[Exploring the Causal Relationship Between Coagulation Function and Gestational Diabetes Mellitus Through Mendelian Randomization]. / å­Ÿå¾·å°”éšæœºåŒ–æŽ¢ç´¢å‡è¡€åŠŸèƒ½ä¸Žå¦Šå¨ æœŸç³–å°¿ç— çš„å› æžœå ³ç³».

Objective: To explore the causal association between coagulation function, including von Willebrand factor (vWF), a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13), activated partial thromboplastin time (aPTT), coagulation factor Ⅷ (FⅧ), coagulation factor Ⅺ (FⅪ), coagulation factor Ⅶ (FⅦ), coagulation factor Ⅹ (FⅩ), endogenous thrombin potential (ETP), plasminogen activator inhibitor-1 (PAI-1), protein C, and plasmin, and gestational diabetes mellitus (GDM) using two-sample two-way Mendelian randomization (MR), and to provide genetic evidence for the association between coagulation function and the pathogenesis of GDM. Methods: The IEU OpenGWAS database was accessed using the R package TwoSampleMR (v 0.5.6) to obtain the statistical data of the genome-wide association study (GWAS) summary of GDM. MR analysis of the causal association between 11 coagulation function and GDM was performed by the inverse-variance weighted method (IVW), the MR-Egger method, and the weighted median method (WM). Results: In this study, the GWAS summary statistics of GDM (covering 5 687 cases and 117 892 controls) were used for MR analysis. It was found that there was a causal relationship between the predicted plasma FⅧ level and the risk for GDM (IVW: [odds ratio, OR]=0.28, 95% confidence interval [CI]: 0.10-0.75, P<0.001; WM: OR=0.30, 95% CI: 0.09-0.98, P<0.001). There was no causal relationship between other coagulation function and the risk for GDM (P>0.05). Conclusion: There is a significant causal relationship between the plasma FⅧ level and the risk for GDM. This finding highlights the complex interaction between coagulation function and glucose metabolism during pregnancy, but further research on this finding is warranted.

GENETIC DETERMINANTS OF THROMBOSIS.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in the United States. VTE is caused by genetic and acquired conditions, but the genetic variants that increase the risk of VTE are not fully characterized. Recent genome-wide association studies (GWAS) have discovered novel genetic loci linked to VTE. Some of these loci have been characterized, uncovering new pathways that regulate VTE. Functional characterization of candidate genes discovered by GWAS may reveal new therapeutic targets to treat and prevent abnormal thrombosis or bleeding.

Coagulation abnormalities and vascular complications are common in PGM1-CDG.

Phosphoglucomutase-1-congenital disorder of glycosylation (PGM1-CDG) is a rare genetic disorder caused by biallelic variants in the PGM1 gene, leading to the deficiency of the PGM1 enzyme. The most common clinical presentations include muscle involvement, failure to thrive, cleft palate, and cardiac involvement. Abnormal serum N-glycosylation, hypoglycemia, and liver function abnormalities including coagulation abnormalities are the most common laboratory abnormalities. While PGM1-CDG has been extensively studied, little is known about the extent of the coagulation abnormalities in individuals with PGM1-CDG. Unlike most CDG, some symptoms of PGM1-CDG are treatable with D-galactose (D-gal) supplementation, though reliable clinical endpoints are necessary to appropriately evaluate the potential improvement with D-gal in PGM1-CDG. Here, we aimed to describe the incidence of coagulation abnormalities in PGM1-CDG and their evolution, their relation to clinical events, and the ability of D-gal treatment to improve them. A retrospective analysis was conducted on 73 reported individuals. All individuals had a molecularly confirmed PGM1-CDG diagnosis. All incidences of antithrombin (AT), aPTT, PT, factor (F) XI, FX, FIX, FVII, protein C and protein S data and major clinical events related to coagulation abnormalities, were collected. Coagulation information was available for only 58.9 % of the reported individuals, out of which 67.4 % of PGM1-CDG individuals were reported to have abnormalities. The most frequently observed abnormality was AT (mean: 30.8% R:80-120 %) deficiency. Four individuals had major thrombotic events. Coagulation status on D-gal treatment, were reported in 19 individuals. Several factors showed improvement including AT (mean: 64.5 %), indicating galactose is beneficial in treating coagulation abnormalities in PGM1-CDG. Due to the scarcity of the reported data on coagulation parameters, we also evaluated data collected in sixteen PGM1-CDG individuals enrolled in the FCDGC Natural History Study. Longitudinal data showed improvements in several coagulant parameters and disease severity improved for almost all patients of whom we had multiple datapoints on D-gal. AT showed significant improvement on D-gal. We conclude that coagulation abnormalities are frequently present in PGM1-CDG and show improvement on D-gal. We recommend coagulation parameters should be routinely checked in individuals with PGM1-CDG or suspected of having PGM1-CDG. Finally, AT may be used as a primary or secondary clinical endpoint for upcoming clinical trials in PGM1-CDG individuals.

