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1.
BMJ Open ; 12(2): e051624, 2022 02 25.
Article in English | MEDLINE | ID: covidwho-1714408

ABSTRACT

BACKGROUND: The mortality rate of COVID-19 is elevated in males compared with females. OBJECTIVE: Determine the extent that the elevated thrombotic risk in males relative to females contributes to excess COVID-19 mortality in males. DESIGN: Observational study. SETTING: Data sourced from electronic medical records from over 200 US hospital systems. PARTICIPANTS: 60 877 patients aged 18 years and older hospitalised with COVID-19. EXPOSURE: Exposure variable: biological sex; key variable of interest: thrombosis. PRIMARY OUTCOME MEASURES: Primary outcome was COVID-19 mortality. We measured: (1) mortality rate of males relative to females, (2) rate of thrombotic diagnoses occurring during hospitalisation for COVID-19 in both sexes and (3) mortality rate when evidence of thrombosis was present. RESULTS: The COVID-19 mortality rate of males was 29.9% higher than that of females. Males had a 35.8% higher rate of receiving a thrombotic diagnosis compared with females. The mortality rate of all patients with a thrombotic diagnosis was 40.0%-over twice that of patients with COVID-19 without a thrombotic diagnosis (adjusted OR 2.50 (2.37 to 2.64), p<0.001). When defining thrombosis as either a documented thrombotic diagnosis or a D-dimer level ≥3.0 µg/mL, 16.4% of the excess mortality in male patients could be explained by increased thrombotic risk. CONCLUSIONS: Our findings suggest the higher COVID-19 mortality rate in males may be significantly accounted for by the elevated risk of thrombosis among males. Understanding the mechanisms that underlie increased male thrombotic risk may allow for the advancement of effective anticoagulation strategies that reduce COVID-19 mortality in males.


Subject(s)
COVID-19 , Thrombosis , Adult , Anticoagulants , COVID-19/complications , COVID-19/mortality , Female , Hospital Mortality , Hospitalization , Humans , Male , SARS-CoV-2 , Thrombosis/mortality , Thrombosis/virology
2.
PLoS One ; 17(1): e0262352, 2022.
Article in English | MEDLINE | ID: covidwho-1606851

ABSTRACT

INTRODUCTION: COVID-19 infection has been hypothesized to precipitate venous and arterial clotting events more frequently than other illnesses. MATERIALS AND METHODS: We demonstrate this increased risk of blood clots by comparing rates of venous and arterial clotting events in 4400 hospitalized COVID-19 patients in a large multisite clinical network in the United States examined from April through June of 2020, to patients hospitalized for non-COVID illness and influenza during the same time period and in 2019. RESULTS: We demonstrate that COVID-19 increases the risk of venous thrombosis by two-fold compared to the general inpatient population and compared to people with influenza infection. Arterial and venous thrombosis were both common occurrences among patients with COVID-19 infection. Risk factors for thrombosis included male gender, older age, and diabetes. Patients with venous or arterial thrombosis had high rates of admission to the ICU, re-admission to the hospital, and death. CONCLUSION: Given the ongoing scientific discussion about the impact of clotting on COVID-19 disease progression, these results highlight the need to further elucidate the role of anticoagulation in COVID-19 patients, particularly outside the intensive care unit setting. Additionally, concerns regarding clotting and COVID-19 vaccines highlight the importance of addressing the alarmingly high rate of clotting events during actual COVID-19 infection when weighing the risks and benefits of vaccination.


Subject(s)
COVID-19/pathology , Thrombosis/pathology , Aged , COVID-19/mortality , Cohort Studies , Comorbidity , Female , Hospitalization , Humans , Male , New Jersey , Retrospective Studies , Thrombosis/mortality , United States
3.
Thromb Haemost ; 122(2): 257-266, 2022 02.
Article in English | MEDLINE | ID: covidwho-1592074

