Safety and Efficacy of the Off-Label Use of Pipeline Embolization Device Based on the 2018 Food and Drug Administration-Approved Indications for Intracranial Aneurysms: A Single-Center Retrospective Cohort Study.

BACKGROUND: The pipeline embolization device (PED; ev3/Covidien) has proven safe and effective for treating selected intracranial aneurysms. This device's versatility and popularity have driven increased interest in expanding the latest 2018 Food and Drug Administration-approved indications. OBJECTIVE: To compare "off-label" and "on-label" PED treatment. METHODS: Retrospective analysis of aneurysms treated with PED at a single center from 2013 to 2019. Comparisons were made based on the 2018 Food and Drug Administration-approved indications. RESULTS: A total of 492 treated aneurysms were included (65.2% on-label and 34.8% off-label). Aneurysm complete and near-complete occlusion rate was nonsignificantly lower in the off-label group (80.9% vs 85.7%; P = .19). Off-label treatment had higher rate of poor functional outcomes (modified Rankin Scale [mRS] >2: 10.3% vs 3.5%; P = .002). Although pretreatment mRS was already higher in the off-label group (5.3% vs 0.3%; P < .001) and there were no differences in mRS worsening during follow-up (5.5% vs 2.9%; P = .15). We also found a trend to a higher rate of intracranial hemorrhagic complications in the off-label group (4.7% vs 1.6%; P = .05), but there were no differences in hemorrhages requiring surgical intervention (1.8% vs 1.3%; P = .65). There were no differences in retreatment, thromboembolic complications, and mortality rates. CONCLUSION: Off-label PED treatment may be considered for select aneurysms, which are challenging to treat with other techniques. These cases have similar complete and near-complete occlusion rates compared with on-label cases. There are, however, higher risks of poor functional outcomes despite similar rates of thromboembolic and hemorrhagic complications. This is partly explained by the significantly higher pretreatment mRS score in the off-label group.

Late-onset hematological complications post COVID-19: An emerging medical problem for the hematologist.

Coronavirus disease 19 (COVID-19) is considered a multisystemic disease. Several studies have reported persistent symptoms or late-onset complications after acute COVID-19, including post-COVID-19 hematological disorders. COVID-19-induced coagulopathy, an immunothrombotic state, has been linked to thromboembolic and hemorrhagic events. Late-onset thrombocytopenia related to immune system dysregulation has also been reported as a rare manifestation post COVID-19. Close monitoring of laboratory dynamics is considered essential to identify timely abnormal values that need further investigation, providing supportive care whenever indicated. The role of hematologists is essential in terms of the multidisciplinary approach of long COVID-19. This review summarizes all the available evidence on post-acute COVID-19 hematological complications.

Mesenchymal Stem Cells in the Treatment of COVID-19, a Promising Future.

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have a potent self-renewal capacity and can differentiate into multiple cell types. They also affect the ambient tissue by the paracrine secretion of numerous factors in vivo, including the induction of other stem cells' differentiation. In vitro, the culture media supernatant is named secretome and contains soluble molecules and extracellular vesicles that retain potent biological function in tissue regeneration. MSCs are considered safe for human treatment; their use does not involve ethical issues, as embryonic stem cells do not require genetic manipulation as induced pluripotent stem cells, and after intravenous injection, they are mainly found in the lugs. Therefore, these cells are currently being tested in various preclinical and clinical trials for several diseases, including COVID-19. Several affected COVID-19 patients develop induced acute respiratory distress syndrome (ARDS) associated with an uncontrolled inflammatory response. This condition causes extensive damage to the lungs and may leave serious post-COVID-19 sequelae. As the disease may cause systemic alterations, such as thromboembolism and compromised renal and cardiac function, the intravenous injection of MSCs may be a therapeutic alternative against multiple pathological manifestations. In this work, we reviewed the literature about MSCs biology, focusing on their function in pulmonary regeneration and their use in COVID-19 treatment.

Extensive Thromboembolism in a Young Male with Asymptomatic COVID-19 Infection and Heterozygous Factor V Leiden Mutation.

