Myocardial Infarction, Deep Venous Thrombosis, and Pulmonary Embolism in SARs-CoV-2 Hospitalizations; Insights from the National Inpatient Sample 2020 (preprint)

Background: We studied the outcomes of SARS-CoV-2 (COVID) hospitalizations and their association with myocardial injury and thrombosis. Methods: Retrospective analysis of the National Inpatient Sample 2020 database. Results: We identified 335,799 hospitalizations with COVID. Of these, 1.6% (5,355) were diagnosed with non-ST-segment myocardial infarction (COVNSTEMI). The mean age of COVID hospitalizations was 71.7, with 60.50% being males. The population prevalence included 53.10% Whites, 17.80% Blacks, 19.20% Hispanics, and 4.10% Asians. The average length of stay (LOS) was 10 days, and 37.60% of patients died during their hospitalization. The average cost of hospitalization (TOTCHG) was $156,633. The COVSTEMI group comprised 1,364 cases, with a mean age of 67.4, in-hospital mortality of 47.4%, and the mean TOTCHG was $177,600. The DVTCOV group comprised 2,869 cases, while the PECOV group had 4,828 cases. Male predominance was observed in both groups, with mean ages of 66 years in the DVTCOV group and 64 years in the PECOV group. The DVTCOV group had a LOS of 16 days, with 24.71% mortality, while the PECOV group had a LOS of 11 days, with 19.20% mortality. The average TOTCHG in the DVTCOV group was $248,900, whereas it was $145,378 in the PECOV group. Conclusion: Our study revealed significant mortality rates across different groups, including 38% in COVNSTEMI, 47% in COVSTEMI, 25% in DVTCOV, and 19% in PECOV. These findings highlight the severity of COVID-related complications and the substantial financial burden of hospitalization.

Immunohistologic Features of Cerebral Venous Thrombosis Due to Vaccine-Induced Immune Thrombotic Thrombocytopenia.

OBJECTIVES: Vaccine-induced immune thrombotic thrombocytopenia (VITT), a recently described entity characterized by thrombosis at unusual locations such as cerebral venous sinus and splanchnic vein, has been rarely described after adenoviral-encoded COVID-19 vaccines. In this study, we report the immunohistological correlates in 3 fatal cases of cerebral venous thrombosis related to VITT analyzed at an academic medical center. METHODS: Detailed neuropathologic studies were performed in 3 cases of cerebral venous thrombosis related to VITT after adenoviral COVID-19 vaccination. RESULTS: Autopsy revealed extensive cerebral vein thrombosis in all 3 cases. Polarized thrombi were observed with a high density of neutrophils in the core and a low density in the tail. Endothelial cells adjacent to the thrombus were largely destroyed. Markers of neutrophil extracellular trap and complement activation were present at the border and within the cerebral vein thrombi. SARS-CoV-2 spike protein was detected within the thrombus and in the adjacent vessel wall. DISCUSSION: Data indicate that neutrophils and complement activation associated with antispike immunity triggered by the vaccine is probably involved in the disease process.

Fondaparinux Sodium: Recent Advances in the Management of Thrombosis.

Fondaparinux sodium is a chemically synthesized selective factor Xa inhibitor approved for the prevention and treatment of venous thromboembolic events, that is, deep vein thrombosis, pulmonary embolism, and superficial vein thrombosis, in acutely ill (including those affected by COVID-19 or cancer patients) and those undergoing surgeries. Since its approval in 2002, the efficacy and safety of fondaparinux is well demonstrated by many clinical studies, establishing the value of fondaparinux in clinical practice. Some of the advantages with fondaparinux are its chemical nature of synthesis, minimal risk of contamination, 100% absolute bioavailability subcutaneously, instant onset of action, a long half-life, direct renal excretion, fewer adverse reactions when compared with direct oral anticoagulants, and being an ideal alternative in conditions where oral anticoagulants are not approved for use or in patients intolerant to low molecular weight heparins (LMWH). In the last decade, the real-world use of fondaparinux has been explored in other conditions such as acute coronary syndromes, bariatric surgery, in patients developing vaccine-induced immune thrombotic thrombocytopenia (VITT) and in pregnant women with heparin-induced thrombocytopenia (HIT), or those intolerant to LMWH. The emerging data from these studies have culminated in recent updates in the guidelines that recommend the use of fondaparinux under various conditions. This paper aims to review the recent data and the subsequent updates in the recommendations of various guidelines on the use of fondaparinux sodium.

A review of venous thromboembolism in India.

