Crosstalk Between Coagulopathy and Inflammation in Obesity-Related Severe COVID-19 Infection

1. Introduction

Coronavirus disease 2019 (COVID-19) has emerged as one of the most highly contagious disease outbreaks in history, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus. This disease has given rise to the most consequential global economic and health crisis, infecting over 700 million people and causing more than 6.99 million deaths worldwide as of December 2023 [1]. The most common clinical symptoms of COVID-19 are severe cough, fever, fatigue, and dyspnea [2]. However, the disease can lead to severe complications including pneumonia-induced acute respiratory distress syndrome (ARDS), sepsis, organ failure, and eventually death. Many clinical findings have associated severe COVID-19 with obesity, hypertension, diabetes, cardiovascular disease, asthma, and aging [3]. In Malaysia, the crucial determinants of severe COVID-19 include old age, chronic kidney disease, chronic pulmonary diseases, shortness of breath, and high serum C-reactive protein (CRP) (≥5 mg/dL) [4]. Obesity, in particular, has been linked to severe complications of COVID-19, where most patients require intensive care unit (ICU) hospitalization [5]. In most cases, obesity is accompanied by other diseases, such as dyslipidemia, hypertension, and diabetes mellitus, providing an increased risk of developing severe COVID-19 [6].

Obesity is a low degree of chronic inflammation in which adipose tissue expresses a broad spectrum of Toll-like receptors and produces proinflammatory cytokines and chemokines [7]. The prevalence of severe COVID-19 cases among patients with obesity and the associated mortality varies in different countries. However, the consensus is these patients face a higher risk of death than non-obese patients [8]. Previous reports had associated patients with obesity and severe COVID-19, where most of them suffered from ARDS and often required ventilators compared to their normal-weight counterparts [6,9]. In the United States of America (USA), obesity was reported as the most significant association with COVID-19 mortality in patients under 60 years old [10]. In France, approximately 85% of COVID-19 patients with a body mass index (BMI) >40 needed ventilators upon hospitalization [11]. Meanwhile, in Malaysia, comorbidities contribute to the highest incidence (75.4%) of mortality, with 5.8% being obesity [12].

Coagulopathy, or bleeding disorder is seen more in severe COVID-19 patients associated with impairment in the coagulation cascade and clot formation giving rise to disseminated intravascular coagulation (DIC). Importantly, patients with obesity are more susceptible to coagulopathy and cytokine storms (elevation of prothrombin factors and pro-inflammatory cytokines, respectively) when they are affected by COVID-19, and hence the mortality rate in these patients is high [13]. Understanding the mechanisms of inflammation and coagulopathy in obesity-related severe COVID-19 is essential to developing treatment approaches for managing the severity and mortality. Thus, this review comprehensively discussed the association of coagulopathy and inflammation with the development of severe COVID-19 in patients with obesity.

2. Materials and Methods

A comprehensive search on Google Scholar and PubMed databases was conducted for articles published between May 2010 to January 2024. The keywords include “inflammation, coagulation, obesity, SARS-CoV-2, COVID-19, coagulopathy, and cytokine storms”. We also include COVID-19 data from the World Health Organization (WHO) 2023.

3. Mechanisms of Inflammation and Coagulopathy in Severe COVID-19

3.1. Entry and Life Cycle of SARS-CoV-2 Virus

SARS-CoV-2 viral entry occurs via a host cell receptor known as angiotensin-converting enzyme 2 (ACE2), previously recognized as a SARS-CoV-2 receptor; a process mediated via its spike (S) protein, which consists of S1 and S2 subunits [14]. ACE2 is a functional receptor that is highly expressed in pulmonary epithelial cells. This receptor is also present in cells of other vital organs, such as gastrointestinal tracts, heart, endothelial cells, and kidneys [15]. During SARS-CoV-2 infection, the S1 protein binds to ACE2, leading to exposure of another cleavage site, called the ‘S2 site’ on S2 subunit, which is subsequently cleaved by host proteases [16]. These host proteases, namely type II transmembrane serine protease (TMPRSS2) and lysosomal cathepsins are critical for S2 subunit activation, resulting in dissociation of S1 and drastic structural change in S2, exposing fusion peptide, promoting membrane fusion [17]. S2 subunit activation at the plasma membrane surface is stimulated by TMPRSS2, while that in endosomes is induced by lysosomal cathepsin, which can also compensate for viral invasion into cells lacking TMPRSS2 [17]. Following membrane fusion, the viral RNA genome is released into the cytosol of the host cell via fusion pore, inducing viral polymerase translation and RNA replication by host cell mechanisms, which subsequently leads to virion assembly and exocytosis of the newly synthesized virion, which can infect new host cells and continue the replication cycle [18].

