Publications by authors named "Alfred I Lee"

35 Publications

Hospitalisation among vaccine breakthrough COVID-19 infections.

Lancet Infect Dis 2021 Sep 7. Epub 2021 Sep 7.

Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT 06511, USA. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(21)00558-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423430PMC
September 2021

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: May 2021 update on the use of intermediate intensity anticoagulation in critically ill patients.

Blood Adv 2021 Sep 2. Epub 2021 Sep 2.

McMaster University, Hamilton, Canada.

Background: COVID-19 related critical illness is associated with an increased risk of venous thromboembolism (VTE).

Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19-related critical illness who do not have confirmed or suspected VTE.

Methods: ASH formed a multidisciplinary guideline panel, including three patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including performing systematic evidence reviews (up to March 5, 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment. This is an update on guidelines published in February 2021.

Results: The panel agreed on one additional recommendation. The panel issued a conditional recommendation in favor of prophylactic-intensity over intermediate-intensity anticoagulation in patients with COVID-19 related-critical illness who do not have confirmed or suspected VTE.

Conclusions: This recommendation was based on low certainty in the evidence, underscoring the need for further high-quality, randomized controlled trials comparing different intensities of anticoagulation in critically ill patients. Other key research priorities include better evidence on predictors of thrombosis and bleeding risk in critically ill patients with COVID-19 and the impact of non-anticoagulant therapies (e.g., antiviral agents, corticosteroids) on thrombotic risk.
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http://dx.doi.org/10.1182/bloodadvances.2021005493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416320PMC
September 2021

Cerebral venous sinus thrombosis after vaccination: the UK experience.

Lancet 2021 Sep 6;398(10306):1107-1109. Epub 2021 Aug 6.

Section of Hematology, Yale School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1016/S0140-6736(21)01788-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346246PMC
September 2021

Challenges in interpreting cytokine data in COVID-19 affect patient care and management.

PLoS Biol 2021 08 6;19(8):e3001373. Epub 2021 Aug 6.

Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.

Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic.
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http://dx.doi.org/10.1371/journal.pbio.3001373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372945PMC
August 2021

Association of obesity with venous thromboembolism and myocardial injury in COVID-19.

Obes Res Clin Pract 2021 Jul 16. Epub 2021 Jul 16.

Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT, 06510, USA. Electronic address:

Introduction: Although both obesity and coronavirus disease 2019 (COVID-19) independently induce inflammation and thrombosis, the association between obesity class and risk of thrombosis in patients with COVID-19 remains unclear.

Methods: This retrospective cohort study included consecutive patients hospitalized with COVID-19 at a single institution. Patients were categorized based on obesity class. The main outcomes were venous thromboembolism (VTE) and myocardial injury, a marker of microvascular thrombosis in COVID-19. Adjustments were made for sociodemographic variables, cardiovascular disease risk factors and comorbidities.

Results: 609 patients with COVID-19 were included. 351 (58%) patients were without obesity, 110 (18%) were patients with class I obesity, 76 (12%) were patients with class II obesity, and 72 (12%) were patients with class III obesity. Patients with class I and III obesity had significantly higher risk-adjusted odds of VTE compared to patients without obesity (OR = 2.54, 95% CI: 1.05-6.14 for class I obesity; and OR = 3.95, 95% CI: 1.40-11.14 for class III obesity). Patients with class III obesity had significantly higher risk-adjusted odds of myocardial injury compared to patients without obesity (OR = 2.15, 95% CI: 1.12-4.12). Both VTE and myocardial injury were significantly associated with greater risk-adjusted odds of mortality.

Conclusion: This study demonstrates that both macrovascular and microvascular thromboses may contribute to the elevated morbidity and mortality in patients with obesity and COVID-19.
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http://dx.doi.org/10.1016/j.orcp.2021.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283573PMC
July 2021

A Brewing Back Pain.

N Engl J Med 2021 Jul;385(1):66-72

From the Department of Medicine, Section of Infectious Diseases (L.P.), the Division of Cardiac Surgery (A.G.), the Department of Internal Medicine and Pediatrics (R.A.M.), and the Department of Internal Medicine, Section of Hematology (A.I.L.), Yale School of Medicine, the Department of Epidemiology of Microbial Diseases, Yale School of Public Health (L.P.), and the Department of Infection Prevention, Yale New Haven Health (R.A.M.), New Haven, and Hartford Hospital, Hartford (J.M.) - all in Connecticut.

