Changes in anticoagulant and antiplatelet drug supply at US hospitals before and during the COVID-19 pandemic (2018-2021).

PURPOSE: Antithrombotic agents have a role in coronavirus disease 2019 (COVID-19) treatment, but the pandemic disrupted medication supply. This study examined changes in the volume of oral and parenteral anticoagulant and antiplatelet medications at US hospitals during the pandemic. METHODS: IQVIA National Sales Perspective (NSP) data was used to determine the monthly volume of anticoagulants and antiplatelets purchased at US hospitals between January 2018 and February 2021. Mean monthly medication volumes, reported as extended units (EUs), and year-over-year changes in medication volume were determined. A single-group interrupted time series analysis was used to evaluate changes in the rate of growth of monthly medication volumes before (January 2019-February 2020) and during (March 2020-February 2021) the COVID-19 pandemic. RESULTS: Overall, there was a 43.4% decline in the total volume of anticoagulants and antiplatelets at US hospitals in March 2020, driven by a decrease in heparin volume. Mean monthly volumes decreased significantly (P < 0.05) for parenteral anticoagulants (-106,691,340 EU [95% CI, -200,033,910 to -13,348,780]), oral anticoagulants (-354,800 EU [95% CI, -612,180 to -97,420]), and parenteral antiplatelets (-391,880 EU [95% CI, -535,420 to -248,330]). During the pandemic, the monthly volume of oral anticoagulants, parenteral anticoagulants, and parenteral antiplatelets grew significantly more than in the prepandemic period. This growth was primarily seen in volumes of apixaban, argatroban, enoxaparin, heparin, eptifibatide, and tirofiban. Apixaban and heparin volumes continued a prepandemic uptrend, while argatroban and eptifibatide volumes reversed trend. CONCLUSION: Rapid changes in anticoagulant and antiplatelet volume at US hospitals during the COVID-19 pandemic highlight the need for institutional protocols to manage fluctuating medication volume demands.

The Signaling Pathway of the ADP Receptor P2Y12 in the Immune System: Recent Discoveries and New Challenges.

P2Y12 is a G-protein-coupled receptor that is activated upon ADP binding. Considering its well-established role in platelet activation, blocking P2Y12 has been used as a therapeutic strategy for antiplatelet aggregation in cardiovascular disease patients. However, receptor studies have shown that P2Y12 is functionally expressed not only in platelets and the microglia but also in other cells of the immune system, such as in monocytes, dendritic cells, and T lymphocytes. As a result, studies were carried out investigating whether therapies targeting P2Y12 could also ameliorate inflammatory conditions, such as sepsis, rheumatoid arthritis, neuroinflammation, cancer, COVID-19, atherosclerosis, and diabetes-associated inflammation in animal models and human subjects. This review reports what is known about the expression of P2Y12 in the cells of the immune system and the effect of P2Y12 activation and/or inhibition in inflammatory conditions. Lastly, we will discuss the major problems and challenges in studying this receptor and provide insights on how they can be overcome.

3-Arylidene-2-oxindoles as GSK3ß inhibitors and anti-thrombotic agents.

Development of novel agents that prevent thrombotic events is an urgent task considering increasing incidence of cardiovascular diseases and coagulopathies that accompany cancer and COVID-19. Enzymatic assay identified novel GSK3ß inhibitors in a series of 3-arylidene-2-oxindole derivatives. Considering the putative role of GSK3ß in platelet activation, the most active compounds were evaluated for antiplatelet activity and antithrombotic activity. It was found that GSK3ß inhibition by 2-oxindoles correlates with inhibition of platelet activation only for compounds 1b and 5a. Albeit, in vitro antiplatelet activity matched well with in vivo anti-thrombosis activity. The most active GSK3ß inhibitor 5a exceeds antiplatelet activity of acetylsalicylic acid in vitro by 10.3 times and antithrombotic activity in vivo by 18.7 times (ED50 7.3 mg/kg). These results support the promising role of GSK3ß inhibitors for development of novel antithrombotic agents.

Immune response to BNT162b2 SARS-CoV-2 vaccine in patients living with HIV: The COVIH-DAPT study.

