Faculty Bibliography

BACKGROUND:Posttraumatic venous thromboembolism (VTE) remains prevalent in severely injured patients despite chemoprophylaxis. Importantly, although platelets are central to thrombosis, they are not routinely targeted in prevention of posttraumatic VTE. Furthermore, platelets from injured patients show ex vivo evidence of increased activation yet impaired aggregation, consistent with functional exhaustion. However, the relationship of this platelet functional phenotype with development of posttraumatic VTE is unknown. We hypothesized that, following injury, impaired ex vivo platelet aggregation (PA) is associated with the development of posttraumatic VTE. METHODS:We performed a secondary analysis of 133 severely injured patients from a prospective observational study investigating coagulation and inflammation (2011-2019). Platelet aggregation in response to stimulation with adenosine diphosphate (ADP), collagen, and thrombin was measured at presentation (preresuscitation) and 24 hours (postresuscitation). Viscoelastic clot strength and lysis were measured in parallel by thromboelastography. Multivariable regression examined relationships between PA at presentation, 24 hours, and the change (δ) in PA between presentation and 24 hours with development of VTE. RESULTS:The 133 patients were severely injured (median Injury Severity Score, 25), and 14% developed VTE (all >48 hours after admission). At presentation, platelet count and PA were not significantly different between those with and without incident VTE. However, at 24 hours, those who subsequently developed VTE had significantly lower platelet counts (126 × 10 9 /L vs. 164 × 10 9 /L, p = 0.01) and lower PA in response to ADP ( p < 0.05), collagen ( p < 0.05), and thrombin ( p = 0.06). Importantly, the magnitude of decrease in PA (δ) from presentation to 24 hours was independently associated with development of VTE (adjusted odds ratios per 10 aggregation unit decrease: δ-ADP, 1.31 [ p = 0.03]; δ-collagen, 1.36 [ p = 0.01]; δ-thrombin, 1.41 [ p < 0.01]). CONCLUSION:Severely injured patients with decreasing ex vivo measures of PA despite resuscitation have an increased risk of developing VTE. This may have implications for predicting development of VTE and for studying platelet targeted chemoprophylaxis regimens. LEVEL OF EVIDENCE:Prognostic/Epidemiological; Level III.

BACKGROUND:Male sex, elevated troponin levels, and elevated D-dimer levels are associated with more complicated COVID-19 illness and greater mortality; however, while there are known sex differences in the prognostic value of troponin and D-dimer in other disease states, it is unknown whether they exist in the setting of COVID-19. OBJECTIVE:We assessed whether sex modified the relationship between troponin, D-dimer, and severe COVID-19 illness (defined as mechanical ventilation, ICU admission or transfer, discharge to hospice, or death). METHODS:We conducted a retrospective cohort study of patients hospitalized with COVID-19 at a large, academic health system. We used multivariable regression to assess associations between sex, troponin, D-dimer, and severe COVID-19 illness, adjusting for demographic, clinical, and laboratory covariates. To test whether sex modified the relationship between severe COVID-19 illness and troponin or D-dimer, models with interaction terms were utilized. RESULTS:Among 4,574 patients hospitalized with COVID-19, male sex was associated with higher levels of troponin and greater odds of severe COVID-19 illness, but lower levels of initial D-dimer when compared with female sex. While sex did not modify the relationship between troponin level and severe COVID-19 illness, peak D-dimer level was more strongly associated with severe COVID-19 illness in male patients compared to female patients (males: OR=2.91, 95%CI=2.63-2.34, p<0.001; females: OR=2.31, 95%CI=2.04-2.63, p<0.001; p-interaction=0.005). CONCLUSION/CONCLUSIONS:Sex did not modify the association between troponin level and severe COVID-19 illness, but did modify the association between peak D-dimer and severe COVID-19 illness, suggesting greater prognostic value for D-dimer in males with COVID-19.

