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The Performance of CRUSADE and ACUITY Bleeding Risk Scores in Ticagrelor-Treated ACS Patients Who Underwent PCI.

The Performance of CRUSADE and ACUITY Bleeding Risk Scores in Ticagrelor-Treated ACS Patients Who Underwent PCI.

Thromb Haemost. 2017 Oct 10;117(11):

Authors: Xi S, Zhou S, Wang X, Liu J, Qin L, Liu J, Yin T, Chen Y

Abstract
The performance of the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) and ACUITY (Acute Catheterization and Urgent Intervention Triage strategy) risk scores for the prediction of major bleeding in ticagrelor-treated acute coronary syndrome (ACS) patients who underwent percutaneous coronary intervention (PCI) is unknown. The aim of the present study is to validate the performance of both scores in a contemporary Chinese cohort of ACS patients hospitalized for PCI and administrated with ticagrelor. From January 2013 to December 2014, a total of 629 ticagrelor-treated ACS patients who underwent PCI were recruited consecutively. The overall rate of major bleeding defined by the BARC (Bleeding Academic Research Consortium) criteria was 1.7%. This incidence increased with the risk category of both the CRUSADE (very low, 0.6%; low, 1.3%; moderate, 1.1%; high, 7.0%; and very high, 13.0%; p = 0.001) and the ACUITY score (low, 0.6%; moderate, 1.4%; high, 4.9%; and very high, 7.0%; p = 0.003). The CRUSADE score demonstrated adequate calibration and discriminatory capacity for the patients as a whole (HL-p [Hosmer-Lemeshow goodness-of-fit test p-value] >0.3; AUC [area under the curve]: 0.78), with the excellent performance in the subgroups of acute myocardial infarction, men, diabetes and those implanted with more than two DESs (AUC: 0.85, 0.80, 0.93 and 0.93, respectively). For the ACUITY score, adequate calibration and discriminatory capacity could be observed for the whole patients (HL-p > 0.3; AUC: 0.78), with excellent performance for the patients with diabetes or those implanted with more than two DESs (AUC: 0.90 and 0.97, respectively). In conclusion, both CRUSADE and ACUITY risk scores performed adequate discriminatory power for the prediction of major bleeding within 30 days in ticagrelor-treated ACS patients who underwent PCI.

PMID: 29044298 [PubMed - as supplied by publisher]




Mitochondria and Platelet Cell Death.

Mitochondria and Platelet Cell Death.

Thromb Haemost. 2017 Oct 04;117(11):

Authors: Kholmukhamedov A, Jobe S

PMID: 29044296 [PubMed - as supplied by publisher]




Clinical Decision Rules for Pulmonary Embolism in Hospitalized Patients: A Systematic Literature Review and Meta-analysis.

Clinical Decision Rules for Pulmonary Embolism in Hospitalized Patients: A Systematic Literature Review and Meta-analysis.

Thromb Haemost. 2017 Oct 10;117(11):

