Circulating microparticles and endothelial progenitor cells in atherosclerosis; pharmacological effects of irbesartan.
J Thromb Haemost. 2012 Feb 3;
Authors: Georgescu A, Alexandru N, Andrei E, Titorencu I, Dragan E, Tarziu C, Ghiorghe S, Badila E, Bartos D, Popov D
Abstract
Aims: This study aimed to (a) employ our newly designed model, the hypertensive-hypercholesterolemic hamster (HH) in order to find whether a correlation exist between circulating microparticles (MPs), endothelial progenitor cells (EPCs) and their contribution to vascular dysfunction and (b) to assess the effect of irbesartan treatment on HH animals (HHI). Methods and Results: The results showed that compared to control (C) group, HH displayed: (i) a significantly increase in plasma cholesterol and triglyceride concentration, and an augmentation of systolic and diastolic arterial blood pressure, and of heart rate; (ii) a marked elevation of MPs and a significant decrease in EPCs; (iii) structural modifications of arterial wall correlated with altered protein expression of MMP2, MMP9, MMP12, TIMP1, TIMP2 and collagen type I and III; (iv) a considerably altered reactivity of arterial wall closely correlated with MPs and EPC adherence; (v) an inflammatory process characterised by augmented expression of P-Selectin, E-Selectin, vWF, TF, IL-6, MCP-1, RANTES. Additionally, the experiments showed the potential of irbesartan to correct all altered parameters in HH and to mobilize EPCs by NO, chemokines and adhesion molecules dependent mechanism. Conclusions: Hypertension associated with hypercholesterolemia is accompanied by structural modifications and expression of pro-inflammatory molecules by vessel wall, the alteration of vascular tone, enhanced release of MPs and reduced EPCs; the ratio between the latter two may be considered as a marker of vascular dysfunction. Irbesartan that exhibit a pharmacological control on the levels of MPs and EPCs has the potential to restore homeostasis of the arterial wall.
PMID: 22303879 [PubMed - as supplied by publisher]
Diurnal expression of Thrombopoietin is regulated by Clock.
J Thromb Haemost. 2012 Jan 27;
Authors: Tracey CJ, Pan X, Catterson JH, Harmar AJ, Ahmood Hussain M, Hartley PS
Abstract
Background: Most physiological processes exhibit diurnal fluctuations controlled by the circadian regulation of sleep-wake behaviour and feeding cycles. In addition, many cell types express endogenous circadian rhythms that affect cell-specific processes. Independent reports support the hypothesis that Thrombopoietin (TPO) is under circadian control. Objectives: The current study tested the hypothesis that CLOCK, a circadian transcription factor, may regulate Thpo, the gene encoding TPO. Methods: Circadian gene expression patterns were analysed in mice and human cell lines, siRNAi was used to knock down CLOCK expression in cell lines and gene expression was also examined in CLOCK(Δ19/Δ19) mutant mice. Results: It was found that there was a diurnal rhythm in the expression of Thpo in vivo in mice and this was associated with concomitant rhythms of protein abundance. Thpo was rhythmically expressed in human cell lines, consistent with the gene being directly or indirectly regulated by the circadian clock. Silencing of CLOCK in the Huh7 human hepatoma cell line led to a significant reduction to the rhythmicity of Thpo expression. The expression of Mpl in murine marrow also displayed diurnal rhythmicity in vivo. In CLOCK(Δ19/Δ19) mutant mice, Thpo and Mpl gene expression was disrupted and there was an increase in the number of mature megakaryocytes but no change to the ploidy distribution within the megakaryocyte population. Conclusions: These findings establish that Clock regulates Thpo and Mpl expression in vivo and demonstrate an important link between the body’s circadian timing mechanisms and megakaryopoiesis.
PMID: 22284746 [PubMed - as supplied by publisher]
Background: TGF-β1 is a profibrotic cytokine that plays a major role in vascular biology, and is known to regulate the phenotype and activity of various vascular cell populations. Because most fibrotic diseases, such as Idiopathic Pulmonary Fibrosis (IPF), are associated with vascular remodeling and since endothelial progenitor cells may be involved in this process, we investigated the impact of TGF-β1 modulation of endothelial progenitor cell angiogenic properties. Patients/ methods: TGF-β1 plasma levels were determined in 64 patients with IPF and compared to controls. The effect of TGF-β1 on angiogenesis was studied in vivo in a Matrigel plug model and in vitro on Endothelial Colony Forming Cells (ECFCs). We studied the effects of inhibiting the expression of the three main receptors of TGF-β1 in ECFCs using siRNA. Results: Total TGF-β1 plasma levels were significantly increased in patients with IPF compared to controls (P < 0.0001). TGF-β1 had proangiogenic effects in vivo by increasing hemoglobin content and blood vessels formation in Matrigel-plugs implanted in C57/Bl6 mice and in vitro by enhancing ECFC viability and migration. The effects were abolished by silencing the three main TGF-β1 receptors. Conclusions: TGF-β1 is pro-angiogenic in vivo and induces ECFC angiogenic properties in vitro, suggesting that TGF-β1 may play a role during vascular remodeling in fibrotic disease states via endothelial progenitor cells.
