Intravenous High-dose Anakinra Drops Venous Thrombosis and Myocardial Infarction in Severe and Critical COVID-19 Patients: A Propensity Score Matched Study (preprint)

Introduction: In our study, we aimed to evaluate the effect of high-dose intravenous anakinra treatment on the development of thrombotic events in severe and critical COVID-19 patients. Material and methods: This retrospective observational study was conducted at a tertiary referral center in Aksaray, Turkey. The study population consisted of two groups as follows; the patients receiving high-dose intravenous anakinra (anakinra group) added to background therapy and the patients treated with standard of care (SoC) as a historical control group. Age, gender, mcHIS scores, and comorbidities such as DM, HT, and CHD of the patients were determined as the variables to be matched. Results: We included 114 patients in SoC and 139 patients in the Anakinra group in the study. Development of any thromboembolic event (5% vs 12.3%, p = 0.038; OR:4.3) and PTE (2.9% vs 9.6%, p = 0.023; OR:5.1) were lower in the Anakinra group than SoC. No patient experienced CVA and/or clinically evident DVT both in two arms. After 1:1 PS matching, 88 patients in SoC and 88 patients in the Anakinra group were matched and included in the analysis. In survival analysis, the development of any thromboembolic event, PTE, and MI were higher in SoC compared to Anakinra. Survival rate was also lower in patients with SoC arm than Anakinra in patients who had any thromboembolic event as well as MI. Conclusion: In our study, the development of thrombosis was associated with hyperinflammation in patients with severe and critical COVID-19. Intravenous high-dose anakinra treatment decreases both venous and arterial events in patients with COVID-19.

Thymidine Phosphorylase Mediates SARS-CoV-2 Spike Protein Enhanced Thrombosis in K18-hACE2TG Mice (preprint)

COVID-19, caused by SARS-CoV-2, is associated with arterial and venous thrombosis, thereby increasing mortality. SARS-CoV-2 spike protein (SP), a viral envelope structural protein, is implicated in COVID-19-associated thrombosis. However, the underlying mechanisms remain unknown. Thymidine phosphorylase (TYMP), a newly identified prothrombotic protein, is upregulated in the plasma, platelets, and lungs of patients with COVID-19 but its role in COVID-19-associated thrombosis is not defined. In this study, we found that wild-type SARS-CoV-2 SP significantly promoted arterial thrombosis in K18-hACE2TG mice. SP-accelerated thrombosis was attenuated by inhibition or genetic ablation of TYMP. SP increased the expression of TYMP, resulting in the activation of signal transducer and activator of transcription 3 (STAT3) in BEAS-2B cells, a human bronchial epithelial cell line. A siRNA-mediated knockdown of TYMP inhibited SP-enhanced activation of STAT3. Platelets derived from SP-treated K18-hACE2TG mice also showed increased STAT3 activation, which was reduced by TYMP deficiency. Activated STAT3 is known to potentiate glycoprotein VI signaling in platelets. While SP did not influence ADP- or collagen-induced platelet aggregation, it significantly shortened activated partial thromboplastin time and this change was reversed by TYMP knockout. Additionally, platelet factor 4 (PF4) interacts with SP, which also complexes with TYMP. TYMP enhanced the formation of the SP/PF4 complex, which may potentially augment the prothrombotic and procoagulant effects of PF4. We conclude that SP upregulates TYMP expression, and TYMP inhibition or knockout mitigates SP-enhanced thrombosis. These findings indicate that inhibition of TYMP may be a novel therapeutic strategy for COVID-19-associated thrombosis.