Authors: Bass AR, Fields KG, Goto R, Turissini G, Dey S, Russell LA

Abstract
Background Clinical decision rules (CDRs) for pulmonary embolism (PE) have been validated in outpatients, but their performance in hospitalized patients is not well characterized. Objectives The goal of this systematic literature review was to assess the performance of CDRs for PE in hospitalized patients. Methods We performed a structured literature search using Medline, EMBASE and the Cochrane library for articles published on or before January 18, 2017. Two authors reviewed all titles, abstracts and full texts. We selected prospective studies of symptomatic hospitalized patients in which a CDR was used to estimate the likelihood of PE. The diagnosis of PE had to be confirmed using an accepted reference standard. Data on hospitalized patients were solicited from authors of studies in mixed populations of outpatients and hospitalized patients. Study characteristics, PE prevalence and CDR performance were extracted. The methodological quality of the studies was assessed using the QUADAS instrument. Results Twelve studies encompassing 3,942 hospitalized patients were included. Studies varied in methodology (randomized controlled trials and observational studies) and reference standards used. The pooled sensitivity of the modified Wells rule (cut-off ≤ 4) in hospitalized patients was 72.1% (95% confidence interval [CI], 63.7-79.2) and the pooled specificity was 62.2% (95% CI, 52.6-70.9). The modified Wells rule (cut-off ≤ 4) plus D-dimer testing had a pooled sensitivity 99.7% (95% CI, 96.7-100) and pooled specificity 10.8% (95% CI, 6.7-16.9). The efficiency (proportion of patients stratified into the 'PE unlikely' group) was 8.4% (95% CI, 4.1-16.5), and the failure rate (proportion of low likelihood patients who were diagnosed with PE during follow-up) was 0.1% (95% CI, 0-5.3). Conclusion In symptomatic hospitalized patients, use of the Wells rule plus D-dimer to rule out PE is safe, but allows very few patients to forgo imaging.

PMID: 29044295 [PubMed - as supplied by publisher]




Serum Levels of Anti-PON1 and Anti-HDL Antibodies as Potential Biomarkers of Premature Atherosclerosis in Systemic Lupus Erythematosus.

Serum Levels of Anti-PON1 and Anti-HDL Antibodies as Potential Biomarkers of Premature Atherosclerosis in Systemic Lupus Erythematosus.

Thromb Haemost. 2017 Oct 10;117(11):

Authors: López P, Rodríguez-Carrio J, Martínez-Zapico A, Pérez-Álvarez ÁI, López-Mejías R, Benavente L, Mozo LM, Caminal-Montero L, González-Gay MA, Suárez A

Abstract
The present study aimed to evaluate the possible role of immunoglobulin G (IgG) antibodies against high-density lipoproteins (HDL) and paraoxonase 1 (PON1) as possible biomarkers of cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). To this end, levels of these autoantibodies, PON1 activity and total antioxidant capacity were quantified in serum samples from 198 SLE patients, 100 healthy controls (HC) and 42 non-autoimmune individuals with traditional cardiovascular risk factors. PON1 rs662 polymorphism was analysed in a subgroup of patients and controls. Subclinical CVD were determined by Doppler ultrasound in 118 SLE patients and 30 HC, analysing carotid intima-media thickness (IMT) and blood flow parameters in internal carotid, middle cerebral and basilar arteries. Serum levels of both anti-HDL and anti-PON1 antibodies were increased in SLE patients compared with HC (p < 0.001); however, only anti-PON1 antibodies, in addition to disease activity, were significant predictors of the impaired PON1 function in SLE (β= 0.143, p = 0.045). Conversely, anti-HDL antibodies were associated with higher risk of CVD (odds ratio: 3.69; p = 0.012) and lower HDL levels at disease onset (ρ = 0.324, p = 0.044). Finally, anti-PON1 antibodies were associated with carotid IMT in SLE (β = 0.201, p = 0.008) and inversely related to cranial arteries blood flow velocities in patients with clinical and subclinical CVD (all p < 0.001). In sum, these findings allowed us to propose serum levels of anti-PON1 and anti-HDL antibodies as potential early biomarkers of endothelial damage and premature atherosclerosis in SLE, thus constituting useful therapeutic targets for the prevention of future CVD in these patients.

PMID: 29044294 [PubMed - as supplied by publisher]




Down Regulation of the Munc18b-syntaxin-11 Complex and β1-tubulin Impairs Secretion and Spreading in Neonatal Platelets.

Down Regulation of the Munc18b-syntaxin-11 Complex and β1-tubulin Impairs Secretion and Spreading in Neonatal Platelets.

