Extracardiac Prothrombotic Effects of COVID-19.

COVID-19 infection triggers a heightened inflammatory response which in turn, increases thrombosis and thromboembolism. Microvascular thrombosis has been detected in various tissue beds which may account for some of the multi-system organ dysfunction associated with COVID-19. Additional research is needed to understand which prophylactic and therapeutic drug regimens are best for the prevention and treatment of thrombotic complications of COVID-19.

Anticoagulation in Patients With COVID-19: JACC Review Topic of the Week.

Clinical, laboratory, and autopsy findings support an association between coronavirus disease-2019 (COVID-19) and thromboembolic disease. Acute COVID-19 infection is characterized by mononuclear cell reactivity and pan-endothelialitis, contributing to a high incidence of thrombosis in large and small blood vessels, both arterial and venous. Observational studies and randomized trials have investigated whether full-dose anticoagulation may improve outcomes compared with prophylactic dose heparin. Although no benefit for therapeutic heparin has been found in patients who are critically ill hospitalized with COVID-19, some studies support a possible role for therapeutic anticoagulation in patients not yet requiring intensive care unit support. We summarize the pathology, rationale, and current evidence for use of anticoagulation in patients with COVID-19 and describe the main design elements of the ongoing FREEDOM COVID-19 Anticoagulation trial, in which 3,600 hospitalized patients with COVID-19 not requiring intensive care unit level of care are being randomized to prophylactic-dose enoxaparin vs therapeutic-dose enoxaparin vs therapeutic-dose apixaban. (FREEDOM COVID-19 Anticoagulation Strategy [FREEDOM COVID]; NCT04512079).

Association between warfarin and COVID-19-related outcomes compared with direct oral anticoagulants: population-based cohort study.

BACKGROUND: Thromboembolism has been reported as a consequence of severe COVID-19. Although warfarin is a commonly used anticoagulant, it acts by antagonising vitamin K, which is low in patients with severe COVID-19. To date, the clinical evidence on the impact of regular use of warfarin on COVID-19-related thromboembolism is lacking. METHODS: On behalf of NHS England, we conducted a population-based cohort study investigating the association between warfarin and COVID-19 outcomes compared with direct oral anticoagulants (DOACs). We used the OpenSAFELY platform to analyse primary care data and pseudonymously linked SARS-CoV-2 antigen testing data, hospital admissions and death records from England. We used Cox regression to estimate hazard ratios (HRs) for COVID-19-related outcomes comparing warfarin with DOACs in people with non-valvular atrial fibrillation. We also conducted negative control outcome analyses (being tested for SARS-CoV-2 and non-COVID-19 death) to assess the potential impact of confounding. RESULTS: A total of 92,339 warfarin users and 280,407 DOAC users were included. We observed a lower risk of all outcomes associated with warfarin versus DOACs [testing positive for SARS-CoV-2, HR 0.73 (95% CI 0.68-0.79); COVID-19-related hospital admission, HR 0.75 (95% CI 0.68-0.83); COVID-19-related deaths, HR 0.74 (95% CI 0.66-0.83)]. A lower risk of negative control outcomes associated with warfarin versus DOACs was also observed [being tested for SARS-CoV-2, HR 0.80 (95% CI 0.79-0.81); non-COVID-19 deaths, HR 0.79 (95% CI 0.76-0.83)]. CONCLUSIONS: Overall, this study shows no evidence of harmful effects of warfarin on severe COVID-19 disease.

Pre-medication with oral anticoagulants is associated with better outcomes in a large multinational COVID-19 cohort with cardiovascular comorbidities.

AIMS: Coagulopathy and venous thromboembolism are common findings in coronavirus disease 2019 (COVID-19) and are associated with poor outcome. Timely initiation of anticoagulation after hospital admission was shown to be beneficial. In this study we aim to examine the association of pre-existing oral anticoagulation (OAC) with outcome among a cohort of SARS-CoV-2 infected patients. METHODS AND RESULTS: We analysed the data from the large multi-national Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS) from March to August 2020. Patients with SARS-CoV-2 infection were eligible for inclusion. We retrospectively analysed the association of pre-existing OAC with all-cause mortality. Secondary outcome measures included COVID-19-related mortality, recovery and composite endpoints combining death and/or thrombotic event and death and/or bleeding event. We restricted bleeding events to intracerebral bleeding in this analysis to ensure clinical relevance and to limit reporting errors. A total of 1 433 SARS-CoV-2 infected patients were analysed, while 334 patients (23.3%) had an existing premedication with OAC and 1 099 patients (79.7%) had no OAC. After risk adjustment for comorbidities, pre-existing OAC showed a protective influence on the endpoint death (OR 0.62, P = 0.013) as well as the secondary endpoints COVID-19-related death (OR 0.64, P = 0.023) and non-recovery (OR 0.66, P = 0.014). The combined endpoint death or thrombotic event tended to be less frequent in patients on OAC (OR 0.71, P = 0.056). CONCLUSIONS: Pre-existing OAC is protective in COVID-19, irrespective of anticoagulation regime during hospital stay and independent of the stage and course of disease.

