NEUT-SFL in Patients with COVID-ARDS: A Novel Biomarker for Thrombotic Events?

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped RNA virus first identified in December 2019 in Wuhan, China, and responsible for coronavirus disease 2019 (COVID-19). The ongoing COVID-19 pandemic is impacting healthcare worldwide. Patients who develop coagulopathy have worse outcomes. The pathophysiology of COVID-19 suggests a strong interplay between hemostasis and immune cells, especially neutrophils. Our purpose was to assess neutrophil fluorescence as a potential biomarker of deep vein thrombosis (DVT) in patients with COVID-acute respiratory distress syndrome (COVID-ARDS). Sixty-one patients with COVID-ARDS admitted to the four intensive care units (ICUs) of a French general hospital were included in this prospective study. Neutrophil activation was assessed by measuring neutrophil fluorescence (NEUT-Side Fluorescence Light, NEUT-SFL) with a specific fluorescent dye staining analyzed by a routine automated flow cytometer Sysmex XN-3000™ (Sysmex, Kobe, Japan). DVT was diagnosed by complete duplex ultrasound (CDU). We found that NEUT-SFL was elevated on admission in patients with COVID-ARDS (49.76 AU, reference value 46.40 AU, p < 0.001), but did not differ between patients with DVT (49.99 AU) and those without (49.52 AU, p = 0.555). NEUT-SFL is elevated in patients with COVID-ARDS, reflecting neutrophil activation, but cannot be used as a marker of thrombosis. Because neutrophils are at interface between immune response and hemostasis through release of neutrophil extracellular traps, monitoring their activation could be an interesting approach to improve our management of coagulopathy during COVID-ARDS. Further research is needed to better understand the pathophysiology of COVID-19 and identify high-performance biomarkers.

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.

Pulmonary Vein Thrombosis in COVID-19.

Research on COVID-19, the cause of a rapidly worsening pandemic, has led to the observation of laboratory derangements such as a propensity towards a hypercoagulable state. However, there are currently no reports on the incidence of pulmonary venous thrombosis in the setting of COVID-19. We report a case in which follow-up chest CT scans revealed an expansile filling defect in a branch of the right inferior pulmonary vein, which is consistent with pulmonary venous thrombosis. Our objective was to provide insight into an uncommon sequela of COVID-19 and consequently garner increased clinical suspicion for pulmonary VTE during hospitalization.

Cerebral Venous Thrombosis Associated with COVID-19 Infection: An Observational, Multicenter Study.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (CO-VID-19) has an increased propensity for systemic hypercoagulability and thromboembolism. An association with cerebrovascular diseases, especially cerebral venous thrombosis (CVT), has been reported among these patients. The objective of the present study was to identify risk factors for CVT as well as its presentation and outcome in COVID-19 patients. METHODS: This is a multicenter and multinational observational study. Ten centers in 4 countries (Pakistan, Egypt, Singapore, and the United Arab Emirates) participated in this study. The study included patients (aged >18 years) with symptomatic CVT and recent COVID-19 infection. RESULTS: Twenty patients (70% men) were included. Their mean age was 42.4 years, with a male-to-female ratio of 2.3:1. Headache (85%) and seizures (65%) were the common presenting symptoms, with a mean admission Glasgow Coma Scale (GCS) score of 13. CVT was the presenting feature in 13 cases (65%), while 7 patients (35%) developed CVT while being treated for COVID-19 infection. Respiratory symptoms were absent in 45% of the patients. The most common imaging finding was infarction (65%), followed by hemorrhage (20%). The superior sagittal sinus (65%) was the most common site of thrombosis. Acute inflammatory markers were raised, including elevated serum D-dimer (87.5%), erythrocyte sedimentation rate (69%), and C-reactive protein (47%) levels. Homocysteine was elevated in half of the tested cases. The mortality rate was 20% (4 patients). A good functional outcome was seen in the surviving patients, with a mean modified Rankin Scale score at discharge of 1.3. Nine patients (45%) had a modified Rankin Scale score of 0-1 at discharge. CONCLUSION: COVID-19-related CVT is more common among males at older ages when compared to previously reported non-COVID-19-related CVT cases. CVT should be suspected in COVID-19 patients presenting with headache or seizures. Mortality is high, but functional neurological outcome is good among survivors.

