Risk of thrombotic complications in influenza versus COVID-19 hospitalized patients.

Background: Whereas accumulating studies on patients with coronavirus disease 2019 (COVID-19) report high incidences of thrombotic complications, large studies on clinically relevant thrombosis in patients with other respiratory tract infections are lacking. How this high risk in COVID-19 patients compares to those observed in hospitalized patients with other viral pneumonias such as influenza is unknown. Objectives: To assess the incidence of venous and arterial thrombotic complications in hospitalized patients with influenza as opposed to that observed in hospitalized patients with COVID-19. Methods: This was a retrospective cohort study; we used data from Statistics Netherlands (study period: 2018) on thrombotic complications in hospitalized patients with influenza. In parallel, we assessed the cumulative incidence of thrombotic complications-adjusted for competing risk of death-in patients with COVID-19 in three Dutch hospitals (February 24 to April 26, 2020). Results: Of the 13 217 hospitalized patients with influenza, 437 (3.3%) were diagnosed with thrombotic complications, versus 66 (11%) of the 579 hospitalized patients with COVID-19. The 30-day cumulative incidence of any thrombotic complication in influenza was 11% (95% confidence interval [CI], 9.4-12) versus 25% (95% CI, 18-32) in COVID-19. For venous thrombotic (VTC) complications and arterial thrombotic complications alone, these numbers were, respectively, 3.6% (95% CI, 2.7-4.6) and 7.5% (95% CI, 6.3-8.8) in influenza versus 23% (95% CI, 16-29) and 4.4% (95% CI, 1.9-8.8) in COVID-19. Conclusions: The incidence of thrombotic complications in hospitalized patients with influenza was lower than in hospitalized patients with COVID-19. This difference was mainly driven by a high risk of VTC complications in the patients with COVID-19 admitted to the Intensive Care Unit. Remarkably, patients with influenza were more often diagnosed with arterial thrombotic complications.

Caging the dragon: Research approach to COVID-19-related thrombosis.

The incidence of venous thrombosis, mostly pulmonary embolism (PE), ranging from local immunothrombosis to central emboli, but also deep vein thrombosis (DVT) in people with coronavirus disease 2019 (COVID-19) is reported to be remarkably high. The relevance of better understanding, predicting, treating, and preventing COVID-19-associated venous thrombosis meets broad support, as can be concluded from the high number of research, review, and guideline papers that have been published on this topic. The Dutch COVID & Thrombosis Coalition (DCTC) is a multidisciplinary team involving a large number of Dutch experts in the broad area of venous thrombosis and hemostasis research, combined with experts on virology, critically ill patients, pulmonary diseases, and community medicine, across all university hospitals and many community hospitals in the Netherlands. Within the consortium, clinical data of at least 5000 admitted COVID-19-infected individuals are available, including substantial collections of biobanked materials in an estimated 3000 people. In addition to considerable experience in preclinical and clinical thrombosis research, the consortium embeds virology-hemostasis research models within unique biosafety facilities to address fundamental questions on the interaction of virus with epithelial and vascular cells, in relation to the coagulation and inflammatory system. The DCTC has initiated a comprehensive research program to answer many of the current questions on the pathophysiology and best anticoagulant treatment of COVID-19-associated thrombotic complications. The research program was funded by grants of the Netherlands Thrombosis Foundation and the Netherlands Organization for Health Research and Development. Here, we summarize the design and main aims of the research program.

The Post-Venous Thromboembolism Functional Status Scale: From Call to Action to Application in Research, Extension to COVID-19 Patients, and Its Use in Clinical Practice.

A broad spectrum of long-term sequelae may be present in venous thromboembolism (VTE) survivors, affecting their quality of life and functioning. To monitor recovery and improve the prognosis of patients with persistent functional limitations, the development of a new outcome measure that could better capture the consequences of VTE was an unmet need. Starting as a call to action, the Post-VTE Functional Status (PVFS) scale was developed to meet this need. The PVFS scale is an easy-to-use clinical tool to measure and quantify functional outcomes after VTE by focusing on key aspects of daily life. As the scale was considered useful in coronavirus disease 2019 (COVID-19) patients as well, the Post-COVID-19 Functional Status (PCFS) scale was introduced early in the pandemic after slight adaptation. The scale has been well incorporated into both the VTE and COVID-19 research communities, contributing to the shift of focus toward patient-relevant functional outcomes. Psychometric properties have been evaluated, mainly for the PCFS scale but recently also for the PVFS scale, including validation studies of translations, showing adequate validity and reliability. In addition to serving as outcome measure in studies, guidelines and position papers recommend using the PVFS and PCFS scale in clinical practice. As broad use of the PVFS and PCFS scale in clinical practice is valuable to capture what matters most to patients, widespread implementation is a crucial next step. In this review, we discuss the development of the PVFS scale and introduction in VTE and COVID-19 care, the incorporation of the scale in research, and its application in clinical practice.