In this case report we present a previously healthy 21-year-old male with extensive thromboembolism in the setting of asymptomatic COVID-19 infection and heterozygous factor V Leiden mutation with no additional thrombophilic risk factors.

Nuts and bolts of COVID-19 associated coagulopathy: the essentials for management and treatment.

INTRODUCTION: COVID-19-associated coagulopathy (CAC) is a well-recognized hematologic complication among patients with severe COVID-19 disease, where macro- and micro-thrombosis can lead to multiorgan injury and failure. Major societal guidelines that have published on the management of CAC are based on consensus of expert opinion, with the current evidence available. As a result of limited studies, there are many clinical scenarios that are yet to be addressed, with expert opinion varying on a number of important clinical issues regarding CAC management. METHODS: In this review, we utilize current societal guidelines to provide a framework for practitioners in managing their patients with CAC. We have also provided three clinical scenarios that implement important principles of anticoagulation in patients with COVID-19. CONCLUSION: Overall, decisions should be made on acase by cases basis and based on the providers understanding of each patient's medical history, clinical course and perceived risk.

[Update 2021: COVID-19 from the perspective of cardiology]. / Update 2021: COVID-19 aus Sicht der Kardiologie.

More than one year ago COVID-19 emerged to a rapidly expanding global pandemic. Along with a growing number of individuals infected with SARS-CoV-2, we gained substantial knowledge on development, progression and treatment of the disease. In the light of increasing worldwide infection rates during the current "third wave", we will give a short update on COVID-19 from a cardiological point-of-view.

Impact and role of pulmonary embolism response teams in venous thromboembolism associated with COVID-19.

Venous thromboembolism associated with COVID-19, particularly acute pulmonary embolism, may represent a challenging and complex clinical scenario. The benefits of having a multidisciplinary pulmonary embolism response team (PERT) can be important during such a pandemic. The aim of PERT in the care of such patients is to provide fast, appropriate, multidisciplinary, team-based approach, with the common goal to tailor the best therapeutic decision making, prioritizing always optimal patient care, especially given lack of evidence-based clinical practice guidelines in the setting of COVID-19, which potentially confers a significant prothrombotic state. Herein, we would like to briefly emphasize the importance and potential critical role of PERT in the care of patients in which these two devastating illnesses are present together.

CHA2DS2-VASc score and modified CHA2DS2-VASc score can predict mortality and intensive care unit hospitalization in COVID-19 patients.

In this study, we investigated whether the CHA2DS2-VASc score could be used to estimate the need for hospitalization in the intensive care unit (ICU), the length of stay in the ICU, and mortality in patients with COVID-19. Patients admitted to Merkezefendi State Hospital because of COVID-19 diagnosis confirmed by RNA detection of virus by using polymerase chain reaction between March 24, 2020 and July 6, 2020, were screened retrospectively. The CHA2DS2-VASc and modified CHA2DS2-VASc score of all patients was calculated. Also, we received all patients' complete biochemical markers including D-dimer, Troponin I, and c-reactive protein on admission. We enrolled 1000 patients; 791 were admitted to the general medical service and 209 to the ICU; 82 of these 209 patients died. The ROC curves of the CHA2DS2-VASc and M-CHA2DS2-VASc scores were analyzed. The cut-off values of these scores for predicting mortality were ≥ 3 (2 or under and 3). The CHA2DS2-VASc and M-CHA2DS2-VASc scores had an area under the curve value of 0.89 on the ROC. The sensitivity and specificity of the CHA2DS2-VASc scores were 81.7% and 83.8%, respectively; the sensitivity and specificity of the M-CHA2DS2-VASc scores were 85.3% and 84.1%, respectively. Multivariate logistic regression analysis showed that CHA2DS2-VASc, Troponin I, D-Dimer, and CRP were independent predictors of mortality in COVID-19 patients. Using a simple and easily available scoring system, CHA2DS2-VASc and M-CHA2DS2-VASc scores can be assessed in patients diagnosed with COVID-19. These scores can predict mortality and the need for ICU hospitalization in these patients.

Early experience with arterial thromboembolic complications in patients with COVID-19.

