Incidence and Risk of Post-COVID-19 Thromboembolic Disease and the Impact of Aspirin Prescription; Nationwide Observational Cohort at the US Department of Veteran Affairs. (preprint)

IntroductionCOVID-19 triggers prothrombotic and proinflammatory changes, with thrombotic disease prevalent in up to 30% SARS-CoV-2 infected patients. Early work suggests that aspirin could prevent COVID-19 related thromboembolic disorders in some studies but not others. This study leverages data from the largest integrated healthcare system in the United States to better understand this association. Our objective was to evaluate the incidence and risk of COVID-19 associated acute thromboembolic disorders and the potential impact of aspirin. MethodsThis retrospective, observational study utilized national electronic health record data from the Veterans Health Administration. 334,374 Veterans who tested positive for COVID-19 from March 2, 2020, to June 13, 2022, were included, 81,830 of whom had preexisting aspirin prescription prior to their COVID-19 diagnosis. Patients with and without aspirin prescriptions were matched and the odds of post-COVID acute thromboembolic disorders were assessed. Results10.1% of Veterans had a documented thromboembolic disorder within 12 months following their COVID-19 diagnosis. Those with specific comorbidities were at greatest risk. Preexisting aspirin prescription was associated with a significant decrease risk of post-COVID-19 thromboembolic disorders, including pulmonary embolism (OR [95% CI]: 0.69 [0.65, 0.74]) and deep vein thrombosis (OR [95% CI]: 0.76 [0.69, 0.83], but an increased risk of acute arterial diseases, including ischemic stroke (OR [95% CI]: 1.54 [1.46, 1.60]) and acute ischemic heart disease (1.33 [1.26, 1.39]). ConclusionsFindings demonstrated that preexisting aspirin prescription prior to COVID-19 diagnosis was associated with significantly decreased risk of venous thromboembolism and pulmonary embolism but increased risk of acute arterial disease. The risk of arterial disease may be associated with increased COVID-19 prothrombotic effects superimposed on preexisting chronic cardiovascular disease for which aspirin was already prescribed. Prospective clinical trials may help to further assess the efficacy of aspirin use prior to COVID-19 diagnosis for the prevention of post-COVID-19 thromboembolic disorders.

The Aftermath of COVID-19: Exploring Long-Term Effects on the Organ Systems (preprint)

Background: Post-acute sequelae of SARS-CoV-2 infection (PASC) is a complicated disease that affects millions of people all over the world. Previous studies have shown that PASC impacts 10% of SARS-CoV-2 infected patients of which 50-70% are hospitalized. It has also been shown that 10-12% of those vaccinated against COVID-19 were affected with PASC and its complications. The severity and the later development of PASC symptoms is positively associated with the early intensity of the infection. Results: The generated health complications caused by PASC involve a vast variety of organ systems. Patients affected by PASC have been diagnosed with neuropsychiatric and neurological symptoms. Cardiovascular system also has been involved and several diseases such as myocarditis, pericarditis, and coronary artery diseases were reported. Chronic hematological problems such as thrombotic endothelialitis and hypercoagulability were described as a condition that could increase the risk of clotting disorders and coagulopathy in PASC patients. Chest pain, breathlessness, and cough in PASC patients were associated with respiratory system in long COVID-19 causing respiratory distress syndrome. The observed immune complications were notable, involving several diseases. Renal system also was impacted and result in raising the risk of diseases such as thrombotic issues, fibrosis, and sepsis. Endocrine gland malfunction can lead to diabetes, thyroiditis, and male infertility. Symptoms such as diarrhea, nausea, loss of appetite and taste were also among reported observations due to several gastrointestinal disorders. Skin abnormalities might be an indication of infection and long-term implications such as persistent cutaneous complaints were linked to PASC. Conclusions: Long COVID is a multidimensional syndrome with considerable public health implications, affecting several physiological systems and demanding thorough medical therapy as well as more study to address its underlying causes and long-term effects.

