Imbalanced Coagulation in the Airway of Type-2 High Asthma with Comorbid Obesity

Abstract

Asthma is a common, chronic airway inflammatory disease marked by airway hyperresponsiveness, inflammation, and remodeling. Asthma incidence has increased rapidly in the past few decades and recent multicenter analyses have revealed several unique asthma endotypes. Of these, type-2 high asthma with comorbid obesity presents a unique clinical challenge marked by increased resistance to standard therapies and exacerbated disease development. The extrinsic coagulation pathway plays a significant role in both type-2 high asthma and obesity. The type-2 high asthma airway is marked by increased procoagulant potential, which is readily activated following damage to airway tissue. In this review, we summarize the current understanding of the role the extrinsic coagulation pathway plays in the airway of type-2 high asthma with comorbid obesity. We propose that asthma control is worsened in obesity as a result of a systemic and local airway shift towards a procoagulant and anti-fibrinolytic environment. Lastly, we hypothesize bariatric surgery as a treatment for improved asthma management in type-2 high asthma with comorbid obesity, facilitated by normalization of systemic procoagulant and pro-inflammatory mediators. A better understanding of attenuated coagulation parameters in the airway following bariatric surgery will advance our knowledge of biomolecular pathways driving asthma pathobiology in patients with obesity.

Keywords: asthma; bariatric surgery; coagulation; extrinsic pathway; inflammation; obesity.

Figure 1

Extrinsic Coagulation Cascade in Response to Allergen Exposure-Induced Airway Damage Allergen exposure and/or tissue damage initiates the extrinsic coagulation pathway in the extravascular compartments of the airway. Downstream activation via antigen presenting cells (APCs) promotes clinical features of asthma pathobiology, including AHR, airway inflammation, and fibrosis. In Type 2-high asthma with comorbid obesity, the pathway becomes imbalanced, favoring pro-coagulation (black) and anti-fibrinolysis (blue). The above figure is used to exemplify the coagulation pathway. Created with BioRender.com.

Figure 2

Coagulation and Inflammatory Mediators Promoting Asthma Pathophysiology Increased adiposity promotes pro-inflammatory cytokine and adipokine production leading to chronic low-grade systemic inflammation. These mediators augment procoagulant factor production, contributing to increased asthma pathogenesis in Type-2 high asthma with comorbid obesity. Additionally, the impact of IL-6, TNF-α, IL-1β, monocyte chemoattractant protein-1 (MPC-1), and free fatty acids (FFAs) leads to insulin resistance, hepatic steatosis, and non-alcoholic fatty liver disease. In response to upregulated mediators, the airway experiences increased leukocyte infiltration, fibrosis, narrowing, mucin production, angiogenesis and hyperresponsiveness. The figure only includes coagulation mediators of the extrinsic and common pathway; the intrinsic coagulation mediators are beyond the scope of this review. Red arrows indicates contribution to worsening asthma and green arrows indicate improvement in asthma. Created with BioRender.com.