Superior ophthalmic vein and cavernous sinus thrombosis associated with COVID-19: a case report / Trombose de veia oftálmica superior e seio cavernoso associada à COVID-19: relato de caso

ABSTRACT Cavernous sinus and superior ophthalmic vein thrombosis is a rare clinical condition, and little described in the literature. The clinical presentation is nonspecific and highly variable, and symptoms may include red eye, ophthalmoplegia, coma, and death. The main etiology results from infection of the paranasal sinuses. The final diagnosis must be made through imaging tests such as magnetic resonance imaging. We describe a case of cavernous sinus and superior ophthalmic vein thrombosis after COVID-19 infection in a 64-year-old patient with persistent ocular hyperemia and pain on eye movement. Ophthalmological examination showed preserved visual acuity, conjunctival hyperemia, dilation of episcleral vessels and retinal vascular tortuosity in the right eye. Magnetic resonance imaging confirmed the diagnosis. The association with the COVID-19 was raised, excluding other infectious causes. Enoxaparin and Warfarin were started with significant improvement in the ocular clinical presentation and maintenance of initial visual acuity after 12 months of follow-up.

RESUMO A trombose de seio cavernoso e veia oftálmica superior é uma condição clínica rara e pouco descrita na literatura. A apresentação clínica é inespecífica e altamente variável. Os sintomas podem incluir olho vermelho, oftalmoplegia, coma e morte. A etiologia principal resulta da infecção dos seios paranasais. O diagnóstico final deve ser efetuado por meio de exames de imagem, como ressonância magnética. Descrevemos um caso de trombose de seio cavernoso e veia oftálmica superior após COVID-19 em paciente de 64 anos e com quadro de hiperemia ocular persistente e dor à movimentação ocular. Ao exame oftalmológico, observou-se acuidade visual preservada, hiperemia conjuntival, dilatação de vasos episclerais e tortuosidade vascular retiniana em olho direito. A ressonância confirmou o diagnóstico. A associação com a COVID-19 foi levantada, excluindo-se demais causas infecciosas. Prescrevemos enoxaparina e varfarina, com melhora do quadro clínico ocular e manutenção da acuidade visual inicial após 12 meses de acompanhamento.

Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19.

BACKGROUND: Prior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results. OBJECTIVES: We sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19. METHODS: Patients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit-level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group. RESULTS: Between August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent. CONCLUSIONS: Among noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079).

Heparan Sulfate and Enoxaparin Interact at the Interface of the Spike Protein of HCoV-229E but Not with HCoV-OC43.

It is known that the spike protein of human coronaviruses can bind to a secondary receptor, or coreceptor, to facilitate the virus entry. While HCoV-229E uses human aminopeptidase N (hAPN) as a receptor, HCoV-OC43 binds to 9-O-acetyl-sialic acid (9-O-Ac-Sia), which is linked in a terminal way to the oligosaccharides that decorate glycoproteins and gangliosides on the surface of the host cell. Thus, evaluating the possible inhibitory activity of heparan sulfate, a linear polysaccharide found in animal tissues, and enoxaparin sodium on these viral strains can be considered attractive. Therefore, our study also aims to evaluate these molecules' antiviral activity as possible adsorption inhibitors against non-SARS-CoV. Once the molecules' activity was verified in in vitro experiments, the binding was studied by molecular docking and molecular dynamic simulations confirming the interactions at the interface of the spike proteins.

External validation of the ADA score for predicting thrombosis among acutely ill hospitalized medical patients from the APEX Trial.