PMID: 22284809 [PubMed - as supplied by publisher]
D-Dimer Threshold Increase with Pretest Probability Unlikely for Pulmonary Embolism to Decrease Unnecessary Computerized Tomographic Pulmonary Angiography.
J Thromb Haemost. 2012 Jan 28;
Authors: Kline JA, Hogg MM, Courtney DM, Miller CD, Jones AE, Smithline HA
Abstract
Background: Increasing the threshold to define a positive D-dimer could reduce unnecessary computed tomographic pulmonary angiography (CTPA) for suspected PE but might increase rates of missed PE and missed pneumonia, the most common nonthromboembolic diagnosis seen on CTPA. Objective: Measure the effect of doubling the standard D-dimer threshold for “PE unlikely” Revised Geneva (RGS) or Wells’ scores on the exclusion rate, frequency and size of missed PE and missed pneumonia. Methods: Patients evaluated for suspected PE with 64-channel CTPA were prospectively enrolled from EDs and inpatient units of four hospitals. Pretest probability data were collected in real time and the D-dimer was measured in a central laboratory. Criterion standard was CPTA interpretation by two independent radiologists combined with clinical outcome at 30 days. Results: Of 678 patients enrolled, 126 (19%) were PE+ and 93 (14%) had pneumonia. Use of either Wells≤4 or RGS≤6 produced similar results. For example, with RGS≤6 and standard threshold (<500 ng/mL), D-dimer was negative in 110/678 (16%), and 4/110 were PE+ (posterior probability 3.8%), and 9/110 (8.2%) had pneumonia. With RGS≤6 and a threshold <1000 ng/mL, D-dimer was negative in 208/678 (31%) and 11/208 (5.3%) were PE+, but 10/11 missed PEs were subsegmental, and none had concomitant DVT. Pneumonia was found in 12/208 (5.4%) with RGS≤6 and D-dimer<1000 ng/mL. Conclusions: Doubling the threshold for a positive D-dimer with a PE unlikely pretest probability could reduce CTPA scanning with a slightly increased risk of missed isolated subsegmental PE, and no increase in rate of missed pneumonia.
PMID: 22284935 [PubMed - as supplied by publisher]
Silent Pulmonary Embolism in Patients with Proximal Deep Vein Thrombosis in the Lower Limbs.
J Thromb Haemost. 2012 Jan 31;
Authors: Tzoran I, Saharov G, Brenner B, Delsart D, Román P, Visoná A, Jiménez D, Monreal M,
Abstract
Background: One in every three patients with deep vein thrombosis (DVT) in the lower limbs may have silent pulmonary embolism (PE), but its clinical relevance has not been thoroughly studied. Methods: We used the RIETE Registry data to study patients with proximal DVT and no PE symptoms, but with a systematic search for PE. We compared the outcome of DVT patients with silent PE and those with no PE. Results: Of 2375 patients with DVT, 842 (35%) had silent PE and 1533 had no PE. During the first 15 days of anticoagulation, patients presenting with silent PE had a higher incidence of symptomatic PE events than those with no PE (0.95% vs. 0.13%; p=0.015), with a similar incidence of major bleeding (0.95% vs. 1.63%; p=0.09). In patients with silent PE, the incidence of PE events during the first 15 days was equal to the incidence of major bleeding (8 events each), but in those with no PE the incidence of PE events was 8 times lower (3 vs. 25 bleeding events). Multivariate analysis confirmed that DVT patients with silent PE had a higher incidence of symptomatic PE events during the first 15 days than those with no PE (odds ratio: 4.80; 95% CI: 1.27-18.1), with no differences in bleeding. Conclusions: DVT patients with silent PE at baseline had an increased incidence of symptomatic PE events during the first 15 days of anticoagulant therapy. This effect disappeared after 3 months of anticoagulation.
PMID: 22288520 [PubMed - as supplied by publisher]
INR Targets and Site-Level Anticoagulation Control: Results from the Veterans AffaiRs Study to Improve Anticoagulation (VARIA).