Thromb Haemost. 2017 Oct 10;117(11):

Authors: Caparrós-Pérez E, Teruel-Montoya R, Palma-Barquero V, Torregrosa JM, Blanco JE, Delgado JL, Lozano ML, Vicente V, Sola-Visner M, Rivera J, Martínez C, Ferrer-Marín F

Abstract
Neonatal platelets are hyporeactive and show impaired agonist-induced secretion despite no obvious abnormalities in their granules. Here, we examined, for the first time, the ultrastructure of neonatal and adult platelets following agonist activation. Under resting conditions, neonatal and adult platelets appeared ultrastructurally identical. Following agonist stimulation, however, noticeable degranulation occurred in adult platelets, while granules in neonatal platelets remained clearly visible and apparently unable to centralize or fuse. To investigate the underlying mechanisms, we first examined the expression levels of the main SNARE proteins, which mediate the membrane fusion events required for exocytosis. Neonatal platelets showed significantly reduced levels of syntaxin-11 and its regulator, Munc18b. Since granule centralization depends on contraction of the microtubule ring, we also examined the expression of its main component, β1-tubulin. Noteworthy, we found decreased TUBB1 mRNA and protein levels in neonatal platelets, while TUBB2A and TUBB isoforms were overexpressed, partially compensating for that deficiency. Finally, supporting the functional consequences of defective exocytosis, adhesion kinetic assays, performed in plasma-free medium, demonstrated delayed adhesion and spreading of neonatal platelets. This is the first report showing marked reductions of syntaxin-11-Munc18b complex and β1-tubulin in neonatal platelets, indicating that these proteins, required for platelet degranulation, are developmentally regulated.

PMID: 29044293 [PubMed - as supplied by publisher]




Investigation of the Filamin A-Dependent Mechanisms of Tissue Factor Incorporation into Microvesicles.

Investigation of the Filamin A-Dependent Mechanisms of Tissue Factor Incorporation into Microvesicles.

Thromb Haemost. 2017 Oct 10;117(11):

Authors: Collier M, Collier MEW, Ettelaie C, Goult BT, Maraveyas A, Goodall AH

Abstract
We have previously shown that phosphorylation of tissue factor (TF) at Ser253 increases the incorporation of TF into microvesicles (MVs) following protease-activated receptor 2 (PAR2) activation through a process involving filamin A, whereas phosphorylation of TF at Ser258 suppresses this process. Here, we examined the contribution of the individual phosphorylation of these serine residues to the interaction between filamin A and TF, and further examined how filamin A regulates the incorporation of TF into MVs. In vitro binding assays using recombinant filamin A C-terminal repeats 22-24 with biotinylated phospho-TF cytoplasmic domain peptides as bait showed that filamin A had the highest binding affinities for phospho-Ser253 and double-phosphorylated TF peptides, while the phospho-Ser258 TF peptide had the lowest affinity. Analysis of MDA-MB-231 cells using an in situ proximity ligation assay revealed increased proximity between the C-terminus of filamin A and TF following PAR2 activation, which was concurrent with Ser253 phosphorylation and TF-positive MV release from these cells. Knock-down of filamin A expression suppressed PAR2-mediated increases in cell surface TF procoagulant activity without reducing cell surface TF antigen expression. Disrupting lipid rafts by pre-incubation with methyl-β-cyclodextrin prior to PAR2 activation reduced TF-positive MV release and cell surface TF procoagulant activity to the same extent as filamin A knock-down. In conclusion, this study shows that the interaction between TF and filamin A is dependent on the differential phosphorylation of Ser253 and Ser258. Furthermore, the interaction of TF with filamin A may translocate cell surface TF to cholesterol-rich lipid rafts, increasing cell surface TF activity as well as TF incorporation and release into MVs.

PMID: 29044292 [PubMed - as supplied by publisher]




Preprocedural Leucocyte Count Predicts Risk in Patients with Coronary Chronic Total Occlusion.

Preprocedural Leucocyte Count Predicts Risk in Patients with Coronary Chronic Total Occlusion.

