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2.
Eur Rev Med Pharmacol Sci ; 26(9): 3399-3405, 2022 May.
Article in English | MEDLINE | ID: covidwho-1856627

ABSTRACT

OBJECTIVE: COVID-19 patients have been shown to be hypercoagulable, increasing the risk for thromboembolic events. The kinetics of the blood coagulation process were monitored daily throughout hospitalization in COVID-19 positive patients. PATIENTS AND METHODS: Thromboelastography (TEG) was used to assess blood coagulation in 48 adult patients hospitalized for COVID-19 in this prospective cohort study. Clinical risk was assessed via National Early Warning Scores (NEWS) for each day of hospitalization. RESULTS: During hospitalization, 98% of patients had one or more procoagulable TEG result. Thromboelastography results remained prothrombotic upon discharge in 80% of patients. NEWS significantly decreased by discharge compared to the peak scores. CONCLUSIONS: Overall, patients were discharged from the hospital with significant clinical improvement, but without abnormal TEG results returning to a normal range. All patients in our study survived and few had thromboembolic events, so if and for how long these patients remain at risk for future complications warrants further investigation.


Subject(s)
COVID-19 , Thromboembolism , Thrombophilia , Adult , Blood Coagulation , Humans , Prospective Studies , Thrombelastography/adverse effects , Thrombelastography/methods , Thrombophilia/etiology
4.
Front Immunol ; 13: 834988, 2022.
Article in English | MEDLINE | ID: covidwho-1817941

ABSTRACT

Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibited higher basal levels of activation measured by P-selectin surface expression and had poor functional reserve upon in vitro stimulation. To investigate this question in more detail, we developed an assay to assess the capacity of plasma from COVID-19 patients to activate platelets from healthy donors. Platelet activation was a common feature of plasma from COVID-19 patients and correlated with key measures of clinical outcome including kidney and liver injury, and APACHEIII scores. Further, we identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with in vitro platelet activation. Mechanistically, blocking the signaling of the FcγRIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions. These data identified these potentially actionable pathways as central for platelet activation and/or vascular complications and clinical outcomes in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect.


Subject(s)
Blood Platelets/immunology , COVID-19/immunology , Complement C5a/metabolism , Receptor, Anaphylatoxin C5a/metabolism , Receptors, IgG/metabolism , SARS-CoV-2/physiology , Thromboembolism/immunology , Adult , Aminopyridines/pharmacology , Cells, Cultured , Female , Hospitalization , Humans , Male , Morpholines/pharmacology , Platelet Activation , Pyrimidines/pharmacology , Severity of Illness Index , Signal Transduction , Syk Kinase/antagonists & inhibitors
5.
J Assoc Physicians India ; 70(4): 11-12, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1801199

ABSTRACT

The sars -cov 2 causing covid 19 disease. B/l pneumonia, systemic inflammation, coagulation activation, ards , multiorgan failure are key features of covid 19. Patients need icu admission. Proinflammatory cytokines, tnf, il 6, 8, 1 beta, causes cytokine storm in covid 19 disease. MATERIAL: In this single-center, retrospective, cross sectional study, the clinical and laboratory characteristics of 154 patients with severe covid-19 were collected. 38 Patients with severe covid -19 had incidence of thromboembolism with its symptoms, and 116 patients (ie, the controls) did not have incidence of thromboembolism. A severe case was defined as including at least one of the following criteria: (1) respiratory rate >30/ min. (2) Oxygen saturation ≤90%. (3) Pao2 /fio2 ≤300mm hg. (4) Patients, either with shock or respiratory failure, requiring mechanical ventilation, or combined with other organ failure, requiring admission to intensive care unit (icu). Also pe cases were those patients with high clinical suspicion [tachycardia >100 bpm, systolic arterial tension <100 mmhg or signs of right ventricular pressure overload]. Pe severity was assessed using the simplified pulmonary embolism severity index (s -pesi). OBSERVATION: Of 154 patients with severe covid-19, 38 (24.67%) Had incidence of thromboembolism. Compared with patients with severe covid-19 without incidence of thromboembolism, patients with incidence of thromboembolism were older, susceptible to receiving mechanical ventilation and admission to icu, and had higher mortality. In addition, patients with severe covid-19 with thromboembolism had higher levels of leukocyte count, neutrophil count, high-sensitivity c reaction protein, procalcitonin, ferritin, interleukin (il) 2 receptor, il-6, il-8, tumor necrosis factor α, D-dimer, fibrinogen, lactic dehydrogenase and n-terminal probrain natriuretic peptide. Among patients with severe covid-19 with incidence of thromboembolism, more non-survivors were men (30 (75%) vs women (25%)). Non-survivors had severe inflammatory response, and cardiac, hepatic, renal and coagulation impairment. Finally, the kaplan-meier survival curve showed a trend towards poorer survival in patients with severe covid-19 with incidence of thromboembolism than patients without incidence of thromboembolism. The hr was 2.24 [95% Ci 1.17-4.29], P = 0.015). After adjustment for age, sex, hypertension, cardiovascular disease and cerebrovascular disease by cox regression. The median survival durations from hospital admission in patients with severe covid-19 with and without incidence of thromboembolism were 8 days and 15 days, respectively. CONCLUSION: The mortality rate in patients with severe covid-19 with incidence of thromboembolism is high. Incidence of thromboembolism may lead to an increase in the risk of death.


