Faculty Bibliography

OBJECTIVES/OBJECTIVE:The rate of thromboembolic events among patients with coronavirus disease 2019 is high; however, there is no robust method to identify those at greatest risk. We reviewed thromboelastography studies in critically ill patients with coronavirus disease 2019 to characterize their coagulation states. DESIGN/METHODS:Retrospective. SETTING/METHODS:Tertiary ICU in New York City. PATIENTS/METHODS:Sixty-four patients with coronavirus disease 2019 admitted to the ICU with thromboelastography performed. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Fifty percent of patients had a clotting index in the hypercoagulable range (clotting index > 3) (median 3.05). Reaction time and K values were below the lower limit of normal in 43.8% of the population consistent with a hypercoagulable profile. The median α angle and maximum amplitude (75.8° and 72.8 mm, respectively) were in the hypercoagulable range. The α angle was above reference range in 70.3% of patients indicative of rapid clot formation. Maximum amplitude, a factor of fibrinogen and platelet count and function, and a measure of clot strength was above reference range in 60.1% of patients. Thirty-one percent had thromboembolic events; thromboelastography parameters did not correlate with events in our cohort. Those with D-dimer values greater than 2,000 were more likely to have shorter reaction times compared with those with D-dimer levels less than or equal to 2,000 (4.8 vs 5.6 min; p = 0.001). CONCLUSIONS:A large proportion of critically ill patients with coronavirus disease 2019 have hypercoagulable thromboelastography profiles with additional derangements related to fibrinogen and platelet function. As the majority of patients have an elevated thromboelastography maximum amplitude, a follow-up study evaluating platelet aggregation would be instructive.

BACKGROUND:Current guidelines recommend aggressive management of hypertension. Recent evidence suggested potential harm with low blood pressure targets in patients with peripheral artery disease. We investigated the association of a history of hypertension and office systolic blood pressure (SBP) with major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs). METHODS AND RESULTS/RESULTS:=0.392, respectively). CONCLUSIONS:History of hypertension was not associated with higher hazard for MACE or MALE in patients with peripheral artery disease. In contrast, there was a higher hazard of MACE in patients with out-of-target low and high SBP. High but not low SBP was associated with an increased risk of ischemic limb events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

OBJECTIVE:<0.001). Rates of adverse events increased with the magnitude of D-dimer elevation; individuals with presenting D-dimer >2000 ng/mL had the highest risk of critical illness (66%), thrombotic event (37.8%), acute kidney injury (58.3%), and death (47%). CONCLUSIONS:Abnormal D-dimer was frequently observed at admission with COVID-19 and was associated with higher incidence of critical illness, thrombotic events, acute kidney injury, and death. The optimal management of patients with elevated D-dimer in COVID-19 requires further study.

Variability in daily sleep patterns is an emerging factor linked to metabolic syndrome. However, whether reducing bedtime variability improves markers of disease risk has not been tested. Here, we assessed whether body composition and inflammation were impacted by changes in bedtime variability over a 6-week period, during which, women were instructed to maintain healthy, habitual sleep (HS) patterns (one arm of a randomized trial). Data were available for 37 women (age 34.9 ± 12.4 years, BMI 24.7 ± 2.9 kg/m², sleep duration 7.58 ± 0.49 h/night). Body composition and leukocyte platelet aggregates (LPA) were measured at baseline and endpoint using magnetic resonance imaging and flow cytometry, respectively. Sleep data were collected daily using wrist actigraphy. Change in bedtime variability was calculated as the difference in the standard deviation (SD) of bedtimes measured during the 2-week screening period and the 6-week intervention period. Results showed that women who reduced their bedtime variability (n = 29) during the intervention had reductions in total (P < 0.001) and subcutaneous adipose tissue (P < 0.001) relative to women who increased/maintained (n = 8) bedtime variability. Similar effects were observed for LPA levels between women who reduced vs increased/maintained bedtime variability (P = 0.011). Thus, reducing bedtime variability, without changing sleep duration, could improve cardiometabolic health by reducing adiposity and inflammation.