Thromb Haemost. 2017 Oct 10;117(11):

Authors: Gebhard C, Toma A, Min Z, Stähli BE, Mashayekhi K, Gick M, Ferenc M, Büttner HJ, Neumann FJ

Abstract
Background As technologies of percutaneous coronary intervention (PCI) for coronary chronic total occlusions (CTO) have improved, great uncertainty exists regarding patient selection and long-term benefit of CTO-PCI. Given that white blood cell (WBC) count has been associated with cardiovascular risk, we hypothesized that the latter might provide incremental prognostic value in patients undergoing CTO-PCI. Methods and Results Our study population consisted of 1,262 consecutive patients (76.3% males, mean age of 67.7 ± 10.3 years) who underwent elective PCI at our centre between January 2002 and December 2008. Four hundred seventy-five patients had at least one CTO, while 787 patients with non-occlusive coronary lesions served as controls. Baseline WBC count was higher in CTO patients as compared with controls (8,072 ± 3,459/μL vs. 7,469 c 2,668/μL, p = 0.001) and independently predicted the occurrence of a CTO lesion (odds ratio: 1.8; 95% confidence interval [CI]: 1.3-2.4; p < 0.001). After a median follow-up of 3.1 years (interquartile range: 2.1-4.2 years), CTO patients with WBC counts ranging in the highest tertile had significantly worse outcomes than CTO patients with lower WBC counts (log-rank = 0.009 for all-cause mortality and log-rank = 0.01 for major adverse cardiac events). These associations were not seen in controls. Accordingly, elevated WBC count was identified as a significant predictor for all-cause mortality (adjusted hazard ratio: 3.1; 95% CI: 1.6-6.2; p = 0.001) in CTO patients but not in patients with non-occlusive coronary artery disease (pint = 0.088). Conclusion Assessment of the inflammatory status of CTO patients may be an important element in selecting CTO patients at low risk who may be referred to CTO-PCI.

PMID: 29044291 [PubMed - as supplied by publisher]




Protease-Activated Receptor PAR-4: An Inducible Switch between Thrombosis and Vascular Inflammation?

Protease-Activated Receptor PAR-4: An Inducible Switch between Thrombosis and Vascular Inflammation?

Thromb Haemost. 2017 Oct 10;117(11):

Authors: Fender AC, Rauch BH, Geisler T, Schrör K

Abstract
Thrombin triggers activation of platelets through protease-activated receptor 1 (PAR-1) and PAR-4. Both receptors are widely expressed and exert multiple platelet-independent functions. PAR signalling contributes to healing responses after injury, by promoting cytokine activity and cellular growth and mobility. Uncontrolled PAR activation, however, can prevent timely resolution of inflammation, enhance thrombogenic endothelial function and drive adverse remodelling. The specific role of PAR-4 in thromboinflammatory vascular disease has been largely underestimated, given the relatively limited expression of PAR-4 in non-platelet cells under healthy conditions. However, unlike PAR-1, PAR-4 expression adapts dynamically to numerous stimuli associated with thromboinflammation, including thrombin, angiotensin II, sphingosine-1-phosphate (S1P), high glucose and redox stress, suggesting expression is switched on 'at need'. Prostacyclin negatively regulates PAR-4 expression at the post-transcriptional level, which may serve to fine-tune thrombin responses and limit these to the injury site. PAR-4 elicits inflammatory, mitogenic and proliferative actions not only in response to thrombin but also to numerous other inflammatory proteases, and can cross-talk with other receptor systems such as S1P and adenosine receptors. Accordingly, PAR-4 has emerged as a candidate player in vessel disease and cardiac post-infarction remodelling. Currently, PAR-4 is a particularly promising target for safer anti-thrombotic therapies. Recent studies with the PAR-4 antagonist BMS-986120 lend support to the concept that selective antagonism of PAR-4 may offer both an effective and safe anti-thrombotic therapy in the acute thrombotic setting as well as an anti-inflammatory strategy to prevent long-term progressive atherosclerotic disease in high-risk cardiovascular patients.

PMID: 29044290 [PubMed - as supplied by publisher]