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http://dx.doi.org/10.1056/NEJMcps2034802DOI Listing
July 2021

Immunothrombosis: a COVID-19 concerto.

Br J Haematol 2021 08 7;194(3):491-493. Epub 2021 Jul 7.

Section of Hematology, Yale School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1111/bjh.17666DOI Listing
August 2021

Immunofibrotic drivers of impaired lung function in postacute sequelae of SARS-CoV-2 infection.

JCI Insight 2021 07 22;6(14). Epub 2021 Jul 22.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

BACKGROUNDIndividuals recovering from COVID-19 frequently experience persistent respiratory ailments, which are key elements of postacute sequelae of SARS-CoV-2 infection (PASC); however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity.METHODSWe performed a prospective cohort study of individuals with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors.RESULTSSixty-one participants were enrolled across 2 academic medical centers at a median of 9 weeks (interquartile range, 6-10 weeks) after COVID-19 illness: n = 13 participants (21%) had mild COVID-19 and were not hospitalized, n = 30 participants (49%) were hospitalized but were considered noncritical, and n = 18 participants (30%) were hospitalized and in the intensive care unit (ICU). Fifty-three participants (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P < 0.05) but these values did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered participants by past COVID-19 severity. Lipocalin-2 (LCN2), MMP-7, and HGF identified by our analysis were significantly higher in the ICU group (P < 0.05), inversely correlated with FVC and DLCO (P < 0.05), and were confirmed in a separate validation cohort (n = 53).CONCLUSIONSubjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.FundingNational Heart, Lung, and Blood Institute (K08HL130557 and R01HL142818), American Heart Association (Transformational Project Award), the DeLuca Foundation Award, a donation from Jack Levin to the Benign Hematology Program at Yale University, and Duke University.
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http://dx.doi.org/10.1172/jci.insight.148476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410030PMC
July 2021

Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.

J Hepatol 2021 09 13;75(3):647-658. Epub 2021 May 13.

Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address:

Background And Aims: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19.

Methods: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism.

Results: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling.

Conclusion: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients.

Lay Summary: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.
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http://dx.doi.org/10.1016/j.jhep.2021.04.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285256PMC
September 2021

Ischemic Stroke, Inflammation, and Endotheliopathy in COVID-19 Patients.

Stroke 2021 06 10;52(6):e233-e238. Epub 2021 May 10.

Department of Neurology (L.S.M., A.S.Z., I.M., P.C., P.L., A.S.J., D.N., J.S., K.N.S., S.S., R.S., L.H.S.), Yale University School of Medicine, New Haven, CT.

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.120.031971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140646PMC
June 2021

Delayed production of neutralizing antibodies correlates with fatal COVID-19.

Nat Med 2021 07 5;27(7):1178-1186. Epub 2021 May 5.

Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA.

Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). However, the exact features of antibody responses that govern COVID-19 disease outcomes remain unclear. In this study, we analyzed humoral immune responses in 229 patients with asymptomatic, mild, moderate and severe COVID-19 over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-spike (S) immunoglobulin G (IgG) levels, length of hospitalization and clinical parameters associated with worse clinical progression. Although high anti-S IgG levels correlated with worse disease severity, such correlation was time dependent. Deceased patients did not have higher overall humoral response than discharged patients. However, they mounted a robust, yet delayed, response, measured by anti-S, anti-receptor-binding domain IgG and neutralizing antibody (NAb) levels compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, although sera from 85% of patients displayed some neutralization capacity during their disease course, NAb generation before 14 d of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se but, rather, with the delayed kinetics of NAb production.
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http://dx.doi.org/10.1038/s41591-021-01355-0DOI Listing
July 2021

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection.

bioRxiv 2021 Feb 23. Epub 2021 Feb 23.

Division of Rheumatology, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and, if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., Ang2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.

Summmary: Complement has been implicated in COVID-19. However, whether this is distinctive of COVID-19 remains unanswered. Ma et al report increased complement activation in COVID-19 compared to influenza and non-COVID respiratory failure, and demonstrate alternative pathway activation as a key marker of multiorgan failure and death.
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http://dx.doi.org/10.1101/2021.02.22.432177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924264PMC
February 2021

A neutrophil activation signature predicts critical illness and mortality in COVID-19.