ABSTRACT

BACKGROUND: It is still unclear if patients with community-acquired pneumonia (CAP) and coronavirus disease 2019 (COVID-19) have different rate, typology, and impact of thrombosis on survival. METHODS: In this multicenter observational cohort study, 1,138 patients, hospitalized for CAP (n = 559) or COVID-19 (n = 579) from seven clinical centers in Italy, were included in the study. Consecutive adult patients (age ≥ 18 years) with confirmed COVID-19-related pneumonia, with or without mechanical ventilation, hospitalized from March 1, 2020 to April 30, 2020, were enrolled. COVID-19 was diagnosed based on the World Health Organization interim guidance. Patients were followed-up until discharge or in-hospital death, registering the occurrence of thrombotic events including ischemic/embolic events. RESULTS: During the in-hospital stay, 11.4% of CAP and 15.5% of COVID-19 patients experienced thrombotic events (p = 0.046). In CAP patients all the events were arterial thromboses, while in COVID-19 patients 8.3% were venous and 7.2% arterial thromboses.During the in-hospital follow-up, 3% of CAP patients and 17% of COVID-19 patients died (p < 0.001). The highest mortality rate was found among COVID-19 patients with thrombotic events (47.6 vs. 13.4% in thrombotic-event-free patients; p < 0.001). In CAP, 13.8% of patients experiencing thrombotic events died versus 1.8% of thrombotic event-free ones (p < 0.001). A multivariable Cox-regression analysis confirmed a higher risk of death in COVID-19 patients with thrombotic events (hazard ratio: 2.1; 95% confidence interval: 1.4-3.3; p < 0.001). CONCLUSION: Compared with CAP, COVID-19 is characterized by a higher burden of thrombotic events, different thrombosis typology and higher risk of thrombosis-related in-hospital mortality.


Subject(s)
COVID-19/epidemiology , Community-Acquired Infections/epidemiology , Pneumonia/epidemiology , SARS-CoV-2/physiology , Thrombosis/epidemiology , Aged , COVID-19/mortality , Cohort Studies , Community-Acquired Infections/mortality , Female , Hospitalization , Humans , Italy/epidemiology , Male , Middle Aged , Pneumonia/mortality , Risk Factors , Survival Analysis , Thrombosis/mortality
4.
Front Immunol ; 12: 729251, 2021.
Article in English | MEDLINE | ID: covidwho-1573871

ABSTRACT

Introduction: The World Health Organization declared the coronavirus disease 2019 (COVID-19) pandemic on March 11, 2020. Two vaccine types were developed using two different technologies: viral vectors and mRNA. Thrombosis is one of the most severe and atypical adverse effects of vaccines. This study aimed to analyze published cases of thrombosis after COVID-19 vaccinations to identify patients' features, potential pathophysiological mechanisms, timing of appearance of the adverse events, and other critical issues. Materials and Methods: We performed a systematic electronic search of scientific articles regarding COVID-19 vaccine-related thrombosis and its complications on the PubMed (MEDLINE) database and through manual searches. We selected 10 out of 50 articles from February 1 to May 5, 2021 and performed a descriptive analysis of the adverse events caused by the mRNA-based Pfizer and Moderna vaccines and the adenovirus-based AstraZeneca vaccine. Results: In the articles on the Pfizer and Moderna vaccines, the sample consisted of three male patients with age heterogeneity. The time from vaccination to admission was ≤3 days in all cases; all patients presented signs of petechiae/purpura at admission, with a low platelet count. In the studies on the AstraZeneca vaccine, the sample consisted of 58 individuals with a high age heterogeneity and a high female prevalence. Symptoms appeared around the ninth day, and headache was the most common symptom. The platelet count was below the lower limit of the normal range. All patients except one were positive for PF4 antibodies. The cerebral venous sinus was the most affected site. Death was the most prevalent outcome in all studies, except for one study in which most of the patients remained alive. Discussion: Vaccine-induced thrombotic thrombocytopenia (VITT) is an unknown nosological phenomenon secondary to inoculation with the COVID-19 vaccine. Several hypotheses have been formulated regarding its physiopathological mechanism. Recent studies have assumed a mechanism that is assimilable to heparin-induced thrombocytopenia, with protagonist antibodies against the PF4-polyanion complex. Viral DNA has a negative charge and can bind to PF4, causing VITT. New experimental studies have assumed that thrombosis is related to a soluble adenoviral protein spike variant, originating from splicing events, which cause important endothelial inflammatory events, and binding to endothelial cells expressing ACE2. Conclusion: Further studies are needed to better identify VITT's pathophysiological mechanisms and genetic, demographic, or clinical predisposition of high-risk patients, to investigate the correlation of VITT with the different vaccine types, and to test the significance of the findings.


Subject(s)
/immunology , COVID-19/immunology , SARS-CoV-2/physiology , Thrombosis/epidemiology , /adverse effects , Antigen-Antibody Complex/metabolism , COVID-19/complications , COVID-19/epidemiology , Cerebral Veins/metabolism , Cerebral Veins/pathology , Female , Headache , Humans , Mass Vaccination , Platelet Factor 4/immunology , Sex Factors , Survival Analysis , Thrombosis/etiology , Thrombosis/mortality
5.
Clin Appl Thromb Hemost ; 27: 10760296211051764, 2021.
Article in English | MEDLINE | ID: covidwho-1511654

ABSTRACT

The precise mechanisms of pathology in severe COVID-19 remains elusive. Current evidence suggests that inflammatory mediators are responsible for the manifestation of clinical symptoms that precedes a fatal response to infection. This review examines the nature of platelet activating factor and emphasizes the similarities between the physiological effects of platelet activating factor and the clinical complications of severe COVID-19.


