Thromboembolic Complications In COVID-19 Research Articles

Pulmonary embolism in patients in acute COVID-19, long-COVID and post-COVID syndrome.

COVID-19 is a disease caused by the SARS-CoV-2 virus, which, after entering a living organism, uses the ACE-2 protein as a receptor and several other proteins as cofactors of infection. Disease symptomatology is extensive, involving mostly predominant respiratory symptoms, as well as those of the nervous, gastrointestinal, circulatory and other systems. Incidence of COVID-19 also results in markedly different laboratory findings on the hemostatic system with the predominant feature of increased D-dimer levels. In the pathogenesis of thromboembolic complications in COVID-19, all elements of Virchow's triad are involved: endothelial damage, coagulation disorders and blood flow disorders. Coagulopathy increases with the severity of the clinical course of COVID-19. One of the causes of mortality associated with COVID-19 is pulmonary embolism. SARS-CoV-2 infection increases the risk of thromboembolic complications not only in the acute period of the disease. Also in the period of about a month after recovery, there is an increased risk of venous thrombosis and consequently, life-threatening pulmonary embolism. The classic biomarker of pulmonary embolism in the general population is D-dimers. Among imaging studies, the gold standard for diagnosing this disease is computed tomography of the pulmonary arteries (CTPA). Other useful diagnostic tests are ventilation-perfusion lung scintigraphy (VQ Scans) or echocardiography. Currently reviewed guidelines and recommendations recommend extens ive thromboprophylaxis in COVID-19 patients in both acute and chronic phases of the disease. Keywords: COVID-19, pulmonary embolism, laboratory and imaging diagnostics, thromboprophylaxis.

Thromboembolic Disease and Cardiac Thrombotic Complication in COVID-19: A Systematic Review.

The coronavirus 2019 pandemic has affected many healthcare systems worldwide. While acute respiratory distress syndrome (ARDS) has been well-documented in COVID-19, there are several cardiovascular complications, such as myocardial infarction, ischaemic stroke, and pulmonary embolism, leading to disability and death. The link between COVID-19 and increasing thrombogenicity potentially occurs due to numerous different metabolic mechanisms, ranging from endothelial damage for direct virus infection, associated excessive formation of neutrophil extracellular traps (NETs), pathogenic activation of the renin-angiotensin-aldosterone system (RAAS), direct myocardial injury, and ischemia induced by respiratory failure, all of which have measurable biomarkers. A search was performed by interrogating three databases (MEDLINE; MEDLINE In-Process and Other Non-Indexed Citations, and EMBASE). Evidence from randomized controlled trials (RCT), prospective series, meta-analyses, and unmatched observational studies were evaluated for the processing of the algorithm and treatment of thromboembolic disease and cardiac thrombotic complications related to COVID-19 during SARS-CoV-2 infection. Studies out with the SARS-Cov-2 infection period and case reports were excluded. A total of 58 studies were included in this analysis. The role of the acute inflammatory response in the propagation of the systemic inflammatory sequelae of the disease plays a major part in determining thromboembolic disease and cardiac thrombotic complication in COVID-19. Some of the mechanisms of activation of these pathways, alongside the involved biomarkers noted in previous studies, are highlighted. Inflammatory response led to thromboembolic disease and cardiac thrombotic complications in COVID-19. NETs play a pivotal role in the pathogenesis of the inflammatory response. Despite moving into the endemic phase of the disease in most countries, thromboembolic complications in COVID-19 remain an entity that substantially impacts the health care system, with long-term effects that remain uncertain. Continuous monitoring and research are required.

Incidence of thromboembolic complications in hospitalized COVID-19 patients in a medical ward in Japan: A single-center retrospective and prospective observational study.