The ADA (Age-D-dimer-Albumin) score was developed to identify hospitalized patients at an increased risk for thrombosis in the coronavirus infectious disease-19 (COVID-19) setting. The study aimed to validate the ADA score for predicting thrombosis in a non-COVID-19 medically ill population from the APEX trial. The APEX trial was a multinational, randomized trial that evaluated the efficacy and safety of betrixaban vs. enoxaparin among acutely ill hospitalized patients at risk for venous thromboembolism. The study endpoints included the composite of arterial or venous thrombosis and its components. Metrics of model calibration and discrimination were computed for assessing the performance of the ADA score as compared to the IMPROVE score, a well-validated VTE risk assessment model. Among 7,119 medical inpatients, 209 (2.9%) had a thrombosis event up to 77 days of follow-up. The ADA score demonstrated good calibration for both arterial and venous thrombosis, whereas the IMPROVE score had adequate calibration for venous thrombosis (p > 0.05 from the Hosmer-Lemeshow test). For discriminating arterial and venous thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.620 [95% CI: 0.582 to 0.657] vs. 0.590 [95% CI: 0.556 to 0.624]; ∆ c statistic = 0.030 [95% CI: -0.022 to 0.081]; p = 0.255). Similarly, for discriminating arterial thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.582 [95% CI: 0.534 to 0.629] vs. 0.609 [95% CI: 0.564 to 0.653]; ∆ c statistic = -0.027 [95% CI: -0.091 to 0.036]; p = 0.397). For discriminating venous thrombosis, the ADA score was modestly superior to the IMPROVE score (c statistic = 0.664 [95% CI: 0.607 to 0.722] vs. 0.573 [95% CI: 0.521 to 0.624]; ∆ c statistic = 0.091 [95% CI: 0.011 to 0.172]; p = 0.026). The ADA score had a higher sensitivity (0.579 [95% CI: 0.512 to 0.646]; vs. 0.440 [95% CI: 0.373 to 0.507]) but lower specificity (0.625 [95% CI: 0.614 to 0.637] vs. 0.747 [95% CI: 0.737 to 0.758]) than the IMPROVE score for predicting thrombosis. Among acutely ill hospitalized medical patients enrolled in the APEX trial, the ADA score demonstrated good calibration but suboptimal discrimination for predicting thrombosis. The findings support the use of either the ADA or IMPROVE score for thrombosis risk assessment. The applicability of the ADA score to non-COVID-19 populations warrants further research.Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

The Effectiveness of the Intermediate and Therapeutic Doses of Enoxaparin in COVID-19 Patients: A Comparative Study of Factor Xa Inhibition.

BACKGROUND: Management of anticoagulant therapy in COVID-19 patients is critical. Low-molecular-weight heparin (LMWH) thromboprophylaxis is already recommended, and anti-Factor Xa (anti-FXa) monitoring has been used to titrate LMWH doses. METHODS: Through a cross-sectional study, we evaluated anti-FXa activity in patients admitted to the ICU, receiving intermediate dose (30, 40, 50 mg, subcutaneously [SC], twice daily) or therapeutic dose (1 mg/kg, SC, Q12h) of enoxaparin to find whether the patients in these two groups achieved anti-FXa levels in the accepted thromboprophylaxis range. RESULTS: The occurrence of deep vein thrombosis was 26% in the therapeutic-dose group and 17% in the intermediate-dose group. D-dimer values were nearly 3.5-fold higher in those who received a therapeutic dose of anticoagulants than in those who received intermediate-dose thromboprophylaxis. Patients in the therapeutic-dose group had significantly higher IL-6 levels (p ≤ 0.001). More than one-third of the patients in the therapeutic-dose group (n = 8; 42.18%) and approximately half of the patients in the intermediate-dose group (n = 12; 52.2%) achieved the target range level of anti-FXa. Patients who received therapeutic doses were more likely to have anti-FXa levels above the expected range (47.4 vs 13% in the intermediate-dose group; p < 0.05). CONCLUSION: Therapeutic dose of enoxaparin in critically ill COVID-19-infected patients did not reduce the incidence of thromboembolic events and, on the other hand, may predispose these patients to increased risk of bleeding by increasing anti-FXa activity above the desired level. Administration of intermediate-dose thromboprophylaxis is suggested to achieve anti-FXa levels in the accepted thromboprophylaxis range.

HIGH HEPARANASE LEVEL IN SURVIVORS OF COVID-19 - INDICATOR OF VASCULAR AND PULMONARY RECOVERY?