Venous thromboembolism (VTE), which entails the formation of a thrombus (blood clot) in a vein, has a significant disease burden worldwide. While VTE has traditionally been considered to predominantly affect Caucasian populations, recent studies have indicated a gradual shift in the disease burden towards Asian populations, with added significance of it being a key driver of post-operative mortality. It is imperative to develop a sound understanding of the various factors that affect VTE in stratified local populations. However, there is a glaring paucity of quality data on VTE and its ramifications among Indians - both in terms of quality of life and cost of healthcare. This review aims to throw light on the disease burden, epidemiology, risk factors, environmental factors, food and nutrition that plays a key role in VTE. We also explored the association of VTE with coronavirus disease 2019 to grasp the interplay between the two most significant public health crises of our time. It is vital to place a special emphasis on future research on VTE in India to plug the gaps, which exist in our current knowledge of the disease, particularly with respect to Indian population.

Pathological Effects of SARS-CoV-19 Associated With Hematological Abnormalities (preprint)

The SARS coronavirus 2 (SARS-CoV-2) is the causative agent of the 2019 coronavirus disease (COVID-19) pandemic that has executed 6.9 million people and infected over 765 million. It’s become a major worldwide health alarm and is also known to cause abnormalities in various systems, including the hematologic system. COVID-19 infection primarily affects the lower res-piratory tract and can lead to a cascade of events, including a cytokine storm, intravascular thrombosis, and subsequent complications such as arterial and venous thromboses. COVID-19 can cause thrombocytopenia, lymphopenia, and neutrophilia, which are associated with worse out-comes. Prophylactic anticoagulation is essential to prevent complication and death rate associated with the virus's effect on the coagulation system. It is crucial to recognize these complications early and promptly start therapeutic anticoagulation to improve patient outcomes. While rare, COVID-19-induced disseminated intravascular coagulation exhibits some similarities to DIC induced by sepsis. LDH, D-dimer, ferritin, and CRP biomarker are often increase in serious COVID-19 cases and poor prognosis. Understanding the pathophysiology of the disease and identifying risk factors for adverse outcomes is critical for effective management of COVID-19.

Preexposure Prophylaxis against COVID-19 with Tixagevimab/Cilgavimab in Slovenian National Cohort of Kidney Transplant Recipients (preprint)

Tixagevimab/cilgavimab (TIXA/CILGA) was introduced in early 2022 as a promising new drug for pre-exposure prophylaxis against COVID-19 in immunocompromised patients. The aim of our study was to evaluate the efficacy and safety of TIXA/CILGA in a Slovenian national cohort of kidney transplant recipients as pre-exposure prophylaxis in the Omicron era. Demographic, clinical, laboratory, and therapeutic data were collected from electronic and paper medical rec-ords. Of the 106 patients who received TIXA/CILGA, 6 patients (5.7%) subsequently acquired SARS-CoV-2 breakthrough infection. The incidence of SARS-CoV-2 infection was only slightly lower compared with patients who did not receive TIXA/CILGA (7.0%). All patients who re-ceived TIXA/CILGA had a mild disease course, whereas 20% of patients who did not receive TIXA/CILGA required hospitalization and two patients died. Adverse effects most likely related to TIXA/CILGA occurred in 12% of patients, one of whom experienced deep vein thrombosis. None of the patients suffered acute myocardial infarction or cerebrovascular insult. Overall, the benefit of added protection for kidney transplant patients appears to outweigh the potential risk of adverse events and provide additional protection against severe COVID-19 protection.

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.

Clinically stable covid-19 patients presenting to acute unscheduled episodic care venues have increased risk of hospitalization: secondary analysis of a randomized control trial.