Subject(s)
COVID-19/metabolism , Platelet Activating Factor/metabolism , Animals , COVID-19/complications , COVID-19/mortality , COVID-19/pathology , Humans , Inflammation/complications , Inflammation/metabolism , Inflammation/mortality , Inflammation/pathology , Multiple Organ Failure/complications , Multiple Organ Failure/metabolism , Multiple Organ Failure/mortality , Multiple Organ Failure/pathology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/pathology , SARS-CoV-2/physiology , Severity of Illness Index , Thrombosis/complications , Thrombosis/metabolism , Thrombosis/mortality , Thrombosis/pathology
6.
Br J Haematol ; 196(3): 566-576, 2022 02.
Article in English | MEDLINE | ID: covidwho-1462745

ABSTRACT

Bleeding and thrombosis are major complications in patients supported with extracorporeal membrane oxygenation (ECMO). In this multicentre observational study of 152 consecutive patients (≥18 years) with severe COVID-19 supported by veno-venous (VV) ECMO in four UK commissioned centres during the first wave of the COVID-19 pandemic (1 March to 31 May 2020), we assessed the incidence of major bleeding and thrombosis and their association with 180-day mortality. Median age (range) was 47 years (23-65) and 75% were male. Overall, the 180-day survival was 70·4% (107/152). The rate of major bleeding was 30·9% (47/152), of which intracranial bleeding (ICH) was 34% (16/47). There were 96 thrombotic events (63·1%) consisting of venous 44·7% [68/152 of which 66·2% were pulmonary embolism (PE)], arterial 18·6% (13/152) and ECMO circuit thrombosis 9·9% (15/152). In multivariate analysis, only raised lactate dehydrogenase (LDH) at the initiation of VV ECMO was associated with an increased risk of thrombosis [hazard ratio (HR) 1·92, 95% CI 1·21-3·03]. Major bleeding and ICH were associated with 3·87-fold (95% CI 2·10-7·23) and 5·97-fold [95% confidence interval (CI) 2·36-15·04] increased risk of mortality and PE with a 2·00-fold (95% CI1·09-3·56) risk of mortality. This highlights the difficult balancing act often encountered when managing coagulopathy in COVID-19 patients supported with ECMO.


Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Hemorrhage , SARS-CoV-2/metabolism , Thrombosis , Adult , COVID-19/blood , COVID-19/mortality , COVID-19/therapy , Disease-Free Survival , Female , Hemorrhage/blood , Hemorrhage/mortality , Hemorrhage/therapy , Humans , Male , Middle Aged , Survival Rate , Thrombosis/blood , Thrombosis/mortality , Thrombosis/therapy , United Kingdom/epidemiology
7.
J Cardiovasc Surg (Torino) ; 62(6): 535-541, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1441429

ABSTRACT

The acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 disease, a global pandemic. A strong association has been documented between COVID-19 and cardiovascular events, although the exact pathophysiological mechanism is still unclear. Carotid atherothrombosis and ischemic stroke represents one of the possible severe manifestations of COVID-19, as a leading cause of long-term disability and death. Different complex intertwined mechanisms seem to underlie the endothelitis which is the cause of multiple cardiovascular manifestations. To date, few case series describing COVID-19 and acute ischemic stroke caused by cervical carotid thrombosis have been published. All the patients shared common similar radiographic features, comorbidities, and biomarker profiles. The aim of this brief review was to analyze the impact of COVID-19 pandemic in the management of a Vascular Surgery Department, changing the daily vascular practice, as well as to provide practical suggestions for symptomatic carotid stenosis, while reviewing published literature.


Subject(s)
COVID-19/epidemiology , Carotid Artery Diseases/epidemiology , Ischemic Stroke/epidemiology , Thrombosis/epidemiology , COVID-19/diagnosis , COVID-19/mortality , COVID-19/therapy , Carotid Artery Diseases/diagnosis , Carotid Artery Diseases/mortality , Carotid Artery Diseases/surgery , Humans , Ischemic Stroke/diagnosis , Ischemic Stroke/mortality , Ischemic Stroke/surgery , Risk Assessment , Risk Factors , Thrombosis/diagnosis , Thrombosis/mortality , Thrombosis/surgery , Treatment Outcome , Vascular Surgical Procedures
8.
J Korean Med Sci ; 36(31): e223, 2021 Aug 09.
Article in English | MEDLINE | ID: covidwho-1360701