Illustrated State-of-the-Art Capsules of the ISTH 2022 Congress.

The ISTH London 2022 Congress is the first held (mostly) face-to-face again since the COVID-19 pandemic took the world by surprise in 2020. For 2 years we met virtually, but this year's in-person format will allow the ever-so-important and quintessential creativity and networking to flow again. What a pleasure and joy to be able to see everyone! Importantly, all conference proceedings are also streamed (and available recorded) online for those unable to travel on this occasion. This ensures no one misses out. The 2022 scientific program highlights new developments in hemophilia and its treatment, acquired and other inherited bleeding disorders, thromboinflammation, platelets and coagulation, clot structure and composition, fibrinolysis, vascular biology, venous thromboembolism, women's health, arterial thrombosis, pediatrics, COVID-related thrombosis, vaccine-induced thrombocytopenia with thrombosis, and omics and diagnostics. These areas are elegantly reviewed in this Illustrated Review article. The Illustrated Review is a highlight of the ISTH Congress. The format lends itself very well to explaining the science, and the collection of beautiful graphical summaries of recent developments in the field are stunning and self-explanatory. This clever and effective way to communicate research is revolutionary and different from traditional formats. We hope you enjoy this article and will be inspired by its content to generate new research ideas.

Prevalence, pathophysiology, prediction and health-related quality of life of long COVID: study protocol of the longitudinal multiple cohort CORona Follow Up (CORFU) study.

INTRODUCTION: The variety, time patterns and long-term prognosis of persistent COVID-19 symptoms (long COVID-19) in patients who suffered from mild to severe acute COVID-19 are incompletely understood. Cohort studies will be combined to describe the prevalence of long COVID-19 symptoms, and to explore the pathophysiological mechanisms and impact on health-related quality of life. A prediction model for long COVID-19 will be developed and internally validated to guide care in future patients. METHODS AND ANALYSIS: Data from seven COVID-19 cohorts will be aggregated in the longitudinal multiple cohort CORona Follow Up (CORFU) study. CORFU includes Dutch patients who suffered from COVID-19 at home, were hospitalised without or with intensive care unit treatment, needed inpatient or outpatient rehabilitation and controls who did not suffer from COVID-19. Individual cohort study designs were aligned and follow-up has been synchronised. Cohort participants will be followed up for a maximum of 24 months after acute infection. Next to the clinical characteristics measured in individual cohorts, the CORFU questionnaire on long COVID-19 outcomes and determinants will be administered digitally at 3, 6, 12, 18 and 24 months after the infection. The primary outcome is the prevalence of long COVID-19 symptoms up to 2 years after acute infection. Secondary outcomes are health-related quality of life (eg, EQ-5D), physical functioning, and the prevalence of thromboembolic complications, respiratory complications, cardiovascular diseases and endothelial dysfunction. A prediction model and a patient platform prototype will be developed. ETHICS AND DISSEMINATION: Approval was obtained from the medical research ethics committee of Maastricht University Medical Center+ and Maastricht University (METC 2021-2990) and local committees of the participating cohorts. The project is supported by ZonMW and EuroQol Research Foundation. Results will be published in open access peer-reviewed scientific journals and presented at (inter)national conferences. TRIAL REGISTRATION NUMBER: NCT05240742.

Fibrotic-like abnormalities notably prevalent one year after hospitalization with COVID-19.

BACKGROUND: We investigated whether COVID-19 leads to persistent impaired pulmonary function, fibrotic-like abnormalities or psychological symptoms 12 months after discharge and whether severely ill patients (ICU admission) recover differently than moderately ill patients. METHODS: This single-centre cohort study followed adult COVID-19 survivors for a period of one year after discharge. Patients underwent pulmonary function tests 6 weeks, 3 months and 12 months after discharge and were psychologically evaluated at 6 weeks and 12 months. Computed tomography (CT) was performed after 3 months and 12 months. RESULTS: 66 patients were analysed, their median age was 60.5 (IQR: 54-69) years, 46 (70%) patients were male. 38 (58%) patients had moderate disease and 28 (42%) patients had severe disease. Most patients had spirometric values within normal range after 12 months of follow-up. 12 (23%) patients still had an impaired lung diffusion after 12 months. Impaired pulmonary diffusion capacity was associated with residual CT abnormalities (OR 5.1,CI-95: 1.2-22.2), shortness of breath (OR 7.0, CI-95: 1.6-29.7) and with functional limitations (OR 5.8, CI-95: 1.4-23.8). Ground-glass opacities resolved in most patients during follow-up. Resorption of reticulation, bronchiectasis and curvilinear bands was rare and independent of disease severity. 81% of severely ill patients and 37% of moderately ill patients showed residual abnormalities after 12 months (OR 8.1, CI-95: 2.5-26.4). A minority of patients had symptoms of post-traumatic stress disorder, anxiety, depression and cognitive failure during follow-up. CONCLUSION: Some patients still had impaired lung diffusion 12 months after discharge and fibrotic-like residual abnormalities were notably prevalent, especially in severely ill patients.

