Admission Viscoelastic Hemostatic Assay Parameters Predict Poor Long-Term Intracerebral Hemorrhage Outcomes.

BACKGROUND: Viscoelastic hemostatic assays (VHAs) provide more comprehensive assessments of coagulation compared with conventional coagulation assays. Although VHAs have enabled guided hemorrhage control therapies, improving clinical outcomes in life-threatening hemorrhage, the role of VHAs in intracerebral hemorrhage (ICH) is unclear. If VHAs can identify coagulation abnormalities relevant for ICH outcomes, this would support the need to investigate the role of VHAs in ICH treatment paradigms. Thus, we investigated whether VHA assessments of coagulation relate to long-term ICH outcomes. METHODS: Patients with spontaneous ICH enrolled into a single-center cohort study receiving admission Rotational Thromboelastometry (ROTEM) VHA testing between 2013 and 2020 were assessed. Patients with previous anticoagulant use or coagulopathy on conventional coagulation assays were excluded. Primary ROTEM exposure variables were coagulation kinetics and clot strength assessments. Poor long-term outcome was defined as modified Rankin Scale ≥ 4 at 6 months. Logistic regression analyses assessed associations of ROTEM parameters with clinical outcomes after adjusting for ICH severity and hemoglobin concentration. RESULTS: Of 44 patients analyzed, the mean age was 64 years, 57% were female, and the median ICH volume was 23 mL. Poor 6-month outcome was seen in 64% of patients. In our multivariable regression models, slower, prolonged coagulation kinetics (adjusted odds ratio for every second increase in clot formation time 1.04, 95% confidence interval 1.00-1.09, p = 0.04) and weaker clot strength (adjusted odds ratio for every millimeter increase of maximum clot firmness 0.84, 95% confidence interval 0.71-0.99, p = 0.03) were separately associated with poor long-term outcomes. CONCLUSIONS: Slower, prolonged coagulation kinetics and weaker clot strength on admission VHA ROTEM testing, not attributable to anticoagulant use, were associated with poor long-term outcomes after ICH. Further work is needed to clarify the generalizability and the underlying mechanisms of these VHA findings to assess whether VHA-guided treatments should be incorporated into ICH care.

Admission viscoelastic hemostatic assay parameters predict poor long-term intracerebral hemorrhage outcomes.

Background: Viscoelastic hemostatic assays (VHA) provide more comprehensive assessments of coagulation compared to conventional coagulation assays. While VHAs have enabled guided hemorrhage control therapies, improving clinical outcomes in life-threatening hemorrhage, the role of VHAs in intracerebral hemorrhage (ICH) is unclear. If VHAs can identify coagulation abnormalities relevant for ICH outcomes, this would support the need to investigate the role of VHAs in ICH treatment paradigms. Thus, we investigated whether VHA assessments of coagulation relate to long-term ICH outcomes. Methods: Spontaneous ICH patients enrolled into a single-center cohort study receiving admission Rotational Thromboelastometry (ROTEM) VHA testing between 2013 and 2020 were assessed. Patients with prior anticoagulant use or coagulopathy on conventional coagulation assays were excluded. Primary ROTEM exposure variables were coagulation kinetics and clot strength assessments. Poor long-term outcome was defined as modified Rankin Scale ≥ 4 at 6 months. Logistic regression analyses assessed associations of ROTEM parameters with clinical outcomes after adjusting for ICH severity and hemoglobin concentration. Results: Of 44 patients analyzed, mean age was 64, 57% were female, and the median ICH volume was 23 mL. Poor 6-month outcome was seen in 64%. In our multivariable regression models, slower, prolonged coagulation kinetics (adjusted OR for every second increase in clot formation time: 1.04, 95% CI: 1.00-1.09, p = 0.04) and weaker clot strength (adjusted OR for every millimeter increase of maximum clot firmness: 0.84, 95% CI: 0.71-0.99, p = 0.03) were separately associated with poor long-term outcomes. Conclusions: Slower, prolonged coagulation kinetics and weaker clot strength on admission VHA ROTEM testing, not attributable to anticoagulant use, were associated with poor long-term outcomes after ICH. Further work is needed to clarify the generalizability and the underlying mechanisms of these VHA findings to assess whether VHA guided treatments should be incorporated into ICH care.

Genetic analyses support the contribution of mRNA N6-methyladenosine (m6A) modification to human disease heritability.

N6-methyladenosine (m6A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m6A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m6A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m6A QTLs are largely independent of expression and splicing QTLs and are enriched with binding sites of RNA-binding proteins, RNA structure-changing variants and transcriptional features. Joint analysis of the QTLs of m6A and related molecular traits suggests that the downstream effects of m6A are heterogeneous and context dependent. We identified proteins that mediate m6A effects on translation. Through integration with data from genome-wide association studies, we show that m6A QTLs contribute to the heritability of various immune and blood-related traits at levels comparable to splicing QTLs and roughly half of expression QTLs. By leveraging m6A QTLs in a transcriptome-wide association study framework, we identified putative risk genes of these traits.

A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation.

DNA 5-hydroxymethylcytosine (5hmC) modification is known to be associated with gene transcription and frequently used as a mark to investigate dynamic DNA methylation conversion during mammalian development and in human diseases. However, the lack of genome-wide 5hmC profiles in different human tissue types impedes drawing generalized conclusions about how 5hmC is implicated in transcription activity and tissue specificity. To meet this need, we describe the development of a 5hmC tissue map by characterizing the genomic distributions of 5hmC in 19 human tissues derived from ten organ systems. Subsequent sequencing results enabled the identification of genome-wide 5hmC distributions that uniquely separates samples by tissue type. Further comparison of the 5hmC profiles with transcriptomes and histone modifications revealed that 5hmC is preferentially enriched on tissue-specific gene bodies and enhancers. Taken together, the results provide an extensive 5hmC map across diverse human tissue types that suggests a potential role of 5hmC in tissue-specific development; as well as a resource to facilitate future studies of DNA demethylation in pathogenesis and the development of 5hmC as biomarkers.