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5.
JCI Insight ; 6(17)2021 09 08.
Article in English | MEDLINE | ID: covidwho-1413722

ABSTRACT

Neutrophil-mediated activation and injury of the endothelium play roles in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap-derived [NET-derived] histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the US Food and Drug Administration-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.


Subject(s)
Fibrinolytic Agents/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Polydeoxyribonucleotides/pharmacology , Thrombosis/drug therapy , Animals , Extracellular Traps/drug effects , Extracellular Traps/metabolism , Fibrinolytic Agents/therapeutic use , Histones/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Polydeoxyribonucleotides/therapeutic use , Pyroptosis
7.
Eur J Prev Cardiol ; 28(1): 87-97, 2021 03 23.
Article in English | MEDLINE | ID: covidwho-1387867

ABSTRACT

Along with epidemiologic transitions of the global population, the burden of aortic stenosis (AS) is rapidly increasing and transcatheter aortic valve replacement (TAVR) has quickly spread; indeed, it is nowadays also employed in treating patients with AS at intermediate operative risk. Nonetheless, the less invasive interventional strategy still carries relevant issues concerning post-procedural optimal antithrombotic strategy, given the current indications provided by guidelines are not completely supported by evidence-based data. Geriatric patients suffer from high bleeding and thromboembolic risks, whose balance is particularly subtle due to the presence of concomitant conditions, such as atrial fibrillation and chronic kidney disease, that make the post-TAVR antithrombotic management particularly insidious. This scenario is further complicated by the lack of specific evidence regarding the 'real-life' complex conditions typical of the geriatric syndromes, thus, the management of such a heterogeneous population, ranging from healthy ageing to frailty, is far from being defined. The aim of the present review is to summarize the critical points and the most updated evidence regarding the post-TAVR antithrombotic approach in the geriatric population, with a specific focus on the most frequent clinical settings.


Subject(s)
Aortic Valve Stenosis/drug therapy , Aortic Valve Stenosis/surgery , COVID-19/complications , Fibrinolytic Agents/therapeutic use , Transcatheter Aortic Valve Replacement , Age Factors , Aged , Aortic Valve Stenosis/complications , Humans , Risk Factors
8.
Acta Neurol Scand ; 145(1): 47-52, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1367290

ABSTRACT

OBJECTIVE: Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator is the core medical therapy of acute ischaemic stroke (AIS). COVID-19 infection negatively modifies acute stroke procedures and, due to its pro-coagulative effect, may potentially impact on IVT outcome. Thus, short-term efficacy and safety of IVT were compared in patients with and without evidence of SARS-CoV-2. METHODS: An observational, retrospective study included 70 patients with AIS, including 22 subjects (31%) with evidence of acute COVID-19 infection, consecutively treated with IVT in 4 stroke centres between 15 September and 30 November 2020. RESULTS: Patients infected with COVID-19 were characterized by higher median of National Institute of Health Stroke Scale (NIHSS) score (11.0 vs. 6.5; p < .01) and D-dimers (870 vs. 570; p = .03) on admission, higher presence of pneumonia (47.8% vs. 12%; p < .01) and lower percentage of 'minor stroke symptoms' (NIHSS 1-5 pts.) (2% vs., 18%; p < .01). Hospitalizations were longer in patients with COVID-19 than in those without it (17 vs. 9 days, p < .01), but impact of COVID-19 infection on patients' in-hospital mortality or functional status on dismission has been confirmed neither in uni- or multivariate analysis. CONCLUSION: SARS-CoV-2 infection prolongs length of stay in hospital after IVT, but does not influence in-hospital outcome.


Subject(s)
Brain Ischemia , COVID-19 , Ischemic Stroke , Stroke , Brain Ischemia/complications , Brain Ischemia/drug therapy , Fibrinolytic Agents/therapeutic use , Humans , Retrospective Studies , SARS-CoV-2 , Stroke/complications , Stroke/drug therapy , Thrombolytic Therapy , Tissue Plasminogen Activator/therapeutic use , Treatment Outcome
10.
Shock ; 55(3): 316-320, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1304005

