COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US cohort.

INTRODUCTION: Infection with SARS-CoV-2 is typically compared with influenza to contextualize its health risks. SARS-CoV-2 has been linked with coagulation disturbances including arterial thrombosis, leading to considerable interest in antithrombotic therapy for Coronavirus Disease 2019 (COVID-19). However, the independent thromboembolic risk of SARS-CoV-2 infection compared with influenza remains incompletely understood. We evaluated the adjusted risks of thromboembolic events after a diagnosis of COVID-19 compared with influenza in a large retrospective cohort. METHODS: We used a US-based electronic health record (EHR) dataset linked with insurance claims to identify adults diagnosed with COVID-19 between April 1, 2020 and October 31, 2020. We identified influenza patients diagnosed between October 1, 2018 and April 31, 2019. Primary outcomes [venous composite of pulmonary embolism (PE) and acute deep vein thrombosis (DVT); arterial composite of ischemic stroke and myocardial infarction (MI)] and secondary outcomes were assessed 90 days post-diagnosis. Propensity scores (PS) were calculated using demographic, clinical, and medication variables. PS-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression. RESULTS: There were 417,975 COVID-19 patients (median age 57y, 61% women), and 345,934 influenza patients (median age 47y, 66% women). Compared with influenza, patients with COVID-19 had higher venous thromboembolic risk (HR 1.53, 95% CI 1.38-1.70), but not arterial thromboembolic risk (HR 1.02, 95% CI 0.95-1.10). Secondary analyses demonstrated similar risk for ischemic stroke (HR 1.11, 95% CI 0.98-1.25) and MI (HR 0.93, 95% CI 0.85-1.03) and higher risk for DVT (HR 1.36, 95% CI 1.19-1.56) and PE (HR 1.82, 95% CI 1.57-2.10) in patients with COVID-19. CONCLUSION: In a large retrospective US cohort, COVID-19 was independently associated with higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared with influenza. These findings may inform crucial knowledge gaps regarding the specific thromboembolic risks of COVID-19.

Thromboembolic Rates Are Similar Between Intensive Care Unit and Nonintensive Care Unit Hospitalized Patients With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): A Retrospective Cohort Study.

High rates of thromboembolic events have been described in intensive care unit (ICU) patients. Data regarding thromboembolic events in all hospitalized patients has been less frequently reported, raising concerns that thromboembolic events in non-ICU may be underrecognized. In addition, optimal anticoagulation type and dose is still unsettled at this time. This is a retrospective cohort study of 159 hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia during a 9-month period to determine an association between the frequency of thromboembolic rates and hospitalized patients with COVID-19. Secondary outcomes sought to investigate association of thromboembolic events with relation to place of admission, risk factors, anticoagulation, mortality, hospital length of stay, and discharge disposition. Among the cohort of 159 hospitalized patients who met criteria, 16 (10%) were diagnosed with a thromboembolic event. There were a total of 18 thromboembolic events with 12 venous and 6 arterial. Admission to the ICU was not associated with a higher frequency of thromboembolic events compared with non-ICU patients (37.5% vs 62.5%), p = .71. Patients with a thromboembolic event had a significantly higher mortality compared with those with no thromboembolic event (37.5% vs 13.3%), p = .012. Patients hospitalized with COVID-19 have increased rates of thromboembolic events, both venous and arterial, which contribute to a significant increase in mortality. However, the frequency of thromboembolism in patients admitted to the ICU was similar to events in non-ICU patients. We hope to increase awareness of the increased risk of hypercoagulability in all hospitalized patients with COVID-19 including non-ICU patients.

On-admission versus in-hospital thromboembolism due to COVID-19 infection. What is the particular characteristic of those with early thrombotic events?

