Hypercoagulopathy and Adipose Tissue Exacerbated Inflammation May Explain Higher Mortality in COVID-19 Patients With Obesity

Abstract

COVID-19, caused by SARS-CoV-2, is characterized by pneumonia, lymphopenia, exhausted lymphocytes and a cytokine storm. Several reports from around the world have identified obesity and severe obesity as one of the strongest risk factors for COVID-19 hospitalization and mechanical ventilation. Moreover, countries with greater obesity prevalence have a higher morbidity and mortality risk of developing serious outcomes from COVID-19. The understanding of how this increased susceptibility of the people with obesity to develop severe forms of the SARS-CoV-2 infection occurs is crucial for implementing appropriate public health and therapeutic strategies to avoid COVID-19 severe symptoms and complications in people living with obesity. We hypothesize here that increased ACE2 expression in adipose tissue displayed by people with obesity may increase SARS-CoV-2 infection and accessibility to this tissue. Individuals with obesity have increased white adipose tissue, which may act as a reservoir for a more extensive viral spread with increased shedding, immune activation and pro-inflammatory cytokine amplification. Here we discuss how obesity is related to a pro-inflammatory and metabolic dysregulation, increased SARS-CoV-2 host cell entry in adipose tissue and induction of hypercoagulopathy, leading people with obesity to develop severe forms of COVID-19 and also death. Taken together, it may be crucial to better explore the role of visceral adipose tissue in the inflammatory response to SARS-CoV-2 infection and investigate the potential therapeutic effect of using specific target anti-inflammatories (canakinumab or anakinra for IL-1β inhibition; anti-IL-6 antibodies for IL-6 inhibition), anticoagulant or anti-diabetic drugs in COVID-19 treatment of people with obesity. Defining the immunopathological changes in COVID-19 patients with obesity can provide prominent targets for drug discovery and clinical management improvement.

Keywords: ACE-2; COVID-19; Obesity; SARS-CoV-2; adipose tissue; hypercoagulopathy.

Figure 1

SARS-CoV-2 host cell entry cell depends on the angiotensin-converting enzyme 2 (ACE2) and TMPRSS2. The virus uses the homotrimeric peak glycoprotein S present on viral envelope surface to physically interact with its cell receptor, which facilitates binding to the surface of target cells, enables endocytosis of the virion particle and entry of the viral genome into the host cell cytoplasm. This cell entry process requires priming of protein S by cellular proteases, such as the serine protease TMPRSS2. After endosomal acidification, viral proteins are synthesized in host ER for viral replication and virion particles shedding occurs through Golgi apparatus. ACE2 is expressed in adipocytes and adipose tissue may act as a reservoir for SARS-CoV-2.

Figure 2

Obesity increases SARS-CoV-2 infection vulnerability in affected individuals by interfering in RAAS activation, antiviral immunity, fat tissue accumulation, and differentiation status of pulmonary fibrosis related cells. While lean individuals tend to show adequate RAAS activation, including ACE2 and Ang(1-7) levels, effective antiviral immune responses and absence of both adipose tissue (AT) deposits in airways and LiF-myofibroblast transdifferentiation, subjects with obesity display aberrant RAAS activation, favoring high ACE2 expression and low Ang(1-7) availability, decrease of immune responses against viruses and presence of both AT deposits in airways and LiF-myofibroblast transdifferentiation. ScWAT-derived stem cells (ASCs) could be applied in COVID-19 treatment.

Figure 3

People with obesity display higher risk of mortality and morbidity in COVID-19 due to exacerbated inflammatory status and hypercoagulation tendency. Individuals with obesity show systemic chronic inflammation, which favors macrophage activation, cytokine storm occurrence (aberrant secretion of pro-inflammatory cytokines IL-6, IL-1, and TNF) and cytotoxicity (LDH release). This inflamed status associates with the increased clotting risk (hypercoagulation) presented by these patients. All these features make subjects with obesity more prone to develop pathological alterations in the physiology of lungs, AT, liver, heart, and intestines, which negatively influences gut microbiome composition. The impact of obesity-associated chronic inflammation on systems' physiology, including on antiviral immune responses, and the increased levels of coagulation-inducing mediators (fibrinogen and D-dimer) in COVID-19 patients help to explain the higher risks of these individuals to die of COVID-19 and to suffer with this infection compared to non-obese individuals.

Figure 4

Mechanisms of the hypercoagulopathy and exacerbated inflammation observed in people with obesity. Obesity, which is intimately related with the pathogenesis of hypertension and cardiovascular diseases (CVDs), is characterized by high levels of Plasminogen Activator inhibitor I (PAI), leptin, IL-6, MCP-1, and free fatty acids (FFAs). These molecules induce white adipocyte hypertrophy, which then enables the occurrence of inflammation through cytokine storm. Inflammatory mediators impact on the availability of tissue factor (TF), factor VII (FVII), and thrombin-inhibiting factors, disrupting procoagulant-anticoagulant balance, and leading to hypercoagulation. Moreover, inflammation dysregulates fibrinolytic homeostasis through platelet dysfunction, increased FVIII and PAI-1 levels, and diminished ADMTS 13 activity, which enhance the risk of thrombosis. In addition, endothelial cell dysfunction, common in the obese phenotype, associates with Angiotensin II (Ang II) elevated amounts, von Willebrand factor (vWF) release, and oxidative stress, which induce vasoconstriction and thrombus formation.