3.2. SARS-CoV-2-Induced Coagulopathy

Coagulation is a crucial mechanism to prevent excessive bleeding in the damaged vessel walls. It consists of two main phases, namely primary and secondary hemostasis. During primary hemostasis, following a vascular injury, platelets in circulation begin to adhere to the exposed collagen fibers at the site of injury, facilitated by von Willebrand factor (vWF) (Figure 1). The platelets become activated and secrete their granules, such as adenosine diphosphate (ADP), and produce substances such as thromboxane A2 (TXA2) which promote further platelet aggregation. The coagulation cascades begin in secondary hemostasis when the platelets have formed a temporary plug at the site of injury. Activation of Tissue Factor (TF) subsequently triggers the intrinsic (Factor XII) and/or extrinsic (Factor XII) pathway activation and eventually converges at the activation of factor X, which then combines with other factors to activate prothrombin into thrombin by the prothrombinase complex. Thrombin mediates the conversion of soluble fibrinogen into insoluble fibrin which polymerizes and is cross-linked by factor XIIIa to create a stable blood clot [19,20]. Coagulation is kept in check by two other systems, namely the anti-coagulant, mediated by Thrombomodulin (TM), Protein C and Protein S; and the fibrinolytic involving factors such as plasminogen and its activator [21,22]. The latter system converges on the formation of plasmin which then breaks down fibrin. An imbalance of any of these systems results in coagulopathy, leading to uncontrolled thrombosis or bleeding.

3.3. SARS-CoV-2-Induced Inflammation

Following viral infection alveolar epithelial cells undergo programmed cell death induced by pathogen-associated molecular patterns (PAMPs) such as viral RNA the subsequent release of damage-associated molecular patterns (DAMPs) such as RNA or histone, triggers activation of macrophages that lead to high cytokines secretion, particularly interleukin (IL)-6 and reactive oxygen species (ROS) [23]. Circulation of IL-6 receptor complexes and cytokines indirectly activates a series of cells, including endothelial cells, platelets, and neutrophils, culminating in an exaggerated production of pro-inflammatory cytokines, which ultimately results in a cytokine storm. Cytokine storms occur due to significant overexpression of inflammatory cytokines that initiate lung inflammation and damage, followed by pneumonia, ARDS, septic shock, loss of respiratory functions, and ultimately death [24]. The critical nuclear factor-κB (NF-ĸB) pathway is activated in a cytokine storm, releasing excessive inflammatory cytokines, such as IL-1β, IL-2, IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF), Interferon-γ-inducible protein 10 (IP10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP) 1-A, and tumor necrosis factor (TNF)-α in severe COVID-19 patients and the resulting inflammation may lead to the development and progression of ARDS. COVID-19 patients admitted to the ICU had a higher concentration of these cytokines than healthy individuals, and has been reported in secondary hemophagocytic lymphohistiocytosis (HLH) associated with severe COVID-19 [25,26].

3.4. The Crosstalk Between Inflammation and Coagulation

Crosstalk between factor XIIa in the coagulation cascade and kallikrein and kinin system (KKS) is crucial in the cytokine storm and coagulopathy in COVID-19 patients, activated by SARS-CoV-2 RNA (Figure 2) [27]. Loss of inactivation of the pro-inflammatory des-Arg⁹ bradykinin by ACE2 increases the production of inflammatory cytokines and oxidative stress by activating the kinin B1 receptor (KB1R) [28]. Increased inflammatory cytokines in COVID-19 patients also induce TF and P-selectin in vascular endothelium cells, promoting vascular thrombosis and neutrophil extracellular traps (NETs) formation, respectively [29]. Moreover, inhibition of anticoagulants by IL-1 elevates thrombin production and aggravates vascular thrombosis [30]. Overexpression of P-selectin directly correlates with higher TF levels in monocytes, promoting DIC occurrence [31]. This condition is common in severe COVID-19 patients, where D-dimer induces P-selectin and, subsequently, TF overexpression [32]. Therefore, stimulating P-selectin production via D-dimer and high TF expression level is a mechanism for coagulopathy in severe COVID-19 patients.

