thromboplastin and Pneumonia--Viral

In December 2019, a new and highly contagious infectious disease emerged in Wuhan, China. The etiologic agent was identified as a novel coronavirus, now known as Severe Acute Syndrome Coronavirus-2 (SARS-CoV-2). Recent research has revealed that virus entry takes place upon the union of the virus S surface protein with the type I transmembrane metallo-carboxypeptidase, angiotensin converting enzyme 2 (ACE-2) identified on epithelial cells of the host respiratory tract. Virus triggers the synthesis and release of pro-inflammatory cytokines, including IL-6 and TNF-α and also promotes downregulation of ACE-2, which promotes a concomitant increase in levels of angiotensin II (AT-II). Both TNF-α and AT-II have been implicated in promoting overexpression of tissue factor (TF) in platelets and macrophages. Additionally, the generation of antiphospholipid antibodies associated with COVID-19 may also promote an increase in TF. TF may be a critical mediator associated with the development of thrombotic phenomena in COVID-19, and should be a target for future study.

Topics: Angiotensin-Converting Enzyme 2; Animals; Betacoronavirus; Blood Coagulation; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cytokines; Fibrinolytic Agents; Host-Pathogen Interactions; Humans; Inflammation Mediators; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; SARS-CoV-2; Thromboplastin; Thrombosis

The high rate of thrombotic complications associated with COVID-19 seems likely to reflect viral infection of vascular endothelial cells, which express the ACE2 protein that enables SARS-CoV-2 to invade cells. Various proinflammatory stimuli can promote thrombosis by inducing luminal endothelial expression of tissue factor (TF), which interacts with circulating coagulation factor VII to trigger extrinsic coagulation. The signalling mechanism whereby these stimuli evoke TF expression entails activation of NADPH oxidase, upstream from activation of the NF-kappaB transcription factor that drives the induced transcription of the TF gene. When single-stranded RNA viruses are taken up into cellular endosomes, they stimulate endosomal formation and activation of NADPH oxidase complexes via RNA-responsive toll-like receptor 7. It is therefore proposed that SARS-CoV-2 infection of endothelial cells evokes the expression of TF which is contingent on endosomal NADPH oxidase activation. If this hypothesis is correct, hydroxychloroquine, spirulina (more specifically, its chromophore phycocyanobilin) and high-dose glycine may have practical potential for mitigating the elevated thrombotic risk associated with COVID-19.

Topics: Animals; Antiviral Agents; Betacoronavirus; Blood Coagulation; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Endosomes; Endothelial Cells; Enzyme Activation; Fibrinolytic Agents; Host-Pathogen Interactions; Humans; NADPH Oxidases; Pandemics; Pneumonia, Viral; SARS-CoV-2; Signal Transduction; Thromboplastin; Thrombosis

Topics: Anticoagulants; Betacoronavirus; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Endothelium, Vascular; Extracellular Traps; Extracellular Vesicles; Fibrinolytic Agents; Hemostasis; Humans; Intermittent Pneumatic Compression Devices; Neoplasms; Pandemics; Pneumonia, Viral; Risk; SARS-CoV-2; Thrombophilia; Thromboplastin; Thrombosis; Venous Thromboembolism

Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease that has quickly become a worldwide threat to health, mainly causing severe acute respiratory syndrome. In addition to the widely described respiratory syndrome, COVID-19 may cause life-treating complications directly or indirectly related to this infection. Among these, thrombotic complications have emerged as an important issue in patients with COVID-19 infection, particularly in patients in intensive care units. Thrombotic complications due to COVID-19 are likely to occur due to a pro-coagulant pattern encountered in some of these patients or to a progressive endothelial thrombo-inflammatory syndrome causing microvascular disease. In the present authors' experience, from five different hospitals in Italy and the UK, imaging has proved its utility in identifying these COVID-19-related thrombotic complications, with translational clinical relevance. The aim of this review is to illustrate thromboembolic complications directly or indirectly related to COVID-19 disease. Specifically, this review will show complications related to thromboembolism due to a pro-coagulant pattern from those likely related to an endothelial thrombo-inflammatory syndrome.

Topics: Adult; Aged; Anticoagulants; Brain Ischemia; Cause of Death; Communicable Diseases, Emerging; Coronavirus Infections; COVID-19; Female; Humans; Italy; Male; Middle Aged; Pandemics; Pneumonia, Viral; Pulmonary Embolism; Radiography, Thoracic; Severe Acute Respiratory Syndrome; Survival Analysis; Thromboembolism; Thromboplastin; Tomography, X-Ray Computed

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.

Topics: Betacoronavirus; Blood Platelets; Complement Activation; Coronavirus Infections; COVID-19; Humans; Inflammation; Neutrophils; Pandemics; Peptides, Cyclic; Pneumonia, Viral; SARS-CoV-2; Severity of Illness Index; Thromboplastin; Thrombotic Microangiopathies

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.

Topics: Aged; Betacoronavirus; Complement Activation; Complement Membrane Attack Complex; Coronavirus Infections; COVID-19; Extracellular Traps; Female; Humans; Male; Middle Aged; Neutrophils; Pandemics; Peptides, Cyclic; Pneumonia, Viral; Receptor, Anaphylatoxin C5a; Respiratory Distress Syndrome; SARS-CoV-2; Thrombin; Thromboplastin; Thrombosis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent pathogen responsible for the coronavirus disease 2019 (COVID-19). Since its emergence, the novel coronavirus has rapidly achieved pandemic proportions causing remarkably increased morbidity and mortality around the world. A hypercoagulability state has been reported as a major pathologic event in COVID-19, and thromboembolic complications listed among life-threatening complications of the disease. Platelets are chief effector cells of hemostasis and pathological thrombosis. However, the participation of platelets in the pathogenesis of COVID-19 remains elusive. This report demonstrates that increased platelet activation and platelet-monocyte aggregate formation are observed in severe COVID-19 patients, but not in patients presenting mild COVID-19 syndrome. In addition, exposure to plasma from severe COVID-19 patients increased the activation of control platelets ex vivo. In our cohort of COVID-19 patients admitted to the intensive care unit, platelet-monocyte interaction was strongly associated with tissue factor (TF) expression by the monocytes. Platelet activation and monocyte TF expression were associated with markers of coagulation exacerbation as fibrinogen and D-dimers, and were increased in patients requiring invasive mechanical ventilation or patients who evolved with in-hospital mortality. Finally, platelets from severe COVID-19 patients were able to induce TF expression ex vivo in monocytes from healthy volunteers, a phenomenon that was inhibited by platelet P-selectin neutralization or integrin αIIb/β3 blocking with the aggregation inhibitor abciximab. Altogether, these data shed light on new pathological mechanisms involving platelet activation and platelet-dependent monocyte TF expression, which were associated with COVID-19 severity and mortality.

Topics: Adult; Betacoronavirus; Biomarkers; Blood Coagulation Disorders; Blood Platelets; Case-Control Studies; Coronavirus Infections; COVID-19; Female; Follow-Up Studies; Humans; Male; Middle Aged; Monocytes; P-Selectin; Pandemics; Platelet Activation; Pneumonia, Viral; Prognosis; Prospective Studies; SARS-CoV-2; Survival Rate; Thromboplastin