Patients with COVID-19 Infection and Stroke have Higher than Expected Mortality, Regardless of the Primary Presentation (preprint)

BackgroundCOVID-19 infection is associated with thrombotic events; however, this phenomenon is poorly understood. Few studies have reported the association between COVID-19 and stroke in the hospital setting. MethodsWe retrospectively reviewed and characterized all patients who presented to a single, quaternary medical center between March and December 2020 (N=603). COVID-19 positive patients who developed ischemic or hemorrhagic stroke were included in the analysis (N=66). This cohort was compared with patients who were COVID-19 negative at the time of stroke presentation in the same period (N=537). Statistical significance was evaluated using Pearsons Chi squared test with Yates continuity correction and linear model ANOVA. ResultsSixty-six patients had COVID-19 and Stroke. Of these patients, 22 (33.4%) patients initially presented with stroke and 44 (66.7%) initially presented with COVID-19. Patients who presented with COVID-19 and had a stroke during their hospitalization (COVID-first) had worse outcomes than patients presenting to the hospital with stroke whose COVID test became positive later in the hospitalization (stroke-first). Patients who presented with COVID-19 and had a stroke during their hospitalization had an increased rate of acute renal failure (48.9% vs 19.0%, p=0.021) and need for ventilation (60.0% vs 28.6%, p=0.017). Further, in the COVID-first cohort, the use of heparin prior to the stroke event was not associated with mortality or type of stroke (ischemic or hemorrhagic). ConclusionIn the early pandemic, patients with COVID-19 infection and stroke had a higher mortality rate compared to COVID-19 negative patients with stroke. Among patients with both COVID-19 and stroke, patients presenting with COVID-19 first had worse outcomes than patients presenting with stroke first. The use of heparin prior to the stroke event was not associated with mortality or type of stroke.

COVID-19-associated acute renal failure in critically ill patients correlates with microthrombosis and renal loss of thrombomodulin (preprint)

Critically ill COVID-19 patients have a high degree of acute kidney injury which develops in up to 85% of patients. We have previously shown that circulating levels of angiopoietin-2 increased in critically ill COVID-19 patients correlated to kidney injury, coagulopathy, and mortality. Furthermore, our experiments showed a causal effect on coagulopathy from angiopoietin-2 binding and inhibition of thrombomodulin mediated anticoagulation. In the current study we hypothesize that renal microthrombi may be a mechanism for reduced renal function in critically ill COVID-19 patients, and that local dysregulation of thrombomodulin and angiopoietin-2 may be involved. To investigate our hypothesis, we utilized postmortem kidney tissue from seven COVID-19 patients treated at the intensive care unit. We evaluated kidney function, thrombosis, tubular injury, fibrosis, glomerulosclerosis, glomerular size as well as renal expression of thrombomodulin and angiopoietin-2. Proximity ligation assay was utilized to evaluate the presence of angiopoietin-2 binding to thrombomodulin. Normal kidney tissue came from the healthy part of six nephrectomies due to cancer. Our experiments show renal thrombosis in 6/7 COVID-19 patients, on average 14.7 (6.9-22.5) thrombi per mm2. Most COVID-19 kidneys had extensive kidney injury, especially tubular necrosis, but also glomerular enlargement, glomerulosclerosis, and tubulointerstitial fibrosis which in some cases most likely resulted from underlying disease. Thrombomodulin expression was reduced in glomeruli and peritubular capillaries in kidneys from COVID-19 patients, whereas no change was found for angiopoietin-2. In summary, our study describes a high degree of acute renal failure, renal microthrombosis, and loss of thrombomodulin in postmortem tissue from critically ill COVID-19 patients.

Real-world Nuvaxovid COVID-19 vaccine safety profile after first 100,000 doses in Australia, 2022-2023 (preprint)

Introduction Nuvaxovid became available in Australia from February 2022, a year later than the first COVID-19 vaccines were released. It was a much-anticipated alternative vaccine for people that had either suffered an adverse event to and/or were hesitant to receive one of the mRNA or adenovirus based COVID-19 vaccines. Although safety from clinical trials was reassuring, small trial population size, relatively low administration rates worldwide and limited post-licensure intelligence meant potential rare adverse events were underinformed. Methods We conducted a retrospective observational analysis of adverse events following immunisation (AEFI) spontaneously reported to SAFEVAC, the integrated vaccine safety surveillance system used by Victoria and Western Australia, Australia. Reports received from 14 Feb 2022 to 30 June 2023 were analysed by vaccinee demographics, reported reactions and COVID-19 vaccine dose received and compared as reporting rates (RR) per 100,000 doses administered. Results 356 AEFI reports were received, following 102,946 Nuvaxovid doses administered. Rates were higher post dose 1 than dose 2 (rate ratio 1.5, p=0.0008); primary series than booster (rate ratio 2.4, p<0.0001); in females than males (rate ratio 1.4, p<0.01), especially those aged 30-49 years (RR=1.6, p=0.002). Serious AEFI included 76 chest pain (RR=73.8), two myocarditis (RR=1.9) and 20 pericarditis (RR=19.4). No cases of Guillain Barre or thrombosis with thrombocytopaenia syndromes were reported and no deaths attributable to vaccination. Conclusion The shared SAFEVAC platform enables pooling of clinically reviewed data across jurisdictions, increasing the safety profile evidence base of novel vaccines like Nuvaxovid and improving the odds for identification and description of rare events across all vaccines.

