Inflammatory and Hemostatic Markers in COVID-19 Patients with Arterial Thrombosis Are Significantly Lower at Hospital Admission than in COVID-19 Patients without Thrombosis

Patients with Coronavirus disease 2019 (COVID-19) are at increased risk of venous thromboembolism (VTE); however, data on arterial thromboembolism (ATE) is still limited. We report a case series of thromboembolic events (TE) in 290 COVID-19 patients admitted between October and December 2020 to a Portuguese hospital. Admission levels of various laboratory parameters were evaluated and compared between COVID-19 patients with (TE) and without thrombotic events (non-TE). The overall incidence of isolated ATE was 5.52%, isolated VTE was 2.41% and multiple mixed events was 0.7%. A total of 68% events were detected upon admission to the hospital with 76% corresponding to ATE. Admissions to the Intensive Care Unit were higher in patients with TE, when comparing with the non-TE group (44% vs. 27.2%; p = 0.003). Patients with ATE presented significantly lower levels of CRP (p = 0.007), ferritin (p = 0.045), LDH (p = 0.037), fibrinogen (p = 0.010) and higher monocyte counts (p = 0.033) comparatively to the non-TE patients. These results point to an early occurrence of TE and an increased incidence of ATE over VTE. The less prominent inflammation markers in patients with TE and the early presence of TE in patients with otherwise no reason for hospitalization, may suggest a direct role of SARS-CoV-2 in the thrombotic process.     

Risk of venous thromboembolism in COVID-19 infection

The incidence of venous thromboembolism (VTE) for non-hospitalised patients with coronavirus disease-2019 infection has not been very widely studied. 13 019 persons with a positive SARS-CoV-2 nucleic acid amplification test were identified. In total, 447 (0.2%) VTEs were identified in the study population, 293 (66%) of these were pulmonary embolisms. A positive SARS-CoV-2 test did not increase the risk for VTE in the univariate analysis (odds ratio (OR): 1.0, 95% confidence interval (CI): 0.69–1.4) or multivariable analysis (OR: 1.36, 95% CI: 0.93–1.97).     

Risk Factors of Venous Thromboembolism in Noncritically Ill Patients Hospitalized for Acute COVID-19 Pneumonia Receiving Prophylactic-Dose Anticoagulation

Background: Therapeutic/intermediate-dose heparin reduces the risk of thromboembolic events but increases the risk of major bleeding in patients hospitalized for acute COVID-19 pneumonia. Objectives: To prospectively assess the incidence of objectively proven venous thromboembolism (VTE) and identify predisposing risk factors in a cohort of hospitalized patients with acute COVID-19 pneumonia undergoing prophylactic-dose heparin. Patients and methods: All consecutive patients admitted for acute COVID-19 pneumonia to the General Internal Medicine Unit of Padova University Hospital, Italy between November 2020 and April 2021, and undergoing prophylactic-dose heparin, were enrolled. Demographic and clinical characteristics and laboratory and radiological findings were recorded on admission. Cases were patients who developed VTE during their hospital stay. Univariable and multivariable logistic regression analyses were used to ascertain the risk factors associated with developing in-hospital VTE. Results: 208 patients (median age: 77 years; M/F 98/110) were included; 37 (18%) developed in-hospital VTE during a median follow-up of 10 days (IQR, 4–18). VTE patients were significantly younger (p = 0.004), more obese (p = 0.002), and had a lower Padua prediction score (p < 0.03) and reduced PaO2/FIO2 ratio (p < 0.03) vs. controls. Radiological findings of bilateral pulmonary infiltrates were significantly more frequent in VTE patients than controls (p = 0.003). Multivariable regression showed that obesity (1.75, 95% CI 1.02–3.36; p = 0.04) and bilateral pulmonary infiltrates on X-rays (2.39, 95% CI 1.22–5.69; p = 0.04) were correlated with increased risk of in-hospital VTE. Conclusions: Obesity and bilateral pulmonary infiltrates on imaging may help clinicians to identify patients admitted to medical wards for acute COVID-19 pneumonia at risk of developing VTE despite prophylactic-dose heparin. Further studies are needed to evaluate whether the administration of therapeutic/intermediate-dose heparin may help prevent VTE episodes without further increasing the bleeding risk.     

