Abstract
BackgroundAsthma exacerbations are frequently triggered by rhinovirus infections. Both asthma and respiratory tract infection can activate haemostasis. Therefore we hypothesized that experimental rhinovirus-16 infection and asthmatic airway inflammation act in synergy on the haemostatic balance.Methods28 patients (14 patients with mild allergic asthma and 14 healthy non-allergic controls) were infected with low-dose rhinovirus type 16. Venous plasma and bronchoalveolar lavage fluid (BAL fluid) were obtained before and 6 days after infection to evaluate markers of coagulation activation, thrombin-antithrombin complexes, von Willebrand factor, plasmin-antiplasmin complexes, plasminogen activator inhibitor type-1, endogenous thrombin potential and tissue factor-exposing microparticles by fibrin generation test, in plasma and/or BAL fluid. Data were analysed by nonparametric tests (Wilcoxon, Mann Whitney and Spearman correlation).Results13 patients with mild asthma (6 females, 19-29 y) and 11 healthy controls (10 females, 19-31 y) had a documented Rhinovirus-16 infection. Rhinovirus-16 challenge resulted in a shortening of the fibrin generation test in BAL fluid of asthma patients (t = -1: 706 s vs. t = 6: 498 s; p = 0.02), but not of controls (t = -1: 693 s vs. t = 6: 636 s; p = 0.65). The fold change in tissue factor-exposing microparticles in BAL fluid inversely correlated with the fold changes in eosinophil cationic protein and myeloperoxidase in BAL fluid after virus infection (r = -0.517 and -0.528 resp., both p = 0.01).Rhinovirus-16 challenge led to increased plasminogen activator inhibitor type-1 levels in plasma in patients with asthma (26.0 ng/mL vs. 11.5 ng/mL in healthy controls, p = 0.04). Rhinovirus-16 load in BAL showed a linear correlation with the fold change in endogenous thrombin potential, plasmin-antiplasmin complexes and plasminogen activator inhibitor type-1.ConclusionsExperimental rhinovirus infection induces procoagulant changes in the airways of patients with asthma through increased activity of tissue factor-exposing microparticles. These microparticle-associated procoagulant changes are associated with both neutrophilic and eosinophilic inflammation. Systemic activation of haemostasis increases with Rhinoviral load.Trial registrationThis trial was registered at the Dutch trial registry (http://www.trialregister.nl): NTR1677.
Highlights
It is increasingly recognized that inflammation and haemostasis are interdependent and closely linked processes that can stimulate each other [1,2]
Local activation of coagulation may be clinically relevant for asthmatic individuals, because we have recently shown that the risk of pulmonary embolism (PE) is increased in severe asthma [12]
Out of the 28 patients infected with rhinovirus type 16 (RV16), 13 patients with mild asthma and 11 healthy control subjects had a positive Polymerase chain reaction (PCR) at day 6 and/or a serologic conversion for RV16 at day 42
Summary
It is increasingly recognized that inflammation and haemostasis are interdependent and closely linked processes that can stimulate each other [1,2]. Many chronic inflammatory diseases, including inflammatory bowel diseases [3,4], rheumatic arthritis [5,6], COPD [7,8,9], and sarcoidosis [10], are associated with increased coagulability of blood. This procoagulant state has been observed in the airways of patients with stable asthma as reflected by increased levels of tissue factor (TF), thrombin-antithrombin complexes (TATc) and the plasminogen activator inhibitor-1 (PAI-1), as well as decreased levels of the natural anticoagulant protein C [11]. We hypothesized that experimental rhinovirus-16 infection and asthmatic airway inflammation act in synergy on the haemostatic balance
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