BACKGROUND: Little is known about the arterial complications and hypercoagulability associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We sought to characterize our experience with arterial thromboembolic complications in patients with hospitalized for coronavirus disease 2019 (COVID-19). METHODS: All patients admitted from March 1 to April 20, 2020, and who underwent carotid, upper, lower and aortoiliac arterial duplex, computed tomography angiogram or magnetic resonance angiography for suspected arterial thrombosis were included. A retrospective case control study design was used to identify, characterize and evaluate potential risk factors for arterial thromboembolic disease in SARS-CoV-2 positive patients. Demographics, characteristics, and laboratory values were abstracted and analyzed. RESULTS: During the study period, 424 patients underwent 499 arterial duplex, computed tomography angiogram, or magnetic resonance angiography imaging studies with an overall 9.4% positive rate for arterial thromboembolism. Of the 40 patients with arterial thromboembolism, 25 (62.5%) were SARS-CoV-2 negative or admitted for unrelated reasons and 15 (37.5%) were SARS-CoV-2 positive. The odds ratio for arterial thrombosis in COVID-19 was 3.37 (95% confidence interval, 1.68-6.78; P = .001). Although not statistically significant, in patients with arterial thromboembolism, patients who were SARS-CoV-2 positive compared with those testing negative or not tested tended to be male (66.7% vs 40.0%; P = .191), have a less frequent history of former or active smoking (42.9% vs 68.0%; P = .233) and have a higher white blood cell count (14.5 vs 9.9; P = .208). Although the SARS-CoV-2 positive patients trended toward a higher the neutrophil-to-lymphocyte ratio (8.9 vs 4.1; P = .134), creatinine phosphokinase level (359.0 vs 144.5; P = .667), C-reactive protein level (24.2 vs 13.8; P = .627), lactate dehydrogenase level (576.5 vs 338.0; P = .313), and ferritin level (974.0 vs 412.0; P = .47), these differences did not reach statistical significance. Patients with arterial thromboembolic complications and SARS-CoV-2 positive when compared with SARS-CoV-2 negative or admitted for unrelated reasons were younger (64 vs 70 years; P = .027), had a significantly higher body mass index (32.6 vs 25.5; P = .012), a higher d-dimer at the time of imaging (17.3 vs 1.8; P = .038), a higher average in hospital d-dimer (8.5 vs 2.0; P = .038), a greater distribution of patients with clot in the aortoiliac location (5 vs 1; P = .040), less prior use of any antiplatelet medication (21.4% vs 62.5%; P = .035), and a higher mortality rate (40.0% vs 8.0%; P = .041). Treatment of arterial thromboembolic disease in COVID-19 positive patients included open thromboembolectomy in six patients (40%), anticoagulation alone in four (26.7%), and five (33.3%) did not require or their overall illness severity precluded additional treatment. CONCLUSIONS: Patients with SARS-CoV-2 are at risk for acute arterial thromboembolic complications despite a lack of conventional risk factors. A hyperinflammatory state may be responsible for this phenomenon with a preponderance for aortoiliac involvement. These findings provide an early characterization of arterial thromboembolic disease in SARS-CoV-2 patients.

[Thromboembolic Complications in COVID-19]. / Thromboembolische Komplikationen bei COVID-19.

COVID-19 represents a clinical situation that lacks precedence and clinical experience. It introduces a number of pitfalls in well-established clinical routines and poses unique challenges to diagnostic pathways. This review discusses the current evidence on the thromboembolic risk of COVID-19 patients, the recommendations for thromboprophylaxis and the relevance of abnormal coagulation tests. Pathophysiological concepts are discussed and practical solutions and current guidance recommendations are presented.

