cardiac catheterisation (n=281). Thrombogenicity was estimated by thrombelastographic measurement of thrombin-induced platelet-fibrin clot strength (TIP-FCS) and lipids/lipoproteins were determined by vertical density gradient ultracentrifugation/ELISA. The influence of statin therapy and dose was analysed by the atorvastatin equivalent dose (5–10 mg, 20–40 mg, or 80 mg daily). Statin therapy (n=186) was associated with a dose-dependent reduction in urinary 11-dh TxB₂ (p=0.046) that was independent of LDL and apo B100 levels but was strongly related to TIP-FCS (p=0.006). By multivariate analysis, no statin therapy (n=95) and female gender were independently associated with high urinary 11-dh TxB₂ [OR=2.95 (0.1.57–5.50, p=0.0007); OR=2.25 (1.24–4.05, p=0.007)], respectively. In aspirin-treated patients, statin therapy was independently and inversely associated with inflammation in a dose-dependent manner. Elevated 11-dh TxB₂ was associated with a prothrombotic state indicated by high TIP-FCS. Our data suggest that measurement of urinary 11-dTxB₂ may be a useful method to optimise statin dosing in order to reduce thrombotic risk.

Blood Thrombogenicity Is Independently Associated With Serum TSH Levels in Post–Non-ST Elevation Acute Coronary Syndrome

Higher serum TSH levels, both within the reference range and in those with subclinical hypothyroidism (SCH), have been associated with increased risk of atherosclerosis and cardiovascular (CV) events in a number of cross-sectional and longitudinal studies. Our objective was to evaluate blood thrombogenicity in patients post-non-ST elevation acute coronary syndrome (NSTE-ACS) in relation to their thyroid function. DESIGN, PATIENTS, AND OUTCOME MEASURE: At 1 week after troponin-positive NSTE-ACS, 70 patients who had been treated with optimal antiplatelet and secondary prevention therapy were studied. Patients with known thyroid disease or on medications affecting thyroid function were excluded. Blood thrombogenicity was assessed using the ex vivo Badimon perfusion chamber. Serum TSH was associated with higher thrombus burden (β = .30; P = .01) independent of other well-established CV risk factors. Patients with SCH (n = 12; 17%) had a higher thrombus burden than euthyroid individuals as evidenced by the area of the thrombus: mean (SD) 23 608 (10 498) vs 16 661 (10 902) μm(2)/mm (P = .02). However, this association was not evident when the analysis was limited to patients with serum TSH within the reference range. In addition, neither serum free T4 nor free T3 had any significant association with thrombus area. Serum TSH levels, particularly in the SCH range, are associated with higher thrombus burden despite optimal recommended secondary prevention therapy after NSTE-ACS. This may explain the higher CV risk seen in SCH patients. Future trials to assess the effect of individualized antithrombotic as well as thyroid hormone replacement therapy to reduce atherothrombotic risk in this population are needed.

Statin therapy and thromboxane generation in patients with coronary artery disease treated with high-dose aspirin.

Aspirin and statin therapy are mainstay treatments in patients with coronary artery disease (CAD). The relation between statin therapy, in vivo thromboxane (Tx) generation; a marker of inflammation, and blood thrombogenicity has never been explored. Urinary 11-dehydro (dh) TxB2 was determined in patients with suspected CAD on 325 mg daily aspirin therapy prior to undergoing cardiac catheterisation (n=281). Thrombogenicity was estimated by thrombelastographic measurement of thrombin-induced platelet-fibrin clot strength (TIP-FCS) and lipids/lipoproteins were determined by vertical density gradient ultracentrifugation/ELISA. The influence of statin therapy and dose was analysed by the atorvastatin equivalent dose (5-10 mg, 20-40 mg, or 80 mg daily). Statin therapy (n=186) was associated with a dose-dependent reduction in urinary 11-dh TxB2 (p=0.046) that was independent of LDL and apo B100 levels but was strongly related to TIP-FCS (p=0.006). By multivariate analysis, no statin therapy (n=95) and female gender were independently associated with high urinary 11-dh TxB2 [OR=2.95 (0.1.57-5.50, p=0.0007); OR=2.25 (1.24-4.05, p=0.007)], respectively. In aspirin-treated patients, statin therapy was independently and inversely associated with inflammation in a dose-dependent manner. Elevated 11-dh TxB2 was associated with a prothrombotic state indicated by high TIP-FCS. Our data suggest that measurement of urinary 11-dTxB2 may be a useful method to optimise statin dosing in order to reduce thrombotic risk.