COVID-19 Severity: Lung-Heart Interplay

In December 2019, a novel COVID-19 infection caused by SARS-CoV-2 has emerged as a global emergency. In a few months, the pathogen has infected millions of people in the world. Primarily SARS-CoV-2 infects the pulmonary system which ultimately leads to ARDS and lung failure. The majority of patients develop milder symptoms but the infection turns severe in a huge number of people, which ultimately results in enhanced mortality in COVID-19 patients. Co-morbid conditions, primarily cardiovascular complications and diabetes, have been reported to show a strong correlation with COVID-19 severity. Further, the onset of myocardial injury secondary to pulmonary damage has been observed in critically ill patients who have never reported heart-related ailments before. Due to drastic health risks associated with virus infection, the unprecedented disruption in normal business throughout the world has caused economic misery. Apparently, newer treatments are urgently needed to combat the virus particularly to reduce the severity burden. Therefore, understanding the crosstalk between lung and heart during COVID-19 might give us better clarity for early diagnosis followed by appropriate treatment in patients with the likelihood of developing severe symptoms. Accordingly, the present review highlights the potential mechanisms that may explain the crosstalk between lung and heart so that effective treatment/management strategies can be evolved swiftly in this direction.     

Recurrence of Upper Extremity Deep Vein Thrombosis Secondary to COVID-19

Infection with SARS-CoV-2 leading to COVID-19 induces hyperinflammatory and hypercoagulable states, resulting in arterial and venous thromboembolic events. Deep vein thrombosis (DVT) has been well reported in COVID-19 patients. While most DVTs occur in a lower extremity, involvement of the upper extremity is uncommon. In this report, we describe the first reported patient with an upper extremity DVT recurrence secondary to COVID-19 infection.     

Fixed-Dose Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Pulmonary Embolism Associated with COVID-19

Background. Fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT) rapidly improves hemodynamic parameters and reverses right ventricular dysfunction caused by acute pulmonary embolism (PE). The effectiveness of USAT for acute PE associated with coronavirus disease 2019 (COVID-19) is unknown. Methods and results. The study population of this cohort study consisted of 36 patients with an intermediate-high- or high-risk acute PE treated with a fixed low-dose USAT protocol (r-tPA 10–20 mg/15 h). Of these, 9 patients tested positive for COVID-19 and were age–sex-matched to 27 patients without COVID-19. The USAT protocol included, beyond the infusion of recombinant tissue plasminogen activator, anti-Xa-activity-adjusted unfractionated heparin therapy (target 0.3–0.7 U/mL). The study outcomes were the invasively measured mean pulmonary arterial pressure (mPAP) before and at completion of USAT, and the National Early Warning Score (NEWS), according to which more points indicate more severe hemodynamic impairment. Twenty-four (66.7%) patients were men; the mean age was 67 ± 14 years. Mean ± standard deviation mPAP decreased from 32.3 ± 8.3 to 22.4 ± 7.0 mmHg among COVID-19 patients and from 35.4 ± 9.7 to 24.6 ± 7.0 mmHg among unexposed, with no difference in the relative improvement between groups (p = 0.84). Within 12 h of USAT start, the median NEWS decreased from six (Q1–Q3: 4–8) to three (Q1–Q3: 2–4) points among COVID-19 patients and from four (Q1–Q3: 2–6) to two (Q1–Q3: 2–3) points among unexposed (p = 0.29). One COVID-19 patient died due to COVID-19-related complications 14 days after acute PE. No major bleeding events occurred. Conclusions. Among patients with COVID-19-associated acute PE, mPAP rapidly decreased during USAT with a concomitant progressive improvement of the NEWS. The magnitude of mPAP reduction was similar in patients with and without COVID-19.     

Anti-SARS-CoV-2 Titers Predict the Severity of COVID-19

Coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 is associated with a wide spectrum of disease, ranging from asymptomatic infection to acute respiratory distress syndrome. Some biomarkers may predict disease severity. Among them, the anti-SARS-CoV-2 antibody response has been related to severe disease. The aim of this study was to assess the correlation between the anti-SARS-CoV-2 serological response and COVID-19 outcome. Demographic, clinical, and biological data from nasopharyngeal-PCR confirmed COVID-19 hospitalized patients were prospectively collected between April and August 2020 at our institution. All patients had serial weekly serology testing for a maximum of three blood samples or until discharge. Two different serological assays were used: a chemiluminescent assay and an in-house developed Luminex immunoassay. Kinetics of the serological response and correlation between the antibody titers and outcome were assessed. Among the 70 patients enrolled in the study, 22 required invasive ventilation, 29 required non-invasive ventilation or oxygen supplementation, and 19 did not require any oxygen supplementation. Median duration of symptoms upon admission for the three groups were 13, 8, and 9 days, respectively. Antibody titers gradually increased for up to 3 weeks since the onset of symptoms for patients requiring oxygen supplementation with significantly higher antibody titers for patients requiring invasive ventilation. Antibody titers on admission were also significantly higher in severely ill patients and serology performed well in predicting the necessity of invasive ventilation (AUC: 0.79, 95% CI: 0.67–0.9). Serology testing at admission may be a good indicator to identify severe COVID-19 patients who will require invasive mechanical ventilation.     

