Levels of Vascular Endothelial Growth Factor and Its Association with Pulmonary Embolism in COVID-19.

Coronavirus disease 2019 (COVID-19) is associated with pulmonary embolism, a condition mechanistically related to vascular endothelial growth factor (VEGF). Our objective was to identify whether VEGF levels, measured at hospital admission, may predict the occurrence of pulmonary embolism (and other thrombosis) during hospitalization. Of a total of 139 patients included in the study, a pulmonary embolism occurred in 4%, other thrombosis in 16%, and 80% remained thrombus free. Clinical and laboratory data at admission were similar among groups. VEGF levels were elevated in COVID-19 patients compared with 38 healthy controls (50.7 versus 15.0 pg/mL; P < 0.001), with an area under the receiver operating characteristic curve of 0.776. At a cutoff point >15.7 pg/mL, VEGF showed 64.7% sensitivity, 92.1% specificity, and a positive likelihood ratio of 8.2 to discriminate COVID-19. In COVID-19, VEGF levels were not different in patients with pulmonary embolism, other thrombosis, and thrombus-free patients (15.0 versus 84.0 versus 48.5 pg/mL, respectively; P = 0.19). VEGF correlated with C-reactive protein (ρ = 0.25), fibrinogen (ρ = 0.28), ferritin (ρ = 0.18), and the neutrophil-to-lymphocyte ratio (ρ = 0.20). Our study showed that VEGF is elevated in sera from patients with COVID-19 on arrival at the hospital and its levels correlate with inflammatory markers, although they are unable to predict the appearance of pulmonary embolism during hospitalization.

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication.

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

High incidence of pulmonary thromboembolism in hospitalized SARS-CoV-2 infected patients despite thrombo-prophylaxis.

BACKGROUND: SARS-CoV-2 infected patients present thrombotic complications caused by direct endothelial cells injury of the microvessels. Pulmonary thromboembolism (PE) has been reported by Computed Tomography pulmonary angiogram (CTPA) in patients with COVID-19 pneumonia with high D-dimer levels. OBJECTIVES: We present the characteristics of SARS-CoV-2 infected patients diagnosed of PE by CTPA in our hospital. We also present the comparison of these findings with non-infected patients with PE data. METHODS: Retrospective observational cohort study that included patients over 18 years of age hospitalised consecutively between 26th February and 20th May 2020 in an European Hospital with SARS-CoV2 virus infection, and with suspected infection at beginning of admission but with negative PCR, who were studied with CTPA for suspicion of VTE, during their hospitalization. RESULTS: During the study period, 52 CTPA were performed in our hospital, sixteen in SARS-CoV-2 infected patients, with 4 cases (33%) of PE in the infected group, and 11 (44%) in the non-infected group. No significant differences in age (p = 0.43) and sex (p = 0.31) were found between the two groups, infected and non-infected patients. In the infected group, the patients who had PE had a much lower median age (47.8 years) than those without PE (73.3 years). No differences between infected and non-infected patients were detected in the diagnosis of PE with CTPA, 28.6% versus 27.8% (p = 1.00). Overall patient mortality was 1.9%; one patient died (6.3%) in the infected group, and none in the non-infected group (p = 0.31). CONCLUSION: A considerable incidence of PE diagnosed by CTPA in SARS-CoV-2 infected patients has been observed, despite thrombo-prophylaxis.

Thrombocytopathy vs Platelet hyper-reactivity in COVID-19: diverse pathologies, disease outcomes and therapeutic implications.

Coagulopathy is an evident complication of COVID-19 with predominance of a prothrombotic state. Platelet activation plays a key role. The terms "hyper-reactivity" and "hyperactivity" used in recent literature may not be clear or sufficient to explain the pathological events involved in COVID-related thrombosis (CRT). Inflammation may play a bigger role compared to thrombosis in COVID-related mortality because a smaller percentage of patients with COVID-19 die due to direct effects of thrombosis. Not all COVID-19 patients have thrombocytopenia and a few show thrombocytosis. We believe the platelet pathology is more complex than just activation or hyper-activation, particularly due to the platelets' role in inflammation. Understanding the pathology and consequences of platelets' role may help optimize management strategies and diminish CRT-associated morbidity and mortality. In this viewpoint report, we examine the published evidence of platelet hyper-reactivity in COVID-19 with a focused analysis of the key pathologies, diverse alterations, disease outcomes, and therapeutic targets. We believe that COVID-19 is a disease of inflammation and pathologic platelets, and based on the complexity and diverse pathologies, we propose the term "thrombocytopathy" as a more reflective term of the platelets' involvement in COVID-19. In our opinion, thrombocytopathy is the unpredictable pathologic alterations of platelets in function, morphology and number, caused by different factors with a variety of presentations.

