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Background There is evidence that altered blood coagulation and fibrinolysis are involved in the pathogenesis of asthma. Increased thromboembolic risk has been reported in asthmatics. Objective To investigate whether enhanced thrombin generation and impaired fibrinolysis occur in asthmatics. Methods Plasma thrombin generation profile together with a computational assessment of thrombin dynamics and fibrinolytic capacity expressed as clot lysis time ( CLT) were determined in 164 consecutive patients with stable asthma and 72 controls matched for age, gender, weight and smoking. Results Asthma patients had 20.2% increased endogenous thrombin potential ( ETP), 41.4% higher peak thrombin concentration, 61% higher maximal prothrombin conversion rate, 15.5% faster rate of thrombin formation (all, P < 0.0001) and 10% lower thrombin decay capacity ( P = 0.0004) compared with controls. Asthmatics had also 14.4% longer CLT ( P = 0.001) associated with 21.3% higher plasminogen activator inhibitor-1 ( PAI-1) ( P < 0.0001), and 13% higher plasma α2-macroglobulin ( P = 0.0002). Using ETP and CLT above 75th percentile of the control values as the cut-off levels, we found increased risks of enhanced thrombin generation and hypofibrinolysis in asthmatics, also after correction for potential confounders. ETP and CLT were associated inversely with forced expiratory volume in 1 s/vital capacity ( FEV1/ VC) index, after adjustment for age and body mass index. Non-allergic asthma ( n = 70, 42.6%) was characterized by 17.5% longer CLT ( P = 0.02), which positively associated with PAI-1. Thrombin generation profile was not affected by allergy. Conclusion and Clinical Relevance Asthma is associated with enhanced thrombin generation and impaired fibrinolysis, which might contribute to thromboembolic events in this disease. [ABSTRACT FROM AUTHOR]

Background Eosinophils are one of the major effector cells in bronchial asthma. Their infiltration of airways correlates with the asthma severity. Recruitment and activation of eosinophils are partially mediated by integrins α4β1 and α4β7. Collagens type I and IV constitute important components of extracellular matrix and vascular basement membrane, respectively. Therefore, collagen-binding integrins (α1β1 and α2β1) may also play a role in eosinophil lung infiltration. Objective To evaluate the possible presence of α1β1 and α2β1 integrins on peripheral blood eosinophils from asthmatic subjects. Methods Collagen receptors were studied on eosinophils separated by immunomagnetic CD16-negative method from healthy donors ( n=13) and patients with moderate persistent atopic bronchial asthma ( n=15). Surface receptor identification was performed by flow cytometry and cell adhesion assay. Results Eosinophils isolated from the patients showed increased expression of both α1β1 and α2β1 integrins as compared with healthy controls. Moreover, adhesive function of eosinophils to collagen type IV was inhibited by snake venom disintegrins: viperistatin and obtustatin. These disintegrins contain KTS active motif and are specific inhibitors of α1β1 integrin. Conclusion We demonstrated for the first time that collagen receptors: α1β1 and α2β1 integrins are overexpressed on the surface of peripheral blood eosinophils of asthmatic subjects. Further studies may reveal potential application of KTS-disintegrins or their structural analogs for therapy of bronchial asthma. [ABSTRACT FROM AUTHOR]

Aspirin-induced asthma (AIA), a distinct clinical syndrome, affects about 10% of adult asthmatics. Attacks of asthma precipitated by aspirin are related to the inhibition of cyclo-oxygenase in the lungs of sensitive patients, and not to the body's reaction to the allergen. Immunologic mechanisms may, however, become involved in the course of the disease. Recently, signs of autoimmunity have been observed in some patients with AIA. A 46-year-old woman had been in good health until the age of 21, when she developed chronic watery rhinitis.

Background: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract., Methods: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid., Results: MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline., Conclusions: The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy., (© 2024 Genentech and The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)