Increased activity of lipoprotein-associated phospholipase A2 in non-severe asthma.

BACKGROUND: Given increased risk of cardiovascular events in asthma we hypothesized that lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme involved in atherosclerosis, is associated with proinflammatory and prothrombotic blood alterations in this disease. METHODS: In 164 adult asthmatics (63 with severe asthma) we measured plasma Lp-PLA2 activity using the PLAC test. We determined its relations to inflammation and prothrombotic blood alterations. RESULTS: In asthma, Lp-PLA2 was inversely related to the age (ß = -0.1 [-0.18 to -0.02]) and was lower in women (n = 122 [74%], 205 [182-242] vs. 243 [203-262] nmol/min/ml, p = 0.001). Interestingly, Lp-PLA2 correlated negatively with the asthma severity score (ß = -0.15 [-0.23 to -0.07]), being 10.3% higher in those with non-severe (mild or moderate) asthma (n = 101, 62%) as compared to the severe disease subtype (224 [191-261] vs. 203 [181-229], p = 0.006 after adjustment for potential confounders). Lp-PLA2 activity was positively related to the levels of low-density lipoprotein (ß = 0.1 [0.02-0.18]), triglycerides (ß = 0.11 [0.03-0.19]) and glucose (ß = 0.1 [0.02-0.18]) and inversely to the tumor necrosis factor α (ß = -0.27 [-0.35 to -0.2]), high sensitivity C-reactive protein (ß = -0.1 [-0.19 to -0.02]) and fibrinogen (ß = -0.12 [-0.21 to -0.03]), as well as prothrombin (ß = -0.16 [-0.24 to -0.08]), and parameters describing thrombin generation potential, such as endogenous thrombin potential (ß = -0.14 [-0.21 to -0.06]) and peak thrombin generated (ß = -0.2 [-0.28 to -0.12]). CONCLUSIONS: Elevated Lp-PLA2 activity in non-severe asthmatics suggests increased atherosclerotic risk in this group. Lower Lp-PLA2 activity accompanied by its inverse relationship to inflammatory or prothrombotic blood biomarkers observed in turn in severe asthmatics might be related to the pathogenesis of more severe asthma phenotype.

Increased blood levels of cellular fibronectin in asthma: Relation to the asthma severity, inflammation, and prothrombotic blood alterations.

BACKGROUND: Recently, we have reported that asthma is characterized by prothrombotic blood alterations, which were related to the low-grade inflammatory state. Inflammation, however, may also lead to vascular dysfunction. The aim of this study was to evaluate plasma levels of cellular fibronectin (cFN), a marker of vascular injury in asthmatics, and to analyze their impact on described previously prothrombotic blood alterations. METHODS: In a cross-sectional study, we investigated 164 adult stable asthmatics and 72 matched controls. Plasma cFN was measured using an ELISA. Its relations to inflammation, thrombin generation, fibrinolytic capacity, expressed as clot lysis time (CLT), and platelet markers were evaluated. RESULTS: Asthma was associated with 50.1% higher plasma cFN levels as compared with controls (p < 0.001, after adjustment for potential confounders). There was a positive association of cFN with asthma severity and inverse with the FEV1/VC index (ß = 0.2 [95%CI:0.13-0.28] and ß = -0.15 [95%CI: -0.23 to -0.07], respectively). In asthmatics cFN positively correlated with high-sensitivity C-reactive protein (ß = 0.24 [95%CI:0.16-0.32]), fibrinogen (ß = 0.13 [95%CI:0.04-0.21]), interleukin-6 (ß = 0.23 [95%CI:0.15-0.3]), platelet factor 4 (ß = 0.14 [95%CI:0.06-0.21]), plasminogen (ß = 0.11 [95%CI:0.04-0.19]) and CLT (ß = 0.35 [95%CI:0.28-0.42]). In both groups cFN was related to the endogenous thrombin potential (ETP) (ß = 0.51 [95%CI:0.44-0.57], and ß = 0.17 [95%CI:0.07-0.27], respectively). Multiple regression models showed that cFN was the most potent independent predictor of both ETP and CLT in asthmatics. CONCLUSION: 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.