ABSTRACT

Vaccination with an adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in the rare development of thrombosis with thrombocytopenia mediated by platelet-activating antibodies against platelet factor 4 (PF4). This is a life-threating condition that may be accompanied by bleeding due to thrombocytopenia with thrombosis of the cerebral venous sinus or splanchnic vein. Herein, we describe the first fatal case of thrombosis with thrombocytopenia syndrome in Korea, presenting with intracranial hemorrhage caused by cerebral venous sinus thrombosis. A 33-year-old Korean man received the first dose of the ChAdOx1 nCoV-19 vaccination. He developed severe headache with vomiting 9 days after the vaccination. Twelve days after vaccination, he was admitted to the hospital with neurological symptoms and was diagnosed with cerebral venous sinus thrombosis, which was accompanied by intracranial hemorrhage. Thrombocytopenia and D-dimer elevation were observed, and the result of the PF4 enzyme-linked immunosorbent assay antibody test was reported to be strongly positive. Despite intensive treatment, including intravenous immunoglobulin injection and endovascular mechanical thrombectomy, the patient died 19 days after vaccination. Physicians need to be aware of thrombosis with thrombocytopenia syndrome (TTS) in adenoviral vector-vaccinated patients. Endovascular mechanical thrombectomy might be a useful therapeutic option for the treatment of TTS with cerebral venous sinus thrombosis.


Subject(s)
COVID-19 Vaccines/adverse effects , Cerebral Hemorrhage/mortality , Cerebral Hemorrhage/pathology , Thrombocytopenia/pathology , Thrombosis/pathology , Adenoviridae/immunology , Adult , COVID-19/immunology , COVID-19/prevention & control , Humans , Male , Platelet Factor 4/antagonists & inhibitors , Platelet Factor 4/immunology , Republic of Korea , SARS-CoV-2/immunology , Thrombosis/mortality , Vaccination/adverse effects
9.
N Engl J Med ; 385(18): 1680-1689, 2021 10 28.
Article in English | MEDLINE | ID: covidwho-1352005

ABSTRACT

BACKGROUND: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a new syndrome associated with the ChAdOx1 nCoV-19 adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2. Data are lacking on the clinical features of and the prognostic criteria for this disorder. METHODS: We conducted a prospective cohort study involving patients with suspected VITT who presented to hospitals in the United Kingdom between March 22 and June 6, 2021. Data were collected with the use of an anonymized electronic form, and cases were identified as definite or probable VITT according to prespecified criteria. Baseline characteristics and clinicopathological features of the patients, risk factors, treatment, and markers of poor prognosis were determined. RESULTS: Among 294 patients who were evaluated, we identified 170 definite and 50 probable cases of VITT. All the patients had received the first dose of ChAdOx1 nCoV-19 vaccine and presented 5 to 48 days (median, 14) after vaccination. The age range was 18 to 79 years (median, 48), with no sex preponderance and no identifiable medical risk factors. Overall mortality was 22%. The odds of death increased by a factor of 2.7 (95% confidence interval [CI], 1.4 to 5.2) among patients with cerebral venous sinus thrombosis, by a factor of 1.7 (95% CI, 1.3 to 2.3) for every 50% decrease in the baseline platelet count, by a factor of 1.2 (95% CI, 1.0 to 1.3) for every increase of 10,000 fibrinogen-equivalent units in the baseline d-dimer level, and by a factor of 1.7 (95% CI, 1.1 to 2.5) for every 50% decrease in the baseline fibrinogen level. Multivariate analysis identified the baseline platelet count and the presence of intracranial hemorrhage as being independently associated with death; the observed mortality was 73% among patients with platelet counts below 30,000 per cubic millimeter and intracranial hemorrhage. CONCLUSIONS: The high mortality associated with VITT was highest among patients with a low platelet count and intracranial hemorrhage. Treatment remains uncertain, but identification of prognostic markers may help guide effective management. (Funded by the Oxford University Hospitals NHS Foundation Trust.).


Subject(s)
COVID-19 Vaccines/adverse effects , Purpura, Thrombocytopenic, Idiopathic/etiology , Thrombosis/etiology , Adolescent , Adult , Aged , Anticoagulants , Autoantibodies/blood , COVID-19/prevention & control , Female , Humans , Immunoglobulins, Intravenous/therapeutic use , Intracranial Hemorrhages/etiology , Intracranial Hemorrhages/mortality , Male , Middle Aged , Multivariate Analysis , Platelet Count , Platelet Factor 4/immunology , Prospective Studies , Purpura, Thrombocytopenic, Idiopathic/mortality , Purpura, Thrombocytopenic, Idiopathic/therapy , Risk Factors , Thrombosis/drug therapy , Thrombosis/mortality , United Kingdom/epidemiology , Young Adult
10.
J Thromb Thrombolysis ; 52(3): 746-753, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1263169