Multiple cardiovascular complications of COVID-19 infection in a young patient: a case report.

COVID-19 infection is responsible for many complications, which can lead to a high risk of mortality in some patients. Among them are cardiovascular complications which are classified as the most severe. We report a case of a young woman, with no relevant pathological history, admitted for COVID-19 infection, complicated by myocarditis with severe ventricular dysfunction, cardiogenic shock and a large thrombosis into the left ventricle (LV) that was responsible for a left lower limb ischemia associated with a deep venous thrombosis of right lower limb.

Deep vein thrombosis and pulmonary embolism among hospitalized coronavirus disease 2019-positive patients predicted for higher mortality and prolonged intensive care unit and hospital stays in a multisite healthcare system.

OBJECTIVE: We assessed the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in hospitalized patients with coronavirus disease 2019 (COVID-19) compared with that in a matched cohort with similar cardiovascular risk factors and the effects of DVT and PE on the hospital course. METHODS: We performed a retrospective review of prospectively collected data from COVID-19 patients who had been hospitalized from March 11, 2020 to September 4, 2020. The patients were randomly matched in a 1:1 ratio by age, sex, hospital of admission, smoking history, diabetes mellitus, and coronary artery disease with a cohort of patients without COVID-19. The primary end point was the incidence of DVT/PE and the odds of developing DVT/PE using a conditional logistic regression model. The secondary end point was the hospitalization outcomes for COVID-19 patients with and without DVT/PE, including mortality, intensive care unit (ICU) admission, ICU stay, and length of hospitalization (LOH). Multivariable regression analysis was performed to identify the variables associated with mortality, ICU admission, discharge disposition, ICU duration, and LOH. RESULTS: A total of 13,310 patients had tested positive for COVID-19, 915 of whom (6.9%) had been hospitalized across our multisite health care system. The mean age of the hospitalized patients was 60.8 ± 17.0 years, and 396 (43.3%) were women. Of the 915 patients, 82 (9.0%) had had a diagnosis of DVT/PE confirmed by ultrasound examination of the extremities and/or computed tomography angiography of the chest. The odds of presenting with DVT/PE in the setting of COVID-19 infection was greater than that without COVID-19 infection (0.6% [5 of 915] vs 9.0% [82 of 915]; odds ratio [OR], 18; 95% confidence interval [CI], 8.0-51.2; P < .001). The vascular risk factors were not different between the COVID-19 patients with and without DVT/PE. Mortality (P = .02), the need for ICU stay (P < .001), duration of ICU stay (P < .001), and LOH (P < .001) were greater in the DVT/PE cohort than in the cohort without DVT/PE. On multivariable logistic regression analysis, the hemoglobin (OR, 0.71; 95% CI, 0.46-0.95; P = .04) and D-dimer (OR, 1.0; 95% CI, 0.33-1.56; P = .03) levels were associated with higher mortality. Higher activated partial thromboplastin times (OR, 1.1; 95% CI, 1.00-1.12; P = .03) and higher interleukin-6 (IL-6) levels (OR, 1.0; 95% CI, 1.01-1.07; P = .05) were associated with a greater risk of ICU admission. IL-6 (OR, 1.0; 95% CI, 1.00-1.02; P = .05) was associated with a greater risk of rehabilitation placement after discharge. On multivariable gamma regression analysis, hemoglobin (coefficient, -3.0; 95% CI, 0.03-0.08; P = .005) was associated with a prolonged ICU stay, and the activated partial thromboplastin time (coefficient, 2.0; 95% CI, 0.003-0.006; P = .05), international normalized ratio (coefficient, -3.2; 95% CI, 0.06-0.19; P = .002) and IL-6 (coefficient, 2.4; 95% CI, 0.0011-0.0027; P = .02) were associated with a prolonged LOH. CONCLUSIONS: A significantly greater incidence of DVT/PE occurred in hospitalized COVID-19-positive patients compared with a non-COVID-19 cohort matched for cardiovascular risk factors. Patients affected by DVT/PE were more likely to experience greater mortality, to require ICU admission, and experience prolonged ICU stays and LOH compared with COVID-19-positive patients without DVT/PE. Advancements in DVT/PE prevention are needed for patients hospitalized for COVID-19 infection.