Introduction: Data on immune response to SARS-CoV-2 vaccine in patients living with HIV (PLWH) over a period longer than 3 months are currently limited. We measured the immune response after BNT162b2 vaccination against SARS-CoV-2 in this population. Methods: We prospectively enrolled PLWH on successful antiretroviral therapy, initiating vaccination with two doses of the BNT162b2 SARS-CoV-2 vaccine administered at six-week interval. SARS-CoV-2 humoral and cellular responses and lymphocyte cell subsets were recorded at inclusion and 6 weeks (W6), 3 months (M3) and 6 months (M6) later. Humoral, humoral strong and cellular responders were defined by IgG titers >10, ≥264BAU/mL and IFN-γ T cell release, respectively. Results: Nineteen subjects without SARS-CoV-2 infection were included (74% men, mean age 51 years, CD4 nadir 399/mm3). All subjects were humoral responders, their antibody titer peak reached at M3. Strong responders' rates were 63% and 21% at M3 and M6, respectively. CD19+CD10+ B cells had increased significantly at W6 then decreased at M3, while CD19+CD27+ B cells remained unchanged. Rates of patients with a cellular response increased from 39% at W6 to 69% at M6. Cellular responders had significantly higher CD3+, CD4+ and CD8+ Effector Memory cells at inclusion (p=0.048, p=0.024, p=0.012, respectively) and CD4+ Terminally Differentiated Effector Memory cells at M3 (p=0.044). Discussion: PLWH have a robust immune response after SARS-CoV-2 vaccination, but a rapid decline in humoral response from 3 months onwards, due to a blunted memory B cell response. Analysis of lymphocyte subsets may help identify optimal times for vaccine boosters.

[Clinical analysis of severe/critical 2019 novel coronavirus Omicron variant infection combined with atrial fibrillation].

OBJECTIVE: To investigate the clinical characteristics and prognosis of coronavirus disease 2019 (COVID-19) patients with Omicron variant combined with atrial fibrillation (AF). METHODS: From March 23, 2022 to May 15, 2022, 2 675 aged ≥ 50 years old COVID-19 patients with AF were admitted to Zhoupu Hospital, the designated hospital for COVID-19 in Shanghai. Patients were divided into mild symptoms group, normal group, and serious/critical group according to the symptoms. The clinical data, imaging examination and laboratory results and prognosis of the three group patients were compared. RESULTS: The median age of 2 675 COVID-19 patients was 69.0 (60.0, 81.0) years old, the incidence of AF was 5.05% (135/2 675), the age range of AF patients were from 55 to 101 years old, with a median age of 84.0 (74.0, 89.0), and the number of mild symptoms, normal, serious/critical patients were 68, 30, 37, respectively, including 9 of serious and 28 of critical patients. In the serious/critical patients, aged 55-75 years old accounted for 43.2%, the rate of 2019 novel coronavirus vaccination was 32.4%. The identified new-onset AF was the highest among the three groups, but the rate of persistent AF was the highest in the mild symptoms group (58.8%). The severe/critical group complicated with fever (29.7%), hepatic insufficiency (13.5%), renal insufficiency (46.0%), type 2 diabetes (46.0%), and heart failure were higher in NYHA classification [compared with the mild symptoms and normal group (score): 1.8±1.1 vs. 1.1±0.8, 1.2±0.7, respectively, all P < 0.05]. In term of laboratory examinations, C-reactive protein (CRP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were significantly higher in serious/critical patients compared to the mild symptoms and normal groups [CRP (mg/L): 27.2 (6.0, 60.8) vs. 7.6 (3.1, 19.3), 12.8 (4.9, 26.3), ALT (U/L): 31.3±15.4 vs. 15.4±9.3, 19.3±11.7, AST (U/L): 78.0±21.7 vs. 34.7±15.6, 38.1±24.4, all P < 0.05]. The hemoglobin (Hb) and albumin (ALB) levels were significantly lower than those in the mild symptoms and normal groups [Hb (g/L): 105.3±22.5 vs. 125.8±25.4, 123.0±20.4, ALB (g/L): 33.7±6.0 vs. 39.0±5.5 and 39.6±13.1, all P < 0.05]. In addition, MB isoenzyme of creatine kinase (CK-MB) was significantly higher in the serious/critical group than that in the mild symptoms group [µg/L: 2.5 (1.5, 3.4) vs. 2.2 (1.2, 2.8), P < 0.05]. In terms of the treatment, the percentage of antiplatelet agents and low-molecular heparin ratio compared among the three groups were statistically significant, with the serious/critical group using the lowest percentage of antiplatelet agents (27.0%) and a higher percentage of low-molecular heparin usage than that in mild symptoms group [81.1% (30/37) vs. 51.5% (35/68), P < 0.05]. In terms of prognosis, the mortality of patients with AF was 18.5% (25/135), all of whom were critical ill, including 32.0% (8/25) with cerebral embolism, pulmonary embolism and cerebral hemorrhage. Among them, 40.0% (10/25) died of multiple organ failure (40.0% combined with gastrointestinal hemorrhage), 20.0% (5/25) died of heart failure, and 12.0% (3/25) died of respiratory failure; while there were no death cases recorded in the mild symptoms, normal group and 9 serious patients. CONCLUSIONS: The serious/critical patients infected with COVID-19 Omicron variant with AF, have a worse prognosis and high mortality. Multiple organ failure, heart failure, sudden cardiac death, respiratory failure and embolic disease are the major causes of death.