INTRODUCTION: Increasing evidence has declared a hypercoagulable state in the coronavirus 2019 infection (COVID-19), while the etiology has remained a question. For the first time, the current study has aimed to compare the contributors of thromboembolism among those whose primary manifestations of COVID-19 were thrombosis vs the patients with a thrombotic event during the period of hospitalization. MATERIAL AND METHODS: This case-control study has been conducted on 267 COVID-19 patients, including 59, 48, and 160 ones with an on-admission, in-hospital, and without a thrombotic event, respectively. The events were defined as deep vein thrombosis (DVT), ischemic cerebrovascular accidents (CVA), pulmonary thromboembolism (PTE), or acute myocardial infarction (AMI). The demographic, physical examination, clinical and laboratory assessments of the groups were compared. RESULTS: The DVT (OR: 5.18; 95% CI: 1.01-26.7), AMI (OR: 11.1; 95% CI: 2.36-52.3), and arterial thrombosis (OR: 5.93; 95% CI: 0.63-55.8) were significantly associated with an on-admission thrombosis compared to those who presented in-hospital events. Lower levels of oxygen saturation were the only significant predictor index inversely associated with on-admission thrombosis compared to those with an event during the hospital admission period. CONCLUSION: PTE development was the most common in-hospital thrombotic event, whereas other thromboembolism types were remarkably more often among cases with on-admission events. Oxygen saturation was the only predictor of premature thrombosis that was inversely associated with outpatient events.

Thromboembolic Risk in Hospitalized and Nonhospitalized COVID-19 Patients: A Self-Controlled Case Series Analysis of a Nationwide Cohort.

OBJECTIVE: To assess the associations between coronavirus disease 2019 (COVID-19) infection and thromboembolism including myocardial infarction (MI), ischemic stroke, deep vein thrombosis (DVT), and pulmonary embolism (PE). PATIENTS AND METHODS: A self-controlled case-series study was conducted covering the whole of Scotland's general population. The study population comprised individuals with confirmed (positive test) COVID-19 and at least one thromboembolic event between March 2018 and October 2020. Their incidence rates during the risk interval (5 days before to 56 days after the positive test) and the control interval (the remaining periods) were compared intrapersonally. RESULTS: Across Scotland, 1449 individuals tested positive for COVID-19 and experienced a thromboembolic event. The risk of thromboembolism was significantly elevated over the whole risk period but highest in the 7 days following the positive test (incidence rate ratio, 12.01; 95% CI, 9.91 to 14.56) in all included individuals. The association was also present in individuals not originally hospitalized for COVID-19 (incidence rate ratio, 4.07; 95% CI, 2.83 to 5.85). Risk of MI, stroke, PE, and DVT were all significantly higher in the week following a positive test. The risk of PE and DVT was particularly high and remained significantly elevated even 56 days following the test. CONCLUSION: Confirmed COVID-19 infection was associated with early elevations in risk with MI, ischemic stroke, and substantially stronger and prolonged elevations with DVT and PE both in hospital and community settings. Clinicians should consider thromboembolism, especially PE, among people with COVID-19 in the community.

Overview of Covid-19 Regarding the Cardiovascular Situation in the Light of Current Reports.

Nowadays Coronavirus Disease 2019 (Covid-19) is increasing mortality all over the world mercilessly. We are learning almost every day about its new symptoms and that it mutates quickly. This disease has tied us up and made us desperate. The death rate from this disease has increased in patients who had pre-existing medical conditions, especially cardiovascular ones, by eliminating the angiotensin-converting enzyme (ACE)-2 receptor in the lungs. Also, ACE1 and angiotensin receptor blockers (ARB) may stimulate ACE2 expression and worse the prognosis. Intravenous infusions of ACEIs and ARBs in experimental animals increase the number of ACE2 receptors. Therefore, it may be one of the reasons that COVID-19 infects the cells of patients treating hypertension. However, most of the congress of cardiology do not recommend to discontinue these anti-hypertensive drugs. Therefore, this brief report evaluates Covid-19 in the view of cardiovascular diseases taking into account current reports and suggests some possible solutions to keep the virus under control.

Medically Ill hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis with rivaroxaban ThErapy: Rationale and Design of the MICHELLE Trial.