ABSTRACT: Background: Severe progression of coronavirus disease 2019 (COVID-19) causes respiratory failure and critical illness. Recently, COVID-19 has been associated with heparanase (HPSE)-induced endothelial barrier dysfunction and inflammation, so called endothelitis, and therapeutic treatment with heparin or low-molecular-weight heparin (LMWH) targeting HPSE has been postulated. Because, up to this date, clinicians are unable to measure the severity of endothelitis, which can lead to multiorgan failure and concomitant death, we investigated plasma levels of HPSE and heparin-binding protein (HBP) in COVID-19 intensive care patients to render a possible link between endothelitis and these plasma parameters. Therefore, a prospective prolonged cohort study was conducted, including 47 COVID-19 patients from the intensive care unit. Plasma levels of HPSE, and HBP were measured daily by enzyme-linked immunosorbent assay in survivors (n = 35) and nonsurvivors (n = 12) of COVID-19 from admission until discharge or death. All patients were either treated with heparin or LMWH, aiming for an activated partial thromboplastin time of ≥60 seconds or an anti-Xa level of >0.8 IU/mL using enoxaparin, depending on the clinical status of the patient (patients with extracorporeal membrane oxygenation or >0.1 µg/kg/min noradrenaline received heparin, all others enoxaparin). Results: We found significantly higher plasma levels of HPSE and HBP in survivors and nonsurvivors of COVID-19, compared with healthy controls. Still, interestingly, plasma HPSE levels were significantly higher ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. In contrast, plasma HBP levels were significantly reduced ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. Furthermore, when patients received heparin, they had significantly lower HPSE ( P = 2.22 e - 16) and significantly higher HBP ( P = 0.00013) plasma levels as when they received LMWH. Conclusion: Our results demonstrated that patients, who recover from COVID-19-induced vascular and pulmonary damage and were discharged from the intensive care unit, have significantly higher plasma HPSE level than patients who succumb to COVID-19. Therefore, HPSE is not suitable as marker for disease severity in COVID-19 but maybe as marker for patient's recovery. In addition, patients receiving therapeutic heparin treatment displayed significantly lower heparanse plasma level than upon therapeutic treatment with LMWH.

Acute Mesenteric Ischemia in COVID-19 While Receiving Prophylactic Enoxaparin.

COVID-19 infection is known to cause thromboembolic complications. This is why patients hospitalized with COVID-19 are put on prophylactic anticoagulation. We present the case of a Caucasian woman, aged 71 years, with risk factors of class 1 obesity, hyperlipidemia, and hypertension, initially admitted for COVID-19 pneumonia, and later developed acute mesenteric ischemia followed by pulmonary embolism. These incidents occurred while the patient was receiving high-dose prophylactic enoxaparin (40 mg twice daily). COVID-19 associated acute mesenteric ischemia is a complication with high mortality. Therefore, high suspicion, early recognition, and surgical management is necessary. Apart from that, this case emphasizes the question of whether there is a need for proactively administering therapeutic anticoagulation for high thrombotic risk COVID-19 patients to prevent deadly complications.

Clinical evaluation of the safety and efficacy of enoxaparin in patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), increases thrombotic risk in hospitalised patients. The rate of thrombosis in patients with COVID-19 is unclear. The role of heparin, frequently used in the management of hospitalised patients, also needs to be clarified. In this study, we investigated the efficacy and safety of enoxaparin given at prophylactic or therapeutic dose in hospitalised patients with COVID-19, and evaluated its role in the development of disease in terms of mortality, and incidence of thrombotic and bleeding events. MATERIAL AND METHODS: We included 141 patients with SARS-CoV-2 infection, admitted to five different wards (one intensive care unit, 2 sub-intensive care units, and 2 general infectious disease units) of Cotugno Hospital, a tertiary care hospital in Naples, Italy, between March and May 2020. RESULTS: Over a median time of 17 days (IQR 11-25), enoxaparin was given to 90/141 patients (63.8%) of whom 65 took a prophylactic and 25 a therapeutic dose. We documented 14 episodes of thrombosis (9.9%); almost all were cases of pulmonary embolism. No significant difference in terms of thromboembolic prevention was found between those patients not receiving anticoagulants and those on prophylactic or therapeutic dose of enoxaparin. Five episodes of major bleeding occurred (3.5%); therapeutic dose of enoxaparin was associated with a greater bleeding risk than prophylactic dose (p=0.002). During follow-up, 31 patients (22%) died; these were mostly elderly men with two or more comorbidities at admission. No advantages of enoxaparin, either as prophylaxis or at high doses, in terms of mortality were observed. At multivariate analysis, low estimated glomerular filtration rate, and high total bilirubin and fasting hyperglycemia were independently associated with a higher mortality. DISCUSSION: We did not observe advantages in terms of either thromboembolic prevention or mortality of enoxaparin, which however was more frequently used in patients with more severe disease. Prophylactic enoxaparin was not seen to be associated with bleeding risk.

Central Retinal Vein Occlusion After Discontinuation of Rivaroxaban Therapy in a Young Patient with COVID-19 Pulmonary Embolism: A Case Report.