Introduction/UNASSIGNED:Platelet dysfunction and cardiovascular risk are well-recognized features of chronic kidney disease (CKD). Platelets drive the development and progression of cardiovascular disease (CVD). The relationships between kidney function, platelet activity, and cardiovascular risk are poorly defined. Methods/UNASSIGNED:) using data from the Platelet Activity and Cardiovascular Events study, a prospective cohort study that enrolled adults with peripheral artery disease (PAD) undergoing lower extremity revascularization. Platelet activity was measured using light transmission aggregometry (LTA) in response to submaximal dose agonist stimulation, and the subjects were followed for incident adverse cardiovascular events for a median of 18 months. Results/UNASSIGNED: < 0.05 for each). Following multivariable adjustment, subjects with CKD had elevated risk for myocardial infarction (MI) (adjusted hazard ratio 2.2, 95% confidence interval [1.02-4.9]) and major adverse cardiovascular events (MACE) (1.9 [1.2-3.3]) compared to those without CKD. Platelet aggregation in response to submaximal dose agonist stimulation mediated 7% to 26% of the excess risk for cardiovascular events associated with CKD. Conclusion/UNASSIGNED:Among subjects with PAD undergoing lower extremity revascularization, CKD is associated with increased platelet activity that mediates, in part, elevated cardiovascular risk.

Prior observational studies suggest rivaroxaban is safe and effective among patients with morbid obesity who suffered a venous thromboembolism (VTE) event, but existing data are more limited in the broader population of VTE patients with obesity. This study assessed VTE recurrence, major bleeding, healthcare resource utilization, and healthcare costs among VTE patients with obesity who received rivaroxaban versus warfarin. VTE patients with obesity who initiated rivaroxaban or warfarin after a first VTE (index date) were identified from the IQVIA PharMetrics® Plus database (01/02/2011-09/30/2019). The follow-up period spanned from the index date until health plan disenrollment, end of data availability, cancer diagnosis/treatment, end of the 12 month post-index period, or (for the analysis of major bleeding) anticoagulant discontinuation or switch. Patient characteristics were balanced using inverse probability of treatment weighting. The weighted rivaroxaban (N = 8666) and warfarin cohorts (N = 5946) were well balanced (mean age = 51 years, females = 52%). Over a 9.6 months mean observation period, rivaroxaban users had a significantly lower risk of VTE recurrence [7.0% vs. 8.2%, HR(95% CI) = 0.85(0.75;0.97)] and a similar risk of major bleeding [4.1% vs. 3.6%, HR(95% CI) = 1.11(0.89;1.37)] relative to warfarin users at 12 months. Relative to warfarin users, rivaroxaban users had significantly fewer all-cause outpatient visits [RR(95% CI) = 0.71(0.70;0.74)]. The higher pharmacy costs incurred by rivaroxaban recipients (cost difference = $1252) were offset by lower medical costs (cost difference = - $2515, all p < 0.05) compared with warfarin recipients. Our findings suggest that rivaroxaban is safe and effective versus warfarin, and associated with lower medical costs among VTE patients with obesity.

Aspirin protects against atherothrombosis while increasing the risk of major bleeding. Although it is widely used to prevent cardiovascular disease (CVD), its benefit does not outweigh its risk for primary CVD prevention in large population settings. The recent United States Preventive Services Task Force guidelines on aspirin use to prevent CVD reflect this clinical tradeoff as well as the persistent struggle to define a population that would benefit from prophylactic aspirin therapy. Past clinical trials of primary CVD prevention with aspirin have not included consideration of a biomarker relevant to aspirin's mechanism of action, platelet inhibition. This approach is at odds with the paradigm used in other key areas of pharmacological CVD prevention, including antihypertensive and statin therapy, which combine cardiovascular risk assessment with the measurement of mechanistic biomarkers (eg, blood pressure and LDL [low-density lipoprotein]-cholesterol). Reliable methods for quantifying platelet activity, including light transmission aggregometry and platelet transcriptomics, exist and should be considered to identify individuals at elevated cardiovascular risk due to a hyperreactive platelet phenotype. Therefore, we propose a new, platelet-guided approach to the study of prophylactic aspirin therapy. We think that this new approach will reveal a population with hyperreactive platelets who will benefit most from primary CVD prevention with aspirin and usher in a new era of precision-guided antiplatelet therapy.