COVID-19 in the Healthy Patient Population: Demographic and Clinical Phenotypic Characterization and Predictors of In-Hospital Outcomes.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) can infect patients in any age group including those with no comorbid conditions. Understanding the demographic, clinical, and laboratory characteristics of these patients is important toward developing successful treatment strategies. Approach and Results: In a retrospective study design, consecutive patients without baseline comorbidities hospitalized with confirmed COVID-19 were included. Patients were subdivided into ≤55 and >55 years of age. Predictors of in-hospital mortality or mechanical ventilation were analyzed in this patient population, as well as subgroups. Stable parameters in overall and subgroup models were used to construct a cluster model for phenotyping of patients. Of 1207 COVID-19-positive patients, 157 met the study criteria (80≤55 and 77>55 years of age). Most reliable predictors of outcomes overall and in subgroups were age, initial and follow-up d-dimer, and LDH (lactate dehydrogenase) levels. Their predictive cutoff values were used to construct a cluster model that produced 3 main clusters. Cluster 1 was a low-risk cluster and was characterized by younger patients who had low thrombotic and inflammatory features. Cluster 2 was intermediate risk that also consisted of younger population that had moderate level of thrombosis, higher inflammatory cells, and inflammatory markers. Cluster 3 was a high-risk cluster that had the most aggressive thrombotic and inflammatory feature. CONCLUSIONS: In healthy patient population, COVID-19 remains significantly associated with morbidity and mortality. While age remains the most important predictor of in-hospital outcomes, thromboinflammatory interactions are also associated with worse clinical outcomes regardless of age in healthy patients.

Multi-organ point-of-care ultrasound for COVID-19 (PoCUS4COVID): international expert consensus.

COVID-19 has caused great devastation in the past year. Multi-organ point-of-care ultrasound (PoCUS) including lung ultrasound (LUS) and focused cardiac ultrasound (FoCUS) as a clinical adjunct has played a significant role in triaging, diagnosis and medical management of COVID-19 patients. The expert panel from 27 countries and 6 continents with considerable experience of direct application of PoCUS on COVID-19 patients presents evidence-based consensus using GRADE methodology for the quality of evidence and an expedited, modified-Delphi process for the strength of expert consensus. The use of ultrasound is suggested in many clinical situations related to respiratory, cardiovascular and thromboembolic aspects of COVID-19, comparing well with other imaging modalities. The limitations due to insufficient data are highlighted as opportunities for future research.

Cerebral Venous Sinus Thrombosis in COVID-19 Infection: A Case Series and Review of The Literature.

SARS-CoV-2, the virus responsible for novel Coronavirus (COVID-19) infection, has recently been associated with a myriad of hematologic derangements; in particular, an unusually high incidence of venous thromboembolism has been reported in patients with COVID-19 infection. It is postulated that either the cytokine storm induced by the viral infection or endothelial damage caused by viral binding to the ACE-2 receptor may activate a cascade leading to a hypercoaguable state. Although pulmonary embolism and deep venous thrombosis have been well described in patients with COVID-19 infection, there is a paucity of literature on cerebral venous sinus thrombosis (cVST) associated with COVID-19 infection. cVST is an uncommon etiology of stroke and has a higher occurrence in women and young people. We report a series of three patients at our institution with confirmed COVID-19 infection and venous sinus thrombosis, two of whom were male and one female. These cases fall outside the typical demographic of patients with cVST, potentially attributable to COVID-19 induced hypercoaguability. This illustrates the importance of maintaining a high index of suspicion for cVST in patients with COVID-19 infection, particularly those with unexplained cerebral hemorrhage, or infarcts with an atypical pattern for arterial occlusive disease.

First 70 Days Critical Data Trend for COVID-19 in Four Regions of Northern Italy: A Pilot Study.

The new coronavirus syndrome (COVID-19) is a multi-organ pathological manifestation that, in severe forms, causes greater damage to the respiratory system, especially in the lung district with severe respiratory failure. In many cases, especially in elderly patients with high comorbidity degree, the disease can have a rapid course with a fatal outcome. Specifically, the data relating to the four Italian regions most affected by the effects of the new coronavirus Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2), namely Lombardia, Veneto, Emilia Romagna and Piemonte, were assessed. In this work, we decided to focus the analysis only on data relating to patients admitted to the intensive care unit and to patients who died in Italy with COVID-19 in the period 24 February-4 May 2020. We used a data set where each point was an expression not of a single day, but of a longer period of time (date-points method). The article clearly identifies the phases in which the epidemic was articulated at national level and in the observed regions. Both the overall national data and the data referring to the most affected regions show an initial exponential mortality trend up to March 21st approximately. From this point the restrictive measures adopted from March 10th shows their effects and the trend first increases only linearly and then finally decreases, also thanks to the implementation of therapeutic strategies aimed at modulating respiratory distress and the clinical condition of thromboembolism, typical of critical patient COVID-19.