Concerns regarding Transfusions of Blood Products Derived from Genetic Vaccine Recipients and Proposals for Specific Measures (preprint)

The coronavirus pandemic was declared by the World Health Organization (WHO) in 2020, and a global genetic vaccination program has been rapidly implemented as a fundamental solution. However, many countries around the world have reported that so-called genetic vaccines, such as those using modified mRNA encoding the spike protein and lipid nanoparticles as the drug delivery system, have resulted in post-vaccination thrombosis and subsequent cardiovascular damage, as well as a wide variety of diseases involving all organs and systems, including the nervous system. In this article, based on these circumstances and the volume of evidence that has recently come to light, we call the attention of medical professionals to the various risks associated with blood transfusions using blood products derived from people who have suffered from long COVID and from genetic vaccine recipients, including those who have received mRNA vaccines, and we make proposals regarding specific tests, testing methods, and regulations to deal with these risks. We expect that this proposal will serve as a basis for discussion on how to address post-vaccination syndrome and its consequences following these genetic vaccination programs.

The Role of Thromboelastography as a Predictor of Acute Kidney Injury in COVID-19 Patients in ICU (preprint)

There is evidence that kidney involvement is frequently observed in COVID-19 patients, and can manifest as mild proteinuria to advancing acute kidney injury (AKI). One of the mechanisms is microvascular and macrovascular thrombosis caused by the hypercoagulation phase of the disease. Thromboelastography (TEG) is a valuable examination to detect significant hemostatic abnormalities, including the hypercoagulable state. This study analyzed the coagulation profiles, including TEG parameters, in COVID-19 patients who developed AKI compared to those who did not during their intensive care unit (ICU) stay, to identify predictors of AKI. Our single-center cohort retrospective study involved adult patients of COVID-19 in the ICU of Sardjito Hospital in Yogyakarta, Indonesia between May and September 2021. Patients were divided into two groups of AKI and non-AKI based on 2012 KDIGO definition and the elaboration by Indonesian Society of Nephrology. Variables showing a significant difference in the two groups were then analyzed using univariate and multivariate binary logistic regression. A total of 60 COVID-19 patients were included in the study, and 35% of them developed AKI. Compared to non-AKI patients, those with AKI exhibited a greater prevalence of diabetes mellitus (66.7% versus 35.9%, P = 0.023), higher D-Dimer levels (970 versus 685 ng/mL, P = 0.045), and higher values in TEG parameters of maximum amplitude/MA (74.6 versus 65.9 mm, P = 0.001) and coagulation index/CI (2.3 versus 1.0, P = 0.033). TEG parameter of MA emerged as the sole significant predictor for the development of AKI (OR, 6.33; 95% CI, 1.56 to 25.64). Our study validated the kidney involvement of COVID-19 infection, and showed that diabetes mellitus, high D-Dimer levels, and hypercoagulability serve as prominent risk factors in the development of AKI. Furthermore, TEG parameter of MA exceeding 70 mm is the single independent significant predictor of AKI.

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.

Design and Synthesis of Novel Factor XIa Inhibitors with Bicyclic Isoquinoline and Naphthalene Fragments (preprint)

FXIa has emerged as a promising therapeutic target for treating thrombotic diseases. With the aim to replace the aniline motif of asundexian with novel P2’ fragments, bicyclic isoquinoline and naphthalene rings were designed. The target compounds with isoquinoline ring were synthesized via 13 steps of chemical reactions. Substituents within the rings were investigated to elucidate the structural determinants governing selective or dual inhibition of FXIa and Plasma Kallikrein (PKa). In vitro testing showed that some of designed compounds exhibited comparable potency against both FXIa and PKa, while others achieved up to 94-fold selectivity. Analysis of structure-activity relationships (SARs) uncovered the pivotal role of the carboxylic acid moiety in retaining inhibition of FXIa and PKa, and the steric hindrance and hydrogen-bond receptor functional groups were identified as key factors influencing the selectivity of FXIa inhibition over PKa. The docking study additionally unveiled different binding modes that play a significant role in the observed activity and selectivity. Furthermore, the selected compounds significantly extended the plasma coagulation time in a dose-dependent manner. Altogether, the bicyclic compounds may be promising lead compounds for the development of highly effective FXIa inhibitors.