Background:A high incidence of thromboembolic complications is one of the hallmarks of COVID-19. However, there may be a difference in the incidence of thromboembolic complications between Asian and Western people. In addition, few prospective studies have been conducted to determine the incidence of thromboembolic complications in hospitalized COVID-19 patients in medical wards in Japan.Methods:A single-center retrospective and prospective cohort study was conducted to determine the incidence of thromboembolic complications in symptomatic COVID-19 patients in a medical ward in a Japanese hospital. All 1116 consecutive COVID-19 patients who were admitted to our hospital from November 1, 2020, to October 26, 2021, were included. The primary outcome was any thromboembolic complications, which included venous thromboembolism, myocardial infarction, ischemic stroke, and other arterial embolisms.Results:The median patient age was 50 (IQR, 37–61), 402 (36.0%) were women, 1005 (90.1%) were Japanese, the median body mass index was 24.1 (IQR, 21.6–27.2), and 43 (3.9%) had Padua scores of at least 4 points at admission. Regarding the severity of COVID-19, 543 (48.7%), 315 (28.2%), 204 (18.3%), and 54 (4.8%) patients had mild, moderate, severe, and critical COVID-19, respectively. Nine patients (0.8%) died, and 47 patients (4.2%) were transferred to other hospitals for intensive care. The primary outcome occurred in only 5 patients (0.5%; 95% CI, 0.1–0.8) and consisted of 3 ischemic strokes, 2 limb ischemia events, and one asymptomatic pulmonary embolism. Even in the 204 patients with severe COVID-19, the prevalence of thromboembolic complications was only 2.5% (95% CI, 0.3–4.6).Conclusion:Thromboembolic complications of COVID-19 are rare even in severe cases in a medical ward in a Japanese hospital. Further studies are needed to identify severe COVID-19 patients with a higher risk for thromboembolic complications in Japan.

Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19.

SummaryBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor, a critical component of the kallikrein-kinin system. Its dysregulation may lead to increased vascular permeability and release of inflammatory chemokines. Interactions between the kallikrein-kinin and the coagulation system might further contribute to thromboembolic complications in COVID-19.MethodsIn this observational study, we measured plasma and tissue kallikrein hydrolytic activity, levels of kinin peptides, and myeloperoxidase (MPO)-DNA complexes as a biomarker for neutrophil extracellular traps (NETs), in bronchoalveolar lavage (BAL) fluid from patients with and without COVID-19.FindingsIn BAL fluid from patients with severe COVID-19 (n = 21, of which 19 were mechanically ventilated), we observed higher tissue kallikrein activity (18·2 pM [1·2-1535·0], median [range], n = 9 vs 3·8 [0·0-22·0], n = 11; p = 0·030), higher levels of the kinin peptide bradykinin-(1-5) (89·6 [0·0-2425·0], n = 21 vs 0·0 [0·0-374·0], n = 19, p = 0·001), and higher levels of MPO-DNA complexes (699·0 ng/mL [66·0-142621·0], n = 21 vs 70·5 [9·9-960·0], n = 19, p < 0·001) compared to patients without COVID-19.InterpretationOur observations support the hypothesis that dysregulation of the kallikrein-kinin system might occur in mechanically ventilated patients with severe pulmonary disease, which might help to explain the clinical presentation of patients with severe COVID-19 developing pulmonary oedema and thromboembolic complications. Therefore, targeting the kallikrein-kinin system should be further explored as a potential treatment option for patients with severe COVID-19.FundingResearch Foundation-Flanders (G0G4720N, 1843418N), KU Leuven COVID research fund.

COVID-19-Positive Ruptured Abdominal Aortic Aneurysm Successfully Managed by Open Surgical Repair and Review of Literature

COVID-19 pandemic has affected everyone globally in every walk of life. A rise in the number of patients afflicted with thromboembolic complications of COVID-19 is being reported, both venous and arterial. Elective vascular surgery has been stopped entirely at our institute. However, both COVID-19-positive and negative patients continued to require emergent vascular surgery even during the pandemic. We are reporting a case of COVID-positive, ruptured abdominal aortic aneurysm (AAA) who was successfully managed at our hospital. The principles of open repair of ruptured AAA remained same, with a few special considerations. We did not find any report on open repair of ruptured AAA in COVID-19-positive patient. On search at Medline, we found two cases of ruptured AAA, which were successfully managed with endovascular aneurysm repair (EVAR).

Exosomal miR-145 and miR-885 Regulate Thrombosis in COVID-19.

We hypothesized that exosomal microRNAs could be implied in the pathogenesis of thromboembolic complications in coronavirus disease 2019 (COVID-19). We isolated circulating exosomes from patients with COVID-19, and then we divided our population in two arms based on the D-dimer level on hospital admission. We observed that exosomal miR-145 and miR-885 significantly correlate with D-dimer levels. Moreover, we demonstrate that human endothelial cells express the main cofactors needed for the internalization of the "Severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), including angiotensin converting enzyme 2, transmembrane protease serine 2, and CD-147. Interestingly, human endothelial cells treated with serum from COVID-19 patients release significantly less miR-145 and miR-885, exhibit increased apoptosis, and display significantly impaired angiogenetic properties compared with cells treated with non-COVID-19 serum. Taken together, our data indicate that exosomal miR-145 and miR-885 are essential in modulating thromboembolic events in COVID-19. SIGNIFICANCE STATEMENT: This work demonstrates for the first time that two specific microRNAs (namely miR-145 and miR-885) contained in circulating exosomes are functionally involved in thromboembolic events in COVID-19. These findings are especially relevant to the general audience when considering the emerging prominence of post-acute sequelae of COVID-19 systemic manifestations known as Long COVID.