Development and implementation of a COVID-19 near real-time traffic light system in an acute hospital setting.

Common causes of death in COVID-19 due to SARS-CoV-2 include thromboembolic disease, cytokine storm and adult respiratory distress syndrome (ARDS). Our aim was to develop a system for early detection of disease pattern in the emergency department (ED) that would enhance opportunities for personalised accelerated care to prevent disease progression. A single Trust's COVID-19 response control command was established, and a reporting team with bioinformaticians was deployed to develop a real-time traffic light system to support clinical and operational teams. An attempt was made to identify predictive elements for thromboembolism, cytokine storm and ARDS based on physiological measurements and blood tests, and to communicate to clinicians managing the patient, initially via single consultants. The input variables were age, sex, and first recorded blood pressure, respiratory rate, temperature, heart rate, indices of oxygenation and C-reactive protein. Early admissions were used to refine the predictors used in the traffic lights. Of 923 consecutive patients who tested COVID-19 positive, 592 (64%) flagged at risk for thromboembolism, 241/923 (26%) for cytokine storm and 361/923 (39%) for ARDS. Thromboembolism and cytokine storm flags were met in the ED for 342 (37.1%) patients. Of the 318 (34.5%) patients receiving thromboembolism flags, 49 (5.3% of all patients) were for suspected thromboembolism, 103 (11.1%) were high-risk and 166 (18.0%) were medium-risk. Of the 89 (9.6%) who received a cytokine storm flag from the ED, 18 (2.0% of all patients) were for suspected cytokine storm, 13 (1.4%) were high-risk and 58 (6.3%) were medium-risk. Males were more likely to receive a specific traffic light flag. In conclusion, ED predictors were used to identify high proportions of COVID-19 admissions at risk of clinical deterioration due to severity of disease, enabling accelerated care targeted to those more likely to benefit. Larger prospective studies are encouraged.

Clinical Characteristics of Stroke with COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) potentially increases the risk of thromboembolism and stroke. Numerous case reports and retrospective cohort studies have been published with mixed characteristics of COVID-19 patients with stroke regarding age, comorbidities, treatment, and outcome. We aimed to depict the frequency and clinical characteristics of COVID-19 patients with stroke. METHODS: PubMed and EMBASE were searched on June 10, 2020, to investigate COVID-19 and stroke through retrospective cross-sectional studies, case series/reports according to PRISMA guidelines. Study-specific estimates were combined using one-group meta-analysis in a random-effects model. RESULTS: 10 retrospective cohort studies and 16 case series/reports were identified including 183 patients with COVID-19 and stroke. The frequency of detected stroke in hospitalized COVID-19 patients was 1.1% ([95% confidential interval (CI)]: [0.6-1.6], I2 = 62.9%). Mean age was 66.6 ([58.4-74.9], I2 = 95.1%), 65.6% was male (61/93 patients). Mean days from symptom onset of COVID-19 to stroke was 8.0 ([4.1-11.9], p< 0.001, I2 = 93.1%). D-dimer was 3.3 µg/mL ([1.7-4.9], I2 = 86.3%), and cryptogenic stroke was most common as etiology at 50.7% ([31.0-70.4] I2 = 64.1%, 39/71patients). Case fatality rate was 44.2% ([27.9-60.5], I2 = 66.7%, 40/100 patients). CONCLUSIONS: This systematic review assessed the frequency and clinical characteristics of stroke in COVID-19 patients. The frequency of detected stroke in hospitalized COVID-19 patients was 1.1% and associated with older age and stroke risk factors. Frequent cryptogenic stroke and elevated d-dimer level support increased risk of thromboembolism in COVID-19 associated with high mortality. Further study is needed to elucidate the pathophysiology and prognosis of stroke in COVID-19 to achieve most effective care for this population.

