Faculty Bibliography

Background : Patients with Human Immunodeficiency Virus (HIV) exhibit an activated platelet phenotype and an increased risk of Cardiovascular Disease (CVD). Aims : We conducted a randomized controlled trial to investigate the efficacy of aspirin and clopidogrel (two anti-platelet medications commonly used to prevent CVD) to reduce platelet activation and platelet effector cell properties in HIV patients. Methods : Fifty five HIV positive patients (mean age 53.5 +/- 7.8 years, 42.6% female, mean CD4+ T-cell count 665.6 cells/m 3 ), were enrolled to receive clopidogrel ( n = 22, 75 mg/d), aspirin ( n = 22, 81 mg/d), or no-treatment ( n = 11) for 14-days. Platelet aggregation and platelet receptor expression of p-selectin and pac-1 was assessed at baseline and day 14. To assess the impact of platelet inhibition on the endothelium ( in vitro ), platelets isolated from 6 patients (2/ group) at baseline and follow-up were incubated in HUVECs and proinflammatory HUVEC gene expression was assessed (Nanostring, 594 transcripts). Results : Aspirin treatment significantly reduced platelet aggregation to arachidonic acid (AA) (84% to 31%, P < 0.01) while clopidogrel reduced platelet aggregation to adenosine diphosphate (ADP) (85% to 41%, P < 0.001), confirming study drug compliance. Clopidogrel treatment decreased platelet p-selectin (-5.9%, P = 0.04), p-selectin plus thrombin (-40.8%, P = 0.03), pac-1 expression (-8%, P = 0.02), and pac-1 plus ADP (-24.0%, P = 0.03) and AA (-24.0%, P < 0.01). In contrast, aspirin did not affect p-selectin or pac-1 expression. When compared to no-treatment, HIV patients on clopidogrel exhibited a reduction in the composite pro-inflammatory transcript expression of platelet treated HUVECS (Log2 Fold DELTA -0.07 +/- 0.58 vs. -0.12 +/- 0.53, P < 0.001) while aspirin treated platelets upregulated HUVEC transcript expression (Log2 Fold DELTA-0.07 +/- 0.58 vs. 0.19 +/- 0.59, P < 0.001). Conclusions : Clopidogrel, but not aspirin, reduced platelet activation and HUVEC pro-inflammatory gene expression. Our results suggest that clopidogrel as opposed to aspirin may be preferential to reduce CV risk in HIV; however, larger clinical trials are needed to expand upon these findings

BACKGROUND AND AIMS/OBJECTIVE:Obesity is an independent risk factor for atherosclerotic cardiovascular disease (CVD), and platelet hyperactivation in obesity may contribute to this association. Olive oil consumption is associated with lower cardiovascular disease (CVD) risk in the general population. However, little is known for individuals with obesity. We investigated whether olive oil intake is associated with platelet activation in obesity. METHODS AND RESULTS/RESULTS:. Olive oil intake was stratified into <1 time/week (n = 21), 1-3 times/week (n = 18), ≥4 times/week (n = 24). Strata did not differ by age, BMI or platelet count. Unstimulated P-selectin expression did not differ by olive oil consumption. Subjects with more frequent olive oil intake exhibited lower P-selectin expression on submaximal thrombin exposure. CONCLUSIONS:More frequent olive oil intake is associated with reduced thrombin-induced platelet activation in obesity.

BACKGROUND:Coronavirus disease 2019 (COVID-19) is associated with macro- and micro-thromboses, which are triggered by endothelial cell activation, coagulopathy, and uncontrolled inflammatory response. Conventional antithrombotic agents are under assessment in dozens of randomized controlled trials (RCTs) in patients with COVID-19, with preliminary results not demonstrating benefit in several studies. OBJECTIVES/OBJECTIVE:Given the possibility that more novel agents with antithrombotic effects may have a potential utility for management of patients with COVID-19, we assessed ongoing RCTs including these agents with their potential mechanism of action in this population. METHODS:We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to identify RCTs of novel antithrombotic agents in patients with COVID-19. RESULTS:Based on a systematic literature search, 27 RCTs with 10 novel antithrombotic agents (including nafamostat, dociparstat, rNAPc2, and defibrotide) were identified. The results from these trials have not been disseminated yet. The studied drugs in the ongoing or completed RCTs include agents affecting the coagulation cascade, drugs affecting endothelial activation, and mixed acting agents. Their postulated antithrombotic mechanisms of action and their potential impact on patient management are summarized. CONCLUSION/CONCLUSIONS:Some novel antithrombotic agents have pleiotropic anti-inflammatory and antiviral effects, which may help reduce the viral load or fibrosis, and improve oxygenation. Results from ongoing RCTs will elucidate their actual role in the management of patients with COVID-19.