Relationship of the pulmonary disease severity scoring with thromboembolic complications in COVID-19

PurposeTo correlate thromboembolic (TE) complications secondary to COVID-19 with the extent of the pulmonary parenchymal disease using CT severity scores and other comorbidities.MethodsIn total, 185 patients with COVID-19 and suspected thromboembolic complications were classified into two groups based on the presence or absence of thromboembolic complications. Thromboembolic complications were categorized based on location. Chest CT severity scoring system was used to assess the pulmonary parenchymal disease severity in all patients. Based into severity scores, patients were categorized into three groups (mild, moderate, and sever disease).ResultsThe final study cohort consisted of 171 patients (99 male and 72 female) after excluding 14 patients with non-diagnostic CT pulmonary angiography. The TE group included 53 patients with a mean age of 55.1 ± 7.1, while the non-TE group included 118 patients with a mean age of 52.9 ± 10.8. Patients with BMI > 30 kg/m2 or having a history of smoking and HTN were found more frequently in the TE group (p < 0.05). Patients admitted to ICU were significantly higher in the TE group (p < 0.001). There was statistically significant difference (p = 0.002) in chest CT-SS between the TE group (22.8 ± 11.4) and non-TE group (17.6 ± 10.7). The percentage of severe parenchymal disease in the TE group was significantly higher compared to the non-TE group (p < 0.05). Severe parenchymal disease, BMI > 30 kg/m2, smoking, and HTN had a higher and more significant odds ratio for developing TE complications.ConclusionThe present data suggest that severe pulmonary parenchymal disease secondary to COVID-19 is associated with a higher incidence of thromboembolic complications.

TWO CASES OF ARTERIAL THROMBUS IN COVID-19 INFECTION

TOPIC: Critical Care TYPE: Fellow Case Reports INTRODUCTION: Several studies have observed thrombotic complications in COVID-19 patients with rates as high as 30%. We present two COVID-19 cases of arterial and venous thrombotic complications. CASE PRESENTATION: A 64-year-old African American female was admitted for worsening respiratory failure due to COVID-19. HIT panel was obtained due to worsening thrombocytopenia, as the patient was on heparin for venous thrombosis prophylaxis, which was negative. Duplex of the lower extremities performed on hospital day 12 showed an acute non-occlusive deep vein thrombosis of the left common femoral vein, for which therapeutic heparin was initiated. On hospital day 25, the patient was found to have right digit ischemia with no flow to the right ulnar artery secondary to an occlusive arterial thrombus. Hematology was consulted for severe thrombocytopenia and considered to treat empirically for ITP with IVIG;however, the patient continued to decompensate and the family elected for comfort care measures. The patient expired on hospital day 30.Our second case report is a 64-year-old African American male presented from a local prison with worsening shortness of breath and was found to have COVID-19. Shortly after arrival from the ED to ICU, the patient went into cardiac arrest, ACLS was initiated and ROSC was achieved. The patient was in torsades and Vfib rhythm. He underwent left heart catheterization on hospital day 1 and was found to have 100% occlusion of obtuse marginal and underwent successful percutaneous coronary intervention with a drug-eluting stent to OM2. On hospital day 8, the patient was found to have digit ischemia of the right first through third digits. Arterial and venous duplex showed thrombotic occlusion of the right radial artery from the mid-forearm to the wrist and an acute deep vein thrombus of the left subclavian and axillary veins. DISCUSSION: COVID-19 can be associated with arterial and venous thrombosis as highlighted by our two cases. Even though the pathophysiology of thromboembolic complications in COVID-19 is not reported in the literature, it is implicated due to inflammation, hypoxia, immobilization, and DIC. In a study done by Klok et al in COVID-19 ICU patients, 27% of the study population had CTPE/Ultrasonography confirmed venous thromboembolism and 3.7% had arterial thrombosis compared to 12% of venous thrombosis in the ICU. The mechanism for hyper-coagulability in COVID infection is not known, it has been linked to the inflammatory response rather than specific properties of the virus. This association of excess inflammation and COVID-19 with subsequent activation of coagulation has been implicated in the pathogenesis of thrombosis. CONCLUSIONS: Intermediate to therapeutic anticoagulation may be necessary to prevent venous and arterial thromboembolic events in ICU patients admitted with COVID-19 given their excessive inflammatory state. REFERENCE #1: Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood, The Journal of the American Society of Hematology. 2020 Jun 4;135(23):2033-40. REFERENCE #2: Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation. Intensive Care Medicine. 2020 Apr 28:1-4. REFERENCE #3: Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Muller MC, Bouman CC, Beenen LF, Kootte RS, Heijmans J, Smits LP. Incidence of venous thromboembolism in hospitalized patients with COVID-19. Journal of Thrombosis and Haemostasis. 2020 May 5. DISCLOSURES: No relevant relationships by Sarenthia Epps, source=Web Response No relevant relationships by Harmeen Goraya, source=Web Response No relevant relationships by Raga Deepak Reddy Palagiri, source=Web Response

