ABSTRACT: As part of the Bloodomics collaboration we have several categories of pedigrees with diseases/syndromes relevant to cardiovascular diseases (CVD). One such group, is from individuals who exhibit severe bleeding with an unknown cause. Exome sequencing has been performed as part of a discovery program to ascertain potential causative variants of the clinical phenotype.
Project description:As part of the Bloodomics collaboration we have several categories of pedigrees with diseases/syndromes relevant to cardiovascular diseases (CVD). One such pedigree, hyperfibrinolysis is associated with increased fibrinolytic activity, resulting in increased bleeding. Exome sequencing has been performed as part of a discovery program to ascertain potential causative variants of the clinical phenotype.
Project description:As part of the Bloodomics collaboration we have several categories of pedigrees with diseases/syndromes relevant to cardiovascular diseases (CVD). One such pedigree, Grey Platelet Syndrome (GPS) is a rare congenital bleeding disorder caused by a reduction or absence of alpha granules in platelets. Exome sequencing has been performed as part of a discovery program to ascertain potential causative variants of the clinical phenotype.
Project description:As part of the Bloodomics collaboration we have several categories of pedigrees with diseases/syndromes relevant to cardiovascular diseases (CVD). One such pedigree, is from families who have a platelet collagen defect. Exome sequencing has been performed as part of a discovery program to ascertain potential causative variants of the clinical phenotype.
Project description:As part of the Bloodomics collaboration we have several categories of pedigrees with diseases/syndromes relevant to cardiovascular diseases (CVD). One such group, is from individuals who have a platelet disorder with an unknown cause. Exome sequencing has been performed as part of a discovery program to ascertain potential causative variants of the clinical phenotype.
Project description:Bleeding risk represents a major concern in anticoagulated patients with atrial fibrillation (AF). Several bleeding prediction scores have been described: HAS-BLED, ATRIA, HEMORR2HAGES and ORBIT. Of these, only HAS-BLED considers quality of anticoagulation control amongst vitamin K antagonist (VKA) users. We hypothesised that predictive value of bleeding risk scores other than HAS-BLED could be improved incorporating time in therapeutic range (TTR) in warfarin-treated patients. Of the 127 adjudicated major bleeding events, 21.3% of events occurred in 'low-risk' HAS-BLED category (1.8 per 100 patient-years), compared to higher proportions (?50% of events; ~2.5 per 100 patient-years) in 'low-risk' categories for other scores. Only the 'low-risk' HAS-BLED category was associated with the absence of investigator-defined major bleeding events (OR: 1.46;95% CI: 1.00-2.15). 'High' or 'medium/high' risk categories for the HAS-BLED (p?=?0.023) or ORBIT (p?=?0.022) scores, respectively, conferred significant risk for adjudicated major bleeding events. On Cox regression analysis, adjudicated major bleeding was associated only with HAS-BLED (HR: 1.62;95% CI: 1.06-2.48) and ORBIT (HR: 1.83;95% CI: 1.08-3.09) 'high-risk' categories. Adding 'labile INR' (TTR?<?65%) to ORBIT, ATRIA and HEMORR2HAGES significantly improved their reclassification and discriminatory performances. In conclusion, HAS-BLED categorised adjudicated major bleeding events in low-risk and high-risk patients appropriately, whilst ORBIT and ATRIA categorised most major bleeds into their 'low-risk' patient categories. Adding TTR to ORBIT, ATRIA and HEMORR2HAGES led to improved predictive performance for major bleeding.
Project description:Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterized. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in 3 pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5422 controls. Eleven cases harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included 5 high-impact variants predicted to prevent CalDAG-GEFI expression and 6 missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signaling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical, and dental bleeding from childhood, requiring ≥1 blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to adenosine 5'-diphosphate and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a nonsyndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.
Project description:Importance:A decision to initiate aspirin therapy for primary prevention of cardiovascular disease (CVD) requires consideration of both treatment benefits and harms. The most significant harm associated with aspirin is major bleeding, yet there is a paucity of data on bleeding risk in suitable community populations. Objective:To determine the risk of major bleeding among people without CVD who are not receiving antiplatelet therapy. Design, Setting, and Participants:Prospective cohort study of 359?166 individuals aged 30 to 79 years receiving primary care in New Zealand who had CVD risk assessment between 2002 and 2015. Participants were censored at the earliest date on which they had a first major bleeding event, died, or met any baseline cohort exclusion criteria or the study end date of December 31, 2015. Analyses were repeated after excluding people with medical conditions associated with increased bleeding risk (non-high-risk cohort; n=305?057) and after further excluding people receiving other medications associated with increased bleeding risk (nonmedication cohort; n=240?254). Exposures:Sex and age group in 10-year bands from 30 to 79 years. Main Outcomes and Measures:Risk of a major bleeding event (hospitalization or death associated with bleeding); nonfatal gastrointestinal tract bleeding; and gastrointestinal tract bleeding-related case fatality. Results:Mean participant age was 54 years (SD, 10 years), 44% were women, and 57% were European. Among the 359?166 individuals in the baseline cohort, 3976 had a major bleeding event during 1?281?896 person-years of follow-up. Most had gastrointestinal (GI) bleeding (n=2910 [73%]). There were 274 fatal bleeding events (7%), of which 153 were intracerebral. The risk of a nonfatal GI bleeding event per 1000 person-years was 2.19 (95% CI, 2.11-2.27), 1.77 (95% CI, 1.69-1.85) and 1.61 (95% CI, 1.52-1.69), in the baseline, non-high-risk, and nonmedication cohorts, respectively. Case fatality associated with GI bleeding was 3.4% (95% CI, 2.2%-4.1%), 4.0% (95% CI, 3.2%-5.1%), and 4.6% (95% CI, 3.6%-6.0%) in the baseline, non-high-risk, and nonmedication cohorts, respectively. Conclusions and Relevance:In a population not receiving antiplatelet therapy, the annual risk of major bleeding events and nonfatal major bleeding was estimated. These findings could inform population-level guidelines for primary prevention of CVD.