ABSTRACT

ABSTRACT: The coronavirus disease (COVID-19) pandemic has threatened millions of lives worldwide with severe systemic inflammation, organ dysfunction, and thromboembolic disease. Within our institution, many critically ill COVID-19-positive patients suffered major thrombotic events, prompting our clinicians to evaluate hypercoagulability outside of traditional coagulation testing.We determined the prevalence of fibrinolysis shutdown via rotational thromboelastometry (ROTEM, Instrumentation Laboratories, Bedford, Mass) in patients admitted to the intensive care unit over a period of 3 weeks. In 25 patients who had a ROTEM test, we found that 11 (44%) met criteria for fibrinolysis shutdown. Eight of 9 (73%) of the VTE patients met criteria for fibrinolysis shutdown.Given the high rate of fibrinolysis shutdown in these patients, our data support using viscoelastic testing to evaluate for the presence of impaired fibrinolysis. This may help identify patient subsets who might benefit from the administration of fibrinolytics.


Subject(s)
COVID-19/complications , Fibrinolysis , Intensive Care Units , Thrombelastography , Thrombophilia/diagnosis , Thrombosis/diagnosis , Venous Thromboembolism/diagnosis , Adult , Aged , COVID-19/blood , COVID-19/diagnosis , Clinical Decision-Making , Female , Fibrinolysis/drug effects , Fibrinolytic Agents/therapeutic use , Humans , Male , Middle Aged , Patient Selection , Predictive Value of Tests , Retrospective Studies , Thrombophilia/blood , Thrombophilia/drug therapy , Thrombophilia/etiology , Thrombosis/blood , Thrombosis/drug therapy , Thrombosis/etiology , Venous Thromboembolism/blood , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology
11.
Ann Emerg Med ; 78(4): 511-514, 2021 10.
Article in English | MEDLINE | ID: covidwho-1293546

ABSTRACT

Vaccine-induced thrombotic thrombocytopenia is a newly described disease process in the setting of expanding access to COVID-19 vaccination. The United States Centers for Disease Control and Prevention recommends treatment with an alternative to heparin in patients suspected of having vaccine-induced thrombotic thrombocytopenia. At this time there have been no reported outcomes from the treatment of vaccine-induced thrombotic thrombocytopenia with bivalirudin as a heparin alternative. We describe the early outcomes from the treatment of vaccine-induced thrombotic thrombocytopenia with bivalirudin as a heparin alternative. A 40-year-old Caucasian woman was found to have thrombocytopenia, cerebral venous sinus thrombosis, and pulmonary embolism following vaccination for COVID-19 with Ad26.COV2.S. She exhibited a steady rise in platelet count: 20×109/L at hospital day 0, 115×109/L at discharge on hospital day 6, and 182×109/L on outpatient follow-up on day 9. While the patient exhibited a transient drop in hemoglobin, there was no clinical evidence of bleeding. This patient did not demonstrate any clinical sequelae of thrombosis, and she reported resolution of her headache. Vaccination with Ad26.COV2.S appears to be associated with a small but significant risk for thrombotic thrombocytopenia within 13 days of receipt. The Centers for Disease Control and Prevention guidance to consider an alternative to heparin was not accompanied by specifically recommended alternatives. A single patient treated with bivalirudin for suspected vaccine-induced thrombotic thrombocytopenia subsequently experienced symptom improvement and a rise in platelet count and did not demonstrate any immediate negative outcomes. A provider may consider bivalirudin as an alternative to heparin in patients with suspected vaccine-induced thrombotic thrombocytopenia following Ad26.COV2.S vaccination, pending more definitive research.


Subject(s)
COVID-19 Vaccines/adverse effects , Fibrinolytic Agents/therapeutic use , Peptide Fragments/therapeutic use , Sinus Thrombosis, Intracranial/drug therapy , Thrombocytopenia/drug therapy , Adult , Blood Chemical Analysis , Blood Physiological Phenomena , COVID-19/prevention & control , Female , Hirudins , Humans , Pulmonary Embolism/drug therapy , Pulmonary Embolism/etiology , Recombinant Proteins/therapeutic use , Sinus Thrombosis, Intracranial/etiology , Thrombocytopenia/etiology
13.
Pharmacol Res ; 159: 104965, 2020 09.
Article in English | MEDLINE | ID: covidwho-1279676