Cerebral venous thrombosis after COVID-19. / Cerebral venetrombose etter covid-19.

BACKGROUND: There is emerging evidence of an increased risk of venous thromboembolism as well as several reports of cerebral venous thrombosis in COVID-19. CASE PRESENTATION: A previously healthy man in his fifties was admitted due to sudden confusion and reduced consciousness. One month earlier the patient had symptoms with headache, fever, dry cough, vomiting and diarrhoea and reduced sense of taste and smell. He was diagnosed with COVID-19 and the symptoms were mainly resolved within three weeks. On admission the patient was disorientated with aphasia. Brain imaging revealed a haemorrhagic infarction in the left temporal lobe due to thrombosis of the left transverse sinus and low-molecular weight heparin was instituted. On follow-up four months later, there was clinical improvement with only slight problems with short term memory and concentration. INTERPRETATION: This case illustrates the risk of serious neurological complications due to cerebral venous thrombosis in COVID-19.

Venous Thromboembolism in Hospitalized COVID-19 Patients.

BACKGROUND: Venous thromboembolism (VTE) is increasingly reported in seriously ill patients with COVID-19 infection. Incidence of VTE has been reported before and results varied widely in study cohorts. AREA OF UNCERTAINTY: Incidence of major VTE (segmental pulmonary embolism and above and proximal deep vein thrombosis) which is a contributor to mortality and morbidity is not known. Also, data is unclear on the optimal anticoagulation regimen to prevent VTE. DATA SOURCES: Multiple databases including PubMed were searched until May 12, 2020, to include studies reporting VTE in hospitalized COVID-19 adult patients. MOOSE guidelines were followed in selection, and 11 studies were included. We conducted a systematic review and meta-analysis to quantitatively assess the VTE burden in hospitalized COVID-19 patients and potential benefits of therapeutic dosing of anticoagulation compared with prophylaxis dosing for VTE prevention. THERAPEUTIC ADVANCES: Many societies and experts recommend routine prophylactic anticoagulation with heparin for VTE prevention in hospitalized COVID-19 patients. In this meta-analysis, the pooled rate of major VTE was 12.5% in hospitalized patients and 17.2% in intensive care unit patients. When therapeutic anticoagulation dosing was compared with prophylactic anticoagulation, the pooled odds ratio of VTE was 0.33 (95% confidence interval 0.14-0.75; P = 0.008, I = 0%) suggesting statistical significance with therapeutic dosing of anticoagulation for primary prevention of VTE in all hospitalized patients. However, this should be interpreted with caution as the bleeding events and safety profile could not be ascertained because of lack of adequate information. We recommend applying this finding to hospitalized COVID 19 patients only after carefully weighing individual bleeding risks and benefits. CONCLUSION: Major VTE events, especially pulmonary embolism, seem to be high in COVID-19 patients admitted to the intensive care unit. Therapeutic anticoagulation dosing seems to significantly benefit the odds of preventing any VTE when compared with prophylactic dosing in all hospitalized patients.

Haemostatic and thrombo-embolic complications in pregnant women with COVID-19: a systematic review and critical analysis.