Venous thromboembolic disease genetics: from variants to function.

Venous thromboembolic disease (VTE) is a prevalent and potentially life-threatening vascular disease, including both deep vein thrombosis and pulmonary embolism. This review will focus on recent insights into the heritable factors that influence an individual's risk for VTE. Here, we will explore not only the discovery of new genetic risk variants but also the importance of functional characterization of these variants. These genome-wide studies should lead to a better understanding of the biological role of genes inside and outside of the canonical coagulation system in thrombus formation and lead to an improved ability to predict an individual's risk of VTE. Further understanding of the molecular mechanisms altered by genetic variation in VTE risk will be accelerated by further human genome sequencing efforts and the use of functional genetic screens.

Mutational analysis of pig tissue factor pathway inhibitor α to increase anti-coagulation activity in pig-to-human xenotransplantation.

Blood coagulation mediated by pig tissue factor (TF), which is expressed in pig tissues, causes an instant blood-mediated inflammatory reaction during pig-to-human xenotransplantation. Previously, we generated a soluble pig tissue factor pathway inhibitor α fusion immunoglobulin (TFPI-Ig) which inhibits pig TF activity more efficiently than human TFPI-Ig in human plasma. In this study, we generated several pig TFPI-Ig mutants and tested the efficacy of these mutants in preventing pig-to-human xenogeneic blood coagulation. Structurally important amino acid residues of pig TFPI-Ig were changed into different residues by site-directed mutagenesis. Subsequently, a retroviral vector encoding each cDNA of several pig TFPI-Ig mutants was cloned and transduced into CHO-K1 cells. After establishing stable cell lines expressing each of the pig TFPI-Ig mutants, soluble proteins were produced and purified for evaluating their inhibitory effects on pig TF-mediated blood coagulation in human plasma. The replacement of K36 and K257 with R36 and H257, respectively, in pig TFPI-Ig more efficiently blocked pig TF activity in human plasma when compared with the wild-type pig TFPI-Ig. These results may provide additional information to understand the structure of pig TFPIα, and an improved pig TFPI-Ig variant that more efficiently blocks pig TF-mediated blood coagulation during pig-to-human xenotransplantation.

The molecular landscape of sepsis severity in infants: enhanced coagulation, innate immunity, and T cell repression.

Introduction: Sepsis remains a major cause of mortality and morbidity in infants. In recent years, several gene marker strategies for the early identification of sepsis have been proposed but only a few have been independently validated for adult cohorts and applicability to infant sepsis remains unclear. Biomarkers to assess disease severity and risks of shock also represent an important unmet need. Methods: To elucidate characteristics driving sepsis in infants, we assembled a multi-transcriptomic dataset from public microarray datasets originating from five independent studies pertaining to bacterial sepsis in infant < 6-months of age (total n=335). We utilized a COmbat co-normalization strategy to enable comparative evaluation across multiple studies while preserving the relationship between cases and controls. Results: We found good concordance with only two out of seven of the published adult sepsis gene signatures (accuracy > 80%), highlighting the narrow utility of adult-derived signatures for infant diagnosis. Pseudotime analysis of individual subjects' gene expression profiles showed a continuum of molecular changes forming tight clusters concurrent with disease progression between healthy controls and septic shock cases. In depth gene expression analyses between bacteremia, septic shock, and healthy controls characterized lymphocyte activity, hemostatic processes, and heightened innate immunity during the molecular transition toward a state of shock. Discussion: Our analysis revealed the presence of multiple significant transcriptomic perturbations that occur during the progression to septic shock in infants that are characterized by late-stage induction of clotting factors, in parallel with a heightened innate immune response and a suppression of adaptive cell functionality.

