Asthma is associated with enhanced thrombin generation and impaired fibrinolysis, which might contribute to thromboembolic events in this disease.
Background: Airway structural changes are important in asthma pathology and require further investigations.Objective: We sought to evaluate which computed tomography (CT) indices, bronchial histological traits, or blood and bronchoalveolar lavage (BAL) biomarkers correlate best with lung function abnormalities in asthma. Methods:In 105 white adult asthmatics (53 with a component of fixed airflow obstruction), we determined airway cross-sectional geometry of two proximal (the right upper lobe apical segmental and the left apicoposterior) and two distal (the right and the left basal posterior) bronchi, quantified the low-attenuation lung area (LAA%), and analysed clusters based on airway CT-metrics. We also performed bronchofiberoscopy with BAL and endobronchial biopsy, assessed blood and BAL biomarkers, including interleukin (IL)-4, IL-5, IL-6, IL-10, IL-12p70, IL-17A, IL-23, interferon (INF)γ and periostin, together with circulating a disintegrin and metalloproteinase domain-containing protein (ADAM)33, and investigated interplays between analysed variables.Results: Patients with fixed airflow limitation were characterized by lower lumen area and increased wall area and wall thickness ratios in distal airways, accompanied by raised LAA%. They had also higher blood neutrophilia, blood and BAL eosinophilia, increased circulating fibrinogen, periostin, and ADAM33. Blood neutrophilia, serum high density lipoproteins, thyroid-stimulating hormone, and shortened activated partial thromboplastin time were determinants of thicker reticular basement membrane (RBM). BAL eosinophilia was the only positive predictor of collagen I accumulation. Surprisingly, we observed a negative correlation between RBM thickening and collagen I deposit. Cluster analysis based on CT-metrics of the right lower lobe basal posterior bronchus revealed three well-separated clusters similar in age, asthma duration, and BMI, but different in RBM thickness, collagen I accumulation, and inflammatory markers.Conclusions and clinical relevance: Airway remodelling traits are mainly related to the Th 2 profile, higher circulating ADAM33, and blood neutrophilia. Lung function
Recently, we have reported that asthma is associated with enhanced plasma thrombin formation and impaired fibrinolysis. The mechanisms underlying the prothrombotic state in this disease are unknown. Our aim was to investigate whether prothrombotic alterations in asthmatics are associated with inflammation. We studied 164 adult, white, stable asthmatics and 72 controls matched for age, sex, body mass index (BMI), and smoking. Plasma tumor necrosis factor α (TNFα), interleukin (IL)-6, and serum periostin were evaluated using ELISAs, and their associations with thrombin generation, fibrinolytic capacity, expressed as clot lysis time (CLT), and platelet markers were later analyzed. Asthma was characterized by 62% higher plasma IL-6 and 35% higher TNFα (both, p < 0.0001). Inflammatory cytokines were higher in sporadic and persistent asthmatics compared to controls, also after adjustment for potential confounders. IL-6 was inversely related to the forced expiratory volume in 1 s/vital capacity (FEV1/VC) spirometry index after correction for age, sex, and BMI. IL-6 and TNFα were associated with C-reactive protein in asthmatics (β = 0.6 [95% CI, 0.54–0.67] and β = 0.33 [95% CI, 0.25–0.41], respectively) and controls (β = 0.43 [95% CI, 0.29–0.57] and β = 0.33 [95% CI, 0.18–0.48], respectively). In asthma, IL-6 and TNFα positively correlated with the endogenous thrombin potential (β = 0.35 [95% CI, 0.28–0.42] and β = 0.15 [95% CI, 0.07–0.23], respectively) but not with CLT or platelet markers. However, TNFα predicted CLT in a multiple linear regression model. Periostin was not associated with any hemostatic parameters. Enhanced thrombin generation is driven in asthma by a systemic inflammatory state mediated by IL-6 and to a lesser extent TNFα, however, not periostin. TNFα might contribute to impaired fibrinolysis.
Background. Histidine-rich glycoprotein (HRG) displays anticoagulant and antifibrinolytic properties in animal models, but its effects in humans are unclear. We investigated serum HRG levels and their associations with the disease stage and prothrombotic alterations in lung cancer (LC) patients. Methods. In 148 patients with advanced LC prior to anticancer therapy (87 non-small-cell LC and 61 small-cell LC) versus 100 well-matched controls, we measured HRG levels in association with clot permeability (Ks), clot turbidimetry (lag phase and maximum absorbance), and clot lysis time (CLT). Results. Compared to controls, LC patients had 45.9% lower HRG levels with no associations with demographics and comorbidities. Decreased HRG, defined as the 90th percentile of control values (<52.7 μg/ml), was 16 times more common in subjects with than without LC (OR=16.4, 95% CI 9.2-23.5, p<0.01). HRG<38 μg/ml discriminated stage IIIAB/limited disease from IV/extensive disease (ED) LC. In LC patients, HRG correlated inversely with CLT (r=−0.41, p<0.001), but not with other fibrin variables. Among stage IV/ED LC, HRG correlated significantly with Ks and lag phase (r=0.28 and r=0.33, respectively, both p<0.001). LC patients with low Ks (10th percentile of control values) combined with prolonged CLT (90th percentile of control values) had reduced HRG levels compared to the remainder (p=0.003). No such observations were noted in controls. Conclusions. Our study is the first to show that decreased HRG levels occur in advanced LC and are associated with the disease stage and hypofibrinolysis.
Presented study is the first to show increased plasma cellular fibronectin in asthma, which is associated with disease severity, inflammation, and prothrombotic blood alterations. This novel observation suggests a previously unknown modulator of prothrombotic plasma properties in asthmatics.
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