BACKGROUND: As pregnancy is a physiological prothrombotic state, pregnant women may be at increased risk of developing coagulopathic and/or thromboembolic complications associated with COVID-19. METHODS: Two biomedical databases were searched between September 2019 and June 2020 for case reports and series of pregnant women with a diagnosis of COVID-19 based either on a positive swab or high clinical suspicion where no swab had been performed. Additional registry cases known to the authors were included. Steps were taken to minimise duplicate patients. Information on coagulopathy based on abnormal coagulation test results or clinical evidence of disseminated intravascular coagulation (DIC), and on arterial or venous thrombosis, were extracted using a standard form. If available, detailed laboratory results and information on maternal outcomes were analysed. RESULTS: One thousand sixty-three women met the inclusion criteria, of which three (0.28, 95% CI 0.0 to 0.6) had arterial and/or venous thrombosis, seven (0.66, 95% CI 0.17 to 1.1) had DIC, and a further three (0.28, 95% CI 0.0 to 0.6) had coagulopathy without meeting the definition of DIC. Five hundred and thirty-seven women (56%) had been reported as having given birth and 426 (40%) as having an ongoing pregnancy. There were 17 (1.6, 95% CI 0.85 to 2.3) maternal deaths in which DIC was reported as a factor in two. CONCLUSIONS: Our data suggests that coagulopathy and thromboembolism are both increased in pregnancies affected by COVID-19. Detection of the former may be useful in the identification of women at risk of deterioration.

Cytomegalovirus (CMV)-associated portal vein thrombosis in a healthy, immunocompetent man.

We present a previously healthy man in his 30s who presented with typical viral prodrome symptoms and worsening abdominal pain. He was found to have portal vein thrombosis, with extensive hypercoagulability workup performed. It was determined that the aetiology of thrombus was secondary to acute cytomegalovirus infection. The patient was started on anticoagulation therapy, with later clot resolution demonstrated on abdominal Doppler ultrasound and abdominal CT scan. Given the atypical presentation of this common virus, we performed a literature review of cytomegalovirus-associated portal vein thrombosis in healthy individuals; we found that most patients present with non-specific symptoms of fever and abdominal pain in the setting of a viral prodrome. This case and literature review suggest physicians must consider cytomegalovirus-associated portal vein thrombosis as a potential diagnosis when patients present with abdominal pain and viral symptoms. The literature highlights the need for a consensus on anticoagulation and antiviral therapy.

Superficial Cerebral Venous Thrombosis and Intracerebral Hematoma in a 48-Year-Old Man with SARS-CoV-2 Infection: A Case Report.

BACKGROUND Pandemic coronavirus disease 2019 (COVID-19) originated in Wuhan, China, and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe respiratory symptoms are a hallmark of the disease, which may also include complications related to a hypercoagulable state and central nervous system involvement. These complications can occur during either the acute or the recovery phase. The cerebral involvement typically manifests as intracranial hypertension, intracerebral hemorrhage, diffuse encephalopathy, or cerebral venous thrombosis. The hemorrhagic form of cerebral venous thrombosis can be a diagnostic challenge and is treated by anticoagulation therapy, despite the existence of an intracerebral hemorrhage. This report describes a case of superficial cerebral venous thrombosis and intracerebral hematoma in a 48-year-old man weeks after recovering from the acute phase of SARSCoV-2 infection. CASE REPORT A 48-year-old man with a past medical history of SARS-CoV-2 infection confirmed by SARS-CoV-2 reverse-transcription polymerase chain reaction presented with left upper-limb numbness, weakness, and impaired positional sensorium. After initial stabilization, noncontrast computerized tomography and magnetic resonance imaging confirmed an intracerebral hemorrhage with underlying cerebral venous thrombosis. The patient was successfully treated with enoxaparin anticoagulation therapy, and symptoms improved over the following 12 days. CONCLUSIONS Central nervous system venous thrombosis is an atypical presentation of the hypercoagulable state primarily seen in younger patients, and it can occur in a delayed fashion after recovery from mild forms of COVID-19.

Extensive DVT and Pulmonary Embolism Leading to the Diagnosis of Coronavirus Disease 2019 in the Absence of Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia.

There is growing evidence that coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state. To date, all patients reported with venous thromboembolic disease and COVID-19 have shown evidence of viral pneumonia. Here, we report the case of a 31-year-old patient with unexplained extensive DVT and bilateral pulmonary embolism in the absence of COVID-19 pneumonia, leading to the diagnosis of otherwise asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the context of the COVID-19 pandemic, given the high rates of otherwise asymptomatic patients, testing for SARS-CoV-2 should be performed in all patients with unexplained VTE occurring in COVID-19-endemic areas, even in the absence of other disease manifestations suggestive of SARS-CoV-2 infection.

