Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation

Abstract

The unprecedented outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the WHO, with >34 million people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and with>1 million COVID-19-related deaths worldwide 1. COVID-19 can lead to a disease spectrum ranging from mild respiratory symptoms to acute respiratory distress syndrome (ARDS) and death 2-4. SARS-CoV-2 is now the third highly pathogenic and transmissible coronavirus identified in humans. Human coronaviruses were first dis covered in the 1960s 5 , but it was not until the 21st century that coronaviruses were recognized as major threats to public health. SARS-CoV 6-9 , Middle East respiratory syndrome coronavirus (MERS-CoV) 10 and SARS-CoV-2 all cause severe respiratory tract infections and have been associated with global pandemics. SARS-CoV was first reported in China in 2003 and infected >8,000 indivi duals, causing 774 deaths worldwide 11. A decade later, MERS was first reported in Saudi Arabia and infected >2,494 individuals and caused 858 deaths, with an extremely high death rate of 34% in part owing to the lack of effective therapies 12,13. SARS-CoV, MERS-CoV and SARS-CoV-2 belong to the Betacoronavirus genus, which is one of four genera of coronavirus 14. Phylogenetic analysis revealed that SARS-CoV-2 is closely related to two bat-derived SARS-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21 (with around 88% sequence identity), SARS-CoV (approximately 79% sequence identity) and MERS-CoV (approximately 50% sequence identity) 15. Homology modelling revealed that the receptor-binding domain structures in SARS-CoV and SARS-CoV-2 are similar, despite some amino acid variations 15. MERS-CoV infects human cells by binding to the dipeptidyl peptidase 4 receptor 16 , whereas both SARS-CoV 17 and SARS-CoV-2 (refs 18,19) use angiotensin-converting enzyme 2 (ACE2) as a receptor to infect cells. For SARS-CoV-2 infection, in addition to ACE2, one or more proteases including transmembrane protease serine 2 (TMPRSS2), basigin (also known as CD147) and potentially cathepsin B or cathepsin L are required 18,19. Acute respiratory distress syndrome (ArDs). A syndrome characterized by severe acute respiratory failure arising from inflammation and fluid build-up in the lungs.

Hematologic disorders associated with COVID-19: a review

“…Critically ill patients are at an increased risk of venous thromboembolism (VTE) due to immobilization, systemic inflammation induced by a critical illness such as sepsis or acute pancreatitis, dehydration, endothelial dysfunction, and stasis [7]. The presence of metabolic syndrome (hypertension, diabetes, obesity), coronary artery disease, peripheral artery disease, a previous history of VTE, and hereditary thrombophilia are some of the patient-related risk factors which predispose to VTE formation [8,9]. Infections in critically ill patients are known to cause disseminated intravascular coagulation (DIC) via endothelial damage, neutrophil activation, and activation of intravascular coagulation [10].…”

“…The coagulopathy associated with COVID-19 meets SIC or DIC criteria in a scoring system published by the International Society on Thrombosis and Hemostasis (ISTH) in 2009 [12]. There is also a consensus that COVID-19-associated coagulopathy is more analogous to thrombotic microangiopathy and complement activation leading to endothelial damage [9,13,14]. Figure 1 outlines the hematologic manifestations due to COVID-19.…”

Intravenous Administration of Umbilical Cord Mesenchymal Stromal Cells in Advanced-stage Critical COVID-19: a Case Report

“…Importantly, intravenous administration of UC-MSCs was not associated with serious adverse events. This is particularly important in the context of severe/critical COVID-19, due to a thromboin ammatory state [27].…”

Viremia and Interaction of Endothelial Cells, Erythrocytes, Leukocytes and Platelets in Type 2 Diabetes Mellitus and COVID-19: A Closer Look at Proposed Mechanisms

“…Platelets are classically known for their roles in hemostasis and pathological thrombosis along with the wound healing response to injury. Thrombotic complications in both the arterial and venous vascular beds are a major cause of morbidity and mortality in patients with COVID-19 [79]. Intravascular clotting or thrombosis due to thromboinflammation involves platelets, RBCs, fibrinogen-fibrin, thrombin and the coagulation cascade that is activated via inflammation (cytokine storm) and oxidative-redox stress-storm (RONS) that is tightly associated with an endotheliopathy (sections 4.1. and 4.2.…”

“…), a hemoglobinopathy of the RBCs (section 5.1.) and the current section involving thrombocytopathy that eventually results in a coagulopathy with increased morbidity and mortality in COVID-19 [79].…”