Blood Adv 2021 03;5(5):1164-1177

Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, and.

Pathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of more than 3300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, hepatocyte growth factor, interleukin-8, and granulocyte colony-stimulating factor, which were the strongest predictors of critical illness. Evidence of neutrophil activation was present on the first day of hospitalization in patients who would only later require transfer to the intensive care unit, thus preceding the onset of critical illness and predicting increased mortality. In the health system database, early elevations in developing and mature neutrophil counts also predicted higher mortality rates. Altogether, these data suggest a central role for neutrophil activation in the pathogenesis of severe COVID-19 and identify molecular markers that distinguish patients at risk of future clinical decompensation.
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http://dx.doi.org/10.1182/bloodadvances.2020003568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908851PMC
March 2021

Immuno-fibrotic drivers of impaired lung function in post-acute sequelae of SARS-CoV-2 infection (PASC).

medRxiv 2021 Apr 21. Epub 2021 Apr 21.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, NC, 27710.

Introduction: Subjects recovering from COVID-19 frequently experience persistent respiratory ailments; however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity.

Methods: We performed a prospective cohort study of subjects with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors.

Results: Sixty-one subjects were enrolled across two academic medical centers at a median of 9 weeks (interquartile range 6-10) after COVID-19 illness: n=13 subjects (21%) mild/non-hospitalized, n=30 (49%) hospitalized/non-critical, and n=18 subjects (30%) hospitalized/intensive care ("ICU"). Fifty-three subjects (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P<0.05), but did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered subjects by past COVID-19 severity. Lipocalin 2 (LCN2), matrix metalloproteinase-7 (MMP-7), and hepatocyte growth factor (HGF) identified by the model were significantly higher in the ICU group (P<0.05) and inversely correlated with FVC and DLCO (P<0.05), and were confirmed in a separate validation cohort (n=53).

Conclusions: Subjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.

Funding: The study was funded in part by the NHLBI (K08HL130557 to BDK and R01HL142818 to HJC), the DeLuca Foundation Award (AP), a donation from Jack Levin to the Benign Hematology Program at Yale, and Divisional/Departmental funds from Duke University.
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http://dx.doi.org/10.1101/2021.01.31.21250870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872384PMC
April 2021

Changes in inflammatory and immune drivers in response to immunomodulatory therapies in COVID-19.

medRxiv 2020 Dec 25. Epub 2020 Dec 25.

As the global community strives to discover effective therapies for COVID-19, immunomodulatory strategies have emerged as a leading contender to combat the cytokine storm and improve clinical outcomes in patients with severe disease. Systemic corticosteroids and selective cytokine inhibitory agents have been utilized both as empiric therapies and in clinical trials. While multiple randomized, placebo controlled trials have now demonstrated that corticosteroids improve survival in patients with COVID-19, IL-6 inhibition, which gained significant early interest based on observational studies, has not demonstrated reliable efficacy in randomized, placebo controlled trials. To better understand the mechanistic basis of immunomodulatory therapies being implemented for treatment of COVID-19, we assessed longitudinal biochemical changes in response to such approaches in hospitalized patients with COVID-19. We demonstrate broad suppression of multiple immunomodulatory factors associated with adverse clinical outcomes in COVID-19 in patients who received corticosteroids, but no such response was seen in patients who either received tocilizumab or no immunomodulatory therapy. Our findings provide early insights into molecular signatures that correlate with immunomodulatory therapies in COVID-19 which may be useful in understanding clinical outcomes in future studies of larger patient cohorts.
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http://dx.doi.org/10.1101/2020.12.23.20248547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781335PMC
December 2020

Circulating markers of angiogenesis and endotheliopathy in COVID-19.

Pulm Circ 2020 Oct-Dec;10(4):2045894020966547. Epub 2020 Nov 25.

Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT, USA.

Increase in thrombotic and microvascular complications is emerging to be a key feature of patients with critical illness associated with COVID-19 infection. While endotheliopathy is thought to be a key factor of COVID-19-associated coagulopathy, markers indicative of this process that are prognostic of disease severity have not been well-established in this patient population. Using plasma profiling of patients with COVID-19, we identified circulating markers that segregated with disease severity: markers of angiogenesis (VEGF-A, PDGF-AA and PDGF-AB/BB) were elevated in hospitalized patients with non-critical COVID-19 infection, while markers of endothelial injury (angiopoietin-2, FLT-3L, PAI-1) were elevated in patients with critical COVID-19 infection. In survival analysis, elevated markers of endothelial injury (angiopoietin-2, follistatin, PAI-1) were strongly predictive of in-hospital mortality. Our findings demonstrate that non-critical and critical phases of COVID-19 disease may be driven by distinct mechanisms involving key aspects of endothelial cell function, and identify drivers of COVID-19 pathogenesis and potential targets for future therapies.
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http://dx.doi.org/10.1177/2045894020966547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691906PMC
November 2020

Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation.

