Assessment of endogenous fibrinolysis in clinical using novel tests - Ready for clinical roll-out?

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The occurrence of thrombotic complications, which can result in excess mortality and morbidity, represent an imbalance between the pro-thrombotic and fibrinolytic equilibrium.The mainstay treatment of these complications involves the use of antithrombotic agents but despite advances in pharmacotherapy, there remains a significant proportion of patients who continue to remain at risk.Endogenous fibrinolysis is a physiological counter-measure against lasting thrombosis and may be measured using several techniques to identify higher risk patients who may benefit from more aggressive pharmacotherapy. However, the assessment of the fibrinolytic systemis not yet accepted into routine clinical practice.In this review, we will revisit the different methods of assessing endogenous fibrinolysis (factorial assays, turbidimetric lysis assays, viscoelastic and the global thrombosis tests), including the strengths, limitations, correlation to clinical outcomes of each method and howwe might integrate the assessment of endogenous fibrinolysis into clinical practice in the future.Peer reviewedFinal Published versio

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Sputum microbiomic clustering in asthma and COPD reveals a Haemophilus‐predominant subgroup

BACKGROUND:Airway ecology is altered in asthma and chronic obstructive pulmonary disease (COPD). Anti-microbial interventions might have benefit in subgroups of airway disease. Differences in sputum microbial profiles at acute exacerbation of airways disease are reflected by the γProteobacteria:Firmicutes (γP:F) ratio. We hypothesized that sputum microbiomic clusters exist in stable airways disease, which can be differentiated by the sputum γP:F ratio. METHODS:Sputum samples were collected from 63 subjects with severe asthma and 78 subjects with moderate-to-severe COPD in a prospective single centre trial. Microbial profiles were obtained through 16S rRNA gene sequencing. Topological data analysis was used to visualize the data set and cluster analysis performed at genus level. Clinical characteristics and sputum inflammatory mediators were compared across the clusters. RESULTS:Two ecological clusters were identified across the combined airways disease population. The smaller cluster was predominantly COPD and was characterized by dominance of Haemophilus at genus level (n = 20), high γP:F ratio, increased H influenzae, low diversity measures and increased pro-inflammatory mediators when compared to the larger Haemophilus-low cluster (n = 121), in which Streptococcus demonstrated the highest relative abundance at the genus level. Similar clusters were identified within disease groups individually and the γP:F ratio consistently differentiated between clusters. CONCLUSION:Cluster analysis by airway ecology of asthma and COPD in stable state identified two subgroups differentiated according to dominance of Haemophilus. The γP:F ratio was able to distinguish the Haemophilus-high versus Haemophilus-low subgroups, whether the Haemophilus-high group might benefit from treatment strategies to modulate the airway ecology warrants further investigation

Severe exacerbations in moderate-to-severe asthmatics are associated with increased pro-inflammatory and type 1 mediators in sputum and serum.

BACKGROUND: Asthma is a heterogeneous disease and understanding this heterogeneity will enable the realisation of precision medicine. We sought to compare the sputum and serum inflammatory profiles in moderate-to-severe asthma during stable disease and exacerbation events. METHODS: We recruited 102 adults and 34 children with asthma. The adults were assessed at baseline, 3, 6, and 12-month follow-up visits. Thirty-seven subjects were assessed at onset of severe exacerbation. Forty sputum mediators and 43 serum mediators were measured. Receiver-operator characteristic (ROC) curves were constructed to identify mediators that distinguish between stable disease and exacerbation events. The strongest discriminating sputum mediators in the adults were validated in the children. RESULTS: The mediators that were significantly increased at exacerbations versus stable disease and by ≥1.5-fold were sputum IL-1β, IL-6, IL-6R, IL-18, CXCL9, CXCL10, CCL5, TNFα, TNF-R1, TNF-R2, and CHTR and serum CXCL11. No mediators decreased ≥1.5-fold at exacerbation. The strongest discriminators of an exacerbation in adults (ROC area under the curve [AUC]) were sputum TNF-R2 0.69 (95% CI: 0.60 to 0.78) and IL-6R 0.68 (95% CI: 0.58 to 0.78). Sputum TNF-R2 and IL-6R were also discriminatory in children (ROC AUC 0.85 [95% CI: 0.71 to 0.99] and 0.80 [0.64 to 0.96] respectively). CONCLUSIONS: Severe asthma exacerbations are associated with increased pro-inflammatory and Type 1 (T1) immune mediators. In adults, sputum TNF-R2 and IL-6R were the strongest discriminators of an exacerbation, which were verified in children