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.

Thrombotic and thromboembolic events, with or without thrombocytopenia, following viral vector-based COVID-19 vaccines administration: a systematic review protocol. (preprint)

BackgroundViral vector-based COVID-19 vaccines have proven to be effective and safe in clinical trials and post-authorization studies. Although infrequent, some serious thrombotic and thromboembolic events following immunization have emerged, and causality assessment committees must consider and critically assess different sources of evidence to inform their decisions about whether these events supposedly attributable to vaccination or immunization (ESAVI) are associated with the vaccine or are coincidental. Therefore, this systematic review aims to gather information on the association and biological mechanisms between thrombotic and thromboembolic events, with or without thrombocytopenia, and the administration of viral vector-based COVID-19 vaccines. MethodsWe will conduct a systematic review following the evidence synthesis framework proposed by the Pan American Health Organization to support the ESAVI causality assessment. We will search for primary clinical and preclinical studies in the Epistemonikos COVID-19 L.OVE (Living Overview of the Evidence) repository, a comprehensive and validated source of COVID-19 evidence. We will include studies reporting any thrombotic or thromboembolic event, with or without thrombocytopenia, after the administration of a viral vector-based COVID-19 vaccine. The screening and data extraction will be performed by two independent authors. We will assess the risk of bias by two reviewers using the appropriate tool for each study design. Discrepancies will be discussed or resolved by a third author. We will use GRADE to assess the certainty of evidence for clinical studies and prepare summary of findings tables. For individual-based (case series and case reports) and preclinical studies, we will summarize the results in descriptive tables. Expected results and implicationsThis will be the first systematic review using the evidence synthesis framework for ESAVI causality assessment, currently under validation by the Pan American Health Organization and the Epistemonikos Foundation. By gathering clinical and preclinical evidence, it is expected to inform about the risks of thromboembolic events following vaccination with viral vector-based COVID-19 vaccines, and also the possible underlying biological mechanisms. Policymakers, such as safe vaccination committees, and other evidence synthesis authors could replicate this novel methodology to strengthen the evidence-based ESAVI causality assessment.

Inadvertent Exposure to Pharmacologically Designed Lipid Nanoparticles Via Bodily Fluids: Biologic Plausibility and Potential Consequences (preprint)

Exposure to vaccine lipid nanoparticles, mRNA, adenoviral DNA, and or Spike protein from one of the approved Covid-19 vaccines, or through secondary exposure, as through blood transfusion, is a potential source of harm. Blood reactions are an acknowledged side-effect of Covid-19 vaccination, not limited to hemolysis, paroxysmal nocturnal hemoglobinuria, chronic cold agglutinin disease, immune thrombocytopenia, haemophagocytosis, hemophagocytic lymphohistiocytosis, and many other blood related conditions. The observation of adverse events has motivated investigation into the cardiovascular mechanisms of harm by Covid-19 vaccines, and the biodistribution of vaccine contents. Biodistribution may not be limited to the body of the vaccine recipient, as a growing body of evidence demonstrates the possibility of secondary exposure to vaccine particles. These can be via bodily fluids and include the following routes of exposure: blood transfusion, organ transplantation, breastfeeding, and possibly other means. As covid-19 vaccines are associated with an increased risk of stroke, the persistence of vaccine artifacts in the blood presents a possible threat to a recipient of a blood donation from a vaccinated donor who suffered from vaccine induced thrombosis or thrombocytopenia. (VITT) We assess the feasibility and significance of these risks through an overview of the case report literature of blood disorders in vaccinated individuals, pharmacovigilance reports from the US Vaccine Adverse Events Reporting System (VAERS) and a meta-analysis of the available literature on organ transplants from vaccinated organ donors. Our analysis establishes biological mechanistic plausibility, a coherent safety signal in pharmacovigilance databases for secondary vaccine contents exposure (for the cases of blood transfusion and breastfeeding) and also an elevated level of adverse events in organ transplants from VITT-deceased donors, echoing increases in organ transplantation related complications seen in national statistics for some countries. Secondary exposure to vaccine artifacts is a potential explanation for some of the cases put forth, and requires a deeper investigation.