ABSTRACT

Patients with Coronavirus Disease-2019 (COVID-19) have haemostatic dysfunction and are at higher risk of thrombotic complications. Although age is a major risk factor for outcome impairment in COVID-19, its impact on coagulative patterns here is still unclear. We investigated the association of Endogenous Thrombin Potential (ETP) with thrombotic and haemorrhagic events according to different ages in patients admitted for COVID-19. A total of 27 patients with COVID-19-related pneumonia, without need for intensive care unit admission or mechanical ventilation at hospital presentation, and 24 controls with non-COVID-19 pneumonia were prospectively included. ETP levels were measured on admission. Patients were evaluated for major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, stroke, transient ischemic attack, venous thromboembolism) and bleeding complications [according to Bleeding Academic Research Consortium (BARC) definition] during in-hospital stay. COVID-19 patients had similar ETP levels compared to controls (AUC 93 ± 24% vs 99 ± 21%, p = 0.339). In the COVID-19 cohort, patients with in-hospital MACE showed lower ETP levels on admission vs those without (AUC 86 ± 14% vs 95 ± 27%, p = 0.041), whereas ETP values were comparable in patients with or without bleeding (AUC 82 ± 16% vs 95 ± 26%, p = 0.337). An interaction between age and ETP levels for both MACE and bleeding complications was observed, where a younger age was associated with an inverse relationship between ETP values and adverse event risk (pint 0.018 for MACE and 0.050 for bleeding). Patients with COVID-19 have similar thrombin potential on admission compared to those with non-COVID-19 pneumonia. In younger COVID-19 patients, lower ETP levels were associated with a higher risk of both MACE and bleeding.


Subject(s)
COVID-19/complications , Hemostasis , Hospitalization , Thrombin/metabolism , Thrombosis/etiology , Age Factors , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/mortality , COVID-19/therapy , Case-Control Studies , Female , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Risk Assessment , Risk Factors , Thrombosis/blood , Thrombosis/mortality , Thrombosis/therapy , Time Factors
11.
Platelets ; 32(8): 1009-1017, 2021 Nov 17.
Article in English | MEDLINE | ID: covidwho-1258665

ABSTRACT

Platelets may be a target of bacteria and viruses, which can directly or indirectly activate them so promoting thrombosis. In accordance with this, community-acquired pneumonia (CAP) is complicated by ischemia-related vascular disease (myocardial infarction and stroke) in roughly 10% of patients while the incidence of venous thrombosis is uncertain. In CAP platelet biosynthesis of TxA2 is augmented and associated with myocardial infarction; however, a cause-effect relationship is still unclear as unclear is if platelet activation promotes thrombosis or functional changes of coronary tree such vasospasm. Retrospective studies suggested a potential role of aspirin in reducing mortality but the impact on vascular disease is still unknown. Coronavirus disease 2019 (Covid-19) is complicated by thrombosis in roughly 20% of patients with an almost equivalent localization in arterial and venous circulation. Platelet activation seems to have a pivot role in the thrombotic process in Covid-19 as consistently evidenced by its involvement in promoting Tissue Factor up-regulation via leucocyte interaction. Until now, antiplatelet treatment has been scarcely considered for the treatment of Covid-19; interventional trials, however, are in progress to explore this issue. The aim of this review is 1) to compare the type of vascular diseases complicating CAP and Covid-19 2) to assess the different role of platelets in both diseases and 3) to discuss if antiplatelet treatment is potentially useful to improve clinical outcomes.


Subject(s)
Aspirin/therapeutic use , Blood Platelets/metabolism , COVID-19 , Myocardial Infarction , SARS-CoV-2/metabolism , Stroke , Thrombosis , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/mortality , Humans , Myocardial Infarction/drug therapy , Myocardial Infarction/metabolism , Myocardial Infarction/mortality , Stroke/drug therapy , Stroke/metabolism , Stroke/mortality , Thrombosis/drug therapy , Thrombosis/metabolism , Thrombosis/mortality
12.
Thromb Haemost ; 122(1): 131-141, 2022 01.
Article in English | MEDLINE | ID: covidwho-1258614

ABSTRACT

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Enoxaparin/administration & dosage , SARS-CoV-2 , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , COVID-19/complications , COVID-19/mortality , Cohort Studies , Critical Care , Dose-Response Relationship, Drug , Enoxaparin/adverse effects , Extracorporeal Membrane Oxygenation , Female , Hemorrhage/chemically induced , Humans , Intensive Care Units , Iran/epidemiology , Kaplan-Meier Estimate , Male , Middle Aged , Pandemics , Thrombosis/etiology , Thrombosis/mortality
13.
JAMA ; 325(16): 1620-1630, 2021 04 27.
Article in English | MEDLINE | ID: covidwho-1239957