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

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

Influence of thromboembolic events in the prognosis of COVID-19 hospitalized patients. Results from a cross sectional study.

BACKGROUND: COVID-19 may predispose to both venous and arterial thromboembolism event (TEE). Reports on the prevalence and prognosis of thrombotic complications are still emerging. OBJECTIVE: To describe the rate of TEE complications and its influence in the prognosis of hospitalized patients with COVID-19 after a cross-sectional study. METHODS: We evaluated the prevalence of TEE and its relationship with in-hospital death among hospitalized patients with COVID-19 who were admitted between 1st March to 20th April 2020 in a multicentric network of sixteen Hospitals in Spain. TEE was defined by the occurrence of venous thromboembolism (VTE), acute ischemic stroke (AIS), systemic arterial embolism or myocardial infarction (MI). RESULTS: We studied 1737 patients with proven COVID-19 infection of whom 276 died (15.9%). TEE were presented in 64 (3.7%) patients: 49 (76.6%) patients had a VTE, 8 (12.5%) patients had MI, 6 (9.4%%) patients had AIS, and one (1.5%) patient a thrombosis of portal vein. TEE patients exhibited a diffuse profile: older, high levels of D-dimer protein and a tendency of lower levels of prothrombin. The multivariate regression models, confirmed the association between in-hospital death and age (odds ratio [OR] 1.12 [95% CI 1.10-1.14], p<0.001), diabetes (OR 1.49 [95% CI 1.04-2.13], p = 0.029), chronic obstructive pulmonary disease (OR 1.61 [95% CI 1.03-2.53], p = 0.039), ICU care (OR 9.39 [95% CI 5.69-15.51], p<0.001), and TTE (OR 2.24 [95% CI 1.17-4.29], p = 0.015). CONCLUSIONS: Special attention is needed among hospitalized COVID-19 patients with TTE and other comorbidities as they have an increased risk of in-hospital death.

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review.

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

Pathophysiological Association of Endothelial Dysfunction with Fatal Outcome in COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19) caused by the betacoronavirus SARS-CoV-2 is now a worldwide challenge for healthcare systems. Although the leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure due to viral pneumonia and acute respiratory distress syndrome, accumulating evidence has shown that the risk of thromboembolism is substantially high in patients with severe COVID-19 and that a thromboembolic event is another major complication contributing to the high morbidity and mortality in patients with COVID-19. Endothelial dysfunction is emerging as one of the main contributors to the pathogenesis of thromboembolic events in COVID-19. Endothelial dysfunction is usually referred to as reduced nitric oxide bioavailability. However, failures of the endothelium to control coagulation, inflammation, or permeability are also instances of endothelial dysfunction. Recent studies have indicated the possibility that SARS-CoV-2 can directly infect endothelial cells via the angiotensin-converting enzyme 2 pathway and that endothelial dysfunction caused by direct virus infection of endothelial cells may contribute to thrombotic complications and severe disease outcomes in patients with COVID-19. In this review, we summarize the current understanding of relationships between SARS-CoV-2 infection, endothelial dysfunction, and pulmonary and extrapulmonary complications in patients with COVID-19.

Multisystem outcomes and predictors of mortality in critically ill patients with COVID-19: Demographics and disease acuity matter more than comorbidities or treatment modalities.