Clot Twist - D-dimer analysis of healthy adults receiving heterologous or homologous booster COVID-19 vaccine after a single prime dose of Ad26.COV2.S in a phase II randomised open-label trial, BaSiS. (preprint)

BaSiS (Booster After Sisonke Study) is a prospectively enrolled open-label trial in which healthy adults, with controlled co-morbidities and no prior thrombosis, who received a single Ad26.COV2.S prime vaccination primarily through the Sisonke phase IIIB open label implementation study in South Africa. An exploratory objective evaluated the clotting profiles of participants who were enrolled across 4 sites in South Africa and randomised 1:1:1:1 to receive one of full-dose Ad26.COV2.S, half-dose Ad26.COV2.S, full-dose Comirnaty or half-dose Comirnaty booster. D-dimer testing (INNOVANCE D-Dimer Assay), as a coagulopathy marker, was conducted pre-booster (baseline) and 2 weeks post-booster. The median age among 285 participants was 42.2 years (IQR:35.5-48.7), 235/285 (82.5%) were female, 269/285 (94.4%) were Black African. Of the 40.4% (115/285) people living with HIV (PLHIV), 79.1% (91/115) were well-controlled on antiretroviral therapy. At baseline, 39.3% (112/285) had elevated d-dimers; all asymptomatic. Females and obese participants were significantly more likely to have elevated baseline d-dimers (OR=4.17; 95% CI:1.88 to 9.26 and OR=2.64; 95% CI:1.57 to 4.43, respectively). Of 169 with normal baseline d-dimers, 29 (17.2%) became elevated 2 weeks post-booster: median increase 0.23ug/ml (IQR:0.15-0.42); those receiving full-dose Comirnaty exhibited lower risk of d-dimer elevation post vaccination, compared to other booster vaccination arms (OR:0.26; 95% CI:0.07 to 0.98). PLHIV experienced significantly higher median increases compared to HIV uninfected participants (0.43 vs 0.17, p=0.004). Elevated d-dimers in asymptomatic, low-risk adults were unexpectedly common but were not associated with thromboembolism, supporting the rationale of using d-dimers only if clinically indicated. Trial Registration: South African Clinical Trails Register number DOH-27-012022-7841.

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.

RISK OF THROMBOEMBOLISM AFTER COVID-19 VACCINATION AND COVID-19 INFECTION. (preprint)

Background: Vaccine safety monitoring systems worldwide have reported cases of venous thromboembolism and arterial thromboembolism following a COVID-19 vaccination. However, evidence shows that the association between thromboembolism and SARS-CoV-2 infection is stronger, compared to SARS-CoV-2 vaccination. Hence, weighing the risks and benefits of vaccination should also encounter the roles of vaccination in reducing infection rate, and potentially indirectly lowering the risk of thromboembolism caused by infection. Methods: We conducted a self-controlled case series study (SCCS) from Dec 1st 2020 to 31st August 2022 (before the bivalent vaccine was available) to examinate the association between the first two doses Pfizer/Moderna vaccination and thrombotic events among patients in Corewell Health East (CHE, formerly known as Beaumont Health) healthcare system. We also investigated the effect SARS-CoV-2 infection on the risk of thrombosis events and observed a significant increased risk using the SCCS design. However, because of misclassification bias, SCCS indeed overestimated incidence rate ratio (IRR) of acute event after infection, we then proposed a case-control study addressing this misclassification issues and obtained odd ratio comparing effect of exposure on thrombosis and a subset of controls group. Finally, we analyzed the risk of thromboembolism between vaccinated and unvaccinated groups by a simple diagram, explaining possible factors that affects the probability of experiencing an acute thromboembolism event after a COVID-19 vaccination. Results: Using EHR data at Corewell East, we found an increased risk of thrombosis after the first two doses of COVID-19 vaccination, with incidence rate ratios after the first dose is 1.16 (CI: [1.04, 1.29]), and after the second dose of 1.19 (CI: [1.07,1.32]). The association between thromboembolism and SARS-Cov-2 infection depends on prior vaccination status, as the conditional OR among unvaccinated and vaccinated groups are 1.77 (CI: [1.48,\ 2.1]) and 1.34 (CI: [1.09,\ 1.66]) respectively. Encountering the vaccine efficacy (VE), receiving the COVID-19 vaccine decreases the risk of thromboembolism, and the benefits of COVID-19 vaccines are much stronger in the period of high infection rate.