ABSTRACT

Little is still known about the clinical features associated with the occurrence of acute respiratory distress syndrome (ARDS) in hospitalized patients with Coronavirus disease 2019 (COVID-19). The aim of the present study was to describe the prevalence of pre-admission antithrombotic therapies in patients with COVID-19 and to investigate the potential association between antithrombotic therapy and ARDS, as disease clinical presentation, or in-hospital mortality. We enrolled 192 consecutive patients with laboratory-confirmed COVID-19 admitted to emergency department of five Italian hospitals. The study population was divided in two groups according to the evidence of ARDS at chest computed tomography at admission. Propensity score weighting adjusted regression analysis was performed to assess the risk ARDS at admission, and death during hospitalization, in patients treated or not with antiplatelet and anticoagulant agents. ARDS was reported in 73 cases (38 %), who showed more likely hypertension compared to those without ARDS (57.8 % vs 49.6 %; P = 0.005). Thirty-five patients (18.5 %) died during the hospitalization. Not survived COVID-19 patients showed a statistically significant increased age (77 ± 8.31 vs 65.57 ± 8.31; P = 0.001), hypertension (77.1 % vs 53.5 %; P = 0.018) and coronary artery disease prevalence (28.6 % vs 10.2 %; P = 0.009). Both unadjusted and adjusted regression analyses showed no difference in the risk of ARDS at admission, or death during hospitalization, between patients treated or not with antiplatelets or anticoagulants. Pre-admission antithrombotic therapy, both antiplatelet and anticoagulant, does not seem to show a protective effect in severe forms of COVID-19 with ARDS at presentation and rapidly evolving toward death.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Fibrinolytic Agents/therapeutic use , Pneumonia, Viral/drug therapy , Aged , Aged, 80 and over , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/mortality , Drug Administration Schedule , Female , Fibrinolytic Agents/administration & dosage , Hospital Mortality , Humans , Italy/epidemiology , Male , Middle Aged , Pandemics , Patient Admission , Pneumonia, Viral/complications , Pneumonia, Viral/mortality , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2
14.
Vasc Health Risk Manag ; 17: 273-298, 2021.
Article in English | MEDLINE | ID: covidwho-1262578

ABSTRACT

COVID-19 sepsis is characterized by acute respiratory distress syndrome (ARDS) as a consequence of pulmonary tropism of the virus and endothelial heterogeneity of the host. ARDS is a phenotype among patients with multiorgan dysfunction syndrome (MODS) due to disseminated vascular microthrombotic disease (VMTD). In response to the viral septicemia, the host activates the complement system which produces terminal complement complex C5b-9 to neutralize pathogen. C5b-9 causes pore formation on the membrane of host endothelial cells (ECs) if CD59 is underexpressed. Also, viral S protein attraction to endothelial ACE2 receptor damages ECs. Both affect ECs and provoke endotheliopathy. Disseminated endotheliopathy activates two molecular pathways: inflammatory and microthrombotic. The former releases inflammatory cytokines from ECs, which lead to inflammation. The latter initiates endothelial exocytosis of unusually large von Willebrand factor (ULVWF) multimers and FVIII from Weibel-Palade bodies. If ADAMTS13 is insufficient, ULVWF multimers activate intravascular hemostasis of ULVWF path. In activated ULVWF path, ULVWF multimers anchored to damaged endothelial cells recruit circulating platelets and trigger microthrombogenesis. This process produces "microthrombi strings" composed of platelet-ULVWF complexes, leading to endotheliopathy-associated VMTD (EA-VMTD). In COVID-19, microthrombosis initially affects the lungs per tropism causing ARDS, but EA-VMTD may orchestrate more complex clinical phenotypes, including thrombotic thrombocytopenic purpura (TTP)-like syndrome, hepatic coagulopathy, MODS and combined micro-macrothrombotic syndrome. In this pandemic, ARDS and pulmonary thromboembolism (PTE) have often coexisted. The analysis based on two hemostatic theories supports ARDS caused by activated ULVWF path is EA-VMTD and PTE caused by activated ULVWF and TF paths is macrothrombosis. The thrombotic disorder of COVID-19 sepsis is consistent with the notion that ARDS is virus-induced disseminated EA-VMTD and PTE is in-hospital vascular injury-related macrothrombosis which is not directly  related to viral pathogenesis. The pathogenesis-based therapeutic approach is discussed for the treatment of EA-VMTD with antimicrothrombotic regimen and the potential need of anticoagulation therapy for coinciding macrothrombosis in comprehensive COVID-19 care.