BACKGROUND: We sought to describe characteristics, multisystem outcomes, and predictors of mortality of the critically ill COVID-19 patients in the largest hospital in Massachusetts. METHODS: This is a prospective cohort study. All patients admitted to the intensive care unit (ICU) with reverse-transcriptase-polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection between March 14, 2020, and April 28, 2020, were included; hospital and multisystem outcomes were evaluated. Data were collected from electronic records. Acute respiratory distress syndrome (ARDS) was defined as PaO2/FiO2 ratio of ≤300 during admission and bilateral radiographic pulmonary opacities. Multivariable logistic regression analyses adjusting for available confounders were performed to identify predictors of mortality. RESULTS: A total of 235 patients were included. The median (interquartile range [IQR]) Sequential Organ Failure Assessment score was 5 (3-8), and the median (IQR) PaO2/FiO2 was 208 (146-300) with 86.4% of patients meeting criteria for ARDS. The median (IQR) follow-up was 92 (86-99) days, and the median ICU length of stay was 16 (8-25) days; 62.1% of patients were proned, 49.8% required neuromuscular blockade, and 3.4% required extracorporeal membrane oxygenation. The most common complications were shock (88.9%), acute kidney injury (AKI) (69.8%), secondary bacterial pneumonia (70.6%), and pressure ulcers (51.1%). As of July 8, 2020, 175 patients (74.5%) were discharged alive (61.7% to skilled nursing or rehabilitation facility), 58 (24.7%) died in the hospital, and only 2 patients were still hospitalized, but out of the ICU. Age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.04-1.12), higher median Sequential Organ Failure Assessment score at ICU admission (OR, 1.24; 95% CI, 1.06-1.43), elevated creatine kinase of ≥1,000 U/L at hospital admission (OR, 6.64; 95% CI, 1.51-29.17), and severe ARDS (OR, 5.24; 95% CI, 1.18-23.29) independently predicted hospital mortality.Comorbidities, steroids, and hydroxychloroquine treatment did not predict mortality. CONCLUSION: We present here the outcomes of critically ill patients with COVID-19. Age, acuity of disease, and severe ARDS predicted mortality rather than comorbidities. LEVEL OF EVIDENCE: Prognostic, level III.

Concomitant acute limb ischemia and multiple acute ischemic strokes complicating COVID-19: a case report.

Since the spread of the coronavirus disease 2019 (COVID-19) pandemic, cardiovascular complications are interestingly increasing, particularly thrombotic events, especially in those requiring intensive care. Venous thromboembolism is well known to occur in patients infected by the SARS-CoV-2, but only a few arterial thromboembolism cases have been previously reported. Herein, we report the case of a COVID-19 complicated by a concomitant acute right limb ischemia and multiple acute ischemic strokes. This rare case emphasizes the hypercoagulable state described in COVID-19 patients and the need for anticoagulation therapy to prevent these severe complications.

Epidemiology of COVID-19 Infection in Hospitalized End-Stage Kidney Disease Patients in a Predominantly African-American Population.

BACKGROUND: End-stage kidney disease patients on dialysis are particularly susceptible to COVID-19 infection due to comorbidities, age, and logistic constraints of dialysis making social distancing difficult. We describe our experience with hospitalized dialysis patients with COVID-19 and factors associated with mortality. METHODS: From March 1, 2020, to May 31, 2020, all dialysis patients admitted to 4 Emory Hospitals and tested for COVID-19 were identified. Sociodemographic information and clinical and laboratory data were obtained from the medical record. Death was defined as an in-hospital death or transfer to hospice for end-of-life care. Patients were followed until discharge or death. RESULTS: Sixty-four dialysis patients with COVID-19 were identified. Eighty-four percent were African-American. The median age was 64 years, and 59% were males. Four patients were on peritoneal dialysis, and 60 were on hemodialysis for a median time of 3.8 years, while 31% were obese. Fever (72%), cough (61%), and diarrhea (22%) were the most common symptoms at presentation. Thirty-three percent required admission to intensive care unit, and 23% required mechanical ventilation. The median length of stay was 10 days, while 11 patients (17%) died during hospitalization and 17% were discharged to a temporary rehabilitation facility. Age >65 years (RR 13.7, CI: 1.9-100.7), C-reactive protein >100 mg/dL (RR 8.3, CI: 1.1-60.4), peak D-dimer >3,000 ng/mL (RR 4.3, CI: 1.03-18.2), bilirubin >1 mg/dL (RR 3.9, CI: 1.5-10.4), and history of peripheral vascular disease (RR 3.2, CI: 1.2-9.1) were associated with mortality. Dialysis COVID-19-infected patients were more likely to develop thromboembolic complications than those without COVID-19 (RR 3.7, CI: 1.3-10.1). CONCLUSION: In a predominantly African-American population, the mortality of end-stage kidney disease patients admitted with COVID-19 infection was 17%. Age, C-reactive protein, D-dimer, bilirubin, and history of peripheral vascular disease were associated with worse survival.

Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study.

OBJECTIVE: To evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United States. DESIGN: Observational cohort study. SETTING: Nationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated national healthcare system. PARTICIPANTS: All 4297 patients admitted to hospital from 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation. MAIN OUTCOME MEASURES: The main outcome was 30 day mortality. Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion. RESULTS: Of 4297 patients admitted to hospital with covid-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospital stay. Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) among those who did not. Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation. Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05). Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 for 30 day mortality). Results persisted in several sensitivity analyses. CONCLUSIONS: Early initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with covid-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events. These findings provide strong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission.

