A scoping review of the pathophysiology of COVID-19.

COVID-19 is a highly heterogeneous and complex medical disorder; indeed, severe COVID-19 is probably amongst the most complex of medical conditions known to medical science. While enormous strides have been made in understanding the molecular pathways involved in patients infected with coronaviruses an overarching and comprehensive understanding of the pathogenesis of COVID-19 is lacking. Such an understanding is essential in the formulation of effective prophylactic and treatment strategies. Based on clinical, proteomic, and genomic studies as well as autopsy data severe COVID-19 disease can be considered to be the connection of three basic pathologic processes, namely a pulmonary macrophage activation syndrome with uncontrolled inflammation, a complement-mediated endothelialitis together with a procoagulant state with a thrombotic microangiopathy. In addition, platelet activation with the release of serotonin and the activation and degranulation of mast cells contributes to the hyper-inflammatory state. Auto-antibodies have been demonstrated in a large number of hospitalized patients which adds to the end-organ damage and pro-thrombotic state. This paper provides a clinical overview of the major pathogenetic mechanism leading to severe COVID-19 disease.

The Impact of COVID-19 on Vascular Surgery Practice: A Systematic Review.

BACKGROUND: COVID-19 is characterized by a pulmonary interstitial compromise which can require intensive care unit (ICU) and mechanical ventilation. Covid patients develop a wide range of pathologies. This study aims to identify the impact of COVID-19 in diseases commonly treated by vascular surgeons. METHODS: Four conditions were selected: venous thromboembolism (VTE), pulmonary embolism (PE), peripheral arterial disease (PAD), and microangiopathy. A systematic review of the literature using PRISMA guidelines was. RESULTS: Out of 1195 papers reviewed for conditions in COVID-19 patients relevant to routine vascular surgery practice, 43 papers were included and analyzed. Venous thrombosis was found to be the most common COVID-19 associated pathology with a cumulative incidence of 25% at 7 days and 48% at 14 days. Additionally, D-dimer levels proved to be a good predictor, even in the early stages of the disease with a sensitivity of 85%, specificity of 88.5% and a negative predictive value of 94.7%. Patients in the ICU demonstrated a significantly higher risk of developing VTE, even when receiving pharmacologic thromboprophylaxis. Although evidence of arterial thrombosis was less common (1% to 16.3%), its consequences were typically more serious, including limb loss and death even in young individuals (OR = 25, 95% CI). Finally, microangiopathy has a wide spectrum of clinical presentations from retinal microangiopathy to other more severe manifestations such as myocardial injury, pulmonary compromise and potential multiple organ dysfunction syndrome. CONCLUSIONS: Although the pathophysiological pathway by which COVID-19 produces thrombosis is not completely clear, the incidence of both arterial and venous thrombosis is increased. D-dimer screening should be done in all COVID-19 patients, as a predictor of thrombotic complications.

Severe COVID-19: A multifaceted viral vasculopathy syndrome.

The objective of this study was to elucidate the pathophysiology that underlies severe COVID-19 by assessing the histopathology and the in situ detection of infectious SARS-CoV-2 and viral capsid proteins along with the cellular target(s) and host response from twelve autopsies. There were three key findings: 1) high copy infectious virus was limited mostly to the alveolar macrophages and endothelial cells of the septal capillaries; 2) viral spike protein without viral RNA localized to ACE2+ endothelial cells in microvessels that were most abundant in the subcutaneous fat and brain; 3) although both infectious virus and docked viral spike protein was associated with complement activation, only the endocytosed pseudovirions induced a marked up-regulation of the key COVID-19 associated proteins IL6, TNF alpha, IL1 beta, p38, IL8, and caspase 3. Importantly, this microvasculitis was associated with characteristic findings on hematoxylin and eosin examination that included endothelial degeneration and resultant basement membrane zone disruption and reduplication. It is concluded that serious COVID-19 infection has two distinct mechanisms: 1) a microangiopathy of pulmonary capillaries associated with a high infectious viral load where endothelial cell death releases pseudovirions into the circulation, and 2) the pseudovirions dock on ACE2+ endothelial cells most prevalent in the skin/subcutaneous fat and brain that activates the complement pathway/coagulation cascade resulting in a systemic procoagulant state as well as the expression of cytokines that produce the cytokine storm. The data predicts a favorable response to therapies based on either removal of circulating viral proteins and/or blunting of the endothelial-induced response.

Diagnostic Considerations in H1N1 Influenza-induced Thrombotic Microangiopathy.