The impact of platelets on pulmonary microcirculation throughout COVID-19 and its persistent activating factors.

Patients with COVID-19 often have hypoxemia, impaired lung function, and abnormal imaging manifestations in acute and convalescent stages. Alveolar inflammation, pulmonary vasculitis, and thromboembolism synergistically damage the blood-air barrier, resulting in increased pulmonary permeability and gas exchange disorders. The incidence of low platelet counts correlates with disease severity. Platelets are also involved in the impairment of pulmonary microcirculation leading to abnormal lung function at different phases of COVID-19. Activated platelets lose the ability to protect the integrity of blood vessel walls, increasing the permeability of pulmonary microvasculature. High levels of platelet activation markers are observed in both mild and severe cases, short and long term. Therefore, the risk of thrombotic events may always be present. Vascular endothelial injury, immune cells, inflammatory mediators, and hypoxia participate in the high reactivity and aggregation of platelets in various ways. Microvesicles, phosphatidylserine (PS), platelets, and coagulation factors are closely related. The release of various cell-derived microvesicles can be detected in COVID-19 patients. In addition to providing a phospholipid surface for the synthesis of intrinsic factor Xase complex and prothrombinase complex, exposed PS also promotes the decryption of tissue factor (TF) which then promotes coagulant activity by complexing with factor VIIa to activate factor X. The treatment of COVID-19 hypercoagulability and thrombosis still focuses on early intervention. Antiplatelet therapy plays a role in relieving the disease, inhibiting the formation of the hypercoagulable state, reducing thrombotic events and mortality, and improving sequelae. PS can be another potential target for the inhibition of hypercoagulable states.

Platelet activation and coronavirus disease 2019 mortality: Insights from coagulopathy, antiplatelet therapy and inflammation.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with an inflammatory cytokine burst and a prothrombotic coagulopathy. Platelets may contribute to microthrombosis, and constitute a therapeutic target in COVID-19 therapy. AIM: To assess if platelet activation influences mortality in COVID-19. METHODS: We explored two cohorts of patients with COVID-19. Cohort A included 208 ambulatory and hospitalized patients with varying clinical severities and non-COVID patients as controls, in whom plasma concentrations of the soluble platelet activation biomarkers CD40 ligand (sCD40L) and P-selectin (sP-sel) were quantified within the first 48hours following hospitalization. Cohort B was a multicentre cohort of 2878 patients initially admitted to a medical ward. In both cohorts, the primary outcome was in-hospital mortality. RESULTS: In cohort A, median circulating concentrations of sCD40L and sP-sel were only increased in the 89 critical patients compared with non-COVID controls: sP-sel 40,059 (interquartile range 26,876-54,678)pg/mL; sCD40L 1914 (interquartile range 1410-2367)pg/mL (P<0.001 for both). A strong association existed between sP-sel concentration and in-hospital mortality (Kaplan-Meier log-rank P=0.004). However, in a Cox model considering biomarkers of immunothrombosis, sP-sel was no longer associated with mortality, in contrast to coagulopathy evaluated with D-dimer concentration (hazard ratio 4.86, 95% confidence interval 1.64-12.50). Moreover, in cohort B, a Cox model adjusted for co-morbidities suggested that prehospitalization antiplatelet agents had no significant impact on in-hospital mortality (hazard ratio 1.05, 95% CI 0.80-1.37; P=0.73). CONCLUSIONS: Although we observed an association between excessive biomarkers of platelet activation and in-hospital mortality, our findings rather suggest that coagulopathy is more central in driving disease progression, which may explain why prehospitalization antiplatelet drugs were not a protective factor against mortality in our multicentre cohort.