Nat Rev Cardiol 2021 03 19;18(3):194-209. Epub 2020 Nov 19.

Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.

The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.
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http://dx.doi.org/10.1038/s41569-020-00469-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675396PMC
March 2021

Circulating Markers of Angiogenesis and Endotheliopathy in COVID-19.

medRxiv 2020 Jul 1. Epub 2020 Jul 1.

Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, New Haven, Connecticut.

Despite over 9.3 million infected and 479,000 deaths, the pathophysiological factors that determine the wide spectrum of clinical outcomes in COVID-19 remain inadequately defined. Importantly, patients with underlying cardiovascular disease have been found to have worse clinical outcomes,1 and autopsy findings of endotheliopathy as well as angiogenesis in COVID-19 have accumulated.2,3 Nonetheless, circulating vascular markers associated with disease severity and mortality have not been reliably established. To address this limitation and better understand COVID-19 pathogenesis, we report plasma profiling of factors related to the vascular system from a series of patients admitted to Yale-New Haven Hospital with confirmed diagnosis of COVID-19 via PCR, which demonstrate significant increase in markers of angiogenesis and endotheliopathy in patients hospitalized with COVID-19.
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http://dx.doi.org/10.1101/2020.06.29.20140376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340194PMC
July 2020

Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study.

Lancet Haematol 2020 Aug 30;7(8):e575-e582. Epub 2020 Jun 30.

Section of Hematology, New Haven, CT, USA. Electronic address:

Background: An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications. Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy. To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19.

Methods: In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital. Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range. We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable. We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality. Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival.

Findings: 68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014). VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients. We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients. In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087).

Interpretation: Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death. Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19.

Funding: This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3026(20)30216-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326446PMC
August 2020

Cryptic Cachexia.

N Engl J Med 2020 07;383(1):68-74

From the Department of Medicine (C.D.O., C.R.O., J.J.), Section of Hematology (A.I.L.), and the Department of Pathology, Section of Digestive Diseases (D.J.), Yale School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1056/NEJMcps1817531DOI Listing
July 2020

Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes.

Chest 2020 10 15;158(4):1397-1408. Epub 2020 Jun 15.

Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT.

Background: Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series.

Research Question: The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19.

Study Design And Methods: This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity.

Results: Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002).

Interpretation: A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.
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http://dx.doi.org/10.1016/j.chest.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831876PMC
October 2020

Statin therapy associated with improved thrombus resolution in patients with deep vein thrombosis.

J Vasc Surg Venous Lymphat Disord 2019 03 16;7(2):169-175.e4. Epub 2019 Jan 16.

Section of Vascular Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Conn. Electronic address:

Objective: Statin therapy has been associated with a decreased incidence of venous thromboembolism (VTE) in clinical trials and enhanced thrombus resolution in animal models. The effect of statins on thrombus resolution has not been reported clinically. This study investigates the association of statins with thrombus resolution or improvement in patients with deep venous thrombosis (DVT).

Methods: A retrospective study of the electronic medical records of consecutive adult patients presenting with lower extremity DVT was performed. Patients were divided into two groups based on statin therapy (statin group) or lack thereof (nonstatin group). The two groups were compared with respect to demographics, comorbidities, and risk factors for VTE. Initial as well as all subsequent ultrasound reports were reviewed for each patient to determine extent of DVT and subsequent change in thrombus characteristics. Long-term outcomes examined were mortality, VTE recurrence, and thrombus improvement or resolution on follow-up ultrasound examination. Multivariable analysis was used to determine independent predictors of thrombus resolution or improvement, VTE recurrence, and mortality.