Acute Arterial Thromboembolism in Patients with COVID-19 in the New York City Area.

BACKGROUND: Coronavirus disease 2019 (COVID-19) predisposes to arterial and venous thromboembolic complications. We describe the clinical presentation, management, and outcomes of acute arterial ischemia and concomitant infection at the epicenter of cases in the United States. METHODS: Patients with confirmed COVID-19 infection between March 1, 2020 and May 15, 2020 with an acute arterial thromboembolic event were reviewed. Data collected included demographics, anatomical location of the thromboembolism, treatments, and outcomes. RESULTS: Over the 11-week period, the Northwell Health System cared for 12,630 hospitalized patients with COVID-19. A total of 49 patients with arterial thromboembolism and confirmed COVID-19 were identified. The median age was 67 years (58-75) and 37 (76%) were men. The most common preexisting conditions were hypertension (53%) and diabetes (35%). The median D-dimer level was 2,673 ng/mL (723-7,139). The distribution of thromboembolic events included upper 7 (14%) and lower 35 (71%) extremity ischemia, bowel ischemia 2 (4%), and cerebral ischemia 5 (10%). Six patients (12%) had thrombus in multiple locations. Concomitant deep vein thrombosis was found in 8 patients (16%). Twenty-two (45%) patients presented with signs of acute arterial ischemia and were subsequently diagnosed with COVID-19. The remaining 27 (55%) developed ischemia during hospitalization. Revascularization was performed in 13 (27%) patients, primary amputation in 5 (10%), administration of systemic tissue- plasminogen activator in 3 (6%), and 28 (57%) were treated with systemic anticoagulation only. The rate of limb loss was 18%. Twenty-one patients (46%) died in the hospital. Twenty-five (51%) were successfully discharged, and 3 patients are still in the hospital. CONCLUSIONS: While the mechanism of thromboembolic events in patients with COVID-19 remains unclear, the occurrence of such complication is associated with acute arterial ischemia which results in a high limb loss and mortality.

Malignant Cerebral Ischemia in A COVID-19 Infected Patient: Case Review and Histopathological Findings.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is responsible for an unprecedented worldwide pandemic that has severely impacted the United States. As the pandemic continues, a growing body of evidence suggests that infected patients may develop significant coagulopathy with resultant thromboembolic complications including deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic stroke. However, this data is limited and comes from recent small case series and observational studies on stroke types, mechanisms, and outcomes.1-14 Furthermore, evidence on the role of therapeutic anticoagulation in SARS-CoV-2 infected patients with elevated inflammatory markers, such as D-dimer, is also limited. We report the case of a middle-aged patient who presented with a large vessel ischemic stroke likely resulting from an underlying inflammatory response in the setting of known novel coronavirus infection (COVID-19). Histopathologic analysis of the patient's ischemic brain tissue revealed hypoxic neurons, significant edema from the underlying ischemic insult, fibrin thrombi in small vessels, and fibroid necrosis of the vascular wall without any signs of vasculature inflammation. Brain biopsy was negative for the presence of SARS-CoV-2 RNA (RT-PCR assay). Along with a growing body of literature, our case suggests that cerebrovascular thromboembolic events in COVID-19 infection may be related to acquired hypercoagulability and coagulation cascade activation due to the release of inflammatory markers and cytokines, rather than virus-induced vasculitis. Further studies to investigate the mechanism of cerebrovascular thromboembolic events and their prevention is warranted.

Thromboembolic risks in patients with COVID-19: major concern to consider in our management.

COVID-19 pandemic is an emergent cardiovascular risk factor and a major cause of mortality worldwide. Thromboembolism is highly suspected as a leading cause of death in these patients through vascular inflammation caused by SARS COV2. Until now there is no real treatment of COVID-19 and many proposed drugs are under clinical trials. Considering the high incidence of thromboembolic events in critically ill patients with COVID-19, prevention of this disorder should be essential in order to reduce mortality in these patients.