The Effectiveness of Antiplatelet Therapy and the Factors Influencing It in Patients with Acute Coronary Syndrome before and during the COVID-19 Pandemic.

Background and Objectives: Dual antiplatelet therapy (DAPT) is essential in the treatment of patients with acute coronary syndrome (ACS). The objective of this study was to evaluate the effectiveness of antiplatelet medication in our practice and to investigate the factors that influence it. Materials and Methods: A prospective cohort observational study was conducted, in which 193 patients with ACS were enrolled. The patients were stented in the catheterization laboratory between May 2019 and October 2020, before and during the COVID-19 pandemic, and were receiving DAPT. Their platelet functions were tested using a Multiplate Analyzer. In addition to this, clinical data, demographics, laboratory tests, and cardiovascular risk factors were also analyzed. Results: 43.46% of the patients treated with aspirin were found to be resistant to it. This phenomenon was more common in men (48.17% vs. 31.48%, p = 0.036), and it was associated with being under the age of 50 (OR: 2.08; 95% CI: 1.11-3.90) and weighing over 70 kg (OR: 3.00; 95% CI: 1.21-7.40). Most of the patients treated with clopidogrel were in the optimal treatment window, while about half of the patients treated with ticagrelor had an exaggerated pharmacological response. Among the laboratory parameters, leukocytosis and platelet count were found to be determinants of platelet reactivity for both the aspirin and ticagrelor treatments. Conclusions: Many patients treated with antiplatelet agents are outside of the treatment window. The results obtained showed that low doses of gastro-resistant aspirin tablets are ineffective, and their efficacy can be influenced by various clinical and laboratory factors. Patients receiving ticagrelor have significantly reduced platelet reactivity, influenced only by certain laboratory indicators. The pandemic significantly influenced the results of the platelet aggregation tests only in patients treated with clopidogrel.

ISTH guidelines for antithrombotic treatment in COVID-19.

Antithrombotic agents reduce risk of thromboembolism in severely ill patients. Patients with coronavirus disease 2019 (COVID-19) may realize additional benefits from heparins. Optimal dosing and timing of these treatments and benefits of other antithrombotic agents remain unclear. In October 2021, ISTH assembled an international panel of content experts, patient representatives, and a methodologist to develop recommendations on anticoagulants and antiplatelet agents for patients with COVID-19 in different clinical settings. We used the American College of Cardiology Foundation/American Heart Association methodology to assess level of evidence (LOE) and class of recommendation (COR). Only recommendations with LOE A or B were included. Panelists agreed on 12 recommendations: three for non-hospitalized, five for non-critically ill hospitalized, three for critically ill hospitalized, and one for post-discharge patients. Two recommendations were based on high-quality evidence, the remainder on moderate-quality evidence. Among non-critically ill patients hospitalized for COVID-19, the panel gave a strong recommendation (a) for use of prophylactic dose of low molecular weight heparin or unfractionated heparin (LMWH/UFH) (COR 1); (b) for select patients in this group, use of therapeutic dose LMWH/UFH in preference to prophylactic dose (COR 1); but (c) against the addition of an antiplatelet agent (COR 3). Weak recommendations favored (a) sulodexide in non-hospitalized patients, (b) adding an antiplatelet agent to prophylactic LMWH/UFH in select critically ill, and (c) prophylactic rivaroxaban for select patients after discharge (all COR 2b). Recommendations in this guideline are based on high-/moderate-quality evidence available through March 2022. Focused updates will incorporate future evidence supporting changes to these recommendations.

International Perspectives on the Impact of the COVID-19 Pandemic on Adherence to Prescribed Dual Antiplatelet Therapy: A Window Into Acute Cardiovascular Care.

