Infection with SARS-CoV-2 triggers the simultaneous activation of innate inflammatory pathways including the complement system and the kallikrein-kinin system (KKS) generating in the process potent vasoactive peptides that contribute to severe acute respiratory syndrome (SARS) and multi-organ failure. The genome of SARS-CoV-2 encodes four major structural proteins – the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein. However, the role of these proteins in either binding to or activation of the complement system and/or the KKS is still incompletely understood. In these studies, we used: solid phase ELISA, hemolytic assay and surface plasmon resonance (SPR) techniques to examine if recombinant proteins corresponding to S1, N, M and E: (a) bind to C1q, gC1qR, FXII and high molecular weight kininogen (HK), and (b) activate complement and/or the KKS. Our data show that the viral proteins: (a) bind C1q and activate the classical pathway of complement, (b) bind FXII and HK, and activate the KKS in normal human plasma to generate bradykinin and (c) bind to gC1qR, the receptor for the globular heads of C1q (gC1q) which in turn could serve as a platform for the activation of both the complement system and KKS. Collectively, our data indicate that the SARS-CoV-2 viral particle can independently activate major innate inflammatory pathways for maximal damage and efficiency. Therefore, if efficient therapeutic modalities for the treatment of COVID-19 are to be designed, a strategy that includes blockade of the four major structural proteins may provide the best option.
Hypercoagulability has emerged as a prominent consequence of COVID-19. This presents challenges not only in the clinic, but also in thrombosis research. Health and safety considerations, the status of the blood and plasma supply, the infection status of individual donors, and the mechanisms by which SARS-CoV-2 activates coagulation are all of concern. In this review, we discuss these topics from the basic research perspective. As in other respiratory illnesses, blood and plasma from COVID-19 positive patients carries minimal to no risk of infection to practitioners or researchers. There are currently no special regulatory mandates directing individual donors (for research purposes), blood centers/services or vendors (for blood products for research) to test blood/plasma for SARS-CoV-2 or antibodies. We discuss current theories about how SARS-CoV-2 leads to hyper-coagulant state in severe cases of COVID-19. Our current understanding of the mechanisms behind COVID-19 associated thromboembolic events have centered around three different pathways: (1) direct activation of platelets, enhancing coagulation; (2) direct infection and indirect activation (e.g. cytokine storm) of endothelial cells by SARS-CoV-2, shifting endothelium from an anti-thrombotic to a pro-thrombotic state; and (3) direct activation of complement pathways, promoting thrombin generation. Further investigation on how SARS-CoV-2 affects thrombosis in COVID-19 patients may bring novel anti-thrombotic therapies to combat the disease.
Coronary artery disease is the second leading cause of death in the United States. Models of coronary arteries have been widely used to understand the hemodynamic drivers of the disease. Fluid‐Structure Interaction (FSI) modeling of the coronary arteries provides information on both the forces that are created by the blood and the forces distributed into the artery wall. A better understanding of the artery health and markers of disease progression may be discernable by performing a spatiotemporal analysis of the coronary artery hemodynamics and solid mechanics. The goals of this investigation were: 1) to create a three‐dimensional (3D) FSI model of the left anterior descending coronary artery and 2) to evaluate disease progression using multiple mechanical descriptors in both space and time domains using COMSOL Multiphysics. The 3D geometry reconstruction was based on a patient's computer tomography angiography (CTA) data. The fluid domain representing the blood volume and solid domain representing the artery wall were fully coupled. The artery wall was modeled using a 5‐parameter hyperelastic Mooney‐Rivlin material model. We assessed time averaged wall shear stress, wall shear stress gradient, and oscillatory shear index (OSI) along the fluid‐structure interface. Artery wall strain (along the three principal directions) and Von‐Mises stress were assessed within regions of the solid (i.e., the vascular wall). A virtual calculation of the Fractional Flow Reserve (vFFR), which is used for clinical diagnosis of cardiac ischemia, was performed. These analyses were collected from three different regions along the artery, proximal to, at, and distal to an area of narrowing in the artery throughout the cardiac cycle. Clear differences were observed between the regions. The distal region to the narrowing had variable OSI and high time averaged wall shear stress, but the lowest average Von‐Mises stress. The vFFR was 0.96 which is comparable to the average FFR in the left anterior descending artery. This type of model reconstruction and analysis can be used to evaluate plaque vulnerabilities. It may also have clinical implications when assessing the patient's specific coronary artery mechanical environment that may lead to plaque development and instability.
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