Overexpression of both angiotensin II (AngII) and angiotensin II receptor type 1 (AT1R) can also lead to overproduction of TF by monocytes and vascularized endothelial cells [33]. Activated platelets have also been shown to stimulate TF expression by monocytes, via P-selectin and integrin αIIb/β3 [34], thus promoting a TF-dependent coagulation pathway. AngII/AT1R axis also inhibits the fibrinolytic pathway by increasing plasminogen activator inhibitor 1 (PAI-1) expression, further promoting a hypercoagulable state [35]. Moreover, overexpression of AngII and AT1R leads to the upregulation of both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in vascular endothelium, promoting leucocyte adhesion, and therefore associated with the severity of COVID-19 disease [36,37]. The resultant activation of endothelial cells is reflected by elevated levels of D-dimer, which is considered a biomarker for coagulopathy and associated with poor prognosis in COVID-19 patients. Although D-dimer represents the degradation of clots by the fibrinolytic pathway hence generated in the late stage of the coagulation pathway, the mechanisms of D-dimer elevation in COVID-19 patients are not fully understood.

Systemic inflammation in COVID-19 resulting from the severe elevation of inflammatory cytokines has been observed in association with the activation of coagulation cascades, thrombosis formation, and endothelial cell dysfunction [38]. The resultant hyperinflammatory and hypercoagulability condition, characterized by cytokine storm and overstimulated coagulation cascade with impaired fibrinolytic system, respectively, is aptly coined as immuno-thrombosis [37]. Generation of vascular microthrombi eventually leads to systemic DIC, followed eventually by multi-organ failure [37]. In addition, the formation of platelet-neutrophil complexes (PNCs) and toxic NETs promote coagulopathy in several ways, including further cellular recruitment, activation of platelet and coagulation cascade pathways; and inhibition of anti-coagulant and fibrinolytic pathways which could confer detrimental effects in endothelial injury, lung damage, and thrombosis [39,40].

Disseminated intravascular coagulopathy is a condition where the formation of blood clots and thrombosis in vessels obstruct blood flow due to inflammation-mediated activation of the blood coagulation cascade [41]. DIC, accompanied by fibrin formation in blood vessels, leads to organ dysfunction and increased patient mortality [42]. Coagulopathy occurs when the balance between coagulation and anticoagulant factors is disturbed [43]. On one hand, pro-inflammatory cytokines and CRP can induce blood coagulation cascade through TF/factor VIIa complex activation, primarily driven by the vascular endothelium cells. On the other hand, when these cells encounter pathogens or inflammatory cytokines, they lose their antithrombin (AT) properties, resulting in overall favorable conditions for coagulation [44,45]. In addition, hypoxic conditions due to lung damage in COVID-19 patients exacerbate the stimulation of TF production by the endothelium; thus, high TF levels are predictors of increased morbidity and mortality [46].

The TF pathway activation by cytokines IL-1, IL-6, and TNF-α also downregulates anticoagulant factors such as AT, thrombomodulin (TM), and endothelial protein C receptor (EPCR), thus preventing fibrinolysis and promoting DIC [47,48]. Nevertheless, the relationship between inflammation and coagulation is not unidirectional. Coagulation can lead to inflammatory responses by protease-activated receptors (PARs) located on the endothelium of vessels and platelets. PARs bind to factor VIIa upon activation and increase inflammatory cytokines production, including IL-1β and TNF-α and ROS-induced oxidative stress [49,50]. Furthermore, TM/activated protein C (APC) and its EPCR are essential in eliminating coagulation factors, such as factor Va and VIIIa [51]. The APC downregulation leads to endotheliopathy and vascular thrombosis[52].

High levels of coagulation factors, such as von Willebrand factor (vWF), factor VIII, and soluble TM indicate endothelial damage in severe COVID-19 found in patients’ lung samples [53]. The TNF-α and IL-1 cytokines play an important role in activating the endothelial damage biomarkers in this process, indicating the activation of coagulation cascades by inflammatory cytokines [54]. In addition, downregulated AT levels have been reported in hospitalized COVID-19 patients, which led to increased ventilator requirement and mortality [55]. Therefore, AT administration is recommended for critical COVID-19 patients hospitalized in the ICU, but discrepancies have been highlighted between studies [56].