Subject(s)
COVID-19/epidemiology , Endothelial Cells/metabolism , Fibrinolytic Agents/therapeutic use , Hemostasis/physiology , SARS-CoV-2 , Sepsis/complications , Thrombosis/etiology , COVID-19/complications , Humans , Pandemics , Phenotype , Sepsis/metabolism , Thrombosis/drug therapy , Thrombosis/metabolism
15.
J Am Coll Cardiol ; 77(15): 1903-1921, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1235916

ABSTRACT

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.


Subject(s)
COVID-19/drug therapy , Fibrinolytic Agents/therapeutic use , Thromboembolism/prevention & control , COVID-19/complications , Humans , Randomized Controlled Trials as Topic , Thromboembolism/virology
17.
J Investig Med High Impact Case Rep ; 8: 2324709620963567, 2020.
Article in English | MEDLINE | ID: covidwho-1223701

ABSTRACT

The incidence of mechanical valve thrombosis (MVT) is around 0.4 per 100 patient-years. Mitral valve thrombosis has a higher incidence than aortic valve thrombosis with a nearly 5-fold increase. Various factors contribute to MVT. The most common cause of valve thrombosis is poor adherence/disruption of anticoagulation therapy. Low cardiac output is known to increase the risk of prosthetic valve thrombosis. Other factors such as diabetes, hypertension, and other patient comorbidities might also play a role. Decreased flow promotes hypercoagulability. Lower pressure in the left atrium (and higher velocities in the left ventricle) can partially contribute to the higher incidence of mitral MVT versus aortic MVT. The presenting symptoms usually depend on the severity of the valve thrombosis; nonobstructive valve thrombosis patients have progressive dyspnea, signs of heart failure, and systemic embolization with strokes being the most common complication. In this article, we present a case of a middle-aged woman with a history of mitral and aortic mechanical prosthesis who presented with an ST-segment elevation myocardial infarction and pulmonary edema due to mechanical aortic valve prosthesis thrombosis. She had an isolated mechanical aortic valve prosthesis thrombosis with intact mitral valve, which, to the best of our knowledge, has not yet been described. We performed a literature review by searching PubMed and Embase using the keywords "mechanical valve," "thrombosis," "aortic," and "mitral," our search did not show similar cases.


Subject(s)
Aortic Valve , Heart Valve Prosthesis/adverse effects , Mitral Valve , ST Elevation Myocardial Infarction/etiology , Thrombosis/drug therapy , Cardiac Output, Low , Coronary Angiography , Echocardiography , Female , Fibrinolytic Agents/therapeutic use , Humans , Middle Aged , Platelet Aggregation Inhibitors/therapeutic use , Pulmonary Edema/diagnosis , Pulmonary Edema/drug therapy , ST Elevation Myocardial Infarction/drug therapy , Thrombosis/diagnosis
18.
J Am Heart Assoc ; 10(3): e019650, 2021 02 02.
Article in English | MEDLINE | ID: covidwho-1221678

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2, which has posed a significant threat to global health. Although the infection is frequently asymptomatic or associated with mild symptoms, in a small proportion of patients it can produce an intense inflammatory and prothrombotic state that can lead to acute respiratory distress syndrome, multiple organ failure, and death. Angiotensin-converting enzyme 2, highly expressed in the respiratory system, has been identified as a functional receptor for severe acute respiratory syndrome coronavirus-2. Notably, angiotensin-converting enzyme 2 is also expressed in the cardiovascular system, and there are multiple cardiovascular implications of COVID-19. Cardiovascular risk factors and cardiovascular disease have been associated with severe manifestations and poor prognosis in patients with COVID-19. More important, patients with COVID-19 may have thrombotic and coagulation abnormalities, promoting a hypercoagulable state and resulting in an increased rate of thrombotic and thromboembolic events. This review will describe the pathophysiological characteristics of the cardiovascular involvement following infection by severe acute respiratory syndrome coronavirus-2, with a focus on thrombotic and thromboembolic manifestations and implications for antithrombotic management.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , Fibrinolytic Agents/therapeutic use , Pandemics , Platelet Aggregation Inhibitors/therapeutic use , Thromboembolism/prevention & control , COVID-19/epidemiology , Humans , Thromboembolism/etiology , Treatment Outcome
19.
Nat Rev Cardiol ; 18(9): 666-682, 2021 09.
Article in English | MEDLINE | ID: covidwho-1220034