OBJECTIVE:Heightened inflammation, dysregulated immunity, and thrombotic events are characteristic of hospitalized COVID-19 patients. Given that platelets are key regulators of thrombosis, inflammation, and immunity they represent prime candidates as mediators of COVID-19-associated pathogenesis. The objective of this study was to understand the contribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the platelet phenotype via phenotypic (activation, aggregation) and transcriptomic characterization. APPROACH AND RESULTS/UNASSIGNED:In a cohort of 3915 hospitalized COVID-19 patients, we analyzed blood platelet indices collected at hospital admission. Following adjustment for demographics, clinical risk factors, medication, and biomarkers of inflammation and thrombosis, we find platelet count, size, and immaturity are associated with increased critical illness and all-cause mortality. Bone marrow, lung tissue, and blood from COVID-19 patients revealed the presence of SARS-CoV-2 virions in megakaryocytes and platelets. Characterization of COVID-19 platelets found them to be hyperreactive (increased aggregation, and expression of P-selectin and CD40) and to have a distinct transcriptomic profile characteristic of prothrombotic large and immature platelets. In vitro mechanistic studies highlight that the interaction of SARS-CoV-2 with megakaryocytes alters the platelet transcriptome, and its effects are distinct from the coronavirus responsible for the common cold (CoV-OC43). CONCLUSIONS:Platelet count, size, and maturity associate with increased critical illness and all-cause mortality among hospitalized COVID-19 patients. Profiling tissues and blood from COVID-19 patients revealed that SARS-CoV-2 virions enter megakaryocytes and platelets and associate with alterations to the platelet transcriptome and activation profile.

[Figure: see text].

Regional variations exist in the epidemiology of peripheral artery disease (PAD), in comorbidities, use of secondary prevention, and outcomes. Large studies of these variations in worldwide populations are rare. The EUCLID (Examining Use of tiCagreLor In peripheral artery Disease) trial included 13,885 patients with PAD from four geographical regions (Central/South America, Europe, Asia, North America) and compared monotherapy with ticagrelor and clopidogrel. Inclusion criteria were either an ankle-brachial index < 0.80 or a prior revascularization. The primary efficacy endpoint was time to first occurrence of any event in the composite of cardiovascular death, myocardial infarction, or ischemic stroke and did not differ between the study arms. This post hoc analysis of EUCLID confirmed that regional differences occurred in the inclusion criteria with more prior revascularization in North America (73.9%) and Asia (72.5%) compared with Central/South America (34.0%) and Europe (51.6%). The characteristics of patients also differed. Prior amputation at baseline was most frequent in Central/South America (6.3%) compared with other regions (1.6-2.8%). A history of stroke was most common in Asia, coronary heart disease in North America, and diabetes in Central/South America compared with other regions. The incidence of outcomes in patients with PAD varied by region. North America had the highest rate of the primary combined endpoint (5.97 events/100 patient-years). Corresponding rates were 4.80, 3.95, and 3.87 for Asia, Europe, and Central/South America, respectively. Hospitalization for acute limb ischemia (events/100 patient-years) was most frequent in Europe (0.75) and North America (0.74) compared with Asia (0.60) and Central/South America (0.33). Adjustment for inclusion criteria and relevant PAD characteristics did not have a major impact on these regional differences. Further adjustment for concomitant disease, risk factors, and preventive medication modified the regional differences only marginally. In conclusion, substantial regional differences were found in cardiovascular and limb outcomes in patients with PAD and were not explained by variation in the category of included patients, concomitant disease, risk factors, and prevention. Such differences, which may be due to variation in other factors such as background population rates or clinical care, need to be considered when designing and interpreting large international studies (ClinicalTrials.gov Identifier: NCT01732822).

[Figure: see text].

PURPOSE OF REVIEW/OBJECTIVE:Psoriasis is a chronic inflammatory skin condition that is associated with increased cardiovascular risk compared to those without psoriasis. This review will cover emerging mechanisms of cardiovascular risk, key pathways targeted with biologic therapies, and the current evidence on therapies to modulate this risk in patients with psoriasis. RECENT FINDINGS/RESULTS:Recent scientific work has highlighted mechanisms that contribute to this enhanced risk, including the role of vascular endothelial dysfunction, platelet activation, dyslipidemia, and increased cardiometabolic comorbidities. Newer biologic and targeted synthetic therapies have transformed psoriasis treatment with high rates of clinical remission and durable skin disease control now possible. Epidemiological evidence suggests that many of these therapies may lower cardiovascular risk in psoriasis, although prospective interventional data is lacking (or mixed). Recently, caution has also been raised that some treatments may negatively affect cardiovascular risk. Overall, the current data suggests a positive or neutral ability to reduce cardiovascular risk for TNF, IL-17A, and IL-12/23p40 inhibitors, but current evidence remains conflicting for anti-IL-23/p19 and JAK inhibitors. More studies that include prospective cohorts, larger number of patients, treatment duration, and validated surrogate outcomes are needed to better evaluate the role of biologic therapies on cardiovascular risk in psoriasis.