Codon switching of conserved Ser residues in coagulation and fibrinolytic proteases.

BACKGROUND: Unique among all amino acids, Ser is encoded by 2 sets of codons, TCN and AGY (N = any nucleotide, Y = pyrimidine), that cannot interconvert through single nucleotide substitutions. Both codons are documented at the essential residues S195 and S214 within the active site of serine proteases. However, it is not known how the codons interconverted during evolution because replacement of S195 or S214 by other amino acids typically results in loss of activity. OBJECTIVE: To characterize the prevalence of codon switching among essential and non-essential Ser residues in coagulation and fibrinolytic proteases from different vertebrate lineages. METHODS: TCN and AGY codon usage was analyzed in >550 sequences. RESULTS: Evolutionary pressure to preserve the codon of S195 is absolute, with no evidence of interconversion. Pressure to preserve the codon of S214 is also strong, but an AGY↔TCN interconversion is observed in factor VII-inactive and protein C from ray-finned fish. In both cases, the interconversion occurred in genes that were rapidly evolving. In contrast, codon switching at nonessential Ser residues in the kringle domains of coagulation and fibrinolytic proteases is quite common and could be identified in half of the kringles analyzed. CONCLUSION: Codon interconversion of essential Ser residues of coagulation and fibrinolytic proteases only occurred in genes that were rapidly evolving and that-at least in some cases-evolved following genome duplication. Interconversion is common at nonessential Ser residues as found in kringle domains.

Exploring the role of coagulation-related genes in renal cell carcinoma: Implications for tumor microenvironment and prognostic biomarkers.

PURPOSE: Clear cell renal cell carcinoma (ccRCC) frequently progresses to advanced stages due to tumor thrombus (TTs) formation. In this study, we aimed to investigate the role of coagulation-related pathway activation in the progression of ccRCC. METHODS: Consensus clustering was used to identify coagulation-related molecular clusters of ccRCC patients from The Cancer Genome Atlas Program (TCGA) database. The function of coagulation and its correlation with the immune microenvironment were investigated. Protein-protein interactions and differential expression analysis were used to identify the key gene, which was verified by external experiments. The coagulation-associated risk score was constructed by cox proportional hazards regression. RESULTS: Notable disparities were detected in immune characteristics, prognostic differentiation and drug sensitivity between two coagulation-related clusters. Through the integration of clinical stage significance and protein-protein interactions, the key gene MMP9 was screened and it was significantly correlated with CD4+T cells, CD8+T cells and Treg cells. A coagulation-related risk score prognostic model was developed in the Cancer Genome Atlas (TCGA) cohort for risk stratification and prognosis prediction. The prognostic predictive values of the coagulation-related risk score were further authenticated in both TCGA-KIRC and E-MTAB-1980 cohorts. CONCLUSION: There is an obvious correlation between the coagulation and the tumor microenvironment in ccRCC. As a key coagulation-related gene, MMP9 may promote the progression of renal cell carcinoma by influencing immune infiltration of CD8+T cells and Treg cells. Additionally, the risk score could be used as a durable prognostic biomarker, which could assist in clinical decision making for ccRCC patients.

Evaluating the Predictive Value of a Coagulation-Related Gene Model in Glioma.

AIM: To evaluate coagulation related gene model as a biomarker for predicting prognosis of gliomas. MATERIAL AND METHODS: The mRNA expression and clinical data of glioma were downloaded from the TCGA and CGGA databases. Coagulation-related genes were downloaded from the KEGG database. The expression model was constructed using LASSO regression. The GBM data were divided into high and low-risk expression groups based on the median risk score, and the differences in overall survival and progression-free survival between them were calculated. The prognostic model was further validated using the TCGA-LGG and CGGA glioma databases, respectively. The accuracy of the risk score was calculated by ROC analysis for 1 year and 3 years. RESULTS: Four model genes, namely the SERPINA5, PLAUR, BDKRB1, and PTGIR, were identified, and the risk score was calculated as follows: risk score= SERPINA5*0.126264111304559 + PLAUR*0.288587629696211 + BDKRB1*0.349215422945011 + PTGIR*0.17334527969703, respectively. Based on glioma data from three groups, patients were divided into high and low-risk groups according to the median risk score. The overall survival, progression-free survival, and risk scores of the high-risk score group were worse than the low-risk group. The ROC curve analysis showed that the AUC values of the coagulation-related gene model at 1 year, 3 years, and 5 years were more than 0.65, validating the reliability of the prognostic model. CONCLUSION: This study established the correlation between the coagulation-related gene model and glioma prognosis, providing deeper insight into the mechanism and treatment of glioma.