Thromboelastography demonstrates progressive hypercoagulability in COVID-19 patients admitted to ICU with respiratory failure.

Thromboembolic complications are associated with COVID-19 owing to the hypercoagulable nature of the disease. Although patients with COVID-19 often have higher levels of fibrinogen and D-dimers, hypercoagulability has been attributed to various other factors too. In this prospective observational study conducted between April 2020 and June 2020, we compared coagulation parameters using thromboelastography in COVID-19 patients to non-COVID-19 patients admitted to ICU with respiratory failure. This study demonstrated a significant difference between the cohorts in functional fibrinogen (CFF) progressively from third day of ICU admission whilst there was no difference in the Clauss fibrinogen levels. COVID-19 patients also demonstarted supranormal R time indicating hypocoagulability. These mixed coagulation changes suggest targeting fibrinogen or platelets may prevent thromboembolic complications in COVID-19.

Advocacy of targeting protease-activated receptors in severe coronavirus disease 2019.

Identifying drug targets mitigating vascular dysfunction, thrombo-inflammation and thromboembolic complications in COVID-19 is essential. COVID-19 coagulopathy differs from sepsis coagulopathy. Factors that drive severe lung pathology and coagulation abnormalities in COVID-19 are not understood. Protein-protein interaction studies indicate that the tagged viral bait protein ORF9c directly interacts with PAR2, which modulates host cell IFN and inflammatory cytokines. In addition to direct interaction of SARS-CoV-2 viral protein with PARs, we speculate that activation of PAR by proteases plays a role in COVID-19-induced hyperinflammation. In COVID-19-associated coagulopathy elevated levels of activated coagulation proteases may cleave PARs in association with TMPRSS2. PARs activation enhances the release of cytokines, chemokines and tissue factor expression to propagate IFN-dependent inflammation, leukocyte-endothelial interaction, vascular permeability and coagulation responses. This hypothesis, corroborated by in vitro findings and emerging clinical evidence, will focus targeted studies of PAR1/2 blockers as adjuvant drugs against cytokine release syndrome and COVID-19-associated coagulopathy. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc.

Thromboembolic Complications in Covid-19: From Clinical Scenario to Laboratory Evidence.

SARS-Cov-2 infection, a pandemic disease since March 2020, is associated with a high percentage of cardiovascular complications mainly of a thromboembolic (TE) nature. Although clinical patterns have been described for the assessment of patients with increased risk, many TE complications occur in patients with apparently moderate risk. Notably, a recent statement from the European Society of Cardiology (ESC) atherosclerosis and vascular biology working group pointed out the key role of vascular endothelium for the recruitment of inflammatory and thrombotic pathways responsible for both disseminated intravascular coagulation and cardiovascular complications. Therefore, a better understanding of the pathophysiological process linking infection to increased TE risk is needed in order to understand the pathways of this dangerous liaison and possibly interrupt it with appropriate treatment. In this review, we describe the histological lesions and the related blood coagulation mechanisms involved in COVID-19, we define the laboratory parameters and clinical risk factors associated with TE events, and propose a prophylactic anticoagulation treatment in relation to the risk category. Finally, we highlight the concept that a solid risk assessment based on prospective multi-center data would be the challenge for a more precise risk stratification and more appropriate treatment.

Obesity and COVID-19: 2 The ominous duet affecting the renin-angiotensin system.

The World population is facing a health challenge never seen since the Spanish influenza of one hundred years ago. During the last months, the scientific community has been debating on the potential harmful effect of Angiotensin-converting-enzyme inhibitors (ACEi) or Angiotensin II receptor Type 1 receptor blockers (AT1-Receptor blockers, ARBs) during the COVID-19 pandemic. That is because the S spike protein of SARS8 CoV viruses utilizes the angiotensin-converting enzyme 2 (ACE2) as a receptor to enter alveolar epithelial cells. Obesity, often associated to type 2 Diabetes, was shown to worsen the prognosis of SARS-CoV2 infection. Herein we discuss the complex interaction between the Renin-Angiotensin-Aldosterone System (RAAS), its receptors, and the interaction with the Kallikrein-Kinin-System (KKS) and the potential activation of the coagulation cascade. Alteration of the equilibrium between the RAAS system and the KKS cascade may explain the frequent thromboembolic complications of COVID-19 mainly seen in obese and diabetic-obese patients. In contrast, angiotensin (1-7) contributes to maintaining a correct balance between RAAS and KKS system. Our conclusion is that the higher mortality rate in patients with obesity is linked to the alteration of RAS and RAS-KKS interaction consequent to SARS-CoV2-cell entrance. At present, no data support the necessity of modifying ACEi or ARBs treatment in hypertensive patients.