Subject(s)
COVID-19 , Thromboembolism , COVID-19/complications , Cross-Sectional Studies , Female , Humans , Male , Retrospective Studies , SARS-CoV-2 , Thromboembolism/epidemiology , Thromboembolism/etiology
7.
Ann Palliat Med ; 11(4): 1317-1325, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1786443

ABSTRACT

BACKGROUND: There currently exists a paucity of data on whether pre-admission anticoagulants use may have benefits among COVID-19 patients by preventing COVID-19 associated thromboembolism. The aim of this study was to assess the association between pre-admission anticoagulants use and COVID-19 adverse outcomes. METHODS: We conducted a population-based cohort studying using the Health Insurance Review and Assessment Service (HIRA) claims data released by the South Korean government. Our study population consisted of South Koreans who were aged 40 years or older and hospitalized with COVID-19 between 1 January 2020 through 15 May 2020. We defined anticoagulants users as individuals with inpatient and outpatient prescription records in 120 days before cohort entry. Our primary endpoint was a composite of all-cause death, intensive care unit (ICU) admission, and mechanical ventilation use. Individual components of the primary endpoint were secondary endpoints. We compared the risk of endpoints between the anticoagulants users and non-users by logistic regression models, with the standardized mortality ratio weighting (SMRW) adjustment. RESULTS: In our cohort of 4,349 patients, for the primary endpoint of mortality, mechanical ventilation and ICU admission, no difference was noted between anticoagulants users and non-users (SMRW OR 1.11, 95% CI: 0.60-2.05). No differences were noted, among individual components. No effect modification was observed by age, sex, history of atrial fibrillation and thromboembolism, and history of cardiovascular disease. When applying the inverse probability of treatment weighting (IPTW) and SMRW with doubly robust methods in sensitivity analysis, anticoagulants use was associated with increased odds of the primary endpoint. CONCLUSIONS: Pre-admission anticoagulants were not determined to have a protective role against severe COVID-19 outcomes.


Subject(s)
COVID-19 , Thromboembolism , Anticoagulants/therapeutic use , Humans , Prognosis , SARS-CoV-2 , Thromboembolism/chemically induced
8.
BMJ ; 377: o817, 2022 04 06.
Article in English | MEDLINE | ID: covidwho-1779338
9.
Neurosurgery ; 90(6): 700-707, 2022 Jun 01.
Article in English | MEDLINE | ID: covidwho-1759804

ABSTRACT

BACKGROUND: The pipeline embolization device (PED; ev3/Covidien) has proven safe and effective for treating selected intracranial aneurysms. This device's versatility and popularity have driven increased interest in expanding the latest 2018 Food and Drug Administration-approved indications. OBJECTIVE: To compare "off-label" and "on-label" PED treatment. METHODS: Retrospective analysis of aneurysms treated with PED at a single center from 2013 to 2019. Comparisons were made based on the 2018 Food and Drug Administration-approved indications. RESULTS: A total of 492 treated aneurysms were included (65.2% on-label and 34.8% off-label). Aneurysm complete and near-complete occlusion rate was nonsignificantly lower in the off-label group (80.9% vs 85.7%; P = .19). Off-label treatment had higher rate of poor functional outcomes (modified Rankin Scale [mRS] >2: 10.3% vs 3.5%; P = .002). Although pretreatment mRS was already higher in the off-label group (5.3% vs 0.3%; P < .001) and there were no differences in mRS worsening during follow-up (5.5% vs 2.9%; P = .15). We also found a trend to a higher rate of intracranial hemorrhagic complications in the off-label group (4.7% vs 1.6%; P = .05), but there were no differences in hemorrhages requiring surgical intervention (1.8% vs 1.3%; P = .65). There were no differences in retreatment, thromboembolic complications, and mortality rates. CONCLUSION: Off-label PED treatment may be considered for select aneurysms, which are challenging to treat with other techniques. These cases have similar complete and near-complete occlusion rates compared with on-label cases. There are, however, higher risks of poor functional outcomes despite similar rates of thromboembolic and hemorrhagic complications. This is partly explained by the significantly higher pretreatment mRS score in the off-label group.