BACKGROUND: Assessment for risks associated with acute stable COVID-19 is important to optimize clinical trial enrollment and target patients for scarce therapeutics. To assess whether healthcare system engagement location is an independent predictor of outcomes we performed a secondary analysis of the ACTIV-4B Outpatient Thrombosis Prevention trial. METHODS: A secondary analysis of the ACTIV-4B trial that was conducted at 52 US sites between September 2020 and August 2021. Participants were enrolled through acute unscheduled episodic care (AUEC) enrollment location (emergency department, or urgent care clinic visit) compared to minimal contact (MC) enrollment (electronic contact from test center lists of positive patients).We report the primary composite outcome of cardiopulmonary hospitalizations, symptomatic venous thromboembolism, myocardial infarction, stroke, transient ischemic attack, systemic arterial thromboembolism, or death among stable outpatients stratified by enrollment setting, AUEC versus MC. A propensity score for AUEC enrollment was created, and Cox proportional hazards regression with inverse probability weighting (IPW) was used to compare the primary outcome by enrollment location. RESULTS: Among the 657 ACTIV-4B patients randomized, 533 (81.1%) with known enrollment setting data were included in this analysis, 227 from AUEC settings and 306 from MC settings. In a multivariate logistic regression model, time from COVID test, age, Black race, Hispanic ethnicity, and body mass index were associated with AUEC enrollment. Irrespective of trial treatment allocation, patients enrolled at an AUEC setting were 10-times more likely to suffer from the adjudicated primary outcome, 7.9% vs. 0.7%; p < 0.001, compared with patients enrolled at a MC setting. Upon Cox regression analysis adjustment patients enrolled at an AUEC setting remained at significant risk of the primary composite outcome, HR 3.40 (95% CI 1.46, 7.94). CONCLUSIONS: Patients with clinically stable COVID-19 presenting to an AUEC enrollment setting represent a population at increased risk of arterial and venous thrombosis complications, hospitalization for cardiopulmonary events, or death, when adjusted for other risk factors, compared with patients enrolled at a MC setting. Future outpatient therapeutic trials and clinical therapeutic delivery programs of clinically stable COVID-19 patients may focus on inclusion of higher-risk patient populations from AUEC engagement locations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498273.

Plantar Vein Thrombosis in a Patient with COVID-19: Case Report.

Plantar thrombophlebitis is a rare abnormality with few cases reported in the literature. Coexistence with severe acute respiratory syndrome coronavirus 2 infection increases its relevance. The disease is generally classified as idiopathic, and it is suggested that it is attributed to conditions that lead to hypercoagulability. We present the case of a 68-year-old female patient with thrombosis of the lateral plantar veins and a diagnosis of coronavirus disease of 2019. The plantar vein thrombosis diagnosis was made by means of Doppler ultrasonography and magnetic resonance imaging. Severe acute respiratory syndrome coronavirus 2 infection was suspected per clinical information and confirmed with reverse-transcriptase polymerase chain reaction technique. Treatment was successful using rivaroxaban and nonsteroidal antiinflammatory drugs.

Prophylactic Inferior Vena Cava Filters for Venous Thromboembolism in Adults With Trauma: An Updated Systematic Review and Meta-Analysis.

Background: Trauma is an independent risk factor for venous thromboembolism (VTE). Due to contraindications or delay in starting pharmacological prophylaxis among trauma patients with a high risk of bleeding, the inferior vena cava (IVC) filter has been utilized as alternative prevention for pulmonary embolism (PE). Albeit, its clinical efficacy has remained uncertain. Therefore, we performed an updated systematic review and meta-analysis on the effectiveness and safety of prophylactic IVC filters in severely injured patients. Methods: Three databases (MEDLINE, EMBASE, and Cochrane) were searched from August 1, 2012, to October 27, 2021. Independent reviewers performed data extraction and quality assessment. Relative risk (RR) at 95% confidence interval (CI) pooled in a randomized meta-analysis. A parallel clinical practice guideline committee assessed the certainty of evidence using the GRADE approach. The outcomes of interest included VTE, PE, deep venous thrombosis, mortality, and IVC filter complications. Results: We included 10 controlled studies (47 140 patients), of which 3 studies (310 patients) were randomized controlled trials (RCTs) and 7 were observational studies (46 830 patients). IVC filters demonstrated no significant reduction in PE and fatal PE (RR, 0.27; 95% CI, 0.06-1.28 and RR, 0.32; 95% CI, 0.01-7.84, respectively) by pooling RCTs with low certainty. However, it demonstrated a significant reduction in the risk of PE and fatal PE (RR, 0.25; 95% CI, 0.12-0.55 and RR, 0.09; 95% CI, 0.011-0.81, respectively) by pooling observational studies with very low certainty. IVC filter did not improve mortality in both RCTs and observational studies (RR, 1.44; 95% CI, 0.86-2.43 and RR, 0.63; 95% CI, 0.3-1.31, respectively). Conclusion: In trauma patients, moderate risk reduction of PE and fatal PE was demonstrated among observational data but not RCTs. The desirable effect is not robust to outweigh the undesirable effects associated with IVC filter complications. Current evidence suggests against routinely using prophylactic IVC filters.

A Comprehensive Review of Risk Factors for Venous Thromboembolism: From Epidemiology to Pathophysiology.