Results: A total of 818 patients with DVT were identified (statin group, n = 279 [34%]; nonstatin group, n = 539 [66%]). The patients in the statin group were significantly older (P < .001). Patients on statins were more likely to have risk factors for and manifestations of atherosclerosis and to be on antiplatelet therapy (P < .001), whereas those in the nonstatin group were more likely to have a hypercoagulable disorder (P = .009) or prior DVT (P = .033). There was no significant difference in provoked DVT, extent of DVT, or association with pulmonary embolism (PE), but patients on statins were more likely to have high-risk PE (P = .046). There was no difference in patients receiving anticoagulation, type and duration of anticoagulation, inferior vena cava filter placement, or treatment with lytic therapy. There was no difference in thrombus resolution, mortality, or recurrence of DVT, PE, or VTE between the groups. On multivariable analysis, age, proximal DVT, CAD, and cancer were associated with higher mortality, whereas anticoagulation with coumadin and direct oral anticoagulants and antiplatelet therapy were associated with lower mortality. Statin therapy, antiplatelet therapy, and younger age were associated with thrombus resolution or improvement.

Conclusions: Statin therapy is associated with greater thrombus resolution or improvement in patients with DVT. However, statin therapy in this study was not associated with different clinical outcomes of VTE recurrence or mortality.
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http://dx.doi.org/10.1016/j.jvsv.2018.10.020DOI Listing
March 2019

NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018.

J Natl Compr Canc Netw 2018 11;16(11):1289-1303

Venous thromboembolism (VTE) is common in patients with cancer and increases morbidity and mortality. VTE prevention and treatment are more complex in patients with cancer. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of VTE in adult patients diagnosed with cancer or in whom cancer is clinically suspected. These NCCN Guidelines Insights explain recent changes in anticoagulants recommended for the treatment of cancer-associated VTE.
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http://dx.doi.org/10.6004/jnccn.2018.0084DOI Listing
November 2018

Reply.

J Vasc Surg Venous Lymphat Disord 2018 07;6(4):560-561

Section of Vascular Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Conn.

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http://dx.doi.org/10.1016/j.jvsv.2018.03.008DOI Listing
July 2018

Internal medicine trainees' knowledge and confidence in using the American Society of Hematology Choosing Wisely guidelines in hemostasis, thrombosis, and non-malignant hematology.

PLoS One 2018 16;13(5):e0197414. Epub 2018 May 16.

Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, Phoenix, Arizona, United States of America.

Background: Several specialty societies participate in the Choosing Wisely (CW) campaign in an attempt to reduce waste in health care spending. We surveyed internal medicine (IM) residents with an objective of classifying knowledge of and confidence in using the American Society of Hematology (ASH) CW principles in hemostasis, thrombosis, and non-malignant hematology.

Methods: Multi-institutional study of IM residents at 5 academic training programs in the United States. A 10-question, case-based multiple choice test, with each question accompanied by a 5-point Likert-scale confidence assessment, was distributed electronically. Responses were summarized with frequencies and percentages or medians and ranges, as appropriate. Two sample t-tests or Wilcoxon rank-sum tests were used to compare confidence and knowledge scores.

Results: Of 892 IM residents, 174 (19.5%) responded to all questions. Overall, residents answered a median of 7 of 10 questions correctly (range 2-10) and median resident confidence in their responses was 3.1 (on a 5-point scale). Correct responses were significantly associated with higher confidence for all but one question. Having a hematology rotation experience was significantly associated with more correct responses and with higher confidence (p = 0.001 and p<0.001, respectively).

Conclusions: IM residents at several academic hospitals have variable knowledge of ASH-CW guidelines in thrombosis and hemostasis/non-malignant hematology. Residents who have done hematology rotations, particularly a hematology consult rotation, were more likely to answer questions correctly and to be more confident that their answers were correct. Adequate clinical exposure and training in cost-effective care is essential to train clinicians who are cost-conscious in any specialty.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197414PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955511PMC
November 2018

Acute Limb Ischemia in an 8-Year-Old Patient: A Case Report.

Ann Vasc Surg 2018 Aug 13;51:327.e1-327.e8. Epub 2018 Apr 13.

Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT.