Establishment and verification of a prognostic model based on coagulation and fibrinolysis-related genes in hepatocellular carcinoma.

BACKGROUND: Studies have shown that coagulation and fibrinolysis (CFR) are correlated with Hepatocellular carcinoma (HCC) progression and prognosis. We aim to build a model based on CFR-correlated genes for risk assessment and prediction of HCC patient. METHODS: HCC samples were selected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases respectively. The Molecular Signatures Database (MSigDB) was used to select the CFR genes. RiskScore model were established by single sample gene set enrichment analysis (ssGSEA), weighted correlation network analysis (WGCNA), multivariate Cox regression analysis, LASSO regression analysis. RESULTS: PCDH17, PGF, PDE2A, FAM110D, FSCN1, FBLN5 were selected as the key genes and designed a RiskScore model. Those key genes were Differential expressions in HCC cell and patients. Overexpression PDE2A inhibited HCC cell migration and invasion. The higher the RiskScore, the lower the probability of survival. The model has high AUC values in the first, third and fifth year prediction curves, indicating that the model has strong prediction performance. The difference analysis of clinicopathological features found that a great proportion of high clinicopathological grade samples showed higher RiskScore. RiskScore were positively correlated with immune scores and TIDE scores. High levels of immune checkpoints and immunomodulators were observed in high RiskScore group. High RiskScore groups may benefit greatly from taking traditional chemotherapy drugs. CONCLUSIONS: We screened CFR related genes to design a RiskScore model, which could accurately evaluate the prognosis and survival status of HCC patients, providing certain value for optimizing the clinical treatment of cancer in the future.

Machine learning identifies novel coagulation genes as diagnostic and immunological biomarkers in ischemic stroke.

BACKGROUND: Coagulation system is currently known associated with the development of ischemic stroke (IS). Thus, the current study is designed to identify diagnostic value of coagulation genes (CGs) in IS and to explore their role in the immune microenvironment of IS. METHODS: Aberrant expressed CGs in IS were input into unsupervised consensus clustering to classify IS subtypes. Meanwhile, key CGs involved in IS were further selected by weighted gene co-expression network analysis (WGCNA) and machine learning methods, including random forest (RF), support vector machine (SVM), generalized linear model (GLM) and extreme-gradient boosting (XGB). The diagnostic performance of key CGs were evaluated by receiver operating characteristic (ROC) curves. At last, quantitative PCR (qPCR) was performed to validate the expressions of key CGs in IS. RESULTS: IS patients were classified into two subtypes with different immune microenvironments by aberrant expressed CGs. Further WGCNA, machine learning methods and ROC curves identified ACTN1, F5, TLN1, JMJD1C and WAS as potential diagnostic biomarkers of IS. In addition, their expressions were significantly correlated with macrophages, neutrophils and/or T cells. GSEA also revealed that those biomarkers may regulate IS via immune and inflammation. Moreover, qPCR verified the expressions of ACTN1, F5 and JMJD1C in IS. CONCLUSIONS: The current study identified ACTN1, F5 and JMJD1C as novel coagulation-related biomarkers associated with IS immune microenvironment, which enriches our knowledge of coagulation-mediated pathogenesis of IS and sheds light on next-step in vivo and in vitro experiments to elucidate the relevant molecular mechanisms.

Validation for the function of protein C in mouse models.