Incidence and Clinical Features of Venous Thromboembolism in Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19) reportedly causes venous thromboembolism (VTE), but the status of this complication in Japan was unclear.Methods and Results:The VTE and COVID-19 in Japan Study is a retrospective, multicenter cohort study enrolling hospitalized patients with COVID-19 who were evaluated with contrast-enhanced computed tomography (CT) examination at 22 centers in Japan between March 2020 and October 2020. Among 1,236 patients with COVID-19, 45 (3.6%) were evaluated with contrast-enhanced CT examination. VTE events occurred in 10 patients (22.2%), and the incidence of VTE in mild, moderate, and severe COVID-19 was 0%, 11.8%, and 40.0%, respectively. COVID-19 patients with VTE showed a higher body weight (81.6 vs. 64.0 kg, P=0.005) and body mass index (26.9 vs. 23.2 kg/m2, P=0.04), and a higher proportion had a severe status for COVID-19 compared with those without. There was no significant difference in the proportion of patients alive at discharge between patients with and without VTE (80.0% vs. 88.6%, P=0.48). Among 8 pulmonary embolism (PE) patients, all were low-risk PE. CONCLUSIONS: Among a relatively small number of patients undergoing contrast-enhanced CT examination in Japanese real-world clinical practice, there were no VTE patients among those with mild COVID-19, but the incidence of VTE seemed to be relatively high among severe COVID-19 patients, although all PE events were low-risk without significant effect on mortality risk.

Screening for venous thromboembolism in patients with COVID-19.

Pulmonary thromboembolism and deep venous thrombosis occur frequently in hospitalised patients with COVID-19, the prevalence increases on the intensive care unit (ICU) and is very high in patients on extracorporeal membrane oxygenation (ECMO). We undertook a literature review to assess the usefulness of screening for peripheral venous thrombosis or pulmonary thrombosis in patients admitted with COVID-19. Outside of the ICU setting, D-dimer elevation on presentation or marked increase from baseline should alert the need for doppler ultrasound scan of the lower limbs. In the ICU setting, consideration should be given to routine screening with doppler ultrasound, given the high prevalence of thrombosis in this cohort despite standard anticoagulant thromboprophylaxis. However, absence of lower limb thrombosis on ultrasound does not exclude pulmonary venous thrombosis. Screening with CT pulmonary angiography (CTPA) is not justified in patients on the general wards, unless there are clinical features and/or marked elevations in markers of COVID-19-associated coagulopathy. However, the risk of pulmonary embolism or pulmonary thrombosis in ICU patients is very high, especially in patients on ECMO, where studies that employed routine screening for thrombosis with CT scanning have uncovered up to 100% incidence of pulmonary thrombosis despite standard anticoagulant thromboprophylaxis. Therefore, in patients at low bleeding risk and high clinical suspicion of venous thromboembolism, therapeutic anticoagulation should be considered even before screening, Our review highlights the need for increased vigilance for VTE, with a low threshold for doppler ultrasound and CTPA in high risk in-patient cohorts, where clinical features and D-dimer levels may not accurately reflect the occurrence of pulmonary thromboembolism.

Pulmonary embolism and COVID-19: A comparative analysis of different diagnostic models performance.