Subject(s)
Embolization, Therapeutic , Intracranial Aneurysm , Thromboembolism , Embolization, Therapeutic/methods , Follow-Up Studies , Humans , Intracranial Aneurysm/therapy , Off-Label Use , Retrospective Studies , Thromboembolism/therapy , Treatment Outcome , United States , United States Food and Drug Administration
12.
Cochrane Database Syst Rev ; 3: CD013739, 2022 03 04.
Article in English | MEDLINE | ID: covidwho-1729087

ABSTRACT

BACKGROUND: The primary manifestation of coronavirus disease 2019 (COVID-19) is respiratory insufficiency that can also be related to diffuse pulmonary microthrombosis and thromboembolic events, such as pulmonary embolism, deep vein thrombosis, or arterial thrombosis. People with COVID-19 who develop thromboembolism have a worse prognosis. Anticoagulants such as heparinoids (heparins or pentasaccharides), vitamin K antagonists and direct anticoagulants are used for the prevention and treatment of venous or arterial thromboembolism. Besides their anticoagulant properties, heparinoids have an additional anti-inflammatory potential. However, the benefit of anticoagulants for people with COVID-19 is still under debate. OBJECTIVES: To assess the benefits and harms of anticoagulants versus active comparator, placebo or no intervention in people hospitalised with COVID-19. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Embase, LILACS and IBECS databases, the Cochrane COVID-19 Study Register and medRxiv preprint database from their inception to 14 April 2021. We also checked the reference lists of any relevant systematic reviews identified, and contacted specialists in the field for additional references to trials. SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs), quasi-RCTs, cluster-RCTs and cohort studies that compared prophylactic anticoagulants versus active comparator, placebo or no intervention for the management of people hospitalised with COVID-19. We excluded studies without a comparator group and with a retrospective design (all previously included studies) as we were able to include better study designs. Primary outcomes were all-cause mortality and necessity for additional respiratory support. Secondary outcomes were mortality related to COVID-19, deep vein thrombosis, pulmonary embolism, major bleeding, adverse events, length of hospital stay and quality of life. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We used Cochrane RoB 1 to assess the risk of bias for RCTs, ROBINS-I to assess risk of bias for non-randomised studies (NRS) and GRADE to assess the certainty of evidence. We meta-analysed data when appropriate. MAIN RESULTS: We included seven studies (16,185 participants) with participants hospitalised with COVID-19, in either intensive care units, hospital wards or emergency departments. Studies were from Brazil (2), Iran (1), Italy (1), and the USA (1), and two involved more than country. The mean age of participants was 55 to 68 years and the follow-up period ranged from 15 to 90 days. The studies assessed the effects of heparinoids, direct anticoagulants or vitamin K antagonists, and reported sparse data or did not report some of our outcomes of interest: necessity for additional respiratory support, mortality related to COVID-19, and quality of life. Higher-dose versus lower-dose anticoagulants (4 RCTs, 4647 participants) Higher-dose anticoagulants result in little or no difference in all-cause mortality (risk ratio (RR) 1.03, 95% CI 0.92 to 1.16, 4489 participants; 4 RCTs) and increase minor bleeding (RR 3.28, 95% CI 1.75 to 6.14, 1196 participants; 3 RCTs) compared to lower-dose anticoagulants up to 30 days (high-certainty evidence). Higher-dose anticoagulants probably reduce pulmonary embolism (RR 0.46, 95% CI 0.31 to 0.70, 4360 participants; 4 RCTs), and slightly increase major bleeding (RR 1.78, 95% CI 1.13 to 2.80, 4400 participants; 4 RCTs) compared to lower-dose anticoagulants up to 30 days (moderate-certainty evidence). Higher-dose anticoagulants may result in little or no difference in deep vein thrombosis (RR 1.08, 95% CI 0.57 to 2.03, 3422 participants; 4 RCTs), stroke (RR 0.91, 95% CI 0.40 to 2.03, 4349 participants; 3 RCTs), major adverse limb events (RR 0.33, 95% CI 0.01 to 7.99, 1176 participants; 2 RCTs), myocardial infarction (RR 0.86, 95% CI 0.48 to 1.55, 4349 participants; 3 RCTs), atrial fibrillation (RR 0.35, 95% CI 0.07 to 1.70, 562 participants; 1 study), or thrombocytopenia (RR 0.94, 95% CI 0.71 to 1.24, 2789 participants; 2 RCTs) compared to lower-dose anticoagulants up to 30 days (low-certainty evidence). It is unclear whether higher-dose anticoagulants have any effect on necessity for additional respiratory support, mortality related to COVID-19, and quality of life (very low-certainty evidence or no data). Anticoagulants versus no treatment (3 prospective NRS, 11,538 participants) Anticoagulants may reduce all-cause mortality but the evidence is very uncertain due to two study results being at critical and serious risk of bias (RR 0.64, 95% CI 0.55 to 0.74, 8395 participants; 3 NRS; very low-certainty evidence). It is uncertain if anticoagulants have any effect on necessity for additional respiratory support, mortality related to COVID-19, deep vein thrombosis, pulmonary embolism, major bleeding, stroke, myocardial infarction and quality of life (very low-certainty evidence or no data). Ongoing studies We found 62 ongoing studies in hospital settings (60 RCTs, 35,470 participants; 2 prospective NRS, 120 participants) in 20 different countries. Thirty-five ongoing studies plan to report mortality and 26 plan to report necessity for additional respiratory support. We expect 58 studies to be completed in December 2021, and four in July 2022. From 60 RCTs, 28 are comparing different doses of anticoagulants, 24 are comparing anticoagulants versus no anticoagulants, seven are comparing different types of anticoagulants, and one did not report detail of the comparator group. AUTHORS' CONCLUSIONS: When compared to a lower-dose regimen, higher-dose anticoagulants result in little to no difference in all-cause mortality and increase minor bleeding in people hospitalised with COVID-19 up to 30 days. Higher-dose anticoagulants possibly reduce pulmonary embolism, slightly increase major bleeding, may result in little to no difference in hospitalisation time, and may result in little to no difference in deep vein thrombosis, stroke, major adverse limb events, myocardial infarction, atrial fibrillation, or thrombocytopenia.  Compared with no treatment, anticoagulants may reduce all-cause mortality but the evidence comes from non-randomised studies and is very uncertain. It is unclear whether anticoagulants have any effect on the remaining outcomes compared to no anticoagulants (very low-certainty evidence or no data). Although we are very confident that new RCTs will not change the effects of different doses of anticoagulants on mortality and minor bleeding, high-quality RCTs are still needed, mainly for the other primary outcome (necessity for additional respiratory support), the comparison with no anticoagulation, when comparing the types of anticoagulants and giving anticoagulants for a prolonged period of time.


Subject(s)
COVID-19 , Thromboembolism , Aged , Anticoagulants/adverse effects , COVID-19/complications , Heparin/adverse effects , Humans , Middle Aged , SARS-CoV-2
13.
J Stroke Cerebrovasc Dis ; 31(5): 106353, 2022 May.
Article in English | MEDLINE | ID: covidwho-1712840

ABSTRACT

Stroke is a common and devastating event and the majority of cases are caused by thromboembolism from the left atrium, left ventricle or left sided valves. This case report describes a case of embolic stroke with the origin of the thrombus from the left inferior pulmonary vein. The importance of this case is twofold. Firstly, it is the fourth case report of pulmonary venous thrombosis, a very rare condition, due to COVID-19 infection and secondly, it focuses attention on the fact that the left atrium is not the most proximal address of arterial thromboembolism-the pulmonary veins are. Thus, it is proposed that a thorough assessment of the pulmonary veins should be done in all cases of arterial thromboembolism.


