Are markers of fibrin turnover in blood and urine increased before and during exacerbation of asthma?
Student thesis: Doctoral Thesis
INTRODUCTION: Asthma is a chronic inflammatory disorder of the airways punctuated by acute exacerbations. Coagulation and fibrinolysis pathways are increasingly recognised in the asthmatic inflammatory milieu and markers of fibrin turnover represent potential asthma biomarkers targets. A biomarker in plasma or urine predicting exacerbation could enable early intervention to attenuate or prevent exacerbation. STUDY DESIGN: A study in 2 parts comparing exacerbation and stable asthma was performed. Part 1 compared adults with exacerbations requiring hospital treatment to clinical recovery. Part 2 prospectively followed a cohort of adult moderate to severe asthmatics when well until exacerbation and through to clinical recovery. METHODS: Plasma was analysed by ELISA for markers of fibrin turnover alongside inflammatory and cellular markers, and comparison was made between exacerbation and recovery. Urine was analysed by latex agglutination for fibrin(ogen) degradation products (FDPs). Symptoms were recorded and a score was derived to distinguish asthma exacerbation from baseline and recovery states. Comparison was made between exacerbation and recovery using multivariate statistical analysis. KEY FINDINGS: Prospectively, the detection of FDP in urine significantly increased the likelihood of subsequent asthma exacerbation in the following 7-14 days between 4 and 6 times that of a negative urine FDP test. FDP +7 days (OR 4.35 (95% CI 1.12, 16.9) p=0.03), FDP +10 days (OR 5.50 (95% CI 1.38, 21.9) p=0.02), FDP +14 days (OR 6.07 (95% CI 1.43, 25.8) p=0.02). Plasma D-dimer was significantly increased from baseline to exacerbation (median 0.07 μgFEU/ml (95% CI -0.01, 0.15) p=0.02). Plasma eosinophils (median 10*9/l (95% CI 0.10, 0.29) p=0.02) and eotaxin (median 12 pg/ml (95% CI 3, 22) p<0.001) increased significantly from exacerbation to recovery, and PF4 significantly increased from exacerbation to follow up (median 9 μg/ml (95 % CI 2, 17), p=0.002). Positive correlations were observed at exacerbation between eosinophils and eotaxin (p<0.001), platelets and PF4 (p=0.02) and platelets and eosinophils (p=0.01). Clinical symptoms and reliever use increased in the 10 days preceding exacerbation and reduced during recovery (p<0.001). CONCLUSIONS: This is the largest study to date examining coagulation and fibrinolysis in acute exacerbation of asthma. Detection of urine FDP in moderate to severe asthma suggests up to 6-fold increased exacerbation risk in the subsequent 14 days. The potential to translate these findings into a point-of-care test for use by patients at home warrants further study. Positive correlations between eosinophils, eotaxin, platelets and platelet factor 4 (PF4) alongside increased PF4, eosinophils and eotaxin in plasma after a period of recovery and treatment support eosinophil and platelet migration into the lung during asthma exacerbation. The symptom score used in this study provides a simple objective measure of asthma exacerbation for use in future research or clinical practice but requires prospective validation.
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