J Thromb Haemost. 2012 Jan 31;
Authors: Rose AJ, Berlowitz DR, Miller DR, Hylek EM, Ozonoff A, Zhao S, Reisman JI, Ash AS
Abstract
Background: Not all clinicians target the same International Normalized Ratio (INR) for patients with a guideline-recommended target range of 2 to 3. A patient’s mean INR value suggests the INR that was actually targeted. We hypothesized that sites would vary by mean INR, and that sites of care with mean values nearest to 2.5 would achieve better anticoagulation control, as measured by percent time in therapeutic range (TTR). Objectives: To examine variations among sites in mean INR and the relationship with anticoagulation control in an integrated system of care. Patients/Methods: We studied 103,897 patients receiving oral anticoagulation with an expected INR target between 2 and 3 at 100 Veterans Health Administration (VA) sites from 10/1/06-9/30/08. Key site-level variables were: proportion near 2.5 (that is, percent of patients with mean INR between 2.3-2.7) and mean risk-adjusted TTR. Results: Site mean INR ranged from 2.22-2.89; proportion near 2.5, from 30-64%. Sites’ proportions of patients near 2.5, below 2.3, and above 2.7 were consistent from year to year. A 10 percentage point increase in the proportion near 2.5 predicted a 3.8 percentage point increase in risk-adjusted TTR (p < 0.001). Conclusions: Proportion of patients with mean INR near 2.5 is a site-level “signature” of care and an implicit measure of targeted INR. This proportion varies by site and is strongly associated with site-level TTR. Our study suggests that sites wishing to improve TTR, and thereby improve patient outcomes, should avoid the explicit or implicit pursuit of non-standard INR targets.
PMID: 22288563 [PubMed - as supplied by publisher]
Human Neutrophil Alpha-Defensins Induce Formation of Fibrinogen and Thrombospondin-1 Amyloid-Like Structures and Activate Platelets via GPIIbIIIa.
J Thromb Haemost. 2012 Jan 23;
Authors: Horn M, Bertling A, Brodde MF, Müller A, Roth J, Van Aken H, Jurk K, Heilmann C, Peters G, Kehrel BE
Abstract
Background: Human neutrophil α-defensins (HNPs) are important constituents of the innate immune system. Beyond their antimicrobial properties, HNPs also have pro-inflammatory features. While HNPs in plasma from healthy individuals are barely detectable, their level is strongly elevated in septic plasma and plasma from patients with acute coronary syndromes. Objectives: Since thrombosis and inflammation are intertwined processes and activation of human PMNL and subsequent degranulation is associated with full activation of surrounding platelets, we studied the effect of HNPs on platelet function. Methods: The effect of HNPs on platelet activation parameters and apoptosis was investigated via aggregometry, flow cytometry, confocal microscopy and ELISA technique. Results: We found that HNPs activate platelets in pathophysiologically relevant doses, inducing fibrinogen and thrombospondin-1 binding, aggregation, granule secretion, sCD40L shedding, and procoagulant activity. HNPs bound directly to the platelet membrane, induced membrane pore formation, microparticle formation, mitochondrial membrane depolarization and caspase-3-activity. Confocal microscopy revealed the HNP-induced formation of polymeric fibrinogen and thrombospondin-1 amyloid-like structures, which bound microorganisms. Platelets adhered to these structures and formed aggregates. Blocking of GPIIbIIIa markedly inhibited HNP-induced platelet activation. In addition, heparin, heparinoid, serpins and α(2) -macroglobulin, which all bind to HNPs, blocked HNP-1 induced platelet activation in contrast to direct thrombin inhibitors like hirudin. Conclusions: HNPs activate platelets and induce platelet apoptosis by formation of amyloid-like proteins. Since these structures entrapped bacteria and fungi, they might reflect an additional function of HNPs in host defense. The described mechanism links again thrombosis and infection.
PMID: 22268819 [PubMed - as supplied by publisher]
Background: Guidelines recommend stopping aspirin and clopidogrel 7 to 10 days before surgery to allow time for replacement of permanently inhibited platelets by newly released uninhibited platelets. Objectives: The purpose of this study was to determine the rate of offset of the anti-platelet effects of aspirin and clopidogrel after stopping treatment and the proportion of untreated donor platelets that are required to reverse their anti-platelet effects. Methods: Cohort 1 consisted of 15 healthy subjects who received aspirin 81 mg/d or clopidogrel 75 mg/d for 7 days and underwent serial blood sampling until platelet function testing results normalized. Cohort 2 consisted of 36 healthy subjects who received aspirin 325mg/d, clopidogrel 75mg/d, aspirin 81mg/d plus clopidogrel 75mg/d or no treatment for 7 days and underwent a single blood sampling. Results: In cohort 1, Arachidonic acid (AA)-induced light transmission aggregation (LTA) returned to baseline levels in all subjects within 4 days of stopping aspirin, coinciding with partial recovery of plasma thromboxane B(2) concentrations. Adenosine diphosphate (ADP)-induced LTA did not return to baseline levels until 10 days after stopping clopidogrel. In cohort 2, AA-induced LTA in patient treated with aspirin reached control levels after mixing with 30% untreated donor platelets whereas ADP-induced LTA in patients treated with clopidogrel reached control levels only after the addition of 90% or more donor platelets. Conclusions: Platelet aggregation recovers within 4 days of stopping aspirin but clopidogrel must be stopped for 10 days to achieve a normal aggregatory response.
PMID: 22268852 [PubMed - as supplied by publisher]
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