OBJECTIVE: Pulmonary embolism (PE) is a common complication of SARS-CoV-2 infection. Several diagnostic prediction rules based on pretest probability and D-dimer have been validated in non-COVID patients, but it remains unclear if they can be safely applied in COVID-19 patients. We aimed to compare the diagnostic accuracy of the standard approach based on Wells and Geneva scores combined with a standard D-dimer cut-off of 500 ng/mL with three alternative strategies (age-adjusted, YEARS and PEGeD algorithms) in COVID-19 patients. METHODS: This retrospective study included all COVID-19 patients admitted to the Emergency Department (ED) who underwent computed tomography pulmonary angiography (CTPA) due to PE suspicion. The diagnostic prediction rules for PE were compared between patients with and without PE. RESULTS: We included 300 patients and PE was confirmed in 15%. No differences were found regarding comorbidities, traditional risk factors for PE and signs and symptoms between patients with and without PE. Wells and Geneva scores showed no predictive value for PE occurrence, whether a standard or an age-adjusted cut-off was considered. YEARS and PEGeD algorithms were associated with increased specificity (19% CTPA reduction) but raising non-diagnosed PE. Despite elevated in all patients, those with PE had higher D-dimer levels. However, incrementing thresholds to select patients for CTPA was also associated with a substantial decrease in sensitivity. CONCLUSION: None of the diagnostic prediction rules are reliable predictors of PE in COVID-19. Our data favour the use of a D-dimer threshold of 500 ng/mL, considering that higher thresholds increase specificity but limits this strategy as a screening test.

Decreased in-hospital mortality associated with aspirin administration in hospitalized patients due to severe COVID-19.

Hypercoagulability and thrombosis caused by coronavirus disease 2019 (COVID-19) are related to the higher mortality rate. Because of limited data on the antiplatelet effect, we aimed to evaluate the impact of aspirin add-on therapy on the outcome of the patients hospitalized due to severe COVID-19. In this cohort study, patients with a confirmed diagnosis of severe COVID-19 admitted to Imam Hossein Medical Center, Tehran, Iran from March 2019 to July 2020 were included. Demographics and related clinical data during their hospitalization were recorded. The mortality rate of the patients was considered as the primary outcome and its association with aspirin use was assessed. Nine hundred and ninety-one patients were included, of that 336 patients (34%) received aspirin during their hospitalization and 655 ones (66%) did not. Comorbidities were more prevalent in the patients who were receiving aspirin. Results from the multivariate COX proportional model demonstrated a significant independent association between aspirin use and reduction in the risk of in-hospital mortality (0.746 [0.560-0.994], p = 0.046). Aspirin use in hospitalized patients with COVID-19 is associated with a significant decrease in mortality rate. Further prospective randomized controlled trials are needed to assess the efficacy and adverse effects of aspirin administration in this population.

Mechanical Thrombectomy in Pulmonary Embolism Associated with COVID-19: A "Clotography" Gallery.

Venous thromboembolism from a "thrombotic storm"-like syndrome is a major cause of morbidity and mortality in patients with active or "recovered" COVID-19. Patients should be risk-stratified, optimally by a pulmonary embolism (PE) response team (PERT), and considered for escalation of care if found with intermediate or high-risk PE. We present a series of patients with COVID-19-associated PE and thrombotic storm with D-dimer >10 000 ng/mL who underwent successful mechanical thrombectomy for intermediate to high-risk PE. All patients had immediate improvement in hemodynamics and large amounts of thrombi were retrieved.

Long-term effects of coronavirus disease 2019 on the cardiovascular system, CV COVID registry: A structured summary of a study protocol.

BACKGROUND: Patients presenting with the coronavirus-2019 disease (COVID-19) may have a high risk of cardiovascular adverse events, including death from cardiovascular causes. The long-term cardiovascular outcomes of these patients are entirely unknown. We aim to perform a registry of patients who have undergone a diagnostic nasopharyngeal swab for SARS-CoV-2 and to determine their long-term cardiovascular outcomes. STUDY AND DESIGN: This is a multicenter, observational, retrospective registry to be conducted at 17 centers in Spain and Italy (ClinicalTrials.gov number: NCT04359927). Consecutive patients older than 18 years, who underwent a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV2 in the participating institutions, will be included since March 2020, to August 2020. Patients will be classified into two groups, according to the results of the RT-PCR: COVID-19 positive or negative. The primary outcome will be cardiovascular mortality at 1 year. The secondary outcomes will be acute myocardial infarction, stroke, heart failure hospitalization, pulmonary embolism, and serious cardiac arrhythmias, at 1 year. Outcomes will be compared between the two groups. Events will be adjudicated by an independent clinical event committee. CONCLUSION: The results of this registry will contribute to a better understanding of the long-term cardiovascular implications of the COVID19.

High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.