BACKGROUND: The devastating Coronavirus disease (COVID-19) pandemic is associated with a high prothrombotic state. It is unclear if the coagulation abnormalities occur because of the direct effect of SARS-CoV-2 or indirectly by the cytokine storm and endothelial damage or by a combination of mechanisms. There is a clear indication of in-hospital pharmacological thromboprophylaxis for every patient with COVID-19 after bleed risk assessment. However, there is much debate regarding the best dosage regimen, and there is no consensus on the role of extended thromboprophylaxis. DESIGN: This study aims to evaluate the safety and efficacy of rivaroxaban 10 mg once daily for 35 ± 4 days versus no intervention after hospital discharge in COVID-19 patients who were at increased risk for VTE and have received standard parenteral VTE prophylaxis during hospitalization. The composite efficacy endpoint is a combination of symptomatic VTE, VTE-related death, VTE detected by bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram on day 35 ± 4 posthospital discharge and symptomatic arterial thromboembolism (myocardial infarction, nonhemorrhagic stroke, major adverse limb events, and cardiovascular death) up to day 35 ± 4 posthospital discharge. The key safety outcome is the incidence of major bleeding according to ISTH criteria. SUMMARY: The MICHELLE trial is expected to provide high-quality evidence around the role of extended thromboprophylaxis in COVID-19 and will help guide medical decisions in clinical practice.1.

Multiple arterial thromboemboli after COVID-19. / Multiple arterielle tromboembolier etter covid-19.

BACKGROUND: We present the case of a man in his fifties who presented with bilateral lower extremity ischaemia three weeks after COVID-19 infection. The patient had known. CASE PRESENTATION: On arrival at the emergency department his left lower extremity had reduced sensation but preserved motor function. His right lower extremity had spontaneously improved on arrival. A CT angiogram showed thromboembolism in both popliteal arteries with extension down the tibiofibular trunk. An acute bilateral mechanical thromboembolectomy of the popliteal artery and tibiofibular trunk was performed. Postoperatively he was hypoxic and a CT thorax angiogram showed bilateral pulmonary embolism, a floating aortic thrombus and ground glass opacification changes typical after COVID-19 viral pneumonia. The patient was systemically anticoagulated. Echocardiography revealed an apical thrombus. There were no signs of cardiac arrhythmia. Haematological diagnostic tests were all negative. INTERPRETATION: It is presumed that a previous COVID-19 infection contributed to the systemic thrombotic events. The patient was discharged after 9 days in good health and able to walk a normal distance.

Thromboembolism risk among patients with diabetes/stress hyperglycemia and COVID-19.

PURPOSE: Individuals with diabetes/stress hyperglycemia carry an increased risk for adverse clinical outcome in case of SARS-CoV-2 infection. The purpose of this study was to evaluate whether this risk is, at least in part, modulated by an increase of thromboembolic complications. METHODS: We prospectively followed 180 hospitalized patients with confirmed COVID-19 pneumonia admitted to the Internal Medicine Units of San Raffaele Hospital. Data from 11 out of 180 patients were considered incomplete and excluded from the analysis. We analysed inflammation, tissue damage biomarkers, hemostatic parameters, thrombotic events (TEs) and clinical outcome according to the presence of diabetes/stress hyperglycemia. RESULTS: Among 169 patients, 51 (30.2%) had diabetes/stress hyperglycemia. Diabetes/stress hyperglycemia and fasting blood glucose (FBG) were associated with increased inflammation and tissue damage circulating markers, higher D-dimer levels, increased prothrombin time and lower antithrombin III activity. Forty-eight venous and 10 arterial TEs were identified in 49 (29%) patients. Diabetes/stress hyperglycemia (HR 2.71, p = 0.001), fasting blood glucose (HR 4.32, p < 0.001) and glucose variability (HR 1.6, p < 0.009) were all associated with an increased risk of thromboembolic complication. TEs significantly increased the risk for an adverse clinical outcome only in the presence of diabetes/stress hyperglycemia (HR 3.05, p = 0.010) or fasting blood glucose ≥7 mmol/L (HR 3.07, p = 0.015). CONCLUSIONS: Thromboembolism risk is higher among patients with diabetes/stress hyperglycemia and COVID-19 pneumonia and is associated to poor clinical outcome. In case of SARS-Cov-2 infection patients with diabetes/stress hyperglycemia could be considered for a more intensive prophylactic anticoagulation regimen.

[Title: Covid-19-associated coagulopathy]. / COVID-19-assoziierte Koagulopathie.