Dysregulation of Protein S in COVID-19

Coronavirus Disease 2019 (COVID-19) has been widely associated with increased thrombotic risk, with many different proposed mechanisms. One such mechanism is acquired deficiency of protein S (PS), a plasma protein that regulates coagulation and inflammatory processes, including complement activation and efferocytosis. Acquired PS deficiency is common in patients with severe viral infections and has been reported in multiple studies of COVID-19. This deficiency may be caused by consumption, degradation, or clearance of the protein, by decreased synthesis, or by binding of PS to other plasma proteins, which block its anticoagulant activity. Here, we review the functions of PS, the evidence of acquired PS deficiency in COVID-19 patients, the potential mechanisms of PS deficiency, and the evidence that those mechanisms may be occurring in COVID-19.     

Dysregulation of Pulmonary Responses in Severe COVID-19

Patients with coronavirus disease 2019 (COVID-19) predominantly have a respiratory tract infection with various symptoms and high mortality is associated with respiratory failure second to severe disease. The risk factors leading to severe disease remain unclear. Here, we reanalyzed a published single-cell RNA-Seq (scRNA-Seq) dataset and found that bronchoalveolar lavage fluid (BALF) of patients with severe disease compared to those with mild disease contained decreased TH17-type cells, decreased IFNA1-expressing cells with lower expression of toll-like receptor 7 (TLR7) and TLR8, increased IgA-expressing B cells, and increased hyperactive epithelial cells (and/or macrophages) expressing matrix metalloproteinases (MMPs), hyaluronan synthase 2 (HAS2), and plasminogen activator inhibitor-1 (PAI-1), which may together contribute to the pulmonary pathology in severe COVID-19. We propose IFN-I (and TLR7/TLR8) and PAI-1 as potential biomarkers to predict the susceptibility to severe COVID-19.     

The Impact of Risk-Adjusted Heparin Regimens on the Outcome of Patients with COVID-19 Infection. A Prospective Cohort Study

Background. According to recent guidelines, all hospitalized patients with COVID-19 should receive pharmacological prophylaxis for venous thromboembolism (VTE), unless there are specific contraindications. However, the optimal preventive strategy in terms of intensity of anticoagulation for these patients is not well established. Objectives. To investigate the impact of individualized regimens of enoxaparin on the development of VTE and on the risk of major bleeding complications during hospitalization in patients with COVID-19 infection. Methods. All consecutive patients admitted to the medical wards of six Italian hospitals between 15 September and 15 October 2020 with COVID-19 infection of moderate severity were administered enoxaparin in subcutaneous daily doses adjusted to the Padua Prediction Score stratification model: No heparin in patients scoring less than 4, 4000 IU daily in those scoring 4, 6000 IU in those scoring 5, and 8000 in those scoring six or more. Objective tests were performed in patients developing clinical symptoms of deep vein thrombosis and/or pulmonary embolism. Bleeding complications were defined according to the ISTH classification. Results. From the 154 eligible patients, enoxaparin was administered in all: 4000 IU in 73 patients, 6000 IU in 53, and 8000 IU in the remaining 28. During the course of hospitalization, 27 patients (17.5%) died. VTE developed in 14 of the 154 patients (9.1%; 95% CI, 4.6% to 13.6%), and was fatal in 1. Major bleeding complications developed in 35 patients (22.7%; 95% CI, 16.1% to 29.3%), and were fatal in 8. Conclusions. Despite the use of risk-adjusted doses of enoxaparin, the rate of VTE events was consistent with that reported in contemporary studies where fixed-dose low-molecular-weight heparin was used. The unexpectedly high risk of bleeding complications should induce caution in administering enoxaparin in doses higher than the conventional low ones.     