Coagulopathy caused by venous thromboembolism (VTE) events and unresponsiveness to prophylactic anticoagulants is common in severe COVID-19 patients in the ICU [57]. This condition promotes heart and brain ischemia, which increases mortality among COVID-19 patients [58]. D-dimer, which is a coagulopathy biomarker, exceeding 1000 ng/mL predicts VTE incidence and mortality in COVID-19 [59]. Furthermore, the upregulation of TF, factor VIII, and vWF and the downregulation of anticoagulant factors, such as protein C and AT III, have been reported in COVID-19 cases [60].

4. Hyperinflammation and Coagulation in COVID-19 Patients with Obesity

The prevalence of obesity has continued to rise in recent years, and approximately a quarter of the world’s population is obese or overweight. Obesity-associated complications and mortality are relatively high due to co-morbidities such as cardiovascular disease (CVD), hypertension, and diabetes mellitus [61]. In light of the recent global pandemic, obesity has been identified as one of the risk factors for severe COVID-19 [62]. Clinical reports have shown that almost half of COVID-19 patients hospitalized in the ICU had a BMI > 30, and the high severity of COVID-19 among young patients was also correlated with obesity [63]. The most critically ill COVID-19 patients admitted to the ICU exhibited hypercoagulopathy symptoms, primarily caused by severe inflammatory responses and endotheliopathy, which activate the coagulation cascade through the TF pathway [64]. These patients also demonstrate high D-dimer levels and long prothrombin time (PT). Therefore, increased inflammation and activation of coagulation pathways lead to coagulopathy, known as thromboinflammation.

A meta-analysis demonstrated that obese subjects are at higher risk of severe disease and mortality due to COVID-19 [65]. Meanwhile, Gao et al. (2020) reported high plasma CRP levels and low lymphocyte counts in COVID-19 patients with obesity [66]. Consequently, these patients had a longer hospital stay (median = 23 days) compared to non-obese COVID-19 patients (median = 18 days) [66]. Therefore, COVID-19 patients with obesity face a higher risk of severe COVID-19, ICU admission, and death compared to non-obese patients. ACE2 overexpression, leptin production, and pre-existing inflammation are reported to contribute to severe COVID-19 in patients with obesity and further reduce their chances of survival.

4.1. Overexpression of ACE2

SARS-CoV-2 utilizes the ACE2 receptor to initiate infection, and the high expression of this receptor has been associated with severe COVID-19 [67]. One of the contributing factors to the high probability of severe COVID-19 among patients with obesity is the high visceral fat tissue, which is associated with the high expression of the ACE2 receptor [68]. Overexpression of the ACE2 gene in adipose tissue has been associated with increased ICU admission, ventilator requirement, and mortality rate in severe patients with obesity (BMI > 40) affected by COVID-19 [68]. Furthermore, high expression of the ACE2 receptor is also found particularly in vital organs such as the lung, heart, kidney, gastrointestinal tract, and visceral tissue could lead to further dissemination and high viral load in COVID-19 patients with obesity [69].

4.1. Leptin

The adipose tissue is a source of energy and essential in regulating inflammatory responses to infections [70]. Adipocytes are responsible for secreting various adiponectins, including leptin, which is abundantly detected in individuals with obesity [71]. High serum leptin in individuals with obesity is an indicator of cell resistance to leptin, impacting the signal transduction pathways Janus kinase-2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), besides promoting inflammatory cytokines including IL-6 and TNF-α production by monocytes [72,73].

Leptin also causes CRP overexpression in hepatocytes, indicating the pro-inflammatory role of this adipokine [74]. Precisely, leptin regulates the inflammatory responses via leptin receptor modulation and upregulates multiple inflammatory cytokines (i.e., TNF-α and IL-6) [72]. Likewise, a surge in leptin levels leads to the activation and proliferation of immune cells, increasing TNF-α and IL-6 levels, thus aggravating the inflammatory responses of obesity with high leptin levels [75]. A previous report highlighted that severe COVID-19 patients hospitalized in ICU and under mechanical ventilation have high leptin levels, providing the basis for ARDS development [76]. High leptin levels render patients with obesity susceptible to inflammation and increase their risk of highly severe COVID-19. High leptin levels positively correlate with neutrophilic lung inflammation, lung damage, and ARDS in COVID-19 patients [77]. Thus, obesity is a significant risk factor for the high severity of COVID-19 due to the high leptin and inflammatory factors production, particularly IL-6, by excessive visceral fat.