We report the case of an 8-year-old patient with a history of nephrotic syndrome, who presented to the emergency department with right foot pain. The patient's mother described intermittent pain that woke her son from sleep and was accompanied by the foot turning purple and becoming cold to touch. Physical examination revealed capillary refill of over 10 seconds in the right and less than 2 seconds in the left foot. Ankle-brachial indices (ABIs) were 0.0 on the right and 0.96 on the left. The patient was admitted and started on therapeutic intravenous heparin. After consultation with his parents, right lower extremity angiography and thrombolysis was performed over 2 days. He subsequently underwent fasciotomy and amputation of the tip of all 5 toes. Eighteen months later, there is no leg length discrepancy, he is walking with foot inserts and has normal ABIs bilaterally.
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http://dx.doi.org/10.1016/j.avsg.2018.02.012DOI Listing
August 2018

Risk factors for presence and severity of pulmonary embolism in patients with deep venous thrombosis.

J Vasc Surg Venous Lymphat Disord 2018 01 23;6(1):7-12. Epub 2017 Oct 23.

Section of Vascular Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Conn. Electronic address:

Objective: The Caprini model estimates patients' risk for venous thromboembolism by 30 different factors. Hemodynamically significant pulmonary embolism (PE), defined as high-risk (massive) or intermediate-risk (submassive) PE, has high morbidity and mortality rates. This study tests whether the Caprini model and deep venous thrombosis (DVT) characteristics correlate with the prevalence of PE and hemodynamically significant PE in patients with DVT.

Methods: A retrospective review of patients diagnosed with DVT between January 2013 and August 2014 in a tertiary care center was performed. Multivariable analysis was used to determine predictors of PE and hemodynamically significant PE.

Results: Of 838 consecutive patients with DVT, 217 (25.9%) had concomitant PE at presentation, of whom 135 had hemodynamically significant PE (101 submassive PE, 34 massive PE). The mean age was 65 years, and 51.0% were women. There was no significant relation between age or gender and the occurrence of PE or hemodynamically significant PE. Patients with PE were less likely to have undergone recent surgery (18.4% vs 30.3%; P = .001), to have sepsis (4.6% vs 11.8%; P = .002), and to have higher Caprini scores (6.1 vs 6.5; P = .047). Patients with DVT were less likely to have hemodynamically significant PE after recent surgery (13.3% vs 27.2%; P = .011) but more likely to have hemodynamically significant PE with proximal DVT (80.7% vs 64.2%). There was no association between Caprini score and hemodynamically significant PE (6.3 vs 5.7; P = .171).

Conclusions: The Caprini model has a poor association with PE or hemodynamically significant PE in patients with DVT. Among all patients with DVT, a concomitant diagnosis of PE or hemodynamically significant PE is less common in those with sepsis or undergoing recent surgery but more common in those with proximal DVT.
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http://dx.doi.org/10.1016/j.jvsv.2017.08.015DOI Listing
January 2018

Wide variations in blood product transfusion practices among providers who care for patients with acute leukemia in the United States.

Transfusion 2017 02 22;57(2):289-295. Epub 2016 Nov 22.

Department of Internal Medicine, Section of Hematology, Cleveland, Ohio.

Background: Transfusion of blood products is a key component of the supportive management in patients with acute leukemia (AL). However high-quality trial evidence and clinical outcome data to support specific transfusion goals for blood products for patients with AL remain limited leading to diverse transfusion practices. The primary objective of this study was to determine the spectrum of transfusion patterns in a variety of care settings among providers who treat AL patients.

Study Design And Methods: A 31-question survey queried providers caring for AL patients about the existence of institutional guidelines for transfusion of blood products, transfusion triggers for hemoglobin (Hb), platelets (PLTs), and fibrinogen in various settings including inpatient and outpatient and before procedures.

Results: We analyzed 130 responses and identified divergent transfusion Hb goals in hospitalized and ambulatory patients, fibrinogen goals for cryoprecipitate transfusions, and variation in practice for use of certain PLTs and red blood cell products. The least variable transfusion patterns were reported for PLT goals in thrombocytopenia and in the setting of invasive procedures such as bone marrow biopsy and lumbar punctures.

Conclusions: This survey confirmed wide variations in blood product transfusion practices across several clinical scenarios in patients with AL. The findings emphasized the need for large prospective randomized trials to develop standardized evidence-based guidelines for blood product transfusions in patients with AL with the goal of limiting unnecessary transfusions without compromising outcomes.
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http://dx.doi.org/10.1111/trf.13934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309168PMC
February 2017

The Hidden Lesion.

N Engl J Med 2016 09;375(12):1199

Yale University School of Medicine, New Haven, CT

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http://dx.doi.org/10.1056/NEJMc1608553DOI Listing
September 2016
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