BACKGROUND We present the report of the first case, to the best of our knowledge, of central retinal vein occlusion (CRVO) that occurred 3 days after anticoagulation discontinuation in a patient with a history of pulmonary embolism in the course of COVID-19. CASE REPORT A previously healthy 38-year-old man was hospitalized in April 2021 with severe COVID-19 pneumonia, complicated by segmental and subsegmental pulmonary embolism. The patient was treated with a concurrent combination of remdesivir, dexamethasone, therapeutic enoxaparin, ceftriaxone, passive oxygen therapy, and convalescent plasma therapy, which led to pulmonary improvement. The treatment with therapeutic enoxaparin (80 mg/0.8 mL twice a day) was continued for 1 month after discharge, followed by 15 mg of rivaroxaban twice a day for 3 weeks and 20 mg of rivaroxaban once a day for 11 weeks. Within 3 days after rivaroxaban discontinuation, the patient experienced a decrease in visual acuity in his right eye, to the level of 5/25. Nonischemic CRVO with cystoid macular edema was diagnosed and an intravitreal injection of ranibizumab was performed. Common identifiable factors contributing to CRVO were excluded, and the treatment with prophylactic enoxaparin was initiated. Two weeks later, macular edema decreased significantly and visual acuity improved to 20/20. The treatment with enoxaparin was discontinued. CONCLUSIONS Rebound hypercoagulability after discontinuation of rivaroxaban therapy can manifest as CRVO in a young patient with a history of COVID-19 pulmonary embolism. It was successfully treated with an intravitreal injection of ranibizumab.

In-hospital Mortality Rates in SARS-CoV-2 Patients Treated with Enoxaparin and Heparin.

OBJECTIVES: This study aimed to investigate in-hospital mortality rates in patients with coronavirus disease (COVID-19) according to enoxaparin and heparin use. METHODS: This retrospective cohort study included 962 patients admitted to two hospitals in Kuwait with a confirmed diagnosis of COVID-19. Cumulative all-cause mortality rate was the primary outcome. RESULTS: A total of 302 patients (males, 196 [64.9%]; mean age, 57.2 ± 14.6 years; mean body mass index, 29.8 ± 6.5 kg/m2) received anticoagulation therapy. Patients receiving anticoagulation treatment tended to have pneumonia (n = 275 [91.1%]) or acute respiratory distress syndrome (n = 106 [35.1%]), and high D-dimer levels (median [interquartile range]: 608 [523;707] ng/mL). The mortality rate in this group was high (n = 63 [20.9%]). Multivariable logistic regression, the Cox proportional hazards, and Kaplan-Meier models revealed that the use of therapeutic anticoagulation agents affected the risk of all-cause cumulative mortality. CONCLUSION: Age, hypertension, pneumonia, therapeutic anticoagulation, and methylprednisolone use were found to be strong predictors of in-hospital mortality. In elderly hypertensive COVID-19 patients on therapeutic anticoagulation were found to have 2.3 times higher risk of in-hospital mortality. All cause in-hospital mortality rate in the therapeutic anticoagulation group was up to 21%.

Low-Molecular-Weight Heparin Resistance and Its Viscoelastic Assessment in Critically Ill COVID-19 Patients.

Critically ill COVID-19 patients present an inflammatory and procoagulant status with a high rate of relevant macro- and microvascular thrombosis. Furthermore, high rates of heparin resistance have been described; yet, individualized anticoagulation by drug monitoring has not been sufficiently researched. We analyzed data from critically ill COVID-19 patients treated at Innsbruck Medical University Hospital with routinely adapted low-molecular-weight heparin (LMWH) doses according to anti-Xa peak levels, and regularly performed ClotPro analyses (a viscoelastic hemostatic whole blood test). A total of 509 anti-Xa peak measurements in 91 patients were categorized as below (<0.008 IU/mL/mg), within (0.008-0-012 IU/mL/mg) or above (> 0.012 IU/mL/mg) expected ranges with respect to the administered LMWH doses. Besides intergroup comparisons, correlations between anti-Xa levels and ClotPro clotting times (CTs) were performed (226 time points in 84 patients). Anti-Xa peak levels remained below the expected range in the majority of performed measurements (63.7%). Corresponding patients presented with higher C-reactive protein and D-dimer but lower antithrombin levels when compared with patients achieving or exceeding the expected range. Consequently, higher enoxaparin doses were applied in the sub-expected anti-Xa range group. Importantly, 47 (51.6%) patients switched between groups during their intensive care unit (ICU) stay. Anti-Xa levels correlated weakly with IN test CT and moderately with Russell's viper venom (RVV) test CT. Critically ill COVID-19 patients present with a high rate of LMWH resistance but with a variable LMWH response during their ICU stay. Therefore, LMWH-anti-Xa monitoring seems inevitable to achieve adequate target ranges. Furthermore, we propose the use of ClotPro's RVV test to assess the coagulation status during LMWH administration, as it correlates well with anti-Xa levels but more holistically reflects the coagulation cascade than anti-Xa activity alone.