ABSTRACT

Thrombosis is the most feared complication of cardiovascular diseases and a main cause of death worldwide, making it a major health-care challenge. Platelets and the coagulation cascade are effectively targeted by antithrombotic approaches, which carry an inherent risk of bleeding. Moreover, antithrombotics cannot completely prevent thrombotic events, implicating a therapeutic gap due to a third, not yet adequately addressed mechanism, namely inflammation. In this Review, we discuss how the synergy between inflammation and thrombosis drives thrombotic diseases. We focus on the huge potential of anti-inflammatory strategies to target cardiovascular pathologies. Findings in the past decade have uncovered a sophisticated connection between innate immunity, platelet activation and coagulation, termed immunothrombosis. Immunothrombosis is an important host defence mechanism to limit systemic spreading of pathogens through the bloodstream. However, the aberrant activation of immunothrombosis in cardiovascular diseases causes myocardial infarction, stroke and venous thromboembolism. The clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is supported by the increased risk of cardiovascular events in patients with inflammatory diseases but also during infections, including in COVID-19. Clinical trials in the past 4 years have confirmed the anti-ischaemic effects of anti-inflammatory strategies, backing the concept of a prothrombotic function of inflammation. Targeting inflammation to prevent thrombosis leaves haemostasis mainly unaffected, circumventing the risk of bleeding associated with current approaches. Considering the growing number of anti-inflammatory therapies, it is crucial to appreciate their potential in covering therapeutic gaps in cardiovascular diseases.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Blood Coagulation/drug effects , Fibrinolytic Agents/therapeutic use , Immune System/drug effects , Inflammation Mediators/antagonists & inhibitors , Inflammation/drug therapy , Thrombosis/prevention & control , Anti-Inflammatory Agents/adverse effects , COVID-19/blood , COVID-19/immunology , Fibrinolytic Agents/adverse effects , Humans , Immune System/immunology , Immune System/metabolism , Inflammation/blood , Inflammation/immunology , Inflammation Mediators/metabolism , Risk Assessment , Risk Factors , Signal Transduction , Thrombosis/blood , Thrombosis/immunology
20.
Ann Vasc Surg ; 75: 128-135, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1210815

ABSTRACT

Investigations have shown that infection from the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) is responsible also for initiating severe inflammatory responses that can lead macrovascular and microvascular thrombosis. Several studies have already described acute limb ischemia and peripheral arterial disease in critically ill patients with Coronavirus disease 2019 (Covid-19), as well as coronary artery disease and ischemic stroke as a manifestation usually associated with respiratory distress. However, what still remains unclear is how long inflammation and thrombotic derangements can last after recovery from the symptoms of Covid-19. Hence, in this article we report 3 cases of arterial thrombotic sequalae after this viral infection. To the best of our knowledge, this is the first cases' series that had described different delayed vascular arterial complications, which occurred after the index infection, with a negative nasopharyngeal swab and Covid-19 systemic symptoms resumption. A better understanding of the coagulopathy in Covid-19 could have an essential role to guide prevention and treatment of arterial thromboembolic events, both during and after the viral infection. Further investigations are required to confirm these data and to estabilish the type, dose and duration of anticoagulant/antiplatelet therapy not just during but also after Covid-19 infection.


Subject(s)
Arterial Occlusive Diseases/etiology , COVID-19/complications , Thrombosis/etiology , Aged , Anticoagulants/therapeutic use , Arterial Occlusive Diseases/diagnostic imaging , Arterial Occlusive Diseases/drug therapy , COVID-19/diagnosis , COVID-19/therapy , Female , Fibrinolytic Agents/therapeutic use , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/therapeutic use , Risk Factors , Thrombolytic Therapy , Thrombosis/diagnostic imaging , Thrombosis/drug therapy , Time Factors , Treatment Outcome
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