Distinct histopathological features of post-COVID-19 cholangiopathy (preprint)

Background: Cholangiopathy has been described in survivors of severe COVID-19, presenting significant clinical parallels to the pre-pandemic condition of secondary sclerosing cholangitis in critically ill patients (SSC-CIP).  Aim: Herein, we examined the liver histopathology of individuals with persistent cholestasis following severe COVID-19.  Methods: Post-COVID-19 cholestasis liver samples were subjected to routine staining techniques and cytokeratin 7 immunostaining, and the portal and parenchymal changes were semi-quantitatively analyzed.  Results: All ten patients, five men, median age 56, interquartile range (IQR) 51–60, requiring mechanical ventilation. The median and IQR liver enzyme concentrations proximal to biopsy were in IU/L: ALP, 605 (390–1,105); GGT, 925 (776–2,169); ALT, 92 (86–110); AST, 90 (68–108); and bilirubin, 3 (1–6) mg/dL. Imaging revealed intrahepatic bile duct anomalies and biliary casts. Biopsies were performed at a median of 203 (150–249) days after molecular confirmation of infection. Portal and periportal fibrosis, moderate-to-severe ductular proliferation, and bile duct dystrophy were found in all patients, while hepatocyte biliary metaplasia was observed in all tested cases. Mild-to-severe parenchymal cholestasis and bile plugs were observed in nine and six cases. Mild swelling of the arteriolar endothelial cells was observed in five patients. A thrombus in a small portal vein branch and mild periductal fibrosis were observed in one case each. One patient developed multiple small biliary infarctions. Ductopenia was not observed in any patient.  Conclusions: The alterations were similar to those observed in SSC-CIP; however, pronounced swelling of endothelial cells, necrosis of the vessel walls, and thrombosis in small vessels were notable.

Long-term cardiovascular safety of COVID-19 vaccination according to brand, dose and combinations: Cohort study of 46 million adults in England (preprint)

Using longitudinal health records from 45.7 million adults in England followed for a year, our study compared the incidence of thrombotic and cardiovascular complications after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the first two years of the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA- 1273) These findings support the wide uptake of future COVID-19 vaccination programs.

Upper deep vein thrombosis in a patient with COVID-19 infection and a giant goiter (preprint)

A 74-year-old female presented with COVID-19 pneumonia and multinodular goiter with right lobe enlargement, occupying medium mediastinum with trachea compression is presented. COVID-19 pro-thrombotic status combined with low dynamic flow due to the large goiter resulted in deep vein thrombosis of subclavian and jugular veins in this case.

Thrombotic microangiopathy with kidney involvement in a patient with coronavirus disease 2019: A case report and literature review (preprint)

Background and aim: Millions of people worldwide have suffered from coronavirus disease 2019 (COVID-19). COVID-19 can lead to coagulopathy and thrombosis, presenting as pulmonary artery thromboembolism, deep vein thrombosis, and thrombotic microangiopathy (TMA), the latter being a rare finding in affected patients’ kidneys. Prior reports have rarely addressed the pathophysiology, clinical presentations, and therapeutic options in patients with COVID-19-associated TMA. Case presentation: We herein described a case of renal biopsy-proven TMA after COVID-19 in a 36-year-old woman. Initial examination revealed inflammation, acute kidney injury (AKI), anemia, and thrombocytopenia. She was diagnosed with hemolytic uremic syndrome, pulmonary infection, and COVID-19. After treatment, her condition stabilized but remained hemodialysis-dependent after discharge. One week later, she was re-hospitalized, and physical examination showed anemia and bilateral lower extremity edema. Abdominal ultrasound showed increased bilateral kidney echogenicity. Whole-exome sequencing detected an unknown variant of the C3 gene associated with hemolytic uremic syndrome susceptibility type 5/complement C3 deficiency. Kidney biopsy showed renal artery lesions, including small arteriole endothelial swelling, intimal thickening, mucinous degeneration, luminal occlusion, and small arterial wall necrosis. She received plasma exchange and steroids with significant renal function recovery. Conclusion: TMA likely contributed to AKI after COVID-19,thus supporting the notion that TMA plays an important role in the pathogenesis of COVID-19-related kidney injury. When diagnosing and treating COVID-19 patients with abnormal renal function, clinicians should incorporate kidney biopsy and genetic testing for the complement system, identify renal-limited and systemic TMA, and treat accordingly, which can improve patient outcomes.

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.

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.

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.

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.