Acute portal vein thrombosis secondary to COVID-19: a case report.

BACKGROUND: COVID-19 pneumonia exhibits several extra-pulmonary complications. CASE PRESENTATION: A 23-year old, asthmatic male with coronavirus pneumonia developed with generalized, acute abdominal pain. Further evaluations revealed a mild ascites and portal vein thrombosis although the patient received proper anticoagulation therapy. Routine lab data regarding the secondary causes of portal vein thrombosis were normal. CONCLUSION: We speculated that the underlying cause of portal vein thrombosis in our case was coronaviruses. Therefore, clinicians should always consider thrombosis and other hypercoagulable diseases in patients with COVID-19.

Predicting Venous Thromboembolic Events in Patients with Coronavirus Disease 2019 Requiring Hospitalization: an Observational Retrospective Study by the COVIDIC Initiative in a Swiss University Hospital.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can result in profound changes in blood coagulation. The aim of the study was to determine the incidence and predictors of venous thromboembolic events (VTE) among patients with COVID-19 requiring hospital admission. Subjects and Methods. We performed a retrospective study at the Lausanne University Hospital with patients admitted because of COVID-19 from February 28 to April 30, 2020. RESULTS: Among 443 patients with COVID-19, VTE was diagnosed in 41 patients (9.3%; 27 pulmonary embolisms, 12 deep vein thrombosis, one pulmonary embolism and deep vein thrombosis, one portal vein thrombosis). VTE was diagnosed already upon admission in 14 (34.1%) patients and 27 (65.9%) during hospital stay (18 in ICU and nine in wards outside the ICU). Multivariate analysis revealed D-dimer value > 3,120 ng/ml (P < 0.001; OR 15.8, 95% CI 4.7-52.9) and duration of 8 days or more from COVID-19 symptoms onset to presentation (P 0.020; OR 4.8, 95% CI 1.3-18.3) to be independently associated with VTE upon admission. D-dimer value ≥ 3,000 ng/l combined with a Wells score for PE ≥ 2 was highly specific (sensitivity 57.1%, specificity 91.6%) in detecting VTE upon admission. Development of VTE during hospitalization was independently associated with D-dimer value > 5,611 ng/ml (P < 0.001; OR 6.3, 95% CI 2.4-16.2) and mechanical ventilation (P < 0.001; OR 5.9, 95% CI 2.3-15.1). CONCLUSIONS: VTE seems to be a common COVID-19 complication upon admission and during hospitalization, especially in ICU. The combination of Wells ≥ 2 score and D - dimer ≥ 3,000 ng/l is a good predictor of VTE at admission.

Neurovascular complications that can be seen in COVID-19 patients.

Coronavirus disease 2019 (COVID-19), a clinical manifestation of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was declared a global pandemic by the World Health Organization on March 11, 2020. Hypercoagulable state has been described as one of the hallmarks of SARS-CoV-2 infection and has been reported to manifest as pulmonary embolisms, deep vein thrombosis, and arterial thrombosis of the abdominal small vessels. Here we present cases of arterial and venous thrombosis pertaining to the head and neck in COVID-19 patients.

Left gonadal vein thrombosis in a patient with COVID-19-associated coagulopathy.

COVID-19 disease is a viral illness that predominantly causes pneumonia and severe acute respiratory distress syndrome. The endothelial injury and hypercoagulability secondary to the inflammatory response predisposes severely ill patients to venous thromboembolism. The exact mechanism of hypercoagulability is still under investigation, but it is known to be associated with poor prognosis. The most common thrombotic complication reported among these patients is pulmonary embolism. To our knowledge, gonadal vein thrombosis is an uncommon phenomenon that has not been reported in the setting of COVID-19-associated coagulopathy. We report an unusual case of ovarian vein thrombosis and pulmonary embolism associated with COVID-19 presenting with abdominal pain. To our knowledge, this is the first reported case of COVID-19 with absent respiratory symptoms and presentation with venous thrombosis in an unusual location.