COVID-19, primarily a respiratory disease, is considered a multi-systemic disease as symptom severity increases. Blood coagulation abnormalities are key features of patients with severe symptoms and indicative of the high risk of both venous and arterial thromboembolism in COVID-19. This prothrombotic condition caused by an interplay of the infectious agent, inflammation, and the blood coagulation system is referred to as COVID-19-associated coagulopathy and characterized by greatly increased D-dimer, high fibrinogen, an extended prothrombin time, and a reduced number of platelets. Due to this high thrombotic potential, prophylactic anticoagulation is recommended in all hospitalized patients. However, the optimal dosage of anticoagulation is still debated. In this article, we provide an overview of the current state of knowledge about COVID-19-associated coagulopathy and discuss clinical therapeutic consequences.

Thromboembolism after COVID-19 vaccine in patients with preexisting thrombocytopenia.

While vaccination is the single most effective intervention to drastically reduce severe disease and death following SARS-CoV-2 infection, as shown in UK and Israel, some serious concerns have been raised for an unusual adverse drug reaction (ADR), including vaccine-induced immune thrombotic thrombocytopenia (VITT) with concurrent low platelets as well as capillary leak syndrome. In fact, the overall safety of the vaccine is highlighted by the low frequency of ADR considering that in UK, by the early June, 40 million first doses and 29 million second doses have been injected; nonetheless, 390 thrombotic events, including 71 fatal events have been reported. Interestingly, the cases reported low platelet counts with the presence of anti-platelet factor-4 (PF4) antibodies, indicating an abnormal clotting reaction. Here, out of three referred cases, we report a post-vaccine clinical case of fatal thrombosis with postmortem examination and whole exome sequencing (WES) analysis, whose pathogenesis appeared associated to a preexisting condition of thrombocytopenia due to myelodysplasia.

COVID-19: Thrombosis, thromboinflammation, and anticoagulation considerations.

Vascular endothelial injury is a hallmark of acute infection at both the microvascular and macrovascular levels. The hallmark of SARS-CoV-2 infection is the current COVID-19 clinical sequelae of the pathophysiologic responses of hypercoagulability and thromboinflammation associated with acute infection. The acute lung injury that initially occurs in COVID-19 results from vascular and endothelial damage from viral injury and pathophysiologic responses that produce the COVID-19-associated coagulopathy. Clinicians should continue to focus on the vascular endothelial injury that occurs and evaluate potential therapeutic interventions that may benefit those with new infections during the current pandemic as they may also be of benefit for future pathogens that generate similar thromboinflammatory responses. The current Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) studies are important projects that will further define our management strategies. At the time of writing this report, two mRNA vaccines are now being distributed and will hopefully have a major impact on slowing the global spread and subsequent thromboinflammatory injury we see clinically in critically ill patients.

Autoimmune connective tissue diseases in the COVID-19 pandemic.

Autoimmune connective tissue diseases are a heterogeneous group of clinical entities sharing a common feature-an impairment of structural components like collagen and elastin, arising by autoimmune mechanisms. Because most patients are on a long-term immunosuppressive therapy, which renders them vulnerable to infections, a new challenge appears in front of physicians in the coronavirus disease 2019 (COVID-19) era. Immune mechanisms are substantial for the control and ceasing of viral infections, and their impairment may cause serious complications; however, data from immunosuppressed transplant patients do not reveal a higher frequency or diseases' severity in those infected by COVID-19. Several immunotherapies used to treat autoimmune connective tissue diseases favorably modulate the immune response of severe acute respiratory syndrome coronavirus (SARS-CoV-2)-infected patients. The present review highlights the problems of susceptibility, severity, and therapeutic options in patients with autoimmune connective tissue diseases during the COVID-19 pandemic. The relationship between autoimmune connective tissue diseases and COVID-19 infection is explained with antiviral protection genes expression, hypercytokinemia, and lymphohistiocytosis/macrophage activation mechanisms. Recommendations concerning therapy for prevention during the pandemic period or in case of concomitant COVID-19 infection are also presented. Clinical trials are ongoing regarding COVID-19 therapy blocking the cytokine response. © 2021 Elsevier Inc. All rights reserved.

Arterial and venous thrombosis in coronavirus 2019 disease (Covid-19): relationship with mortality.