A systematic review of biomarkers among hospitalized patients with COVID-19 predictive of venous thromboembolism: A communication from the Predictive and Diagnostic Variables Scientific and Standardization Committee of the ISTH.

Background: Thrombosis is reported to occur more often among patients with COVID-19 than otherwise expected in the setting of viral pneumonia and sepsis. Systemic inflammatory biomarkers may be associated with venous thromboembolism (VTE) risk. The ISTH subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease aimed to report the evidence on prognostic biomarkers for VTE in hospitalized patients with COVID-19. Methods: Using a standardized Preferred Reporting Items for Systematic Reviews and Meta-analysis methodology, we conducted a systematic literature review to identify studies reporting prognostic biomarkers for VTE among hospitalized patients with COVID-19. Eligible studies included adults hospitalized with COVID-19 and reported the prognostic associations between any biomarker measured on admission, and the subsequent diagnosis of deep vein thrombosis or pulmonary embolism. Two authors reviewed titles and abstracts, and three authors extracted study data and performed review of bias. Results were displayed descriptively. Meta-analysis was not possible. Results: From the initial 196 identified studies, full-text review was performed for 72 studies. Admission D-dimer levels were associated with VTE during hospitalization in five studies, and elevated platelet count was associated with VTE during hospitalization in one study. The risk of bias ranged from low to high for included studies. Overall, there was a paucity of high-quality prognostic studies. Studies on other biomarkers did not meet the systematic review inclusion criteria. Conclusions: Admission D-dimer was associated with VTE diagnosis during hospitalization for COVID-19; however, prospective validation of this finding is needed to identify optimal D-dimer thresholds to guide VTE prophylaxis measures.

Estimating incidence of venous thromboembolism in COVID‐19: Methodological considerations

Background Coagulation abnormalities and coagulopathy are recognized as consequences of severe acute respiratory syndrome coronavirus 2 infection and the resulting coronavirus disease 2019 (COVID‐19). Specifically, venous thromboembolism (VTE) has been reported as a frequent complication. By May 27, 2021, at least 93 original studies and 25 meta‐analyses investigating VTE incidence in patients with COVID‐19 had been published, showing large heterogeneity in reported VTE incidence ranging from 0% to 85%. This large variation complicates interpretation of individual study results as well as comparisons across studies, for example, to investigate changes in incidence over time, compare subgroups, and perform meta‐analyses. Objectives This study sets out to provide an overview of sources of heterogeneity in VTE incidence studies in patients with COVID‐19, illustrated using examples. Methods The original studies of three meta‐analyses were screened and a list of sources of heterogeneity that may explain observed heterogeneity across studies was composed. Results The sources of heterogeneity in VTE incidence were classified as clinical sources and methodologic sources. Clinical sources of heterogeneity include differences between studies regarding patient characteristics that affect baseline VTE risk and protocols used for VTE testing. Methodologic sources of heterogeneity include differences in VTE inclusion types, data quality, and the methods used for data analysis. Conclusions To appreciate reported estimates of VTE incidence in patients with COVID‐19 in relation to its etiology, prevention, and treatment, researchers should unambiguously report about possible clinical and methodological sources of heterogeneity in those estimates. This article provides suggestions for that.

Estimating incidence of venous thromboembolism in COVID-19: Methodological considerations.