The Role of Disordered Regions in Orchestrating the Properties of Multidomain Proteins: The SARS-CoV-2 Nucleocapsid Protein and Its Interaction with Enoxaparin.

Novel and efficient strategies need to be developed to interfere with the SARS-CoV-2 virus. One of the most promising pharmaceutical targets is the nucleocapsid protein (N), responsible for genomic RNA packaging. N is composed of two folded domains and three intrinsically disordered regions (IDRs). The globular RNA binding domain (NTD) and the tethered IDRs are rich in positively charged residues. The study of the interaction of N with polyanions can thus help to elucidate one of the key driving forces responsible for its function, i.e., electrostatics. Heparin, one of the most negatively charged natural polyanions, has been used to contrast serious cases of COVID-19 infection, and we decided to study its interaction with N at the molecular level. We focused on the NTR construct, which comprises the NTD and two flanking IDRs, and on the NTD construct in isolation. We characterized this interaction using different nuclear magnetic resonance approaches and isothermal titration calorimetry. With these tools, we were able to identify an extended surface of NTD involved in the interaction. Moreover, we assessed the importance of the IDRs in increasing the affinity for heparin, highlighting how different tracts of these flexible regions modulate the interaction.

Cerebral venous sinus thrombosis following Russell's viper (Daboia russelii) envenomation: A case report and review of the literature.

Snakebite is a life-threatening and often-neglected public health hazard with high chronic disability and mortality, mainly faced by rural communities in the tropics/subtropics. Stroke and neuromuscular paralysis are the most severe neurological complications. However, cerebral venous sinus thrombosis has rarely been reported among cerebrovascular complications. We report a previously healthy middle-aged Indian woman who developed cerebral venous sinus thrombosis preceded by features of disseminated bleeding diathesis following Russell's viper bite. The cerebral venous sinus thrombosis was diagnosed by magnetic resonance imaging. The patient responded well to treatment with antivenom and subcutaneous enoxaparin and had no demonstrable neurological deficits at three months of follow-up.

Thromboprophylaxis and clinical outcomes in moderate COVID-19 patients: A comparative study.

BACKGROUND: Many thrombotic complications are linked to coronavirus disease 2019 (COVID-19). Antithrombotic treatments are important for prophylaxis against these thrombotic events. OBJECTIVES: This study was designed to compare enoxaparin and rivaroxaban as prophylactic anticoagulants in moderate cases of COVID-19 in terms of efficacy, safety, and clinical outcomes. METHODS: The study involved 124 patients with moderate COVID-19 (pneumonia without hypoxia) divided into two groups. The first group (G1) comprised 66 patients who received enoxaparin subcutaneously at a dose of 0.5 mg/kg every 12 h until discharge from the hospital. The second group (G2) comprised 58 patients who received oral rivaroxaban at a dose of 10 mg once daily until discharge from the hospital. The outcomes evaluated in this study were as follows: intermediate care unit (IMCU) duration, the number of patients transferred from the IMCU to the intensive care unit (ICU), ICU duration, the total length of hospital stay, in-hospital mortality, and thrombotic and bleeding complications. RESULTS: No significant differences in IMCU duration (p = 0.39), ICU duration (p = 0.96), and total length of hospital stay (p = 0.73) were observed between the two groups. The percentage of patients requiring ICU admission after hospitalization was 21.2% in G1 and 22.4% in G2 (p = 0.87). The mortality rate was 12.1% in G1 and 10.3% in G2 (p = 0.76). The proportion of patients who had thrombotic complications was 9.1% in G1 and 12.1% in G2 (p = 0.59). The incidence of mild bleeding was 3% in G1 and 1.7% in G2 (p = 0.64). CONCLUSION: Either enoxaparin or rivaroxaban may be used as thromboprophylaxis agents in managing patients with moderate COVID-19. Either medication has no clear advantage over the other.