Impaired fibrinolysis and lower levels of plasma α2-macroglobulin are associated with an increased risk of severe asthma exacerbations.

Recently we have reported that asthma is associated with enhanced plasma thrombin formation, impaired fibrinolysis and platelet activation. In the present study we investigated whether described prothrombotic blood alterations might predispose to thromboembolic events or asthma exacerbations. In 164 adult asthmatics we assessed clinical events during 3-year follow-up and analyzed their associations with measured at baseline prothrombotic blood parameters. Data were obtained from 157 (95.7%) of the asthma patients. We documented 198 severe asthma exacerbations (64/year), which occurred in 53 subjects (34%). These patients were older (p = 0.004), had worse asthma control (p = 0.02) and lower spirometry values (p = 0.01), at baseline. Interestingly, this subgroup had longer clot lysis time (CLT), as well as lower α2-macroglobulin (p = 0.038 and p = 0.04, respectively, after adjustment for potential confounders). Increased CLT and lower α2-macroglobulin were demonstrated as independent predictors of asthma exacerbation in multiple regression model. Moreover, we documented two episodes of deep vein thrombosis (1.3%), and eight acute coronary syndromes (5.1%). Patients who experienced thromboembolic events (n = 10, 6.4%, 2.1%/year) had lower α2-macroglobulin (p = 0.04), without differences in efficiency of fibrinolysis and thrombin generation. Impaired fibrinolysis and lower levels of α2-macroglobulin might predispose to a higher rate of asthma exacerbations, suggesting new links between disturbed hemostasis and asthma.

Prothrombotic State in Asthma Is Related to Increased Levels of Inflammatory Cytokines, IL-6 and TNFα, in Peripheral Blood.

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 (ß = 0.6 [95% CI, 0.54-0.67] and ß = 0.33 [95% CI, 0.25-0.41], respectively) and controls (ß = 0.43 [95% CI, 0.29-0.57] and ß = 0.33 [95% CI, 0.18-0.48], respectively). In asthma, IL-6 and TNFα positively correlated with the endogenous thrombin potential (ß = 0.35 [95% CI, 0.28-0.42] and ß = 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.

Incidence of aspirin hypersensitivity in patients with chronic rhinosinusitis and diagnostic value of urinary leukotriene E4.

INTRODUCTION: Chronic rhinosinusitis (CRS) with nasal polyposis (NP) may be associated with hypersensitivity to nonsteroidal anti-inflammatory drugs, representing a syndrome of aspirin-exacerbated respiratory disease (AERD). OBJECTIVES: The aim of the study was to validate a simple measurement of urinary leukotriene E4 (uLTE4) excretion for the diagnosis of AERD in patients with CRS and indication for surgery. PATIENTS AND METHODS: Subjects requiring functional endoscopic sinus surgery (FESS) were recruited from the Department of Otolaryngology (n = 24). Before surgery, a standard oral placebo-controlled aspirin challenge was performed to diagnose aspirin hypersensitivity. Urine samples were collected on the placebo day and both before and within 2 to 4 hours after aspirin challenge for uLTE4 measurement. RESULTS: All patients with CRS had sinusitis confirmed by computed tomography. Previous ear, nose, and throat surgery was performed in 70% of the patients, NP was present in 86%, and asthma was diagnosed in 62.5%. AERD was diagnosed in 8 subjects (7 women and 1 man). Five of those patients had bronchoconstriction. At baseline, median uLTE4 was 7.5-times higher in AERD subjects than in the remaining patients. It increased almost 6-fold following the challenge, while remained unchanged in patients without aspirin hypersensitivity. Pretest uLTE4 had a sensitivity of 87.5% and specificity of 93.75% to diagnose aspirin hypersensitivity in patients with CRS. After the challenge, the values improved to 100% sensitivity and 93% specificity. CONCLUSIONS: Among CRS subjects requiring FESS, as many as 33.3% may have AERD and respond to a small provocative dose of aspirin with bronchoconstriction and/or mucosal and skin edema. A simple and inexpensive measurement of uLTE4 can help diagnose AERD in patients with CRS with sensitivity of 87.5%, but its specificity is limited and depends on the arbitrary threshold of uLTE4.