Background: Coagulation abnormalities and coagulopathy are recognized as consequences of severe acute respiratory syndrome coronavirus 2 infection and the resulting coronavirus disease 2019 (COVID-19). Specifically, venous thromboembolism (VTE) has been reported as a frequent complication. By May 27, 2021, at least 93 original studies and 25 meta-analyses investigating VTE incidence in patients with COVID-19 had been published, showing large heterogeneity in reported VTE incidence ranging from 0% to 85%. This large variation complicates interpretation of individual study results as well as comparisons across studies, for example, to investigate changes in incidence over time, compare subgroups, and perform meta-analyses. Objectives: This study sets out to provide an overview of sources of heterogeneity in VTE incidence studies in patients with COVID-19, illustrated using examples. Methods: The original studies of three meta-analyses were screened and a list of sources of heterogeneity that may explain observed heterogeneity across studies was composed. Results: The sources of heterogeneity in VTE incidence were classified as clinical sources and methodologic sources. Clinical sources of heterogeneity include differences between studies regarding patient characteristics that affect baseline VTE risk and protocols used for VTE testing. Methodologic sources of heterogeneity include differences in VTE inclusion types, data quality, and the methods used for data analysis. Conclusions: To appreciate reported estimates of VTE incidence in patients with COVID-19 in relation to its etiology, prevention, and treatment, researchers should unambiguously report about possible clinical and methodological sources of heterogeneity in those estimates. This article provides suggestions for that.

Pulmonary thromboembolic events in COVID-19-A systematic literature review.

Pulmonary thromboembolic events have been linked to coronavirus disease 2019 (COVID-19), but their incidence and long-term sequelae remain unclear. We performed a systematic literature review to investigate the incidence of pulmonary embolism (PE), microthrombi, thrombosis in situ (thromboinflammatory disease), and chronic thromboembolic pulmonary hypertension (CTEPH) during and after COVID-19. PubMed and the World Health Organization Global Research Database were searched on May 7, 2021. Hospital cohort and database studies reporting data for ≥1000 patients and autopsy studies reporting data for ≥20 patients were included. Results were summarized descriptively. We screened 1438 records and included 41 references (32 hospital/database studies and 9 autopsy studies). The hospital/database studies reported the incidence of PE but not CTEPH, microthrombi, or thromboinflammatory disease. PE incidence varied widely (0%-1.1% of outpatients, 0.9%-8.2% of hospitalized patients, and 1.8%-18.9% of patients in intensive care). One study reported PE events occurring within 45 days after hospital discharge (incidence in discharged patients: 0.2%). Segmental arteries were generally the most common location for PE. In autopsy studies, PE, thromboinflammatory disease, and microthrombi were reported in 6%-23%, 43%-100%, and 45%-84% of deceased patients, respectively. Overall, the included studies mostly focused on PE during the acute phase of COVID-19. The results demonstrate the challenges of identifying and characterizing vascular abnormalities using current protocols (e.g., visual computed tomography reads). Further research is needed to detect subtle pulmonary vascular abnormalities, distinguish thromboinflammatory disease from PE, optimize treatment, and assess the incidence of long-term sequelae after COVID-19.

Diagnostic Management of Acute Pulmonary Embolism in COVID-19 and Other Special Patient Populations.

Venous thromboembolism (VTE), in particular acute pulmonary embolism (PE), has been shown to be a frequent and potentially fatal complication of coronavirus disease 2019 (COVID-19). In response to the observed thrombotic complications, a large number of studies has been devoted to the understanding and management of COVID-19-associated coagulopathy. Notably, only a limited number of mostly retrospective studies has focused on the optimal diagnostic strategy for suspected PE in COVID-19 patients. As in other special populations, the accuracy of diagnostic algorithms for PE-exclusion has been debated in this specific patient subgroup as the specificity of D-dimer assays and clinical decision rules (CDRs) may be lower than normal. From this viewpoint, we discuss the current state-of-the-art diagnostic algorithms for acute PE with a focus on patients with COVID-19 in the perspective of other special patient populations. Furthermore, we summarize current knowledge regarding the natural history of PE resolution with anticoagulant treatment in patients with COVID-19.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: January 2022 update on the use of therapeutic-intensity anticoagulation in acutely ill patients.

BACKGROUND: COVID-19-related acute illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation in patients with COVID-19. METHODS: ASH formed a multidisciplinary guideline panel that included patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process and performed systematic evidence reviews (through November 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 to guidelines published in February 2021 as part of the living phase of these guidelines. RESULTS: The panel made one additional recommendation. The panel issued a conditional recommendation in favor of therapeutic-intensity over prophylactic-intensity anticoagulation in patients with COVID-19-related acute illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of risk of thrombosis and bleeding. The panel also noted that heparin (unfractionated or low molecular weight) may be preferred because of a preponderance of evidence with this class of anticoagulants. CONCLUSION: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation in patients with COVID-19-related acute illness.

Prevalence, risk factors, and long-term outcomes of cerebral ischemia in hospitalized COVID-19 patients - study rationale and protocol of the CORONIS study: A multicentre prospective cohort study.