BACKGROUND:Recommended systolic blood pressure (SBP) targets often do not consider the relationship of low diastolic blood pressure (DBP) levels with cardiovascular disease (CVD) and all-cause mortality risk, which is especially relevant for older people with concurrent comorbidities.We examined the relationship of DBP levels to CVD and all-cause mortality in older women in the Women's Health Initiative Long Life Study (WHI-LLS). METHODS:The study sample included 7,875 women (mean age: 79 years) who underwent a BP measurement at an in-person home visit conducted in 2012-2013. CVD and all-cause mortality were centrally adjudicated. Hazard ratios (HR) were obtained from adjusted Cox proportional hazards models. RESULTS:After 5 years follow-up, all-cause mortality occurred in 18.4% of women. Compared to a DBP of 80 mmHg, the fully adjusted hazards ratio (HR) for mortality was 1.33 (95% CI: 1.04-1.71) for a DBP of 50 mmHg and 1.67 (95% CI: 1.29-2.16) for a DBP of 100 mmHg. The HRs for CVD were 1.14 (95% CI: 0.78-1.67) for a DBP of 50 mmHg and HR 1.50 (95% CI: 1.03-2.17) for a DBP of 100 mmHg. The nadir DBP associated with lowest mortality risk was 72 mmHg overall. CONCLUSIONS:In older women, consideration should be given to the potential adverse effects of low and high DBP. Low DBP may serve as a risk marker. DBP target levels between 68 and 75 mmHg may avoid higher mortality risk.

BACKGROUND:Clinical characteristics of patients with acute myocardial infarction after gastrointestinal bleeding are poorly characterized. We sought to evaluate the incidence, management and outcomes of myocardial infarction following hospitalization for gastrointestinal bleeding. METHODS:Patients admitted with a diagnosis of gastrointestinal bleeding with and without subsequent hospital readmissions for acute myocardial infarction within 90 days were identified in the 2014 United States Nationwide Readmission Database. Patients with myocardial infarction with and without a recent prior gastrointestinal bleed were compared to determine differences in management and in-hospital outcomes. Logistic regression models were used to estimate odds of invasive management and all-cause in-hospital mortality after covariate adjustment. RESULTS:A total of 644,622 patients with gastrointestinal bleeding were identified, of which 7,523 (1.2%) were readmitted for myocardial infarction within 90 days. Compared to myocardial infarction patients without recent gastrointestinal bleeding, patients with myocardial infarction within 90 days after gastrointestinal bleeding were older, more likely to be women, have kidney disease, present with non-ST segment elevation MI, and were less likely to undergo invasive management of AMI (28% vs 63%, P<0.01). Prior gastrointestinal bleeding was associated with higher all-cause in-hospital myocardial infarction mortality (22% vs 9%, P<0.01). CONCLUSION/CONCLUSIONS:In the first 3 months after hospitalization for gastrointestinal bleeding, 1 of every 83 patients was readmitted with acute myocardial infarction. Patients with myocardial infarction after gastrointestinal bleeding were less likely to undergo invasive management and coronary revascularization and had higher mortality than those without recent bleeding.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.

Aspirin's clinical efficacy may be influenced by body weight and mass. Although inadequate platelet inhibition by aspirin is suggested as responsible, evidence for this in non-diabetic patients is sparse. We investigated the influence of body weight and mass on aspirin's inhibition of platelet aggregation in healthy adults without diabetes. Cohort one (NYU, n = 84) had light transmission aggregometry (LTA) of platelet-rich plasma to submaximal adenosine diphosphate (ADP) and arachidonic acid (AA) before and following 1 week of daily 81 mg non-enteric coated aspirin. Subjects in the validation cohort (Duke, n = 66) were randomized to 81 mg or 325 mg non-enteric coated aspirin for 4 weeks, immediately followed by 4 weeks of the other dose, with LTA to submaximal collagen, ADP, and AA before and after each dosage period. Body mass index (BMI) range was 18.0-57.5 kg/m² and 25% were obese. Inhibition of platelet aggregation was similar irrespective of BMI, body weight and aspirin dose. There was no correlation between platelet aggregation before or after aspirin with BMI or body weight. Our data demonstrate that aspirin produces potent inhibition of direct and indirect COX1-mediated platelet aggregation in healthy adults without diabetes regardless of body weight or mass - suggesting that other mechanisms explain lower preventive efficacy of low-dose aspirin with increasing body weight/mass.