Project description:OBJECTIVE:To ascertain the genetic and clinical characteristics of the GGCCTG hexanucleotide repeat expansion in the nucleolar protein 56 gene (NOP56) in patients with spinocerebellar ataxia (SCA), sporadic ataxia, or amyotrophic lateral sclerosis (ALS) in Taiwan. METHODS:We conducted clinical and molecular genetic studies of 109 probands with molecularly unassigned SCA from 512 SCA pedigrees, 323 healthy controls, 502 patients with sporadic ataxia syndromes, and 144 patients with ALS. Repeat-primed PCR assays and PCR-fragment analysis for the number of short hexanucleotide repeats (<40 units) were performed to ascertain NOP56 hexanucleotide repeat expansion. Genotyping included 8 microsatellite markers and 17 single nucleotide polymorphisms flanking NOP56 and covering a region of 1.8 Mb to assess a possible founder effect. RESULTS:Eleven individuals from 3 SCA pedigrees have the NOP56 repeat expansions. The 3 pedigrees share a common haplotype spanning 5.3 kb flanking the NOP56 repeat expansions, suggesting a founder effect of spinocerebellar ataxia type 36 (SCA36) in the Han Chinese. The average age at symptom onset was 44.8 ± 3.8 years with truncal ataxia as the initial manifestation. Common features included slowly progressive truncal/limb ataxia, dysarthria, generalized hyperreflexia, and hearing impairment. Evidence of lower motor neuron involvement, including atrophy and fasciculation in the limb muscles and tongue, was mostly found in patients with prolonged disease duration. NOP56 repeat expansion was not detected in controls or patients with sporadic ataxic syndromes or ALS. CONCLUSIONS:SCA36 is an uncommon subtype, which accounted for 0.6% (3/512) of SCA cases in the Han Chinese population.
Project description:BACKGROUND:We compared the risk of bleeding and cardiovascular disease (CVD) events between non-vitamin K antagonist oral anticoagulant (NOAC) and warfarin in people with type 2 diabetes (T2DM). METHODS:862 Incident NOAC users and 626 incident warfarin users with T2DM were identified from within 40 UK general practice (1/4/2017-30/9/2018). Outcomes included incident hospitalisation for bleeding, CVD and re-hospitalisation for CVD within 12 months since first anticoagulant prescription, identified from linked hospitalisation data. A tapered matching method was applied to form comparison cohorts: coarsened exact matching restricted the comparison to areas of sufficient overlap in missingness and characteristics: (i) demographic characteristics; (ii) clinical measurements; (iii) prior bleeding and CVD history; (iv) prescriptions with bleeding; (v) anti-hypertensive treatment(s); (vi) anti-diabetes treatment(s). Entropy balancing sequentially balanced NOAC and warfarin users on their distribution of (i-vi). Weighted logistic regression modelling estimated outcome odds ratios (ORs), using entropy balancing weights from steps i-vi. RESULTS:The 12-month ORs of bleeding with NOAC (n?=?582) vs matched/balanced warfarin (n?=?486) were 1.93 (95% confidence interval 0.97-3.84), 2.14 (1.03-4.44), 2.31 (1.10-4.85), 2.42 (1.14-5.14), 2.41 (1.12-5.18), and 2.51 (1.17-5.38) through steps i-vi. ORs for CVD re-hospitalisation was increased with NOAC treatment through steps i-vi: 2.21 (1.04-4.68), 2.13 (1.01-4.52), 2.47 (1.08-5.62), 2.46 (1.02-5.94), 2.51 (1.01-6.20), and 2.66 (1.02-6.94). CONCLUSIONS:Incident NOAC use among T2DM is associated with increased risk of bleeding hospitalisation and CVD re-hospitalisation compared with incident warfarin use. For T2DM, caution is required in prescribing NOACs as first anticoagulant treatment. Further large-scale replication studies in external datasets are warranted.
Project description:The value of aspirin in primary prevention of cancer and cardiovascular disease (CVD) remains unclear. The aim of this study was to identify women who benefit from alternate-day aspirin with regard to all relevant outcomes, including cancer, CVD and major gastrointestinal bleeding.Long term follow-up data of 27?939 healthy women with baseline plasma samples in the Women's Health Study, a randomised trial of 100?mg alternate-day aspirin versus placebo, were used to develop competing risks models for individualised prediction of absolute risk reduction of the combination of CVD, cancer and major gastrointestinal bleeding by aspirin.Although aspirin was associated with a modestly decreased 15-year risk of colorectal cancer, CVD, and in some women non-colorectal cancer, aspirin treatment resulted in a negative treatment effect in the majority of women if gastrointestinal bleeding was also taken into account. The excess risk of major gastrointestinal bleeding by aspirin increased with age, but the benefits for colorectal cancer and CVD risk were also greater at higher age. Decision curves indicated that selective treatment of women ?65?years may improve net benefit compared to treating all, none and prediction-based treatment. The observed 15-year number needed to treat to prevent one event among women ?65?years was 29 (95% CI 12 to 102).Concurrent evaluation of the absolute effects on cancer, CVD and major gastrointestinal bleeding showed that alternate-day use of low-dose aspirin is ineffective or harmful in the majority of women in primary prevention. Selective treatment of women ?65?years with aspirin may improve net benefit.NCT00000479.