Objectives: Protein C (PC) is an anticoagulant that is encoded by the PROC gene. Validation for the function of PC was carried out in mouse models. Methods: In this study, autosomal recessive PC deficiency (PCD) was selected as the target, and the specific mutation site was chromosome 2 2q13-q14, PROC c.1198G>A (p.Gly400Ser) which targets G399S (GGT to AGC) in mouse models. To investigate the role of hereditary PC in mice models, we used CRISPR/Cas9 gene editing technology to create a mouse model with a genetic PCD mutation. Results: The two F0 generation positive mice produced using the CRISPR/Cas9 gene editing technique were chimeras, and the mice in F1 and F2 generations were heterozygous. There was no phenotype of spontaneous bleeding or thrombosis in the heterozygous mice, but some of them were blind. Blood routine results showed no significant difference between the heterozygous mice and wild-type mice (P > 0.05). Prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) were prolonged in the heterozygous mice, while the level of fibrinogen content (FIB) decreased, suggesting secondary consumptive coagulation disease. The protein C activity of heterozygous mice was significantly lower than that of wild-type mice (P < 0.001), but there was no significant difference in protein C antigen levels (P > 0.05). H&E staining showed steatosis and hydrodegeneration in the liver of heterozygous mice. Necrosis and exfoliated epithelial cells could be observed in renal tubule lumen, forming cell or granular tubules. Hemosiderin deposition was found in the spleen along with splenic hemorrhage. Immunohistochemistry demonstrated significant fibrin deposition in the liver, spleen, and kidney of heterozygous mice. Conclusion: In this study, heterozygotes of the mouse model with a PC mutation were obtained. The function of PC was then validated in a mouse model through genotype, phenotype, and PC function analysis.

C3AR1 is a regulatory factor associated with coagulation cascade and inflammation in sepsis.

Sepsis is a leading cause of mortality in intensive care units. Sepsis is associated with activation of the coagulation cascade and inflammation. The aim of this study was to identify coagulation-related genes in sepsis that may provide translational potential therapeutic targets. The datasets GSE28750, GSE95233, and GSE65682 were downloaded from the gene expression omnibus database. Consensus-weighted gene co-expression network analysis (WGCNA) was used to identify sepsis modules. Gene set enrichment analysis was used to identify genes enriched in the coagulation cascade. The value of hub-gene in immunological analysis was tested in the validation sets (GSE95233). The value of hub-gene in clinical prognosis was tested in the validation sets (GSE65582). One thousand one hundred seventy-six genes with high connectivity in the clinically significant module were identified as hub genes. Ten genes were found to be enriched in coagulation-related signaling pathways. C3AR1 was selected for further analysis. The immune infiltration analysis showed that lower expression of C3AR1 was associated with immune response in sepsis and could be an independent predictor of survival status in sepsis patients. Meanwhile, univariate and multivariate Cox analysis showed that C3AR1 had a significant correlation with survival. C3AR1 may become an effective biomarker for worse outcomes in sepsis patients associated with immune and coagulation cascade.

Comprehensive functional characterization of a novel ANO6 variant in a new patient with Scott syndrome.

BACKGROUND: Scott syndrome is a mild platelet-type bleeding disorder, first described in 1979, with only 3 unrelated families identified through defective phosphatidylserine (PS) exposure and confirmed by sequencing. The syndrome is distinguished by impaired surface exposure of procoagulant PS on platelets after stimulation. To date, platelet function and thrombin generation in this condition have not been extensively characterized. OBJECTIVES: Genetic and functional studies were undertaken in a consanguineous family with a history of excessive bleeding of unknown cause. METHODS: A targeted gene panel of known bleeding and platelet genes was used to identify possible genetic variants. Platelet phenotyping, flow adhesion, flow cytometry, whole blood and platelet-rich plasma thrombin generation, and specialized extracellular vesicle measurements were performed. RESULTS: We detected a novel homozygous frameshift variant, c.1943del (p.Arg648Hisfs∗23), in ANO6 encoding Anoctamin 6, in a patient with a bleeding history but interestingly with normal ANO6 expression. Phenotyping of the patient's platelets confirmed the absence of PS expression and procoagulant activity but also revealed other defects including reduced platelet δ granules, reduced ristocetin-mediated aggregation and secretion, and reduced P-selectin expression after stimulation. PS was absent on spread platelets, and thrombi formed over collagen at 1500/s. Reduced thrombin generation was observed in platelet-rich plasma and confirmed in whole blood using a new thrombin generation assay. CONCLUSION: We present a comprehensive report of a patient with Scott syndrome with a novel frameshift variant in AN06, which is associated with no platelet PS exposure and markedly reduced thrombin generation in whole blood, explaining the significant bleeding phenotype observed.

