Proteasome inhibitors (PIs) are effective against multiple myeloma (MM), but the mechanisms of action and bases of individual susceptibility remain unclear. Recent work linked PI sensitivity to ...protein synthesis and proteasome activity, raising the question whether different levels of proteasome expression and workload underlie PI sensitivity in MM cells (MMCs). Exploiting human MM lines characterized by differential PI sensitivity, we report that highly sensitive MMCs express lower proteasome levels and higher proteasomal workload than relatively PI-resistant MMCs, resulting in the accumulation of polyubiquitinated proteins at the expense of free ubiquitin (proteasome stress). Manipulating proteasome expression or workload alters apoptotic sensitivity to PI, demonstrating a cause-effect relationship between proteasome stress and apoptotic responses in MMCs. Intracellular immunostaining in primary, patient-derived MMCs reveals that polyubiquitinated proteins hallmark neoplastic plasma cells, in positive correlation with immunoglobulin (Ig) content, both intra- and interpatient. Moreover, overall proteasome activity of primary MMCs inversely correlates with apoptotic sensitivity to PI. Altogether, our data indicate that the balance between proteasome workload and degradative capacity represents a critical determinant of apoptotic sensitivity of MMCs to PI, potentially providing a framework for identifying indicators of responsiveness and designing novel combination therapies.
Despite great advances with the introduction of ticagrelor and prasugrel in the treatment of acute coronary syndromes (ACS), the risk of thrombosis and bleeding remains significant and affects the ...choice of clinicians in the treatment of the single patient. Large registries are effective tools to explore patterns of drug administration and adherence to guideline recommendations in real-world clinical practice.
START- antiplatelet is a prospective, observational registry carried out by seven Italian cardiology institutions on patients admitted for ACS aimed to document the real world treatment of ACS patients, adding also data on 12-month follow-up. We present data on the first 1050 patients who have completed 1-year follow-up on a total of 1537 patients. Primary end-points were: 1) MACCE (Major Adverse Cardiovascular and Cerebrovascular Events) including all-cause and cardiovascular mortality, non fatal MI, urgent revascularization, TIA and ischemic stroke; 2) Major and minor bleeding according to TIMI, GUSTO and ISTH classifications.
The dual antiplatelet treatment most prescribed was aspirin plus ticagrelor (47.9%) and aspirin plus clopidogrel (32.1%). At a mean follow-up was 335±131 days, both ticagrelor and prasugrel are associated with a statistically significant reduced total and cardiovascular mortality. Both prasugrel and ticagrelor do not show a significant increased incidence of major and minor bleedings with respect to clopidogrel. Patients with monotherapy had significantly higher incidence of both ischemic stroke and major bleedings.
The analysis of the register has documented that both ticagrelor and prasugrel are associated with a statistically significant reduced total and cardiovascular mortality but both do not show a significant increased incidence of major and minor bleedings with respect to clopidogrel.
Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin ...in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti–β2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.
•Direct anticoagulants are currently used in patients with thromboembolism, irrespective of the presence of antiphospholipid antibodies.•This trial shows an increased rate of events with rivaroxaban compared with warfarin in patients with antiphospholipid syndrome.
Display omitted
Display omitted
•The cytokine storm present in COVID-19 patients induces, together with the imbalance of endothelial functions, a massive cell activation with production of tissue factor, mainly by ...platelets, granulocytes, and MVs.•Plasma MV-associated thrombin generation is present in patients despite prophylactic anticoagulation.•COVID-19 plasma, added to the blood of healthy subjects, induces platelet activation similar to what is observed in vivo. This effect is blunted by pre-incubation with tocilizumab, giving insights into the IL-6–mediated platelet activation that triggers the hypercoagulable state in COVID-19, suggesting the potential effectiveness of anti–IL-6 antibodies and antiplatelet drugs.•Our data provide the bench-to-clinic rationale behind the ongoing clinical trial assessing the potential effectiveness of antiplatelet drugs and IL-6R antagonists in the treatment of COVID-19 patients.
The authors hypothesized that the cytokine storm described in COVID-19 patients may lead to consistent cell-based tissue factor (TF)-mediated activation of coagulation, procoagulant microvesicles (MVs) release, and massive platelet activation. COVID-19 patients have higher levels of TF+ platelets, TF+ granulocytes, and TF+ MVs than healthy subjects and coronary artery disease patients. Plasma MV-associated thrombin generation is present in prophylactic anticoagulated patients. A sustained platelet activation in terms of P-selectin expression and platelet–leukocyte aggregate formation, and altered nitric oxide/prostacyclin synthesis are also observed. COVID-19 plasma, added to the blood of healthy subjects, induces platelet activation similar to that observed in vivo. This effect was blunted by pre-incubation with tocilizumab, aspirin, or a P2Y12 inhibitor.
Obstructive sleep apnoea (OSA) is the most common sleep disorder of breathing in middle-aged and overweight subjects. It features recurrent episodes of upper airway total (apnoea) o partial ...(hypopnea) collapse during sleep, which are associated with a reduction in blood oxygen saturation and with arousal from sleep to re-establish airway patency. An association of OSA with dysregulation of the autonomous nervous system (ANS) and altered catecholamines (CAs) metabolism has been contended for years. However, the pathophysiology mechanisms underlying these alterations remain to be fully clarified. Nonetheless, these alterations are deemed to play a key pathogenic role in the established association of OSA with several conditions besides arterial hypertension (HT), including coronary artery disease, stroke, and, more in general, with increased risk of cardiovascular (CV) events. Hence, in this review we will analyse the relationship between the sleep disturbances associated with OSA and the altered function of the ANS, including CAs metabolism.