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.

The effect of thrombosis-related laboratory values on mortality in Covid-19 infection (preprint)

Objective: Covid-19 may cause thrombosis in both venous and arterial systems. Familiarity with the signs and symptoms of thrombosis and their treatment plays an important role in treating Covid-19 infection and its complications. D-Dimer and Mean platelet volume (MPV) are measurements related to the development of thrombosis. This study investigates whether MPV and D-Dimer values could be used to determine the risk of thrombosis and mortality in Covid-19 early stages. Methods: 424 patients were randomly and retrospectively included in the study, Covid 19 positive according to the World Health Organization (WHO) guidelines. Demographic and clinical characteristics such as age, gender, and length of hospitalization were obtained from the digital records of participants. Participants were divided into living and deceased groups. Results: WBC, neutrophils, and monocytes were significantly different in the two groups (p <0.001), and its values were lower in the living group than in the deceased group. MPV median values do not differ according to prognosis (p = 0.994). Creatinine, Procalcitonin, Ferritin, and the number of hospitalization days in living patients were significantly lower than in patients who died (p <0.001). Median values of D-dimer (mg / L) differ according to prognosis (p <0.001). While the median value was 0.63 in the survivors, it was found as 4.38 in the deceased. Conclusion: Our results did not show any significant relationship between the mortality of Covid-19 patients and their MPV levels. However, a significant association of D-Dimer and mortality in Covid-19 patients was observed. Keywords: COVID-19, MPV, D-Dimer, prognosis, mortality

Renal consequences of the novel coronavirus disease 2019 (COVID-19) and hydrogen sulfide as a potential therapy (preprint)

The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global pandemic which is primarily considered a respiratory illness. However, emerging reports show that the virus exhibits both pulmonary and extra-pulmonary manifestations in humans, with the kidney as a major extra-pulmonary target due to its abundant expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, which facilitate entry of the virus into cells. Acute kidney injury has become prevalent in COVID-19 patients without prior any history of kidney dysfunction. In addition, the virus also worsens kidney conditions and increases mortality of COVID-19 patients with pre-existing chronic kidney disease, renal cancer, diabetic nephropathy, end-stage kidney disease as well as dialysis and kidney transplant patients. In the search for antiviral agents for the treatment of COVID-19, hydrogen sulfide (H2S), the third established member of gasotransmitter family, is emerging as a potential candidate, possessing important therapeutic properties including antiviral, anti-inflammatory, anti-thrombotic and antioxidant properties. A recent clinical study revealed higher serum H2S levels in survivors of COVID-19 pneumonia with reduced interleukin-6 levels compared to fatal cases. In this review, we summarize the global impact of COVID-19 on kidney conditions and discuss the emerging role of H2S as a potential COVID-19 therapy.

Prospective Study of Sars-cov2 Associated Coagulopathy and Role of Complement Activation (preprint)

Sars-CoV2 associated coagulopathy is a complex entity. Platelets, coagulation factors, fibrinolysis, inflammatory cytokines, immunothrombosis, antiphospholipd antibodies, von Willebrand factor/ADAMTS13 axis, complement system have all been demonstrated to be actively involved in the determination of thrombotic events. Til now retrospective studies have analyzed the activaction of vWF/ADAMTS13 axis and complement involvement. We performed a prospective study with the aim of describing clinical and laboratoristic features of Sars-CoV2 associated coagulopathy and its relationship with complement activation. Biochemical variables, vWF/ADAMTS13 axis, complement factors of the enrolled patients have been analyzed. These variables have been correlated to clinical outcome of the disease. Covid associated coagulopathy is neither a Trombotic Trombocitopenc Purpura (TTP) nor and atypical hemolytic uremic syndrome (aSEU). Nevertheless, imbalance of vWF/Adamts13 axis and complement activation simultaneously occurre and are significantly higher in the severe form of disease.

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.