BACKGROUND AND PURPOSE/OBJECTIVE:Patients with the Coronavirus Disease of 2019 (COVID-19) are at increased risk for thrombotic events and mortality. Various anticoagulation regimens are now being considered for these patients. Anticoagulation is known to increase the risk for adverse bleeding events, of which intracranial hemorrhage (ICH) is one of the most feared. We present a retrospective study of 33 patients positive for COVID-19 with neuroimaging-documented ICH and examine anticoagulation use in this population. METHODS:Patients over the age of 18 with confirmed COVID-19 and radiographic evidence of ICH were included in this study. Evidence of hemorrhage was confirmed and categorized by a fellowship trained neuroradiologist. Electronic health records were analyzed for patient information including demographic data, medical history, hospital course, laboratory values, and medications. RESULTS:We identified 33 COVID-19 positive patients with ICH, mean age 61.6 years (range 37-83 years), 21.2% of whom were female. Parenchymal hemorrhages with mass effect and herniation occurred in 5 (15.2%) patients, with a 100% mortality rate. Of the remaining 28 patients with ICH, 7 (25%) had punctate hemorrhages, 17 (60.7%) had small- moderate size hemorrhages, and 4 (14.3%) had a large single site of hemorrhage without evidence of herniation. Almost all patients received either therapeutic dose anticoagulation (in 22 [66.7%] patients) or prophylactic dose (in 3 [9.1] patients) prior to ICH discovery. CONCLUSIONS:Anticoagulation therapy may be considered in patients with COVID-19 though the risk of ICH should be taken into account when developing a treatment regimen.

Importance:Perioperative cardiovascular complications occur in 3% of hospitalizations for noncardiac surgery in the US. This review summarizes evidence regarding cardiovascular risk assessment prior to noncardiac surgery. Observations:Preoperative cardiovascular risk assessment requires a focused history and physical examination to identify signs and symptoms of ischemic heart disease, heart failure, and severe valvular disease. Risk calculators, such as the Revised Cardiac Risk Index, identify individuals with low risk (<1%) and higher risk (≥1%) for perioperative major adverse cardiovascular events during the surgical hospital admission or within 30 days of surgery. Cardiovascular testing is rarely indicated in patients at low risk for major adverse cardiovascular events. Stress testing may be considered in patients at higher risk (determined by the inability to climb ≥2 flights of stairs, which is <4 metabolic equivalent tasks) if the results from the testing would change the perioperative medical, anesthesia, or surgical approaches. Routine coronary revascularization does not reduce perioperative risk and should not be performed without specific indications independent of planned surgery. Routine perioperative use of low-dose aspirin (100 mg/d) does not decrease cardiovascular events but does increase surgical bleeding. Statins are associated with fewer postoperative cardiovascular complications and lower mortality (1.8% vs 2.3% without statin use; P < .001) in observational studies, and should be considered preoperatively in patients with atherosclerotic cardiovascular disease undergoing vascular surgery. High-dose β-blockers (eg, 100 mg of metoprolol succinate) administered 2 to 4 hours prior to surgery are associated with a higher risk of stroke (1.0% vs 0.5% without β-blocker use; P = .005) and mortality (3.1% vs 2.3% without β-blocker use; P = .03) and should not be routinely used. There is a greater risk of perioperative myocardial infarction and major adverse cardiovascular events in adults aged 75 years or older (9.5% vs 4.8% for younger adults; P < .001) and in patients with coronary stents (8.9% vs 1.5% for those without stents; P < .001) and these patients warrant careful preoperative consideration. Conclusions and Relevance:Comprehensive history, physical examination, and assessment of functional capacity during daily life should be performed prior to noncardiac surgery to assess cardiovascular risk. Cardiovascular testing is rarely indicated in patients with a low risk of major adverse cardiovascular events, but may be useful in patients with poor functional capacity (<4 metabolic equivalent tasks) undergoing high-risk surgery if test results would change therapy independent of the planned surgery. Perioperative medical therapy should be prescribed based on patient-specific risk.