Venous thromboembolism (VTE) is the third most common cause of death worldwide. The incidence of VTE varies according to different countries, ranging from 1-2 per 1000 person-years in Western Countries, while it is lower in Eastern Countries (<1 per 1000 person-years). Many risk factors have been identified in patients developing VTE, but the relative contribution of each risk factor to thrombotic risk, as well as pathogenetic mechanisms, have not been fully described. Herewith, we provide a comprehensive review of the most common risk factors for VTE, including male sex, diabetes, obesity, smoking, Factor V Leiden, Prothrombin G20210A Gene Mutation, Plasminogen Activator Inhibitor-1, oral contraceptives and hormonal replacement, long-haul flight, residual venous thrombosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, trauma and fractures, pregnancy, immobilization, antiphospholipid syndrome, surgery and cancer. Regarding the latter, the incidence of VTE seems highest in pancreatic, liver and non-small cells lung cancer (>70 per 1000 person-years) and lowest in breast, melanoma and prostate cancer (<20 per 1000 person-years). In this comprehensive review, we summarized the prevalence of different risk factors for VTE and the potential molecular mechanisms/pathogenetic mediators leading to VTE.

Venous or arterial thrombosis and deaths among COVID-19 cases: a European network cohort study.

BACKGROUND: There are few data on the incidence of thrombosis among COVID-19 cases, with most research concentrated on hospitalised patients. We aimed to estimate the incidence of venous thromboembolism, arterial thromboembolism, and death among COVID-19 cases and to assess the impact of these events on the risks of hospitalisation and death. METHODS: We conducted a distributed network cohort study using primary care records from the Netherlands, Italy, Spain, and the UK, and outpatient specialist records from Germany. The Spanish database was linked to hospital admissions. Participants were followed up from the date of a diagnosis of COVID-19 or positive RT-PCR test for SARS-CoV-2 (index date) for 90 days. The primary study outcomes were venous thromboembolic events, arterial thromboembolic events, and death, all over the 90 days from the index date. We estimated cumulative incidences for the study outcomes. Multistate models were used to calculate adjusted hazard ratios (HRs) for the association between venous thromboembolism or arterial thromboembolism occurrence and risks of hospitalisation or COVID-19 fatality. FINDINGS: Overall, 909 473 COVID-19 cases and 32 329 patients hospitalised with COVID-19 on or after Sept 1, 2020, were studied. The latest index dates across the databases ranged from Jan 30, 2021, to July 31, 2021. Cumulative 90-day incidence of venous thromboembolism ranged from 0·2% to 0·8% among COVID-19 cases, and up to 4·5% for those hospitalised. For arterial thromboembolism, estimates ranged from 0·1% to 0·8% among COVID-19 cases, increasing to 3·1% among those hospitalised. Case fatality ranged from 1·1% to 2·0% among patients with COVID-19, rising to 14·6% for hospitalised patients. The occurrence of venous thromboembolism in patients with COVID-19 was associated with an increased risk of death (adjusted HRs 4·42 [3·07-6·36] for those not hospitalised and 1·63 [1·39-1·90] for those hospitalised), as was the occurrence of arterial thromboembolism (3·16 [2·65-3·75] and 1·93 [1·57-2·37]). INTERPRETATION: Risks of venous thromboembolism and arterial thromboembolism were up to 1% among COVID-19 cases, and increased with age, among males, and in those who were hospitalised. Their occurrence was associated with excess mortality, underlying the importance of developing effective treatment strategies that reduce their frequency. FUNDING: European Medicines Agency.

Acute Myocardial Infarction, Subclavian Vein Thrombosis, and Pulmonary Embolism Secondary to COVID-19-A Case Report.

Introduction: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The majority of infected patients develop the clinical picture of a respiratory disease, although some may develop various complications, such as arterial or venous thrombosis. The clinical case presented herein is a rare example of sequential development and combination of acute myocardial infarction, subclavian vein thrombosis (Paget Schroetter syndrome), and pulmonary embolism in the same patient after COVID-19. Case presentation: A 57-year-old man with a 10-day history of a SARS-CoV-2 infection was hospitalized with a clinical, electrocardiographic, and laboratory constellation of an acute inferior-lateral myocardial infarction. He was treated invasively and had one stent implanted. Three days after implantation, the patient developed shortness of breath and palpitation on the background of a swollen and painful right hand. The signs of acute right-sided heart strain observed on the electrocardiogram and the elevated D-dimer levels strongly suggested pulmonary embolism. A Doppler ultrasound and invasive evaluation demonstrated thrombosis of the right subclavian vein. The patient was administered pharmacomechanical and systemic thrombolysis and heparin infusion. Revascularization was achieved 24 h later via successful balloon dilatation of the occluded vessel. Conclusion: Thrombotic complications of COVID-19 can develop in a significant proportion of patients. Concomitant manifestation of these complications in the same patient is extremely rare, presenting at the same time, quite a therapeutic challenge to clinicians due to the need for invasive techniques and simultaneous administration of dual antiaggregant therapy combined with an anticoagulant treatment. Such a combined treatment increases the hemorrhagic risk and requires a serious accumulation of data for the purpose of a long-term antithrombotic prophylaxis in patients with such pathology.