4.1. Pre-Existing Inflammation

Visceral tissue composition is correlated with metabolic syndrome diseases, such as type 2 diabetes mellitus (T2DM) [78]. High levels of inflammatory factors such as CRP, IL-6, and TNF-α have been detected in obesity, which is attributed to the excessive visceral fat tissue that regulates the body’s metabolism by producing adipokines, chemokines, and various growth factors [79,80]. Thus, subclinical inflammation exists in obesity, creating a suitable environment for other diseases to develop in the long term, such as T2DM [81].

Acute IL-6 upregulation in visceral tissue has been reported in infectious diseases associated with the cytokine storm and various tissue damage [82]. High IL-6 levels often lead to a cytokine storm in COVID-19 patients, particularly those who are obese [83]. The relationship between IL-6 and leptin has been linked to the increased mortality of COVID-19 patients with obesity. High leptin, IL-6, and TNF-α levels have been reported in obesity, which provides a favorable environment for cytokine storms (Figure 3) [84]. Leptin and IL-6 receptors activate the JAK/STAT pathway and increase IL-6 production, causing the phosphorylation of the Akt/PI3K STAT3 signaling pathway [85]. This process triggers the activation of the NF-κB pathway and IL-6 overexpression, giving rise to TNF-α and IL-1 production [86]. Moreover, IL-6 overproduces to increase vascular permeability, resulting in a high viral load [87], intense inflammatory responses, and the overproduction of inflammatory cytokines. This condition activates the TF coagulation pathway, thrombosis, and coagulopathy. This process elucidates the sensitivity of patients with obesity to SARS-CoV-2 infection and their potential vulnerability to the disease severity and mortality. When IL-6 receptor inhibitor (i.e., Tocilizumab) was administered to patients, a reduction in ARDS was observed [88]. In COVID-19 patients with obesity, the dosage of neutralizing antibodies is indiscernible compared to autoimmune antibodies, causing a weak response to infection and high-grade fevers [89].

5. Therapeutic Approach in COVID-19 Patients with Obesity

The development of COVID-19 vaccines has significantly reduced the death toll of this disease worldwide. In general, COVID-19 vaccines can be divided into three types; mRNA, vector, and protein vaccines, all of which target the S protein of the virus[90]. However, there are inter-individual differences in vaccine responses. For example, individuals with obesity were administered with double doses of the BNT162b2 or CoronaVac (Sinovac) vaccine mostly displayed a significantly lower antibody titer than their non-obese counterparts, indicating the poor response of this group to the vaccine [91]. Gender differences in response to the vaccine have also been reported; men with obesity had lower antibody titers compared to women; thus, men are more susceptible to the SARS-CoV-2 infection [92].

Alternatively, inhibition of inflammatory factors, particularly IL-6 and TNF-α, may reduce the severity of COVID-19 in obesity [93]. Lonicera japonica and Astragalus membranaceus have demonstrated inhibitory effects against IL-6 and TNF-α through the upregulation of let-7a, miR-148b, and miR-146a, preventing the cytokine storm in COVID-19 patients [94]. Other IL-6 inhibitors include baricitinib, which reduces the recovery time of COVID-19 patients compared to remdesivir (95% confidence interval [CI], 6 to 8) [95]. In addition, sarilumab binds to the IL-6 receptor and was found to improve the survival of hospitalized patients [96]. Tocilizumab, another IL-6 receptor inhibitor, reduced the mortality of critically ill COVID-19 patients [97]. Administration of IL-6 receptor inhibitors in COVID-19 patients with obesity potentially prevents cytokine storms and improves survival. Therefore, specific treatment strategies for patients with obesity should be established to avoid future complications in this group.

6. Conclusions

Obesity is a risk factor for the highly severe SARS-CoV-2 infection and increases mortality. The primary contributing factors to this condition are pre-subclinical inflammation and high IL-6 levels, which increase one’s risk of severe inflammatory responses by activating inflammatory pathways. These pro-inflammatory factors activate coagulation pathways, such as TF, and provide the basis for thrombosis, DIC, and hypercoagulopathy. Therefore, there is a synergistic interaction between inflammation and coagulation in SARS-CoV-2 infection, whereby inflammation leads to the activation of coagulation cascades. This crosstalk is more severe in COVID-19 patients with obesity, given their background pro-inflammatory state, thus rendering them susceptible to high disease severity and mortality. Inhibiting the inflammatory cytokines IL-6/TNF-α could be a promising treatment option for this group of patients and should be further explored in future studies.