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.

Acute Lower-Extremity Ischemia in a Patient with COVID-19.

BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has become a global pandemic. The typical symptoms are fever, cough, and shortness of breath, but the disease can present with atypical signs, including those associated with a hypercoagulable state. These signs include deep venous thrombosis, pulmonary embolism, ischemic stroke, and acute coronary syndrome. Herein, we present the case of acute bilateral lower-extremity ischemia as a thromboembolic complication in a patient with COVID-19. CASE REPORT A 76-year-old woman presented with acute bilateral lower-extremity ulcerations covered with eschar formation of several weeks' duration. During her hospital course, she underwent a test for COVID-19 and the result was positive. An angiogram of the patient's lower extremities showed occlusions of the right distal posterior tibial artery, right mid-distal anterior tibial artery, right dorsalis pedis artery, left mid-distal anterior tibial artery, left dorsalis pedis artery, and left popliteal vein. Tissue plasminogen activator was administered to treat the occlusions. On the following day, the patient had an acute decline in her neurologic state and was emergently intubated. A computed tomography scan of the brain confirmed a subarachnoid hemorrhage requiring reversal of tissue plasminogen activator. The patient was transitioned to comfort care and ultimately died. CONCLUSIONS In conclusion, acute limb ischemia should be acknowledged as a rare complication associated with COVID-19. It is important to raise awareness of arterial thrombosis as a possible complication of the hypercoagulable state caused by SARS-CoV-2 because prompt recognition is essential for early diagnosis and treatment. These actions could have a significant impact on patients' overall outcome.

A considerable asymptomatic proportion and thromboembolism risk of pregnant women with COVID-19 infection in Wuhan, China.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) had become a worldwide pandemic, however, information is limited on the asymptomatic proportion and thromboembolism risk of pregnant women with infection. METHODS: All 32 pregnant women with COVID-19 who were admitted to the hospital in Wuhan during the outbreak from January 20 to March 18, 2020, were retrospectively reviewed for the clinical records, laboratory tests, chest CT scans, and neonatal outcomes. RESULTS: There were 17 of the 32 patients (53%) with no subjective symptoms before admission, and 13 (41%) remained asymptomatic throughout hospitalization. There were 28 patients (88%) showing typical radiographic evidence of pneumonia on chest CT. The patients with COVID-19 were found in an increased risk of thromboembolism with much higher D-dimer levels than uninfected pregnant women. One neonate with asphyxia and positive immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies was reported. CONCLUSIONS: The considerable asymptomatic proportion of pregnant women with COVID-19 indicates symptom-based screening would miss a number of cases. Chest CT could provide a useful screening resource during the COVID-19epidemic outbreak. Anticoagulation therapy for the postpartum patients may be helpful for good prognosis. The findings provide important information for the hospital isolation, control strategies and clinical therapy.

Mechanisms of thrombosis and cardiovascular complications in COVID-19.

BACKGROUND: The novel coronavirus SARS-CoV-2, responsible for the 2019-2020 global (COVID-19) pandemic, is a respiratory virus associated with the development of thromboembolic complications and respiratory failure in severe cases. Increased risk of pulmonary embolism and thrombosis has been identified in COVID-19 patients, alongside accompanying elevations in potential prognostic biomarkers, including D-dimer, IL-6 and cardiac specific troponins. Our aim was to provide a scoping review of the available literature regarding thrombosis risk, other cardiovascular implications, and their biomarkers in COVID-19 to highlight potential disease mechanisms. METHODS: Authors conducted a literature search in PubMed using MeSH headings "disseminated intravascular coagulation", "pulmonary embolism", "thromb*", "stroke", "myocardial infarction" and "acute lung injury", as well as terms "COVID-19", "SARS-CoV-2", "2019 novel coronavirus" and "2019-nCoV". RESULTS AND CONCLUSIONS: COVID-19 disease is characterised by the interactions between hyperactive coagulation and complement systems - induced by hyper-inflammatory conditions, resulting in a pro-thrombotic state and diffuse tissue injury. There are several promising prognostic markers of disease severity, with D-dimer the most significant. The presence of thrombocytopenia appears to be a key indicator of patient deterioration. Further research is required to understand the underlying pathophysiology in COVID-19 and its implications in disease progression and patient management. Randomised trials are urgently needed to determine the safety of proposed therapeutic anticoagulation with heparin and the role for anti-platelet agents, such as Ticagrelor, in patient management.