An international panel of expert clinicians and researchers in acute cardiac care was convened to review, describe, and contextualize their varied experiences delivering care and maintaining ongoing research during the first year of the COVID-19 pandemic and beyond. A proposed perspective from which care and outcomes could be viewed was the possibility that without routine follow-up and as-accustomed interactions with their care team, patients at risk of acute atherothrombotic events might be less adherent to prescribed antiplatelet medications. This might be manifested by more emergency coronary events or by an increased (and perhaps unidentifiable) incidence of out-of-hospital cardiovascular deaths related to patient anxiety about presenting to hospital during the pandemic. The experiences of the panel members were similar in many regards, which identified opportunities for improvement in cardiac care the next time there is a substantial disruption of usual practice. Regardless of geography or payor system, there was an identified need for better remote care platforms; but stronger infrastructure and consumer facility with remote care technology, improved provider-patient communication to help ensure adherence to primary and secondary prevention medications, and longer-term prescription fills and no-hassle refills on such medications. Profound disruptions in acute cardiovascular research highlighted the need for redundancy or back-up planning for teams engaged in time-sensitive research, to ensure both continuity of protocols and patient safety.

Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients With COVID-19: COVID-PACT.

BACKGROUND: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically ill COVID-19 patients remain uncertain. METHODS: COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial) was a multicenter, 2×2 factorial, open-label, randomized-controlled trial with blinded end point adjudication in intensive care unit-level patients with COVID-19. Patients were randomly assigned to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomly assigned to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death attributable to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win ratio and time-to-first event analysis while patients were on treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was moderate to severe bleeding. Recruitment was stopped early in March 2022 (≈50% planned recruitment) because of waning intensive care unit-level COVID-19 rates. RESULTS: At 34 centers in the United States, 390 patients were randomly assigned between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio, 1.95 [95% CI, 1.08-3.55]; P=0.028). Results were consistent in time-to-event analysis for the primary efficacy end point (full-dose versus standard-dose incidence 19/191 [9.9%] versus 29/191 [15.2%]; hazard ratio, 0.56 [95% CI, 0.32-0.99]; P=0.046). The primary safety end point occurred in 4 (2.1%) on full dose and in 1 (0.5%) on standard dose (P=0.19); the secondary safety end point occurred in 15 (7.9%) versus 1 (0.5%; P=0.002). There was no difference in all-cause mortality (hazard ratio, 0.91 [95% CI, 0.56-1.48]; P=0.70). There were no differences in the primary efficacy or safety end points with clopidogrel versus no antiplatelet therapy. CONCLUSIONS: In critically ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04409834.

Pleiotropic Effects of Ticagrelor: Influence on CYP4F2 Gene and Protein Expression in HUVEC and HepG2, and Escherichia coli Bacterial Survival.

Background: Antiplatelet drugs, such as ticagrelor, which target platelet P2Y12 receptors, are used for prevention of ischemic heart disease. Ticagrelor is also known to have pleiotropic effects of unknown mechanisms. Ticagrelor could influence the expression of molecules involved in resolution of inflammation. This study aimed to investigate if ticagrelor could change the expression of CYP4F2 and its encoded protein concentration and, additionally, to determine ticagrelor possible antibacterial activity against gram-negative bacteria. Methods: CYP4F2 expression was determined in HUVEC and HepG2 cell lines by qPCR. CYP4F2 protein concentration was determined by ELISA. Antibiotic susceptibility testing was performed using a disc diffusion method. Results: Ticagrelor was observed to reduce the expression of CYP4F2 in HUVEC and HepG2 cell lines. It also reduced CYP4F2 protein levels in HUVEC cells. Ticagrelor had no bactericidal activity against gram-negative third generation cephalosporin resistant E. coli. Conclusion: Ticagrelor reduced CYP4F2 protein concentration in HUVEC, and CYP4F2 expression in HUVEC and HepG2 cells, but had no effect on third-generation cephalosporin-resistant E. coli strains.

In critically ill patients with COVID-19, antiplatelet therapy did not increase organ support-free days at 21 d.

SOURCE CITATION: REMAP-CAP Writing Committee for the REMAP-CAP Investigators. Effect of antiplatelet therapy on survival and organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2022;327:1247-59. 35315874.

Antiplatelet Activity of Riamilovir under Conditions of Lipopolysaccharide Intoxication.

We studied the effect of antiviral agent riamilovir on ADP-induced platelet aggregation in the absence and presence of LPS. Unlike acetylsalicylic acid (reference drug), riamilovir did not exhibit antiplatelet effect in vitro. However, it markedly suppressed platelet reactivity in LPS-treated blood samples and was 2.2-fold superior to acetylsalicylic acid in terms of IC50 value. In in vivo experiments, riamilovir under conditions of hypercytokinemia blocked platelet aggregation in rats by 64%.