Thromboembolic Complications in COVID-19

COVID-19 represents a clinical situation that lacks precedence and clinical experience. It introduces a number of pitfalls in well-established clinical routines and poses unique challenges to diagnostic pathways. This review discusses the current evidence on the thromboembolic risk of COVID-19 patients, the recommendations for thromboprophylaxis and the relevance of abnormal coagulation tests. Pathophysiological concepts are discussed and practical solutions and current guidance recommendations are presented.

Vascular Manifestations of COVID-19 - Thromboembolism and Microvascular Dysfunction.

The coronavirus pandemic has reportedly infected over 31.5 million individuals and caused over 970,000 deaths worldwide (as of 22nd Sept 2020). This novel coronavirus, officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), although primarily causes significant respiratory distress, can have significant deleterious effects on the cardiovascular system. Severe cases of the virus frequently result in respiratory distress requiring mechanical ventilation, often seen, but not confined to, individuals with pre-existing hypertension and cardiovascular disease, potentially due to the fact that the virus can enter the circulation via the lung alveoli. Here the virus can directly infect vascular tissues, via TMPRSS2 spike glycoprotein priming, thereby facilitating ACE-2-mediated viral entry. Clinical manifestations, such as vasculitis, have been detected in a number of vascular beds (e.g., lungs, heart, and kidneys), with thromboembolism being observed in patients suffering from severe coronavirus disease (COVID-19), suggesting the virus perturbs the vasculature, leading to vascular dysfunction. Activation of endothelial cells via the immune-mediated inflammatory response and viral infection of either endothelial cells or cells involved in endothelial homeostasis, are some of the multifaceted mechanisms potentially involved in the pathogenesis of vascular dysfunction within COVID-19 patients. In this review, we examine the evidence of vascular manifestations of SARS-CoV-2, the potential mechanism(s) of entry into vascular tissue and the contribution of endothelial cell dysfunction and cellular crosstalk in this vascular tropism of SARS-CoV-2. Moreover, we discuss the current evidence on hypercoagulability and how it relates to increased microvascular thromboembolic complications in COVID-19.

The vascular nature of COVID-19.

A potential link between mortality, D-dimer values and a prothrombotic syndrome has been reported in COVID-19 patients. The National Institute for Public Health of the Netherlands published a report for guidance on diagnosis, prevention and treatment of thromboembolic complications in COVID-19 with a new vascular disease concept. The analysis of all available current medical, laboratory and imaging data on COVID-19 confirms that symptoms and diagnostic tests can not be explained by impaired pulmonary ventilation. Further imaging and pathological investigations confirm that the COVID-19 syndrome is explained by perfusion disturbances first in the lung, but consecutively in all organs of the body. Damage of the microvasculature by SARS 1 and SARS 2 (COVID-19) viruses causes microthrombotic changes in the pulmonary capillaries and organs leading to macrothrombosis and emboli. Therefore anticoagulant profylaxis, close lab and CT imaging monitoring and early anticoagulant therapy are indicated.

Pulmonary embolism in cases of COVID-19.

Emerging reports indicate a high incidence of venous thromboembolism in patients hospitalised for SARS-CoV-2pneumonia during the spring 2020pandemic. The pronounced pulmonary and systemic inflammatory responses observed in these patients may contribute to a transient hypercoagulable state. In this setting, pulmonary embolism may cause further respiratory distress and clinical deterioration. We describe the clinical course of three patients admitted with SARS-CoV-2 infection and respiratory distress, where pulmonary embolism was detected during the course of the hospitalisation. Two of the cases occurred despite early institution of standard dosage of low molecular weight heparin thromboprophylaxis, and in one case, pulmonary embolism was diagnosed during the convalescent phase of an otherwise benign COVID-19 disease course. These cases highlight the importance of awareness of the potentially increased incidence of venous thromboembolism in COVID-19 disease. Further research is required to establish appropriate clinical management guidelines for prevention of thromboembolic complications in COVID-19.