Nitrous oxide misuse: a clue not to be missed in young patients with venous thromboembolism.

A 27-year-old man presented with altered mental status and unilateral right lower limb swelling. Brain imaging and cerebrospinal fluid analysis were unremarkable. He reported history of nitrous oxide misuse after he recovered from his delirium. The diagnosis of drug induced psychosis was made. The right lower limb swelling was found to be due to extensive deep vein thrombosis. In another case, a 21-year-old woman presented with headache, vomiting and dipoplia. Brain imaging showed extensive cerebral venous sinus thrombosis. She also misused nitrous oxide. Both cases had low-normal vitamin B12 and elevated methylmalonic acid, consistent with nitrous oxide misuse. The woman was found to have elevated homocysteine because of functional vitamin B12 deficiency. Homocysteine was not measured in the man. Raised homocysteine is associated with increased thrombosis risk. Fourteen cases of nitrous oxide misuse associated arterial and venous thrombosis have been reported. These two cases highlighted the importance of inquiring about recreational drug use in young patients who presented with apparently unprovoked venous thromboembolism.

Efficacy and safety of two heparin regimens for prevention of venous thromboembolism in hospitalized patients with COVID-19: a meta-analysis.

Venous thromboembolism (VTE) is common in patients with coronavirus disease-2019 (COVID-19). The optimal heparin regimen remains unknown and should balance thromboembolic and bleeding risks. The aim of this study was to evaluate the efficacy and safety of standard or higher heparin regimens for the prevention of VTE in patients hospitalized due to COVID-19. We performed a systematic literature search; studies reporting on hospitalized patients with COVID-19 who received standard heparin prophylaxis vs. high (intermediate or therapeutic) heparin regimens were included if outcome events were reported by treatment group and more than 10 patients were included. Primary study outcome was in-hospital VTE. Secondary study outcomes were major bleeding (MB), all-cause death, fatal bleeding and fatal pulmonary embolism. Overall, 33 studies (11,387 patients) were included. Venous thromboembolic events occurred in 5.2% and in 8.2% of patients who received heparin prophylaxis with at high-dose or standard-dose, respectively (RR 0.71, 95% CI 0.55-0.90, I2 48.8%). MB was significantly higher in patients who received high- compared to the standard-dose (4.2% vs 2.2%, RR 1.94, 95% CI 1.47-2.56, I2 18.1%). Sub-analyses showed a slight benefit associated with high-dose heparin in patients admitted to non-intensive care unit (ICU) but not in those to ICU. No significant differences were observed for mortality outcomes. Heparin prophylaxis at high-dose reduces the risk of VTE, but increased the risk of MB compared to the standard-dose. No clinical benefit for heparin high-dose was observed for ICU setting, but its role in the non-ICU deserves further evaluation. PROSPERO registration number: CRD42021252550.

Risk Of Venous Thrombosis In The Primary Care Setting During The Covid-19 Pandemic.

AIMS: This study aimed to evaluate the variability of risk factors among patients with lower limb venous thrombosis, either Deep Vein Thrombosis (DVT) or Superficial Vein Thrombosis (SVT) in community patients with recent or current SARS-CoV-2 infection compared to a historical cohort. METHODS: We performed a historical retrospective analysis of all patients who presented to a primary health care unit and were diagnosed with DVT or SVT from January 2020 to December 2021. Historic controls were selected from January 2018 to December 2019. Demographic and clinical data were collected, including BMI, use of oral combined contraception, smoking status and date of COVID-19 infection diagnosis. Univariate analysis was performed for data assessment, including Chi-Square and ANOVA tests. RESULTS: Of the 8547 patients who attended a non-programmed consultation in the timeframe, seventy-nine patients (0.9%) were diagnosed with DVT (19) or SVT (60) and were included in the study. Their mean age was 57.3 ± 15.93 years, with a female-to-male ratio of 3.2 to 1. There was no significant association between COVID-19 and the development of DVT or SVT (p=0.151). However, there was a trend observed indicating a shift in the predominant gender in patients diagnosed with these conditions (85% females in 2018 versus 53.8% in 2021; p=0.077). CONCLUSIONS: Outpatients seen by general practitioners during the pandemic of COVID-19 appear to present a trend towards an increased risk of combined DVT and SVT compared with patients of a historical cohort. Further studies are necessary to shed some light on this issue since robust evidence enables clinicians and policymakers to minimize venous thromboembolism risk in patients with SARS-CoV-2 infection.