Subject(s)
COVID-19 , Embolic Stroke , Ischemic Stroke , Pulmonary Embolism , Pulmonary Veins , Thromboembolism , Venous Thrombosis , COVID-19/complications , Embolic Stroke/diagnostic imaging , Embolic Stroke/etiology , Humans , Pulmonary Embolism/etiology , Thromboembolism/complications , Venous Thrombosis/complications
14.
J Am Coll Cardiol ; 79(9): 917-928, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1706820

ABSTRACT

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


Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , Thromboembolism/prevention & control , Thrombosis/prevention & control , COVID-19/therapy , Critical Care , Enoxaparin/therapeutic use , Hospitalization , Humans , Pyrazoles/therapeutic use , Pyridones/therapeutic use , Thromboembolism/virology , Thrombosis/virology
15.
Radiology ; 301(3): E436-E437, 2021 12.
Article in English | MEDLINE | ID: covidwho-1705005
16.
Thromb Res ; 212: 51-57, 2022 04.
Article in English | MEDLINE | ID: covidwho-1701412

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) is characterized by an increased risk of thromboembolic events, a leading cause for adverse outcomes in patients afflicted by the more serious manifestation of the disease. These thromboembolic complications expressed as sepsis-induced coagulopathy, disseminated intravascular coagulation, venous and arterial thromboembolism, pulmonary embolism, microthrombosis, and thrombotic microangiopathy have been observed to affect different organs such as the lungs, heart, kidneys, and brain. Endothelial injury and dysfunction have been identified as the critical pathway towards thrombogenesis, and contributions of other mechanisms such as hypercoagulability, cytokine storm, neutrophils have been studied. However, the contribution of hemodynamic pathways towards thrombosis in severe COVID-19 cases has not been investigated. From the classical theory of Virchow's triad to the contemporary studies on the effect of shear enhanced platelet activation, it is well established that hemodynamics plays a role in the initiation and growth of thrombosis. This article reviews recent studies on COVID-19 related thrombotic events and offers hypotheses on how hemodynamics may be responsible for some of the adverse outcomes observed in severe COVID-19 cases. While thrombogenesis through endothelial injury and the effects of hypercoagulability on thrombosis are briefly addressed, the crux of the discussion is focused on hemodynamic factors such as stasis, turbulent flow, and non-physiological shear stress and their effects on thrombosis. In addition, hemodynamics-dependent venous, arterial, and microvascular thrombosis in COVID-19 cases is discussed. We also propose further investigation of diagnostic and therapeutic options that address the hemodynamics aspects of COVID-19 thrombus formation to assess their potential in patient care.


Subject(s)
COVID-19 , Thromboembolism , Thrombosis , COVID-19/complications , Hemodynamics , Humans , SARS-CoV-2 , Thromboembolism/etiology
17.
Crit Care Med ; 50(6): e557-e568, 2022 Jun 01.
Article in English | MEDLINE | ID: covidwho-1691781

ABSTRACT

OBJECTIVES: Disseminated fibrin-rich microthrombi have been reported in patients who died from COVID-19. Our objective is to determine whether the fibrin clot structure and function differ between critically ill patients with or without COVID-19 and to correlate the structure with clinical coagulation biomarkers. DESIGN: A cross-sectional observational study. Platelet poor plasma was used to analyze fibrin clot structure; the functional implications were determined by quantifying clot turbidity and porosity. SETTING: ICU at an academic medical center and an academic laboratory. PATIENTS: Patients admitted from July 1 to August 1, 2020, to the ICU with severe acute respiratory syndrome coronavirus 2 infection confirmed by reverse transcription-polymerase chain reaction or patients admitted to the ICU with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood was collected from 36 patients including 26 ICU patients with COVID-19 and 10 ICU patients with sepsis but without COVID-19 at a median of 11 days after ICU admission (interquartile range, 3-16). The cohorts were similar in age, gender, body mass index, comorbidities, Sequential Organ Failure Assessment (SOFA) score, and mortality. More patients with COVID-19 (100% vs 70%; p = 0.003) required anticoagulation. Ex vivo fibrin clots formed from patients with COVID-19 appeared to be denser and to have smaller pores than those from patients with sepsis but without COVID-19 (percent area of fluorescent fibrin 48.1% [SD, 16%] vs 24.9% [SD, 18.8%]; p = 0.049). The turbidity and flow-through assays corroborated these data; fibrin clots had a higher maximum turbidity in patients with COVID-19 compared with patients without COVID-19 (0.168 vs 0.089 OD units; p = 0.003), and it took longer for buffer to flow through these clots (216 vs 103 min; p = 0.003). In patients with COVID-19, d-dimer levels were positively correlated with percent area of fluorescent fibrin (ρ = 0.714, p = 0.047). Denser clots (assessed by turbidity and thromboelastography) and higher SOFA scores were independently associated with delayed clot lysis. CONCLUSIONS: We found aberrant fibrin clot structure and function in critically ill patients with COVID-19. These findings may contribute to the poor outcomes observed in COVID-19 patients with widespread fibrin deposition.