Coronary Stent Thrombosis in COVID-19 Patients: A Systematic Review of Cases Reported Worldwide

Approximately 5 million percutaneous coronary interventions are performed worldwide annually. Therefore, stent-related complications pose a serious public health concern. Stent thrombosis, although rare, is usually catastrophic, often associated with extensive myocardial infarction or death. Because little progress has been made in outcomes following stent thrombosis, ongoing research is focusing on further understanding the predictors as well as frequency and timing in various patient subgroups. Coronavirus disease-2019 (COVID-19), a viral illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), activates inflammatory mechanisms that potentially create a prothrombotic environment and increases the risk of local micro thromboembolism and all types of stent thrombosis. In-stent thrombosis occurrence increased during the COVID-19 pandemic, however, there is still lack of comprehensive studies describing this population. This review and worldwide analysis of coronary stent thrombosis cases related to COVID-19 summarizes all available data.     

Cerebral venous thrombosis in COVID-19

Background and aimsInitially, novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was considered primarily a respiratory pathogen. However, with time it has behaved as a virus with the potential to cause multi-system involvement, including neurological manifestations. Cerebral venous sinus thrombosis (CVT) has increasingly been reported in association with coronavirus infectious disease of 2019 (COVID-19). Here, we have shed light upon CVT and its possible mechanisms in the backdrop of the ongoing COVID-19 pandemic.MethodsIn this review, data were collected from PubMed, EMBASE and Web of Science, until March 30, 2021, using pre-specified searching strategies. The search strategy consisted of a variation of keywords of relevant medical subject headings and keywords, including “COVID-19”, “SARS-CoV-2”, “coronavirus”, and “cerebral venous sinus thrombosis”.ResultsCOVID-19 has a causal association with a plethora of neurological, neuropsychiatric and psychological effects. CVT has gained particular importance in this regard. The known hypercoagulable state in SARS-CoV-2 infection is thought to be the main mechanism in COVID-19 related CVT. Other plausible mechanisms may include vascular endothelial dysfunction and altered flow dynamics.ConclusionsAlthough there are no specific clinical characteristics, insidious or acute onset headache, seizures, stroke-like, or encephalopathy symptoms in a patient with, or who has suffered COVID-19, should prompt the attending physician to investigate for CVT. The treatment of COVID-19 associated CVT does not differ radically from the therapy of CVT without the infection, i.e. urgent initiation of parenteral unfractionated heparin or low molecular weight heparin followed by conventional or mostly newer oral anticoagulants.     

An Analysis COVID-19 in Mexico: a Prediction of Severity

BackgroundCoronavirus disease 2019 (COVID-19) causes a mild illness in most cases; forecasting COVID-19-associated mortality and the demand for hospital beds and ventilators are crucial for rationing countries’ resources.ObjectiveTo evaluate factors associated with the severity of COVID-19 in Mexico and to develop and validate a score to predict severity in patients with COVID-19 infection in Mexico.DesignRetrospective cohort.ParticipantsWe included 1,435,316 patients with COVID-19 included before the first vaccine application in Mexico; 725,289 (50.5%) were men; patient’s mean age (standard deviation (SD)) was 43.9 (16.9) years; 21.7% of patients were considered severe COVID-19 because they were hospitalized, died or both.Main MeasuresWe assessed demographic variables, smoking status, pregnancy, and comorbidities. Backward selection of variables was used to derive and validate a model to predict the severity of COVID-19.Key ResultsWe developed a logistic regression model with 14 main variables, splines, and interactions that may predict the probability of COVID-19 severity (area under the curve for the validation cohort = 82.4%).ConclusionsWe developed a new model able to predict the severity of COVID-19 in Mexican patients. This model could be helpful in epidemiology and medical decisions.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-021-07235-0.     

Heart,COVID-19, and echocardiography

Although clinical manifestations of coronavirus disease of 2019 (COVID-19) mainly consist of respiratory symptoms, a severe cardiovascular damage may occur. Moreover, previous studies reported a correlation of cardiovascular metabolic diseases with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and actually, many COVID-19 patients show comorbidities (systemic hypertension, cardio-cerebrovascular disease, and diabetes) and have a raised risk of death. The purpose of this review is to focus the cardiovascular effects of 2019-nCoV on the base of the most recent specific literature and previous learnings from SARS and MERS and analyze the potential role of echocardiography during the current critical period and short- and long-term follow-up.