Coexistence of SARS-CoV-2 and cerebrovascular diseases: does COVID-19 positivity trigger cerebrovascular pathologies?

The objectives of this study were to determine the prevalence of cerebrovascular diseases caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and to assess the pharmacological agents used in such cases as reported in the literature. Patient files were retrospectively scanned to determine the prevalence of neurological symptoms of the central nervous system (headache, dizziness, lack of smell and taste, numbness in arms and legs, change in consciousness, muscle weakness, loss of urine and stool control) and cerebrovascular diseases (ischemic cerebrovascular diseases, cerebral venous sinus thrombosis, intracerebral hemorrhage, subarachnoid/subdural hemorrhage) in 2019 novel coronavirus (2019-nCoV) disease (COVID-19) cases (n = 20,099). The diagnostic laboratory, radiology examinations and treatments applied to these cases were recorded. The data from studies presenting cerebrovascular diseases associated with SARS-Cov-2, which constituted 0.035% of all cases, were systematically evaluated from electronic databases. During the treatment of cerebrovascular diseases, it was discovered that high doses of enoxaparin sodium anti-Xa are combined with apixaban or acetylsalicylic acid or clopidogrel or piracetam, and mannitol, in addition to SARS-CoV-2 treatment modalities. While neurological symptoms of the central nervous system are uncommon in cases of SARS-CoV-2 infection, cerebrovascular diseases are far less common, according to the findings of this study. Acute cerebral ischemia was discovered to be the most common cerebrovascular disease associated with SARS-CoV-2. The mortality rate increases with the association between SARS-CoV-2 and cerebrovascular disease.

Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial.

BACKGROUND: COVID-19 is a viral prothrombotic respiratory infection. Heparins exert antithrombotic and anti-inflammatory effects, and might have antiviral properties. We aimed to investigate whether thromboprophylaxis with enoxaparin would prevent untoward hospitalisation and death in symptomatic, but clinically stable outpatients with COVID-19. METHODS: OVID was a randomised, open-label, parallel-group, investigator-initiated, phase 3 trial and was done at eight centres in Switzerland and Germany. Outpatients aged 50 years or older with acute COVID-19 were eligible if they presented with respiratory symptoms or body temperature higher than 37·5°C. Eligible participants underwent block-stratified randomisation (by age group 50-70 vs >70 years and by study centre) in a 1:1 ratio to receive either subcutaneous enoxaparin 40 mg once daily for 14 days versus standard of care (no thromboprophylaxis). The primary outcome was a composite of any untoward hospitalisation and all-cause death within 30 days of randomisation. Analysis of the efficacy outcomes was done in the intention-to-treat population. The primary safety outcome was major bleeding. The study was registered in ClinicalTrials.gov (NCT04400799) and has been completed. FINDINGS: At the predefined formal interim analysis for efficacy (50% of total study population), the independent Data Safety Monitoring Board recommended early termination of the trial on the basis of predefined statistical criteria having considered the very low probability of showing superiority of thromboprophylaxis with enoxaparin for the primary outcome under the initial study design assumptions. Between Aug 15, 2020, and Jan 14, 2022, from 3319 participants prescreened, 472 were included in the intention-to-treat population and randomly assigned to receive enoxaparin (n=234) or standard of care (n=238). The median age was 57 years (IQR 53-62) and 217 (46%) were women. The 30-day risk of the primary outcome was similar in participants allocated to receive enoxaparin and in controls (8 [3%] of 234 vs 8 [3%] of 238; adjusted relative risk 0·98; 95% CI 0·37-2·56; p=0·96). All hospitalisations were related to COVID-19. No deaths were reported during the study. No major bleeding events were recorded. Eight serious adverse events were recorded in the enoxaparin group versus nine in the control group. INTERPRETATION: These findings suggest thromboprophylaxis with enoxaparin does not reduce early hospitalisations and deaths among outpatients with symptomatic COVID-19. Futility of the treatment under the initial study design assumptions could not be conclusively assessed owing to under-representation of older patients and consequent low event rates. FUNDING: SNSF (National Research Programme COVID-19 NRP78: 198352), University Hospital Zurich, University of Zurich, Dr-Ing Georg Pollert (Berlin), Johanna Dürmüller-Bol Foundation.