BACKGROUND: Coagulopathy is a common abnormality in patients with COVID-19. However, the exact incidence of venous thromboembolic event is unknown in anticoagulated, severe COVID-19 patients. OBJECTIVES: Systematic assessment of venous thromboembolism (VTE) using complete duplex ultrasound (CDU) in anticoagulated COVID-19 patients. PATIENTS AND METHODS: We performed a retrospective study in 2 French intensive care units (ICU) where CDU is performed as a standard of care. A CDU from thigh to ankle at selected sites with Doppler waveforms and images was performed early during ICU stay in patients admitted with COVID-19. Anticoagulation dose was left to the discretion of the treating physician based on the individual risk of thrombosis. Patients were classified as treated with prophylactic anticoagulation or therapeutic anticoagulation. Pulmonary embolism was systematically searched in patients with persistent hypoxemia or secondary deterioration. RESULTS: From March 19 to April 11, 2020, 26 consecutive patients with severe COVID-19 were screened for VTE. Eight patients (31%) were treated with prophylactic anticoagulation, whereas 18 patients (69%) were treated with therapeutic anticoagulation. The overall rate of VTE in patients was 69%. The proportion of VTE was significantly higher in patients treated with prophylactic anticoagulation when compared with the other group (100% vs 56%, respectively, P = .03). Surprisingly, we found a high rate of thromboembolic events in COVID-19 patients treated with therapeutic anticoagulation, with 56% of VTE and 6 pulmonary embolisms. CONCLUSION: Our results suggest considering both systematic screening of VTE and early therapeutic anticoagulation in severe ICU COVID-19 patients.

Thrombotic risk in patients with COVID-19.

Emerging evidences prove that the ongoing pandemic of coronavirus disease 2019 (COVID-19) is strictly linked to coagulopathy even if pneumonia appears as the major clinical manifestation. The exact incidence of thromboembolic events is largely unknown, so that a relative significant number of studies have been performed in order to explore thrombotic risk in COVID-19 patients. Cytokine storm, mediated by pro-inflammatory interleukins, tumor necrosis factor α and elevated acute phase reactants, is primarily responsible for COVID-19-associated hypercoagulopathy. Also comorbidities, promoting endothelial dysfunction, contribute to a higher thromboembolic risk. In this review we aim to investigate epidemiology and clarify the pathophysiological pathways underlying hypercoagulability in COVID-19 patients, providing indications on the prevention of thromboembolic events in COVID-19. Furthermore we aim to reassume the pathophysiological paths involved in COVID-19 infection.

An uncommon presentation of COVID-19: concomitant acute pulmonary embolism, spontaneous tension pneumothorax, pneumomediastinum and subcutaneous emphysema (a case report).

The presenting symptoms and features of COVID-19 are non-specific and may be extrapulmonary complications such as thrombotic disorders but also pneumothorax, pneumomediastinum and subcutaneous emphysema; which are well-known complications of mechanical ventilation. Nevertheless, pneumothorax and/or pneumomediastinum, could complicate the course of a COVID-19 disease even in the absence of barotrauma involved. Herein, we report the case of a 55-year-old man with a previous history of erythroblastopenia due to thymoma admitted for COVID-19-related acute respiratory distress syndrome (ARDS) who simultaneously developed spontaneous tension pneumothorax, pneumomediastinum, subcutaneous emphysema and acute bilateral pulmonary embolism as presenting features of COVID-19 while on high-flow nasal cannula. This rare case highlights the importance of screening for other coexisting alternative diagnoses at the initial presentation of a patient suspected of COVID-19.

Association between D-dimer level and chest CT severity score in patients with SARS-COV-2 pneumonia.

The elevated level of D-dimer and its relationship with poor outcomes in SARS-COV-2 pneumonia patients have been demonstrated. In addition to a hypercoagulable state, D-dimer is also a biomarker of inflammation. We investigated the relationship between D-dimer level and chest computed tomography (CT) severity score, which could reflect the severity of inflammation in SARS-COV-2 pneumonia patients. We retrospectively enrolled 86 consecutive SARS-COV-2 pneumonia patients. CT severity scores were computed to quantify the overall lung involvement. The D-dimer level among CT score tertiles and the association of the D-dimer level with CT score were analyzed. Our results showed that the median D-dimer level was 0.70 mg/L (IQR 0.35-1.76). 42 patients (48.8%) had D-dimer levels above the median level. The D-dimer levels were significantly different across CT score tertiles (0.37 mg/l [IQR 0.31-0.87], 0.66 mg/l [IQR 0.39-1.43], 1.83 mg/l [IQR 0.85-4.41], P < 0.001). The natural logarithm of the D-dimer level was significantly associated with the CT score (rs = 0.586, P < 0.001). In conclusion, the D-dimer level may be associated with the severity of inflammation of SARS-COV-2 pneumonia prior to coagulopathy/thrombosis. This could be an additional explanation for the mechanism of the relationship between elevated D-dimer level and higher mortality.