Clinical Implications of Discrepancy between One-Stage Clotting and Chromogenic Factor IX Activity in Hemophilia B.

BACKGROUND: Discrepancy in factor IX activity (FIX:C) between one-stage assay (OSA) and chromogenic substrate assay (CSA) in patients with hemophilia B (PwHB) introduces challenges for clinical management. AIM: To study the differences in FIX:C using OSA and CSA in moderate and mild hemophilia B (HB), their impact on classification of severity, and correlation with genotype. METHODS: Single-center study including 21 genotyped and clinically characterized PwHB. FIX:C by OSA was measured using ActinFSL (Siemens) and CSA by Biophen (Hyphen). In addition, in vitro experiments with wild-type FIX were performed. Reproducibility of CSA was assessed between three European coagulation laboratories. RESULTS: FIX:C by CSA was consistently lower than by OSA, with 10/17 PwHB having a more severe hemophilia type by CSA. OSA displayed a more accurate description of the clinical bleeding severity, compared with CSA. A twofold difference between OSA:CSA FIX:C was present in 12/17 PwHB; all patients had genetic missense variants in the FIX serine protease domain. Discrepancy was also observed with diluted normal plasma, most significant for values below 0.10 IU/mL. Assessment of samples with low FIX:C showed excellent reproducibility of the CSA results between the laboratories. CONCLUSION: FIX:C was consistently higher by OSA compared with the CSA. Assessing FIX:C by CSA alone would have led to diagnosis of a more severe hemophilia type in a significant proportion of patients. Our study suggests using both OSA and CSA FIX:C together with genotyping to classify HB severity and provide essential information for clinical management.

Biology of factor XI.

ABSTRACT: Unique among coagulation factors, the coagulation factor XI (FXI) arose through a duplication of the gene KLKB1, which encodes plasma prekallikrein. This evolutionary origin sets FXI apart structurally because it is a homodimer with 2 identical subunits composed of 4 apple and 1 catalytic domain. Each domain exhibits unique affinities for binding partners within the coagulation cascade, regulating the conversion of FXI to a serine protease as well as the selectivity of substrates cleaved by the active form of FXI. Beyond serving as the molecular nexus for the extrinsic and contact pathways to propagate thrombin generation by way of activating FIX, the function of FXI extends to contribute to barrier function, platelet activation, inflammation, and the immune response. Herein, we critically review the current understanding of the molecular biology of FXI, touching on some functional consequences at the cell, tissue, and organ level. We conclude each section by highlighting the DNA mutations within each domain that present as FXI deficiency. Together, a narrative review of the structure-function of the domains of FXI is imperative to understand the etiology of hemophilia C as well as to identify regions of FXI to safely inhibit the pathological function of activation or activity of FXI without compromising the physiologic role of FXI.

Developmental adcyap1b loss leads to hemorrhage, disrupted hemostasis, and a blood coagulation cascade in zebrafish.

BACKGROUND: Pituitary adenylate cyclase-activating polypeptide is a neuropeptide with diverse roles in biological processes. Its involvement in the blood coagulation cascade is unclear. OBJECTIVES: This study unraveled adcyap1b's role in blood coagulation using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 in zebrafish. Effects were validated via adcyap1b knockdown. Gene expression changes in adcyap1b mutants were explored, linking them to clotting disorders. An analysis of proca gene splicing illuminated its role in adcyap1b-related anticoagulation deficiencies. METHODS: Zebrafish were genetically modified using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 to induce adcyap1b knockout. Morpholino-mediated gene knockdown was employed for validation. Expression levels of coagulation factors, anticoagulant proteins, and fibrinolytic system genes were assessed in adcyap1b mutant zebrafish. Alternative splicing of proca gene was analyzed. RESULTS: Adcyap1b mutant zebrafish exhibited severe hemorrhage, clotting disorders, and disrupted blood coagulation. Morpholino-mediated knockdown replicated observed phenotypes. Downregulation in transcripts related to coagulation factors V and IX, anticoagulation protein C, and plasminogen was observed. Abnormal alternative splicing of the proca gene was identified, providing a mechanistic explanation for anticoagulation system deficiencies. CONCLUSION: Adcyap1b plays a crucial role in maintaining zebrafish blood coagulation and hemostasis. Its influence extends to the regulation of procoagulant and anticoagulant pathways, with abnormal alternative splicing contributing to observed deficiencies. These findings unveil a novel aspect of adcyap1b function, offering potential insights into similar processes in mammalian systems.