Subject(s)
COVID-19 , Sepsis , Thromboembolism , Thrombosis , Critical Illness , Cross-Sectional Studies , Fibrin , Fibrinolysis , Humans
19.
Ann Intern Med ; 175(4): 541-546, 2022 04.
Article in English | MEDLINE | ID: covidwho-1662825

ABSTRACT

BACKGROUND: In March 2021, several European countries suspended the use of the AZD1222 (Oxford-AstraZeneca) COVID-19 vaccine because of thromboembolic safety concerns. Reports from Norway and Germany subsequently described patients with venous thrombosis and thrombocytopenia within 5 to 16 days of vaccination. OBJECTIVE: To evaluate the risk for outcomes related to thrombosis and thrombocytopenia after AZD1222 or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccination. DESIGN: Nationwide exploratory retrospective cohort study. SETTING: Danish linkable registers on vaccinations, hospitalizations, occupation, and other covariates. PARTICIPANTS: 355 209 Danish frontline personnel designated for priority COVID-19 vaccination followed from 27 December 2020 (the day of the first COVID-19 vaccination in Denmark) to 13 April 2021. MEASUREMENTS: Study outcomes were cerebral venous sinus thrombosis, splanchnic vein thrombosis, pulmonary embolism, deep venous thrombosis, arterial thrombosis, thrombocytopenia, and death. Cumulative incidences of study outcomes within 28 days of vaccination and unvaccinated risk time were compared using adjusted survival curves resulting in risk differences (RDs) at day 28 after vaccination. Adjustment for birth cohort, sex, calendar period, occupation, comorbid conditions, and prescription drug use was included. RESULTS: Vaccination with AZD1222 versus no vaccination was associated with a significant RD at day 28 for deep venous thrombosis (RD, 8.35 [95% CI, 0.21 to 16.49] per 100 000 vaccinations). The RDs for cerebral venous sinus thrombosis (RD, 1.68 [CI, -0.64 to 4.00] per 100 000 vaccinations) and thrombocytopenia (RD, 2.39 [CI, -1.09 to 5.87] per 100 000 vaccinations) were not significant. No adverse associations were seen for BNT162b2 vaccination. LIMITATION: No medical record review; surveillance bias. CONCLUSION: In this exploratory retrospective cohort study among frontline personnel in Denmark, receipt of the AZD1222 vaccine was associated with a small excess risk for deep venous thrombosis. Although the corresponding risks for the more rare and severe thrombotic outcomes (such as cerebral venous sinus thrombosis) were not statistically significantly increased, statistical precision was low, and clinically relevant risks could not be excluded with certainty. There was no statistically significant association of BNT162b2 vaccination with thrombotic or thrombocytopenic events. PRIMARY FUNDING SOURCE: Lundbeck Foundation.


Subject(s)
COVID-19 , Sinus Thrombosis, Intracranial , Thrombocytopenia , Thromboembolism , Thrombosis , Venous Thrombosis , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Occupations , Retrospective Studies , SARS-CoV-2 , Sinus Thrombosis, Intracranial/complications , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Thromboembolism/epidemiology , Thromboembolism/etiology , Thrombosis/etiology , Vaccination/adverse effects , Venous Thrombosis/complications
20.
Cell Mol Life Sci ; 79(2): 94, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1653404

ABSTRACT

Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalysed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metabolism and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochemical nature of arginine citrullination, the enzymatic machinery behind it and also provide information on the pathological consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clinical trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.


Subject(s)
Autoimmune Diseases/pathology , Citrullination/physiology , Inflammation/pathology , Protein Processing, Post-Translational/physiology , Protein-Arginine Deiminases/metabolism , COVID-19/pathology , Citrulline/biosynthesis , Energy Metabolism/physiology , Extracellular Traps/immunology , Gene Expression Regulation/genetics , Humans , Neoplasms/pathology , SARS-CoV-2/immunology , Thromboembolism/pathology
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