BACKGROUND: Patients with coronavirus disease 2019 (Covid-19) may experience venous thrombosis while data regarding arterial thrombosis are sparse. METHODS: Prospective multicenter study in 5 hospitals including 373 patients with Covid-19-related pneumonia. Demographic data, laboratory findings including coagulation tests and comorbidities were reported. During the follow-up any arterial or venous thrombotic events and death were registered. RESULTS: Among 373 patients, 75 (20%) had a thrombotic event and 75 (20%) died. Thrombotic events included 41 venous thromboembolism and 34 arterial thrombosis. Age, cardiovascular disease, intensive care unit treatment, white blood cells, D-dimer, albumin and troponin blood levels were associated with thrombotic events. In a multivariable regression logistic model, intensive care unit treatment (Odds Ratio [OR]: 6.0; 95% Confidence Interval [CI] 2.8-12.6; p < 0.001); coronary artery disease (OR: 2.4; 95% CI 1.4-5.0; p = 0.022); and albumin levels (OR: 0.49; 95% CI 0.28-0.87; p = 0.014) were associated with ischemic events. Age, sex, chronic obstructive pulmonary disease, diabetes, heart failure, coronary heart disease, intensive care unit treatment, in-hospital thrombotic events, D-dimer, C-reactive protein, troponin, and albumin levels were associated with mortality. A multivariable Cox regression analysis showed that in-hospital thrombotic events (hazard ratio [HR]: 2.72; 95% CI 1.59-4.65; p < 0.001), age (HR: 1.035; 95% CI 1.014-1.057; p = 0.001), and albumin (HR: 0.447; 95% CI 0.277-0.723; p = 0.001) predicted morality. CONCLUSIONS: Covid-19 patients experience an equipollent rate of venous and arterial thrombotic events, that are associated with poor survival. Early identification and appropriate treatment of Covid-19 patients at risk of thrombosis may improve prognosis.

Upper extremity arterial thromboembolism in a patient with severe COVID-19 pneumonia: A case report.

Although novel coronavirus-2019 (COVID-19) primarily affects the respiratory system, it can affect multiple organ systems, leading to serious complications, such as acute respiratory distress syndrome (ARDS) and multiple organ failure. Nearly 20 to 55% of patients with COVID-19 experience coagulation disorders that cause high mortality in line with the severity of the clinical picture. Thromboembolism can be observed in both venous and arterial systems. The vast majority of thromboembolic events are associated with the venous system and are often observed as pulmonary embolism. Arterial thromboembolisms often involve the arteries in the lower extremities, followed by those in the upper extremities. Herein, we report a rare case of COVID-19 pneumonia whose left arm was amputated at the forearm level after arterial thromboembolism in the left upper extremity. This case report is valuable, as it is the first reported case of upper extremity arterial thromboembolism in Turkey, as well as the only case in the literature in which the patient underwent four surgical interventions and is still alive.

Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019.

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, exerts far-reaching effects on public health and socio-economic welfare. The majority of infected individuals have mild to moderate symptoms, but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in the activation of both pro- and anticlotting factors in the liver and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2-induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether vitamin K administration plays a role in the prevention and treatment of severe Covid-19.

Role of combining anticoagulant and antiplatelet agents in COVID-19 treatment: a rapid review.

Although primarily affecting the respiratory system, COVID-19 causes multiple organ damage. One of its grave consequences is a prothrombotic state that manifests as thrombotic, microthrombotic and thromboembolic events. Therefore, understanding the effect of antiplatelet and anticoagulation therapy in the context of COVID-19 treatment is important. The aim of this rapid review was to highlight the role of thrombosis in COVID-19 and to provide new insights on the use of antithrombotic therapy in its management. A rapid systematic review was performed using preferred reporting items for systematic reviews. Papers published in English on antithrombotic agent use and COVID-19 complications were eligible. Results showed that the use of anticoagulants increased survival and reduced thromboembolic events in patients. However, despite the use of anticoagulants, patients still suffered thrombotic events likely due to heparin resistance. Data on antiplatelet use in combination with anticoagulants in the setting of COVID-19 are quite scarce. Current side effects of anticoagulation therapy emphasise the need to update treatment guidelines. In this rapid review, we address a possible modulatory role of antiplatelet and anticoagulant combination against COVID-19 pathogenesis. This combination may be an effective form of adjuvant therapy against COVID-19 infection. However, further studies are needed to elucidate potential risks and benefits associated with this combination.