Yolk sac cell atlas reveals multiorgan functions during human early development.

The extraembryonic yolk sac (YS) ensures delivery of nutritional support and oxygen to the developing embryo but remains ill-defined in humans. We therefore assembled a comprehensive multiomic reference of the human YS from 3 to 8 postconception weeks by integrating single-cell protein and gene expression data. Beyond its recognized role as a site of hematopoiesis, we highlight roles in metabolism, coagulation, vascular development, and hematopoietic regulation. We reconstructed the emergence and decline of YS hematopoietic stem and progenitor cells from hemogenic endothelium and revealed a YS-specific accelerated route to macrophage production that seeds developing organs. The multiorgan functions of the YS are superseded as intraembryonic organs develop, effecting a multifaceted relay of vital functions as pregnancy proceeds.

Two to tango: endothelial cell TMEM16 scramblases drive coagulation and thrombosis.

Endothelial cells form a constitutively anticoagulant surface under homeostasis. While loss of this anticoagulant property is a hallmark of many cardiovascular diseases, the molecular mechanisms underlying the procoagulant transition remain incompletely understood. In this issue of the JCI, Schmaier et al. identify the phospholipid scramblases TMEM16E and TMEM16F, which support endothelial procoagulant activity through phosphatidylserine (PS) externalization. Genetic deletion of TMEM16E or TMEM16F or treatment with TMEM16 inhibitors prevented PS externalization and reduced fibrin formation in the vessel wall independently of platelets in a murine laser-injury model of thrombosis. These findings reveal a role for endothelial TMEM16E in thrombosis and identify TMEM16E as a potential therapeutic target for preventing thrombus formation.

The effects of coagulation factors on the risk of endometriosis: a Mendelian randomization study.

BACKGROUND: Endometriosis is recognized as a complex gynecological disorder that can cause severe pain and infertility, affecting 6-10% of all reproductive-aged women. Endometriosis is a condition in which endometrial tissue, which normally lines the inside of the uterus, deposits in other tissues. The etiology and pathogenesis of endometriosis remain ambiguous. Despite debates, it is generally agreed that endometriosis is a chronic inflammatory disease, and patients with endometriosis appear to be in a hypercoagulable state. The coagulation system plays important roles in hemostasis and inflammatory responses. Therefore, the purpose of this study is to use publicly available GWAS summary statistics to examine the causal relationship between coagulation factors and the risk of endometriosis. METHODS: To investigate the causal relationship between coagulation factors and the risk of endometriosis, a two-sample Mendelian randomization (MR) analytic framework was used. A series of quality control procedures were followed in order to select eligible instrumental variables that were strongly associated with the exposures (vWF, ADAMTS13, aPTT, FVIII, FXI, FVII, FX, ETP, PAI-1, protein C, and plasmin). Two independent cohorts of European ancestry with endometriosis GWAS summary statistics were used: UK Biobank (4354 cases and 217,500 controls) and FinnGen (8288 cases and 68,969 controls). We conducted MR analyses separately in the UK Biobank and FinnGen, followed by a meta-analysis. The Cochran's Q test, MR-Egger intercept test, and leave-one-out sensitivity analyses were used to assess the heterogeneities, horizontal pleiotropy, and stabilities of SNPs in endometriosis. RESULTS: Our two-sample MR analysis of 11 coagulation factors in the UK Biobank suggested a reliable causal effect of genetically predicted plasma ADAMTS13 level on decreased endometriosis risk. A negative causal effect of ADAMTS13 and a positive causal effect of vWF on endometriosis were observed in the FinnGen. In the meta-analysis, the causal associations remained significant with a strong effect size. The MR analyses also identified potential causal effects of ADAMTS13 and vWF on different sub-phenotypes of endometrioses. CONCLUSIONS: Our MR analysis based on GWAS data from large-scale population studies demonstrated the causal associations between ADAMTS13/vWF and the risk of endometriosis. These findings suggest that these coagulation factors are involved in the development of endometriosis and may represent potential therapeutic targets for the management of this complex disease.