Background: COVID-19 is often complicated by thrombo-embolic events including ischemic stroke. The underlying mechanisms of COVID-19-associated ischemic stroke, the incidence and risk factors of silent cerebral ischemia, and the long-term functional outcome in these patients are currently unknown. Patients and methods: CORONavirus and Ischemic Stroke (CORONIS) is a multicentre prospective cohort study investigating the prevalence, risk factors and long-term incidence of (silent) cerebral ischemia, and the long-term functional outcome among patients with COVID-19. We aim to include 200 adult patients hospitalized with COVID-19 without symptomatic ischemic stroke to investigate the prevalence of silent cerebral ischemia compared with 60 (matched) controls with MRI. In addition, we will identify potential risk factors and/or causes of cerebral ischemia in COVID-19 patients with (n = 70) or without symptomatic stroke (n = 200) by means of blood sampling, cardiac workup and brain MRI. We will measure functional outcome and cognitive function after 3 and 12 months with standardized questionnaires in all patients with COVID-19. Finally, the long-term incidence of (new) silent cerebral ischemia in patients with COVID-19 will be assessed with follow up MRI (n = 120). Summary: The CORONIS study is designed to add further insight into the prevalence, long-term incidence and risk factors of cerebral ischemia, and the long-term functional outcome in hospitalized adult patients with COVID-19.

Outpatient Pulmonary Rehabilitation in Patients with Long COVID Improves Exercise Capacity, Functional Status, Dyspnea, Fatigue, and Quality of Life.

BACKGROUND: COVID-19 survivors face the risk of long-term sequelae including fatigue, breathlessness, and functional limitations. Pulmonary rehabilitation has been recommended, although formal studies quantifying the effect of rehabilitation in COVID-19 patients are lacking. METHODS: We conducted a prospective observational cohort study including consecutive patients admitted to an outpatient pulmonary rehabilitation center due to persistent symptoms after COVID-19. The primary endpoint was change in 6-min walk distance (6MWD) after undergoing a 6-week interdisciplinary individualized pulmonary rehabilitation program. Secondary endpoints included change in the post-COVID-19 functional status (PCFS) scale, Borg dyspnea scale, Fatigue Assessment Scale, and quality of life. Further, changes in pulmonary function tests were explored. RESULTS: Of 64 patients undergoing rehabilitation, 58 patients (mean age 47 years, 43% women, 38% severe/critical COVID-19) were included in the per-protocol-analysis. At baseline (i.e., in mean 4.4 months after infection onset), mean 6MWD was 584.1 m (±95.0), and functional impairment was graded in median at 2 (IQR, 2-3) on the PCFS. On average, patients improved their 6MWD by 62.9 m (±48.2, p < 0.001) and reported an improvement of 1 grade on the PCFS scale. Accordingly, we observed significant improvements across secondary endpoints including presence of dyspnea (p < 0.001), fatigue (p < 0.001), and quality of life (p < 0.001). Also, pulmonary function parameters (forced expiratory volume in 1 s, lung diffusion capacity, inspiratory muscle pressure) significantly increased during rehabilitation. CONCLUSION: In patients with long COVID, exercise capacity, functional status, dyspnea, fatigue, and quality of life improved after 6 weeks of personalized interdisciplinary pulmonary rehabilitation. Future studies are needed to establish the optimal protocol, duration, and long-term benefits as well as cost-effectiveness of rehabilitation.

Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development.

BACKGROUND: A substantial portion of people with COVID-19 subsequently experience lasting symptoms including fatigue, shortness of breath, and neurological complaints such as cognitive dysfunction many months after acute infection. Emerging evidence suggests that this condition, commonly referred to as long COVID but also known as post-acute sequelae of SARS-CoV-2 infection (PASC) or post-COVID-19 condition, could become a significant global health burden. MAIN TEXT: While the number of studies investigating the post-COVID-19 condition is increasing, there is no agreement on how this new disease should be defined and diagnosed in clinical practice and what relevant outcomes to measure. There is an urgent need to optimise and standardise outcome measures for this important patient group both for clinical services and for research and to allow comparing and pooling of data. CONCLUSIONS: A Core Outcome Set for post-COVID-19 condition should be developed in the shortest time frame possible, for improvement in data quality, harmonisation, and comparability between different geographical locations. We call for a global initiative, involving all relevant partners, including, but not limited to, healthcare professionals, researchers, methodologists, patients, and caregivers. We urge coordinated actions aiming to develop a Core Outcome Set (COS) for post-COVID-19 condition in both the adult and paediatric populations.