Studies of a microchip flow-chamber system to characterize whole blood thrombogenicity in healthy individuals

A whole blood flow-chamber system, the Total Thrombus-formation Analysis System (T-TAS), was developed for quantitative analysis of platelet thrombus formation (PTF) using microchips with thrombogenic surfaces (collagen, PL chip; collagen plus tissue thromboplastin, AR chip) under shear stress conditions. We evaluated the usefulness of the T-TAS for assessing individual thrombogenicity compared with other platelet function tests. Blood samples from 31 healthy volunteers were applied to the T-TAS to measure PTF starting time (T10: time to reach 10 kPa), occlusion time (T60 for PL chip; T80 for AR chip), and area under the curve (AUC10, area under curve until 10 min for PL chip; AUC30, 30 min for AR chip) under various shear rates (1000, 1500, 2000s(-1) for PL chip; 300 s(-1) for AR chip). Platelet functions were also tested using platelet aggregometry, the PFA-100 (collagen and epinephrine [C/EPI], collagen and adenosine diphosphate [C/ADP]), and the VerifyNow P2Y12 assay. Individual pressure waveforms, including PTF starting and ending points, varied among healthy subjects. In the PL chip, T10 and AUC10 showed a shear-dependent correlation with C/EPI or C/ADP. VerifyNow P2Y12 values were not significantly associated with the parameters of the T-TAS. Platelet counts were correlated with all AR measurements, and mostly with PL measurements. The results of the T-TAS were associated with those of the PFA-100 in many respects, indicating that its characteristics are related to shear-induced PTF. The T-TAS showed few correlations with platelet aggregometry and the VerifyNow P2Y12 assay. The T-TAS may allow for the measurement of comprehensive parameters of individual thrombogenicity under whole blood flow conditions.

The level of blood thrombogenicity was not elevated in stable patients with disrupted coronary plaque

BackgroundAlthough extremely high blood thrombogenicity has been reported in patients with acute myocardial infarction, it has not been clarified if the increased blood thrombogenicity is a cause of acute myocardial infarction or a mere result induced by thrombus formation at the disrupted plaque. Therefore, we examined if blood thrombogenicity is extremely increased as in acute myocardial infarction patients when disrupted plaque is present in patients with stable coronary artery disease. Methods and resultsConsecutive patients (n=38) with stable coronary artery disease who received angioscopic examination were included. Patients were divided into two groups according to presence or absence of disrupted plaque that accompanied thrombus. Blood thrombogenicity was evaluated by blood vulnerability index and compared between the patients with and without disrupted plaque. Among 38 study patients, 16 had disrupted plaque and 22 did not. Blood vulnerability index was not different between the patients with and without disrupted plaque (2395±612 vs. 3013±1476, p=0.12). Multivariate analysis revealed no significant association between blood vulnerability index and the presence of disrupted plaque. ConclusionThe presence of disrupted plaque, in comparison with its absence, was not associated with higher blood thrombogenicity evaluated by blood vulnerability index.

Regulation of the Tissue Factor Isoform Expression and Thrombogenicity of HMEC-1 by miR-126 and miR-19a

Regulation of the Tissue Factor Isoform Expression and Thrombogenicity of HMEC-1 by miR-126 and miR-19a Endothelial cells modulate the vascular wall homeostasis and blood thrombogenicity. Inflammatory conditions induce the Tissue Factor (TF) isoform expression and cellular thrombogenicity in endothelial cells. MicroRNAs (miRNAs) posttranscriptionally regulate gene expression. MiRNA-19 (miR-19) was shown to downregulate the TF expression in breast cancer cells. The role of miRNAs, such as miR-19a or the endothelial cellspecific miR-126 in the modulation of the endothelial TF expression and activity is unknown.

Combined inhibition of complement (C5) and CD14 markedly attenuates blood thrombogenicity, inflammation and hemodynamic changes in porcine sepsis

Combined inhibition of complement (C5) and CD14 markedly attenuates blood thrombogenicity, inflammation and hemodynamic changes in porcine sepsis

Commentary on ‘Simvastatin Decreases Free Radicals Formation in the Human Abdominal Aortic Aneurysm Wall via NF-κB’