Importance/UNASSIGNED:While many features of stable ischemic heart disease vary by sex, differences in ischemia, coronary anatomy, and symptoms by sex have not been investigated among patients with moderate or severe ischemia. The enrolled ISCHEMIA trial cohort that underwent coronary computed tomographic angiography (CCTA) was required to have obstructive coronary artery disease (CAD) for randomization. Objective/UNASSIGNED:To describe sex differences in stress testing, CCTA findings, and symptoms in ISCHEMIA trial participants. Design, Setting, and Participants/UNASSIGNED:This secondary analysis of the multicenter ISCHEMIA randomized clinical trial analyzed baseline characteristics of patients with stable ischemic heart disease. Individuals were enrolled from July 2012 to January 2018 based on local reading of moderate or severe ischemia on a stress test, after which blinded CCTA was performed in most. Core laboratories reviewed stress tests and CCTAs. Participants with no obstructive CAD or with left main CAD of 50% or greater were excluded. Those who met eligibility criteria including CCTA (if performed) were randomized to a routine invasive or a conservative management strategy (N = 5179). Angina was assessed using the Seattle Angina Questionnaire. Analysis began October 1, 2018. Interventions/UNASSIGNED:CCTA and angina assessment. Main Outcomes and Measures/UNASSIGNED:Sex differences in stress test, CCTA findings, and symptom severity. Results/UNASSIGNED:Of 8518 patients enrolled, 6256 (77%) were men. Women were more likely to have no obstructive CAD (<50% stenosis in all vessels on CCTA) (353 of 1022 [34.4%] vs 378 of 3353 [11.3%]). Of individuals who were randomized, women had more angina at baseline than men (median [interquartile range] Seattle Angina Questionnaire Angina Frequency score: 80 [70-100] vs 90 [70-100]). Women had less severe ischemia on stress imaging (383 of 919 [41.7%] vs 1361 of 2972 [45.9%] with severe ischemia; 386 of 919 [42.0%] vs 1215 of 2972 [40.9%] with moderate ischemia; and 150 of 919 [16.4%] vs 394 of 2972 [13.3%] with mild or no ischemia). Ischemia was similar by sex on exercise tolerance testing. Women had less extensive CAD on CCTA (205 of 568 women [36%] vs 1142 of 2418 men [47%] with 3-vessel disease; 184 of 568 women [32%] vs 754 of 2418 men [31%] with 2-vessel disease; and 178 of 568 women [31%] vs 519 of 2418 men [22%] with 1-vessel disease). Female sex was independently associated with greater angina frequency (odds ratio, 1.41; 95% CI, 1.13-1.76). Conclusions and Relevance/UNASSIGNED:Women in the ISCHEMIA trial had more frequent angina, independent of less extensive CAD, and less severe ischemia than men. These findings reflect inherent sex differences in the complex relationships between angina, atherosclerosis, and ischemia that may have implications for testing and treatment of patients with suspected stable ischemic heart disease. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01471522.

Background: COVID-19 is a global pandemic with patients at increased risk for thrombosis. Platelets are central protagonists of thrombosis, and virus-platelet interactions are linked to viral pathogenesis and increased thrombotic risk.
Aim(s): To investigate the relationship between in vivo platelet activity markers, and thrombosis or death in hospitalized patients with COVID-19.
Method(s): Plasma samples were collected from 100 hospitalized patients on the day of PCR-confirmed COVID-19 diagnosis. Thromboxane B2 (TxB2), P-selectin (P-selectin), and soluble CD40 ligand (sCD40L) were measured in plasma, and mean platelet volume (MPV) assessed. Subjects were followed until discharge or death, and thrombotic events recorded.
Result(s): Among 100 patients, the median age was 65 years (IQR: 55, 75), 39% were female, and 32 died or experienced a thrombotic event. Baseline platelet activation markers were higher in patients who developed an adverse clinical event. After adjustment for age, sex, race/ethnicity, platelet count, antiplatelet therapy, and chronic obstructive pulmonary disease, TxB2 (p = 0.006), P-selectin (p = 0.005), sCD40L (p = 0.016), and MPV (p = 0.012) were independentlyassociated with thrombosis or death (Table 1). Correlation analysis between biomarkers identified that TxB2 is correlated with P-selectin (rho=0.42, p < 0.0001) and platelet count (rho=0.35, p = 0.0004), MPV is correlated with platelet count (rho=-0.31, p = 0.002), and P-selectin is correlated with sCD40L (rho=0.67, p < 0.0001).
Conclusion(s): Biomarkers of platelet activation are significantly associated with death or thrombosis in patients hospitalized with COVID-19. Our findings suggest multiple platelet activation mechanisms may contribute to adverse events. Further investigation into the mechanistic role of platelets in COVID-19 pathogenesis and the potential role of antiplatelet therapy is warranted