ABSTRACT

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/complications , Enoxaparin/administration & dosage , Extracorporeal Membrane Oxygenation , Oxygen Inhalation Therapy/methods , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , COVID-19/mortality , Drug Administration Schedule , Enoxaparin/adverse effects , Female , Hemorrhage/chemically induced , Hospitalization , Humans , Intensive Care Units , Iran , Length of Stay/statistics & numerical data , Male , Middle Aged , Odds Ratio , Outcome Assessment, Health Care , Pulmonary Embolism/epidemiology , Thrombocytopenia/chemically induced , Thrombosis/etiology , Thrombosis/mortality , Treatment Outcome , Venous Thrombosis/epidemiology , Venous Thrombosis/mortality
14.
Semin Thromb Hemost ; 47(4): 400-418, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1203469

ABSTRACT

von Willebrand factor (VWF) is a large adhesive multimeric protein involved in hemostasis. The larger the size (or number of VWF multimers), the greater the functionality of the protein. A deficiency or defect of VWF can lead to von Willebrand disease (VWD) and cause bleeding. Conversely, an increase in VWF may create an environment that promotes thrombosis. ADAMS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), sometimes called VWF-cleaving protease, is primarily responsible for controlling the size of VWF. The most severe deficiency (<10% of normal levels) of ADAMTS-13 arises in thrombotic thrombocytopenic purpura, a condition characterized by the presence of ultralarge VWF and clinically resulting in enhanced risk of thrombosis. However, ADAMTS-13 deficiency may result from other pathological processes. Of relevance is the recent finding that COVID-19 (coronavirus disease 2019) is associated with both increased levels and activity of VWF as well as generally decreased (or occasionally normal) activity levels of ADAMTS-13. Thus, in COVID-19 there is an alteration in the VWF/ADAMTS-13 axis, most often described by increased VWF/ADAMTS-13 ratio (or reduced ADAMTS-13/VWF ratio). COVID-19 is also associated with high prothrombotic risk. Thus, the imbalance of VWF and ADAMTS-13 in COVID-19 may be providing a milieu that promotes (micro)thrombosis, in a clinical picture resembling a secondary thrombotic microangiopathy in some patients. This review therefore assesses the literature on VWF, ADAMTS-13, and COVID-19. Whenever reported in COVID-19, VWF has always been identified as raised (compared with normal reference ranges or control populations). Reports have included VWF level (i.e., VWF antigen) and in some cases one or more VWF "activity" (e.g., collagen binding; platelet glycoprotein Ib [GPIb] binding, using ristocetin cofactor or more modern versions including VWF:GPIbR [recombinant] and VWF:GPIbM [mutant]). Whenever reported, ADAMTS-13 has been reported as "normal" or reduced; however, it should be recognized that "normal" levels may still identify a relative reduction in individual cases. Some reports also discuss the raised VWF/ADAMTS-13 (or reduced ADAMTS-13/VWF) ratio, but very few provide actual numerical data.


Subject(s)
ADAMTS13 Protein/blood , COVID-19 , SARS-CoV-2/metabolism , Thrombosis , von Willebrand Factor/metabolism , COVID-19/blood , COVID-19/complications , COVID-19/mortality , Humans , Thrombosis/blood , Thrombosis/etiology , Thrombosis/mortality
15.
Thromb Haemost ; 121(12): 1610-1621, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1172583

ABSTRACT

BACKGROUND: High levels of D-dimer and low platelet counts are associated with poor outcome in coronavirus disease 2019 (COVID-19). As anticoagulation appeared to improve survival, hospital-wide recommendations regarding higher doses of anticoagulation were implemented on April 9, 2020. OBJECTIVES: To investigate if trends in D-dimer levels and platelet counts were associated with death, thrombosis, and the shift in anticoagulation. METHODS: Retrospective cohort study of 429 patients with COVID-19 at Karolinska University Hospital. Information on D-dimer levels and platelet counts was obtained from laboratory databases and clinical data from medical records. RESULTS: Thirty-day mortality and thrombosis rates were 19% and 18%, respectively. Pulmonary embolism was common, 65/83 (78%). Increased D-dimer levels in the first week in hospital were significantly associated with death and thrombosis (odds ratio [OR]: 6.06; 95% confidence interval [CL]: 2.10-17.5 and 3.11; 95% CI: 1.20-8.10, respectively). If platelet count increased more than 35 × 109/L per day, the mortality and thrombotic risk decreased (OR: 0.16; 95% CI: 0.06-0.41, and OR: 0.36; 95% CI: 0.17-0.80). After implementation of updated hospital-wide recommendations, the daily mean significantly decreased regarding D-dimer levels while platelet counts rose; -1.93; 95% CI: -1.00-2.87 mg/L FEU (fibrinogen-equivalent unit) and 65; 95% CI: 54-76 ×109/L, and significant risk reductions for death and thrombosis were observed; OR: 0.48; 95% CI: 0.25-0.92 and 0.35; 95% CI: 0.17-0.72. CONCLUSION: In contrast to D-dimer levels, increase of platelet count over the first week in hospital was associated with improved survival and reduced thrombotic risk. The daily mean levels of D-dimer dropped while the platelet counts rose, coinciding with increased anticoagulation and a decline in thrombotic burden and mortality.