The complex biological processes associated with abdominal aortic aneurysm (AAA) include oxidative stress and proteolysis in relation toboth leukocyte recruitment andplatelet activation, leading to immuno-inflammatory response, cell death and extracellular matrix breakdown. A key player in regulating immune-inflammatory processes is nuclear factor-kB (NF-kB), a redox-sensitive transcription factor involved in the transmission of various signals from the cytoplasm to the nucleus of numerous cell types, activating genes which codify products such as adhesion molecules, chemoattractants, proinflammatory enzymes and procoagulant proteins. Piechota’s paper confirms that NF-kB could be involved in the pathogenesis of AAA, as suggested by previous data.1 Statins have proved the greatest impact on cardiovascular disease since aspirin. Their pleiotropic effects beyond lipid lowering are still being researched. Recent findings suggest that the clinical benefit of these drugs could be related to a reduction in oxidative stress, blood thrombogenicity and to anti-inflammatory and immunomodulatory properties. Piechota et al offer new interesting data on the effect of simvastatin on inflammation and free radicals generation within the aortic wall. The current results are somewhat baffling, as the authors have obtained an increase in catalase activity, and a decrease in TNFa concentration and NF-kB expression in the AAA wall samples treated with simvastatin, but not superoxide dismutase (SOD) activity or H2O2. This is not the first study to show a significant inhibition of statins on both NF-kB activity2 and oxidant enzymes such as NADPH oxidase and myeloperoxidase,3 as well as an up-regulation of the activity of anti-

Beyond Hyperglycemia in Diabetes: Role of Statin Treatment on Thrombogenesis Triggered by Inflammation

Type 2 diabetes mellitus (T2D) constitutes a growing global public health problem and its prevalence is estimated to increase during the next decades, especially in the developing countries. To date, 15 % of the whole population is considered at high risk to develop T2D [1]. T2D is associated with a decrease of health-related quality of life and overall life expectancy, mainly due to an increased risk for cardiovascular disorders. Indeed, T2D is commonly associated with both microvascular and macrovascular complications [2]. Macrovascular complications manifest themselves as accelerated atherosclerosis, clinically resulting in premature coronary artery disease, increased risk of cerebrovascular disease, and severe peripheral vascular disease [2]. Patients with T2D have a a twoto four-fold increase in the risk of coronary artery disease (CAD) and patients with DM but without previous myocardial infarction (MI) carry the same level of risk for subsequent acute coronary events as non-diabetic patients with previous MI [3, 4] so that T2D has been defined a CAD equivalent. T2D is associated with a prothrombotic state characterized by a number of changes in thrombotic and fibrinolytic coagulation factor level/activity, which together increase the risk of thrombus formation. Both glucose and insulin seem to play a role in the pathogenesis of this prothrombotic state [5]. In vitro induced thrombin generation is increased in platelet-rich plasma from diabetics compared with that from healthy subjects and a significant elevation of thrombin levels can be demonstrated in T2D patients in poor metabolic control when compared with well controlled patients [6].Moreover, a significant correlation can be observed between improved glycemic control and blood thrombogenicity, as reflected by a reduction in ex-vivo thrombus formation in a Badimon perfusion chamber [7]. Improved glycemic control is the only significant predictor of a decrease in blood thrombogenicity, irrespective of treatment allocation [7]. Enhanced levels of prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes (TAT) have been shown in T2D patients in comparison with healthy subjects [8]. A hypercoagulable state, detected by thrombin generation tests, was reported in patients with T2D, explaining, at least partially, the high incidence of vascular events in these patients [9]. Platelets of patients with DM are characterized by dysregulation of several signaling pathways, leading to an hyperreactive phenotype with enhanced adhesion, aggregation, and activation [10]. Chronic hyperglycemia has been clearly identified as a causal factor for in vivo platelet activation [11]. Our group firstly demonstrated enhanced thromboxane (TX) biosynthesis in T2D, providing evidence for its platelet origin. Moreover, tight metabolic control led to reduction of TX metabolite urinary levels [11]. Interestingly, inflammatory mediators (such as CD40L) derived from platelets expand the functional repertoire of platelets from players of hemostasis and thrombosis to powerful amplifiers of inflammation by promoting the release of cytokines and chemokines, cell activation and cell–cell interactions [12]. T2D is frequently associated with a dyslipidemic state that may accelerate the progression of atherosclerotic F. Perego Internal Medicine III, Luigi Sacco Hospital, University of Milan, Milan, Italy

113 Blood thrombogenicity is inversely related to coronary lesion severity in patients with non ST-elevation acute coronary syndrome and type 2 diabetes mellitus

In patients with type 2 diabetes mellitus (T2DM), non-ST elevation–acute coronary syndrome (NSTE-ACS) occurs frequently secondary to non-obstructive coronary lesions than those without T2DM. Pathophysiological events leading to acute myocardial...