The year 1222 has traditionally been accepted as the University of Padua’s founding date. The University of Padua is a prestigious center for learning and research, and over the centuries, it has ...produced luminaries in the most significant disciplines, including medicine, law, philosophy, theology, literature, engineering, astronomy, physics, politics, and religion. The Studium of the teaching of Medicine began around 1250 with the establishment of the Collegium of Medical and Arts Doctors. The history of Medicine at Padua University is extraordinarily rich and counts on the contribution of masters such as Vesalius, Falloppia, Girolamo Fabrici d’Acquapendente, William Harvey, Vallisneri, Ramazzini, Morgagni and many others including Galileo Galilei himself. This year marks the 800th anniversary of the University of Padua, and to commemorate this historic event, the Editor has asked the three of us to summarize the university’s most significant contributions to the fields of hemostasis and thrombosis over the past eight decades. Among all, it should be mentioned the relevant contribution of Prof. Antonio Girolami, who was the founder of the group of Thrombosis and Hemostasis in Padua and one of the Italian and international leaders in the field of the diagnosis and treatment of congenital bleeding disorders. However, due to the large number of outstanding scientists and significant research conducted in these fields at Padua University, it was extremely difficult for us to provide a concise summary of the university’s numerous contributions. Eventually, we concluded that it would be more useful to share with the Readers the experiences we have had over the past several decades, focusing on specific aspects of our research, work, and life at Padua University, and attempting to highlight the aspects that we believe have contributed most to the advancement of knowledge in the fields of thrombosis and hemostasis. Therefore, three topics have been selected and presented separately in a narrative format as pieces of our lives and of the history of our university.
There are limited real-world data on prevalence and predictors of dual antiplatelet therapy (DAPT) prolongation beyond one year after acute coronary syndrome (ACS). We have explored such issue in the ...START ANTIPLATELET Registry, which is a prospective, observational, multicenter, Italian registry performed in seven Italian cardiology institutions including patients admitted for ACS and followed up to one year. Out of a total population of 840 ACS patients, 596 patients had completed 12-month follow-up being on DAPT. Decision to prolong DAPT beyond one year was taken in 79 patients (13%), whereas in 517 patients DAPT was stopped. The strongest predictors of DAPT continuation were a new cardiovascular events after the index admission event (OR 3.3, 95% CI 1.4-7.7), no bleeding complications (OR 3.2, 95% CI 1.2-8.3) and no anemia during one-year follow-up (OR 2.6, 95% CI 1.1-5.9); other independent predictors were renal failure (OR 2.5, 95% CI 1.3-5.0) and peripheral artery disease (OR 1.8, 95% CI 1.1-3.0). The choice of DAPT prolongation was not correlated with younger ager, presence of diabetes mellitus, coronary angioplasty as initial treatment strategy or type of implanted stent (drug-eluting vs bare metal). In conclusion, this study provides a real-world snapshot on the factors influencing the option to continue DAPT beyond one year after ACS; a low bleeding risk seems to influence the choice to prolong DAPT more than a high ischemic risk.
Abstract Some previous observations suggest that a low platelet count is associated with an increased risk of adverse outcomes in patients with acute coronary syndromes (ACS). However, most of the ...data come from post-hoc analyses of randomized controlled trials and from studies including thrombocytopenia developed during hospital stay. Our aim was to assess the impact of low platelet count at admission on cardiovascular outcomes and treatment approach in patients hospitalized for ACS in a current real-life setting in Italy. Patients admitted to Italian coronary care units for ACS were enrolled in the START-ANTIPLATELET registry. Baseline clinical characteristics and treatment at discharge were recorded. Patients were followed-up at 6 months, 1 year and yearly thereafter. Low platelet count was defined as a count at admission < 150 > 100 k/µl or < 100 k/µL. Among 1894 enrolled patients, 157 (8.3%) had a platelet count < 150 > 100 k/µl and 30 (1.6%) < 100 k/µl. The median follow-up was 12.3 months (0.4–50.1). patients with low platelets were older (72 ± 10.4 vs 66 ± 12.4 years, p = 0.006), more frequently males (82.9 vs 72.1%, p = 0.001), hypertensive (90.0% vs 70.4%, p = 0.03), with non-valvular atrial fibrillation (NVAF) (17.1 vs 8.6%, p = 0.02), and peripheral arterial disease (11.5 vs 6.2% p = 0.01) and/or had a previous myocardial infarction (40 vs 18.7%, p = 0.008) and/or a PCI (14.6 vs 7.8%, p = 0.001) than patients with normal platelets. A slightly, but significantly, lower percentage of thrombocytopenic patients were treated with primary PCI (78.1 vs 84.4%, p = 0.04) and they were more frequently discharged on aspirin plus clopidogrel rather than aspirin plus newer P2Y 12 antagonists (51.9 vs 65.4%, p = 0.01). MACE-free survival was significantly shorter in thrombocytopenic patients compared to patients with normal platelets (< 150 > 100 k/µl: 37.6 vs 41.8 months, p = 0.002; HR = 2.7, 95% CIs 1.4–5.2; < 100 k/µl: 31.7 vs 41.8 months, p = 0.01; HR = 6.5, 95% CIs 1.5–29.1). At multivariate analysis, low platelet count, age at enrollment, low glomerular filtration rate, low ejection fraction, a previous ischemic stroke and NVAF were independent predictors of MACE. A low platelet count at admission identifies a subgroup of ACS patients with a significantly increased risk of MACE and these patients should be managed with special care to prevent excess adverse outcomes.
PDF