Subject(s)
Anticoagulants/administration & dosage , Blood Platelets/drug effects , COVID-19/drug therapy , Fibrin Fibrinogen Degradation Products/metabolism , Thrombosis/drug therapy , Administration, Oral , Aged , Anticoagulants/adverse effects , Biomarkers/blood , Blood Platelets/metabolism , COVID-19/blood , COVID-19/diagnosis , COVID-19/mortality , Female , Hospital Mortality , Humans , Male , Middle Aged , Retrospective Studies , Sweden/epidemiology , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/mortality , Time Factors , Treatment Outcome
16.
Trends Neurosci ; 44(7): 527-537, 2021 07.
Article in English | MEDLINE | ID: covidwho-1171720

ABSTRACT

Prior to COVID-19, only two human-tropic coronaviruses resulted in epidemics and cerebrovascular disease was rarely reported. Evidence now suggests that 1-6% of hospitalized COVID-19 patients develop stroke. According to some reports, stroke risk is more than sevenfold greater in patients with COVID-19 than influenza. Concerningly, outcomes of COVID-19-related stroke are often worse than in stroke patients without COVID-19 from the same cohorts. In this review, we highlight the emerging association between COVID-19 and stroke and discuss putative pathogenetic mechanisms. Etiology of stroke in COVID-19 patients is likely multifactorial, related to coagulopathy, inflammation, platelet activation, and alterations to the vascular endothelium. Significant work remains to be done to better understand the pathogenesis of COVID-19-related stroke and for designing optimal primary and secondary prevention strategies.


Subject(s)
COVID-19/complications , COVID-19/virology , SARS-CoV-2/pathogenicity , Stroke/complications , Stroke/virology , COVID-19/epidemiology , Humans , Prevalence , Stroke/mortality , Thrombosis/complications , Thrombosis/mortality , Thrombosis/virology
17.
Eur Rev Med Pharmacol Sci ; 25(3): 1684-1707, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1102756

ABSTRACT

The mortality of COVID-19 patients is increasing in logarithmic fashion and is mostly observed in older age people and patients having history of chronic ailments like chronic obstructive pulmonary disease (COPD), hypertension, diabetes, cardiovascular & cerebrovascular dysfunction, compromised immunity, renal comorbidities, hepatic, obesity problems etc., and recently investigated thrombotic complications. The molecular underpinnings linking the chronic human diseases with COVID-19 related morbidity and mortality are evolving and poorly understood. The aim of the present review is to discuss the mortality and morbidity in COVID-19 in relation to preexisting comorbidities across the globe, upcoming molecular mechanisms associated with expression profile of ACE2 and viral load, evolving pathophysiology of COVID-19 with special reference to thrombotic complication ('Storm of Blood Clots') and related predictive markers. The levels of plasminogen/plasmin in comorbid diseases of COVID-19 have been elaborated in the framework of risk and benefits of fibrinolysis in COVID-19. We have also attempted to discuss the puzzle of prescribing ARBs and ACEI drugs in COVID-19 management which are routinely prescribed for the management of hypertension in COVID-19 patients. A focused discourse on risk of cardiovascular complications and diabetes in concert with COVID-19 pathogenesis has been presented along with dynamics of SARS-CoV-2 induced immune dysfunctions in COVID-19 patients.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/mortality , SARS-CoV-2 , Thrombosis/mortality , COVID-19/blood , COVID-19/complications , Comorbidity , Humans , Morbidity/trends , Mortality/trends , Receptors, Coronavirus , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/blood , Thrombosis/etiology , Viral Load
18.
J Thromb Thrombolysis ; 51(3): 595-607, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1082169