Influenza virus can trigger atypical hemolytic uremic syndrome and present with complement-driven thrombotic microangiopathy (TMA). When administered promptly, complement-blocking therapies can spare organ injury and be lifesaving. However, diagnosing TMA in the setting of a severe viral infection can be challenging, as a significant overlap of symptoms and disease complications exists. This is particularly true in influenza virus infections and more recently, Coronavirus disease 2019 (COVID-19) infections. We present a 16-year-old male with H1N1 influenza-induced atypical hemolytic uremic syndrome who quickly improved with complement-blocking therapy, highlighting an urgent need to include TMA in the differential diagnosis of severe viral infections.

Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13.

Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.

Coagulopathy, endothelial dysfunction, thrombotic microangiopathy and complement activation: potential role of complement system inhibition in COVID-19.

Coronavirus disease-2019 (COVID-19) is a rapidly evolving health crisis caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is a novel disease entity and we are in a learning phase with regards to the pathogenesis, disease manifestations, and therapeutics. In addition to the primary lung injury, many patients especially the ones with moderate to severe COVID-19 display evidence of endothelial damage, complement activation, which leads to a pro-coagulable state. While there are still missing links in our understanding, the interplay of endothelium, complement system activation, and immune response to the SARS-CoV-2 virus is a surprisingly major factor in COVID-19 pathogenesis. One could envision COVID-19 becoming a novel hematological syndrome. This review is to discuss the available literature with regards to the involvement of the complement system, and coagulation cascade and their interaction with endothelium.

Diffuse alveolar damage and thrombotic microangiopathy are the main histopathological findings in lung tissue biopsy samples of COVID-19 patients.

BACKGROUND: Since the outbreak of the novel coronavirus disease-2019 (COVID-19) in December 2019, limited studies have investigated the histopathologic findings of patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). MATERIAL AND METHODS: This study was conducted on 31 deceased patients who were hospitalized for COVID-19 in a tertiary hospital in Tehran, Iran. A total of 52 postmortem tissue biopsy samples were obtained from the lungs and liver of decedents. Clinical characteristics, laboratory data, and microscopic features were evaluated. Reverse transcription polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 was performed on specimens obtained from nasopharyngeal swabs and tissue biopsies. RESULTS: The median age of deceased patients was 66 years (range, 30-87 years) and 25 decedents (81 %) were male. The average interval from symptom onset to death was 13 days (range, 6-34 days). On histopathologic examination of the lung specimens, diffuse alveolar damage and thrombotic microangiopathy were the most common findings (80 % and 60 %, respectively). Liver specimens mainly showed macrovesicular steatosis, portal lymphoplasmacytic inflammation and passive congestion. No definitive viral inclusions were observed in any of the specimens. In addition, 92 % of lung tissue samples tested positive for SARS-CoV-2 by RT-PCR. CONCLUSIONS: Further studies are needed to investigate whether SARS-CoV-2 causes direct cytopathic changes in various organs of the human body.

Complement and coagulation: key triggers of COVID-19-induced multiorgan pathology.

In a stunningly short period of time, the unexpected coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has turned the unprepared world topsy-turvy. Although the rapidity with which the virus struck was indeed overwhelming, scientists throughout the world have been up to the task of deciphering the mechanisms by which SARS-CoV-2 induces the multisystem and multiorgan inflammatory responses that, collectively, contribute to the high mortality rate in affected individuals. In this issue of the JCI, Skendros and Mitsios et al. is one such team who report that the complement system plays a substantial role in creating the hyperinflammation and thrombotic microangiopathy that appear to contribute to the severity of COVID-19. In support of the hypothesis that the complement system along with neutrophils and platelets contributes to COVID-19, the authors present empirical evidence showing that treatment with the complement inhibitor compstatin Cp40 inhibited the expression of tissue factor in neutrophils. These results confirm that the complement axis plays a critical role and suggest that targeted therapy using complement inhibitors is a potential therapeutic option to treat COVID-19-induced inflammation.

Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications.

Reports of widespread thromboses and disseminated intravascular coagulation (DIC) in patients with coronavirus disease 19 (COVID-19) have been rapidly increasing in number. Key features of this disorder include a lack of bleeding risk, only mildly low platelet counts, elevated plasma fibrinogen levels, and detection of both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complement components in regions of thrombotic microangiopathy (TMA). This disorder is not typical DIC. Rather, it might be more similar to complement-mediated TMA syndromes, which are well known to rheumatologists who care for patients with severe systemic lupus erythematosus or catastrophic antiphospholipid syndrome. This perspective has critical implications for treatment. Anticoagulation and antiviral agents are standard treatments for DIC but are gravely insufficient for any of the TMA disorders that involve disorders of complement. Mediators of TMA syndromes overlap with those released in cytokine storm, suggesting close connections between ineffective immune responses to SARS-CoV-2, severe pneumonia and life-threatening microangiopathy.