A tricompartmental model of lung oxygenation disruption to explain pulmonary and systemic pathology in severe COVID-19.

The emergent 21st century betacoronaviruses, including SARS-CoV-2, lead to clinicopathological manifestations with unusual features, such as early-onset chest pain, pulmonary infarction, and pulmonary and systemic thromboembolism that is pathologically linked to extensive capillary, arteriolar, and venular thrombosis. Early ground glass opacities detected by CT, which are reminiscent of lung infarcts associated with pulmonary embolism, point to a novel vascular pathology in COVID-19. Under physiological conditions, normal parenchymal oxygenation is maintained by three sources: the alveolus itself and dual oxygen supply from the pulmonary and bronchial artery circulations. We propose a model in which these three components are disrupted in COVID-19 pneumonia, with severe viral alveolitis and concomitant immunothrombotic obstruction of the pulmonary and bronchiolar circulation. Tricompartmental disruption might have two main consequences: systemic clot embolisation from pulmonary vein territory immunothrombosis, and alveolar-capillary barrier disruption with systemic access of thrombogenic viral material. Our model encompasses the known pathological and clinical features of severe COVID-19, and has implications for understanding patient responses to immunomodulatory therapies, which might exert an anti-inflammatory effect within the vascular compartments.

Marine sulfated polysaccharides as potential antiviral drug candidates to treat Corona Virus disease (COVID-19).

The viral infection caused by SARS-CoV-2 has increased the mortality rate and engaged several adverse effects on the affected individuals. Currently available antiviral drugs have found to be unsuccessful in the treatment of COVID-19 patients. The demand for efficient antiviral drugs has created a huge burden on physicians and health workers. Plasma therapy seems to be less accomplishable due to insufficient donors to donate plasma and low recovery rate from viral infection. Repurposing of antivirals has been evolved as a suitable strategy in the current treatment and preventive measures. The concept of drug repurposing represents new experimental approaches for effective therapeutic benefits. Besides, SARS-CoV-2 exhibits several complications such as lung damage, blood clot formation, respiratory illness and organ failures in most of the patients. Based on the accumulation of data, sulfated marine polysaccharides have exerted successful inhibition of virus entry, attachment and replication with known or unknown possible mechanisms against deadly animal and human viruses so far. Since the virus entry into the host cells is the key process, the prevention of such entry mechanism makes any antiviral strategy effective. Enveloped viruses are more sensitive to polyanions than non-enveloped viruses. Besides, the viral infection caused by RNA virus types embarks severe oxidative stress in the human body that leads to malfunction of tissues and organs. In this context, polysaccharides play a very significant role in providing shielding effect against the virus due to their polyanionic rich features and a molecular weight that hinders their reactive surface glycoproteins. Significantly the functional groups especially sulfate, sulfate pattern and addition, uronic acids, monosaccharides, glycosidic linkage and high molecular weight have greater influence in the antiviral activity. Moreover, they are very good antioxidants that can reduce the free radical generation and provokes intracellular antioxidant enzymes. Additionally, polysaccharides enable a host-virus immune response, activate phagocytosis and stimulate interferon systems. Therefore, polysaccharides can be used as candidate drugs, adjuvants in vaccines or combination with other antivirals, antioxidants and immune-activating nutritional supplements and antiviral materials in healthcare products to prevent SARS-CoV-2 infection.

Acute pulmonary embolism in a child following SARS-CoV-2 infection: a case report.

In children, coronavirus disease 2019 infection is rarely symptomatic. Severe forms with respiratory distress are rare, thromboembolic complications are exceptional. We report a rare case of a 14 years old girl with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who was admitted to the hospital for bilateral pulmonary embolism with intracardiac thrombus. The girl progressed well on anticoagulation.