ABSTRACT

A prothrombotic state is reported with severe COVID-19 infection, which can manifest in venous and arterial thrombotic events. Coagulopathy is reflective of more severe disease and anticoagulant thromboprophylaxis is recommended in hospitalized patients. However, the prevalence of thrombosis on the intensive care unit (ICU) remains unclear, including whether this is sufficiently addressed by conventional anticoagulant thromboprophylaxis. We aimed to identify the rate of thrombotic complications in ICU-treated patients with COVID-19, to inform recommendations for diagnosis and management. A systematic review was conducted to assess the incidence of thrombotic complications in ICU-treated patients with COVID-19. Observational studies and registries reporting thrombotic complications in ICU-treated patients were included. Information extracted included patient demographics, use of thromboprophylaxis or anticoagulation, method of identifying thrombotic complications, and reported patient outcomes. In 28 studies including 2928 patients, thrombotic complications occurred in 34% of ICU-managed patients, with deep venous thrombosis reported in 16.1% and pulmonary embolism in 12.6% of patients, despite anticoagulant thromboprophylaxis, and were associated with high mortality. Studies adopting systematic screening for venous thrombosis with Duplex ultrasound reported a significantly higher incidence of venous thrombosis compared to those relying on clinical suspicion (56.3% vs. 11.0%, p < 0.001). Despite thromboprophylaxis, there is a very high incidence of thrombotic complications in patients with COVID-19 on the ICU. Systematic screening identifies many thrombotic complications that would be missed by relying on clinical suspicion and should be employed, with consideration given to increased dose anticoagulant thromboprophylaxis, whilst awaiting results of prospective trials of anticoagulation in this cohort.


Subject(s)
COVID-19/complications , Thrombosis/mortality , Thrombosis/virology , Anticoagulants/therapeutic use , Extracorporeal Membrane Oxygenation , Hospital Mortality , Humans , Intensive Care Units/statistics & numerical data , Thrombosis/prevention & control
19.
Am Heart J ; 235: 12-23, 2021 05.
Article in English | MEDLINE | ID: covidwho-1070993

ABSTRACT

BACKGROUND: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. STUDY DESIGN: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. CONCLUSIONS: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.


Subject(s)
COVID-19/complications , Factor Xa Inhibitors/therapeutic use , Hospitalization , Outpatients , Rivaroxaban/therapeutic use , Thrombosis/prevention & control , Adult , COVID-19/mortality , Cause of Death , Double-Blind Method , Extremities/blood supply , Factor Xa Inhibitors/adverse effects , Female , Hemorrhage/chemically induced , Hemorrhage/mortality , Hospital Mortality , Humans , Ischemia/etiology , Ischemic Stroke/etiology , Male , Middle Aged , Myocardial Infarction/etiology , Placebos/therapeutic use , Rivaroxaban/adverse effects , Thrombosis/mortality , Venous Thromboembolism/mortality , Venous Thromboembolism/prevention & control
20.
Arterioscler Thromb Vasc Biol ; 40(10): 2404-2407, 2020 10.
Article in English | MEDLINE | ID: covidwho-1015733

ABSTRACT

OBJECTIVE: Alveolar-capillary endothelial cells can be activated by severe acute respiratory syndrome coronavirus 2 infection leading to cytokine release. This could trigger endothelial dysfunction, pyroptosis, and thrombosis, which are the vascular changes, commonly referred to as coronavirus disease 2019 (COVID-19) endotheliopathy. Thus, this study aimed to identify tissue biomarkers associated with endothelial activation/dysfunction and the pyroptosis pathway in the lung samples of patients with COVID-19 and to compare them to pandemic influenza A virus H1N1 subtype 2009 and control cases. Approach and Results: Postmortem lung samples (COVID-19 group =6 cases; H1N1 group =10 cases, and control group =11 cases) were analyzed using immunohistochemistry and the following monoclonal primary antibodies: anti-IL (interleukin)-6, anti-TNF (tumor necrosis factor)-α, anti-ICAM-1 (intercellular adhesion molecule 1), and anticaspase-1. From the result, IL-6, TNF-α, ICAM-1, and caspase-1 showed higher tissue expression in the COVID-19 group than in the H1N1 and control groups. CONCLUSIONS: Our results demonstrated endothelial dysfunction and suggested the participation of the pyroptosis pathway in the pulmonary samples. These conditions might lead to systemic thrombotic events that could impair the clinical staff's efforts to avoid fatal outcomes. One of the health professionals' goals should be to identify the high risk of thrombosis patients early to block endotheliopathy and its consequences.


Subject(s)
Coronavirus Infections/pathology , Endothelial Cells/cytology , Endothelium, Vascular/pathology , Pneumonia, Viral/pathology , Thrombosis/pathology , Vascular Diseases/pathology , Autopsy , Biopsy, Needle , COVID-19 , Cause of Death , Coronavirus Infections/mortality , Endothelial Cells/pathology , Endothelium, Vascular/physiopathology , Female , Humans , Immunohistochemistry , Male , Pandemics , Pneumonia, Viral/mortality , Risk Assessment , Thrombosis/etiology , Thrombosis/mortality , Vascular Diseases/mortality , Vascular Diseases/physiopathology
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