Association between COVID-19 Diagnosis and Coronary Artery Thrombosis: A Narrative Review

Abstract

Coronavirus disease 2019 is characterized by its severe respiratory effects. Data early on indicated an increased risk of mortality in patients with cardiovascular comorbidities. Early reports highlighted the multisystem inflammatory syndrome, cytokine storm, and thromboembolic events as part of the disease processes. The aim of this review is to assess the association between COVID-19 and its thrombotic complications, specifically related to the cardiovascular system. The role of neutrophil extracellular traps (NETs) is explored in the pathogenesis of the disease. The structure and anatomy of the virus are pivotal to its virulence in comparison to other α and β Coronaviridae (HCoV-229E, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1). In particular, the host interaction and response may explain the variability of severity in patients. Angio tensin-converting enzyme 2 (ACE2) activation may be implicated in the cardiovascular and throm bogenic potential of the disease. The virus may also have direct effects on the endothelial lining affecting hemostasis and resulting in thrombosis through several mechanisms. Dipyridamole may have a therapeutic benefit in NET suppression. Therapeutic avenues should be concentrated on the different pathophysiological steps involving the virus and the host.

Keywords: COVID-19; SARS-CoV-2 infection; coronary artery thrombosis; neutrophil extracellular traps (NETs).

Figure 1

Host cell interaction. S protein has a polybasic sequence motif constituted by Arg–Arg–Ala–Arg (RRAR) in S1/S2 boundary site. This is a cleavage point for the protein convertase furin [48,49]. After furin interaction, S1 and S2 are noncovalently linked with Transmembrane serine protease 2 (TMPRSS2), further priming S2. This process has a key role in the enhanced spreading of SARS-CoV-2, matching it with other viruses with the same site of anchorage upon the cell surface. Polybasic cleavage site causes a more pathogenic action of virus, enabling it to fuse with the host cell. Furin cleavage forms a C-terminus in S1 protein with a ⁶⁸²RRAR⁶⁸⁵ that can interact with RXXROH (where R is arginine and X is any amino acid; R may be substituted by lysine). This terminus sequence conforms to the C-end rule (CendR) and is a ligand for neuropilin receptors 1 and 2 (NRP1 and NRP2). Cryo-electron microscopy demonstrated that S1/S2 is a constituent of a loop that may be bound to receptors [50,51]. Extracellular regions of NRP1 and NRP2 contains the b1 do-main which has the specific binding site for CendR peptides. After cleavage action, the virus fuses to the cell membrane and enters into the cytoplasm via endosomic transport. Valid SARS-2-S activation by TMPRSS2 and airway epithelium cell entry are related to S1/S2 priming [52]. Eighteen proteases, many of which are coded in human airways, are part of the type II transmembrane serine protease (TTSP) family, in which TMPRSS2 is included. Two recent analyses showed that TMPRSS13 is a second prominent activator of the SARS-CoV-2 S protein [53,54]. Abbreviations: ACE-2: angiotensin-converting enzyme 2; CAT B/L: catalase B/L; NRP 1: neuropilin-1; NRP 2: neuropilin-2; RRAR Arg–Arg–Ala–Arg sequence; RXXR: where R is arginine and X is any amino acid (R may be substituted by lysine); S1: spike glycoprotein 1; S2: spike glycoprotein 2; TMPRSS-2: transmembrane serine protease 2.

Figure 2

SARS-CoV-2 causes activation of neutrophils mediated by IL-8, G-CSF, resistin, lipocalin-2, hepatocyte growth factor and NET release. The immune response of NK and T lymphocytes con-tributes to the formation of NETs with the activation of the complement system (C5 and C3). The result is the development of microvascular thrombosis, which leads to organ damage. Abbreviations: C, complement; GF, growth factor; IL, interleukin; NK, natural killer cells. Other abbreviations are provided in the text. Arrows explain the increase or decrease of relative component.

Figure 3

Renin–angiotensin–aldosterone system: summary of pathophysiologic effects and its importance in SARS-CoV-2 infection. Abbreviations: ACE: angiotensin-converting enzyme, type 1 or type 2; AT1R: angiotensin receptor type 1; MASR mitochondrial assembly receptor; RAAS: renin–angiotensin–aldosterone system; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

Figure 4

Mechanisms of cytokine cascade and activation of the coagulation system in SARS-CoV-2 infection, showing the autoinduction of interleukins and the amplification of the inflammatory cascade. Abbreviations: IL: interleukin; PAI: plasminogen activator inhibitor; TNF: tumor necrosis factor alpha; ICAM: intercellular adhesion molecule; sVCAM: serum vascular cell adhesion molecule; vWF: von Willebrand factor.

Figure 5

Summary of the dysregulations in coagulation system after SARS-CoV-2. SARS-CoV-2 coagulopathy is supported by the following pathological events: DIC, cytokine storm process, and direct action of the virus, inducing damage and activation of macrophages. RAAS overactivation associated with platelet and complement overactivation (direct and indirect) leads to fibrinolysis inhibition. Abbreviations are as shown in previous figures. Arrows explain the increase or decrease of relative component.

Figure 6

Summary of the mechanism that induces heart damage from NET formation in patients with severe COVID-19. Three distinct processes result in heart damage: vascular inflammation, thrombogenesis, and NETosis. Abbreviations: HMGB1, high-mobility group box 1; ISG-15; interferon-stimulated gene; LDG, low-density granulocyte; LL37, active cathelicidin; NDG, normal density granulocyte; NAD, nicotine adenine dinucleotide; ROS, reactive oxygen species; SIRT3, Sirtuin 3. Other abbreviations are as shown in previous figures. Arrows explain the increase or decrease of relative component.