Good practice statements for antithrombotic therapy in the management of COVID-19: Guidance from the SSC of the ISTH.

Despite the emergence of high quality randomized trial data with the use of antithrombotic agents to reduce the risk of thromboembolism, end-organ failure, and possibly mortality in patients with coronavirus disease 2019 (COVID-19), questions still remain as to optimal patient selection for these strategies, the use of antithrombotics in outpatient settings and in-hospital settings (including critical care units), thromboprophylaxis in special patient populations, and the management of acute thrombosis in hospitalized COVID-19 patients. In October 2021, the International Society on Thrombosis and Haemostasis (ISTH) formed a multidisciplinary and international panel of content experts, two patient representatives, and a methodologist to develop recommendations on treatment with anticoagulants and antiplatelet agents for COVID-19 patients. The ISTH Guideline panel discussed additional topics to be well suited to a non-Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for Good Practice Statements (GPS) to support good clinical care in the antithrombotic management of COVID-19 patients in various clinical settings. The GPS panel agreed on 17 GPS: 3 in the outpatient (pre-hospital) setting, 12 in the hospital setting both in non-critical care (ward) as well as intensive care unit settings, and 2 in the immediate post-hospital discharge setting based on limited evidence or expert opinion that supports net clinical benefit in enacting the statements provided. The antithrombotic therapies discussed in these GPS should be available in low- and middle-income countries.

Repurposing the Antiplatelet Agent Ticlopidine to Counteract the Acute Phase of ER Stress Condition: An Opportunity for Fighting Coronavirus Infections and Cancer.

Different pathological conditions, including viral infections and cancer, can have a massive impact on the endoplasmic reticulum (ER), causing severe damage to the cell and exacerbating the disease. In particular, coronavirus infections, including SARS coronavirus-2 (SARS-CoV-2), responsible for COVID-19, cause ER stress as a consequence of the enormous amounts of viral glycoproteins synthesized, the perturbation of ER homeostasis and the modification of ER membranes. Therefore, ER has a central role in the viral life cycle, thus representing one of the Achilles' heels on which to focus therapeutic intervention. On the other hand, prolonged ER stress has been demonstrated to promote many pro-tumoral attributes in cancer cells, having a key role in tumor growth, metastasis and response to therapies. In this report, adopting a repurposing approach of approved drugs, we identified the antiplatelet agent ticlopidine as an interferent of the unfolded protein response (UPR) via sigma receptors (SRs) modulation. The promising results obtained suggest the potential use of ticlopidine to counteract ER stress induced by viral infections, such as COVID-19, and cancer.

Risk assessment in COVID-19: Prognostic importance of cardiovascular parameters.

BACKGROUND: Cardiovascular risk factors and comorbidities are highly prevalent among COVID-19 patients and are associated with worse outcomes. HYPOTHESIS: We therefore investigated if established cardiovascular risk assessment models could efficiently predict adverse outcomes in COVID-19. Furthermore, we aimed to generate novel risk scores including various cardiovascular parameters for prediction of short- and midterm outcomes in COVID-19. METHODS: We included 441 consecutive patients diagnosed with SARS-CoV-2 infection. Patients were followed-up for 30 days after the hospital admission for all-cause mortality (ACM), venous/arterial thromboembolism, and mechanical ventilation. We further followed up the patients for post-COVID-19 syndrome for 6 months and occurrence of myocarditis, heart failure, acute coronary syndrome (ACS), and rhythm events in a 12-month follow-up. Discrimination performance of DAPT, GRACE 2.0, PARIS-CTE, PREDICT-STABLE, CHA2-DS2-VASc, HAS-BLED, PARIS-MB, PRECISE-DAPT scores for selected endpoints was evaluated by ROC-analysis. RESULTS: Out of established risk assessment models, GRACE 2.0 score performed best in predicting combined endpoint and ACM. Risk assessment models including age, cardiovascular risk factors, echocardiographic parameters, and biomarkers, were generated and could successfully predict the combined endpoint, ACM, venous/arterial thromboembolism, need for mechanical ventilation, myocarditis, ACS, heart failure, and rhythm events. Prediction of post-COVID-19 syndrome was poor. CONCLUSION: Risk assessment models including age, laboratory parameters, cardiovascular risk factors, and echocardiographic parameters showed good discrimination performance for adverse short- and midterm outcomes in COVID-19 and outweighed discrimination performance of established cardiovascular risk assessment models.