Higher body mass index raises immature platelet count: potential contribution to obesity-related thrombosis.

Higher body mass index (BMI) is a risk factor for thrombosis. Platelets are essential for hemostasis but contribute to thrombosis when activated pathologically. We hypothesized that higher BMI leads to changes in platelet characteristics, thereby increasing thrombotic risk. The effect of BMI on platelet traits (measured by Sysmex) was explored in 33 388 UK blood donors (INTERVAL study). Linear regression showed that higher BMI was positively associated with greater plateletcrit (PCT), platelet count (PLT), immature platelet count (IPC), and side fluorescence (SFL, a measure of mRNA content used to derive IPC). Mendelian randomization (MR), applied to estimate a causal effect with BMI proxied by a genetic risk score, provided causal estimates for a positive effect of BMI on both SFL and IPC, but there was little evidence for a causal effect of BMI on PCT or PLT. Follow-up analyses explored the functional relevance of platelet characteristics in a pre-operative cardiac cohort (COPTIC). Linear regression provided observational evidence for a positive association between IPC and agonist-induced whole blood platelet aggregation. Results indicate that higher BMI raises the number of immature platelets, which is associated with greater whole blood platelet aggregation in a cardiac cohort. Higher IPC could therefore contribute to obesity-related thrombosis.

Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy.

Thrombomodulin-associated coagulopathy (TM-AC) is a newly recognized dominant bleeding disorder in which a p.Cys537Stop variant in the thrombomodulin (TM) gene THBD, results in high plasma TM levels and protein C-mediated suppression of thrombin generation. Thrombin in complex with TM also activates thrombin-activatable fibrinolysis inhibitor (TAFI). However, the effect of the high plasma TM on fibrinolysis in TM-AC is unknown. Plasma from TM-AC cases and high-TM model control samples spiked with recombinant soluble TM showed reduced tissue factor-induced thrombin generation. Lysis of plasma clots from TM-AC cases was significantly delayed compared with controls but was completely restored when TM/thrombin-mediated TAFI activation was inhibited. Clots formed in blood from TM-AC cases had the same viscoelastic strength as controls but also showed a TAFI-dependent delay in fibrinolysis. Delayed fibrinolysis was reproduced in high-TM model plasma and blood samples. Partial restoration of thrombin generation with recombinant activated factor VII or activated prothrombin complex concentrate did not alter the delayed fibrinolysis in high-TM model blood. Our finding of a previously unrecognized fibrinolytic phenotype indicates that bleeding in TM-AC has a complex pathogenesis and highlights the pivotal role of TM as a regulator of hemostasis.

Scoping Review of Factors Associated with Stem Cell Mobilization and Collection in Allogeneic Stem Cell Donors.

There is wide interindividual variation in the efficacy of CD34+ cell mobilization and collection in healthy allogenic hematopoietic stem cell donors. Donor characteristics, blood cell counts, and various factors related to mobilization and collection have been associated with blood CD34+ cell count and CD34+ cell yield after granulocyte colony-stimulating factor (G-CSF) mobilization and collection. Given the heterogenous nature of the literature reporting these associations, in this scoping review we clarify the determinants of CD34+ count and yield. Studies published between 2000 and 2023 reporting allogeneic donors undergoing G-CSF mobilization and peripheral blood stem cell (PBSC) collection were evaluated. Eligible studies were those that assessed blood CD34+ cell count or CD34+ cell yield in the first PBSC collection after mobilization with 4 or 5 days of G-CSF treatment. Associations were recorded between these outcomes and donor factors (age, sex, weight, ethnicity), mobilization factors (G-CSF scheduling or dose), collection factors (venous access, processed blood volume [PBV]) or laboratory factors (blood cell counts at baseline or after mobilization). The 52 studies evaluated between 15 and 20,884 donors. Forty-three studies were retrospective, 33 assessed blood CD34+ cell counts, and 39 assessed CD34+ cell yield from PBSCs. Blood CD34+ cell counts consistently predicted CD34+ cell yield. Younger donors usually had higher blood CD34+ cell counts and CD34+ cell yield. Most studies that investigated the effect of donor ancestry found that donors of non-European ancestry had higher blood CD34+ cell counts after mobilization and higher CD34+ cell yields from collection. The poor consensus about the best predictors of blood CD34+ cell count and yield necessitates further prospective studies, particularly of the role of donor ancestry. The current focus on donor sex as a major predictor requires re-evaluation.

PIK3R3 is a candidate regulator of platelet count in people of Bangladeshi ancestry.

Background: Blood platelets are mediators of atherothrombotic disease and are regulated by complex sets of genes. Association studies in European ancestry populations have already detected informative platelet regulatory loci. Studies in other ancestries can potentially reveal new associations because of different allele frequencies, linkage structures, and variant effects. Objectives: To reveal new regulatory genes for platelet count (PLT). Methods: Genome-wide association studies (GWAS) were performed in 20,218 Bangladeshi and 9198 Pakistani individuals from the Genes & Health study. Loci significantly associated with PLT underwent fine-mapping to identify candidate genes. Results: Of 1588 significantly associated variants (P < 5 × 10-8) at 20 loci in the Bangladeshi analysis, most replicated findings in prior transancestry GWAS and in the Pakistani analysis. However, the Bangladeshi locus defined by rs946528 (chr1:46019890) did not associate with PLT in the Pakistani analysis but was in the same linkage disequilibrium block (r2 ≥ 0.5) as PLT-associated variants in prior East Asian GWAS. The single independent association signal was refined to a 95% credible set of 343 variants spanning 8 coding genes. Functional annotation, mapping to megakaryocyte regulatory regions, and colocalization with blood expression quantitative trait loci identified the likely mediator of the PLT phenotype to be PIK3R3 encoding a regulator of phosphoinositol 3-kinase (PI3K). Conclusion: Abnormal PI3K activity in the vessel wall is already implicated in the pathogenesis of atherothrombosis. Our identification of a new association between PIK3R3 and PLT provides further mechanistic insights into the contribution of the PI3K pathway to platelet biology.

Alterations in platelet proteome signature and impaired platelet integrin αIIbß3 activation in patients with COVID-19.

BACKGROUND: Patients with COVID-19 are at increased risk of thrombosis, which is associated with altered platelet function and coagulopathy, contributing to excess mortality. OBJECTIVES: To characterize the mechanism of altered platelet function in COVID-19 patients. METHODS: The platelet proteome, platelet functional responses, and platelet-neutrophil aggregates were compared between patients hospitalized with COVID-19 and healthy control subjects using tandem mass tag proteomic analysis, Western blotting, and flow cytometry. RESULTS: COVID-19 patients showed a different profile of platelet protein expression (858 altered of the 5773 quantified). Levels of COVID-19 plasma markers were enhanced in the platelets of COVID-19 patients. Gene ontology pathway analysis demonstrated that the levels of granule secretory proteins were raised, whereas those of platelet activation proteins, such as the thrombopoietin receptor and protein kinase Cα, were lowered. Basally, platelets of COVID-19 patients showed enhanced phosphatidylserine exposure, with unaltered integrin αIIbß3 activation and P-selectin expression. Agonist-stimulated integrin αIIbß3 activation and phosphatidylserine exposure, but not P-selectin expression, were decreased in COVID-19 patients. COVID-19 patients had high levels of platelet-neutrophil aggregates, even under basal conditions, compared to controls. This association was disrupted by blocking P-selectin, demonstrating that platelet P-selectin is critical for the interaction. CONCLUSIONS: Overall, our data suggest the presence of 2 platelet populations in patients with COVID-19: one of circulating platelets with an altered proteome and reduced functional responses and another of P-selectin-expressing neutrophil-associated platelets. Platelet-driven thromboinflammation may therefore be one of the key factors enhancing the risk of thrombosis in COVID-19 patients.

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of ß cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery.

'Schizophrenia postdrome': a study of low-level psychotic experience after remission of first-episode schizophrenia.

BACKGROUND: Despite remission being the primary objective following the first episode of schizophrenia, clinically stabilized patients nevertheless relapse. AIM: To assess the extent and fluctuation of low-level psychotic symptoms in patients who are in remission after first-episode schizophrenia and consider whether this is equivalent to symptomatology experienced by those at 'ultra high risk' (UHR) of developing first-episode psychosis. METHODS: We examined the phenomenological characteristics of 11 patients who fulfilled international remission criteria using the Structured Interview for Prodromal Symptoms and compared this cohort with an UHR sample. RESULTS: Remitted patients were experiencing attenuated positive symptoms (73%) and brief limited intermittent psychotic symptoms (18%), features that were similarly prevalent in the UHR group. There was no significant fluctuation in these low-level symptoms over the course of four interviews. CONCLUSIONS: Although further research is required in this novel field, such features could form the building blocks for better prediction of psychotic relapse.