VEGFA rs3025020 Polymorphism Contributes to CALR -Mutation Susceptibility and Is Associated with Low Risk of Deep Vein Thrombosis in Primary Myelofibrosis
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ABSTRACT:
SUBMITTER: Villani L
PROVIDER: S-EPMC8577885 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We evaluated the association of VEGFA rs3025039 polymorphism with clinical co-variates and outcomes in 849 subjects with primary myelofibrosis (PMF) and 250 healthy controls. Minor T-allele frequency was higher in subjects with JAK2V617F compared with those without JAK2V617F (18% vs. 13%; p = 0.014). In subjects with JAK2V617F, the TT genotype was associated at diagnosis with lower platelet concentrations (p = 0.033), higher plasma LDH concentration (p = 0.005), higher blood CD34-positive cells (p = 0.027), lower plasma cholesterol concentration (p = 0.046), and higher concentration of high-sensitivity C-reactive protein (p = 0.018). These associations were not found in subjects with PMF without JAK2V617F. In subjects with the TT genotype, risk of death was higher compared with subjects with CC/CT genotypes (HR = 2.12 [1.03, 4.35], p = 0.041). Finally, the TT genotype was associated with higher frequency of deep vein thrombosis in typical sites (12.5% vs. 2.5%; OR = 5.46 [1.51, 19.7], p = 0.009). In conclusion, in subjects with PMF, the VEGFA rs3025039 CT or TT genotypes are more common in those with JAK2V617F than in those without JAK2V67F mutation and are associated with disease severity, poor prognosis, and risk of deep vein thrombosis.
| S-EPMC8393853 | biostudies-literature
Project description:AbstractNeutrophils contribute to deep vein thrombosis (DVT) by releasing prothrombotic neutrophil extracellular traps (NETs). NET formation (known as NETosis) is an energy-intensive process that requires an increased rate of aerobic glycolysis. The metabolic enzymes pyruvate dehydrogenase kinases (PDKs) inhibit the pyruvate dehydrogenase complex to divert the pyruvate flux from oxidative phosphorylation toward aerobic glycolysis. Herein, we identified that the combined deletion of PDK2 and PDK4 (PDK2/4-/-) renders mice less susceptible to DVT (measured by thrombus incidence, weight, and length) in the inferior vena cava-stenosis model at day 2 after surgery. Compared with wild-type (WT) mice, the venous thrombus obtained from PDK2/4-/- mice exhibited reduced citrullinated histone content, a known marker of NETs. In line with in vivo observations, phorbol 12-myristate 13-acetate (PMA)-stimulated PDK2/4-/- neutrophils displayed reduced NETosis and secretion of cathepsin G and elastase compared with PMA-stimulated WT neutrophils. The formation of platelet aggregates mediated by PMA-stimulated PDK2/4-/- neutrophils were significantly reduced compared with PMA-stimulated WT neutrophils. Finally, PDK2/4-/- neutrophils exhibited reduced levels of intracellular Ca2+ concentration, extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation, and glycolytic proton efflux rate (a measure of aerobic glycolysis), known to facilitate NETosis. Together, these findings elucidate, to our knowledge, for the first time, the fundamental role of PDK2/4 in regulating NETosis and acute DVT.
| S-EPMC11321300 | biostudies-literature
Project description:Deep vein thrombosis is one of the common complications of orthopedic surgery. Studies indicated that genetic factors played a considerable role in the pathogenesis of deep vein thrombosis. Endothelial nitric oxide synthase which encoded by nitric oxide synthase 3 (NOS3), can generate nitric oxide in endothelial cells. As a predominant regulator for vascular homeostasis, nitric oxide might be involved in the pathogenesis of thrombosis. It had been proved that the NOS3 polymorphism (rs1799983) was associated with the development of cardiovascular diseases. Our objective was to evaluate the association between the NOS3 polymorphism (rs1799983) and deep vein thrombosis after orthopedic surgery in Chinese Han population. The polymorphism was genotyped in 224 subjects with deep vein thrombosis after orthopedic surgery and 580 controls. Allele and genotype frequencies were compared between subjects with deep vein thrombosis and control subjects. The allele and genotype frequencies of the NOS3 polymorphism (rs1799983) were significantly different between subjects with deep vein thrombosis and control subjects. There were also significant differences when the subjects were stratified by gender, surgery type and hypertension status. These findings suggested that the NOS3 polymorphism (rs1799983) was associated with susceptibility to the deep vein thrombosis after orthopedic surgery in Chinese Han population, and NOS3 might play a role in the development of deep vein thrombosis after orthopedic surgery.
| S-EPMC3724670 | biostudies-literature
Project description:Abstract This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of different treatment interventions for people with distal (below the knee) deep vein thrombosis (DVT).
| S-EPMC6738897 | biostudies-literature
Project description: Not available
| S-EPMC6464997 | biostudies-literature
Project description:Approximately 10% of all deep vein thromboses occur in the upper extremity, and that number is increasing due to the use of peripherally inserted central catheters. Sequelae of upper extremity deep vein thrombosis (UEDVT) are similar to those for lower extremity deep vein thrombosis (LEDVT) and include postthrombotic syndrome and pulmonary embolism. In addition to systemic anticoagulation, there are multiple interventional treatment options for UEDVT with the potential to reduce the incidence of these sequelae. To date, there have been no randomized trials to define the optimal management strategy for patients presenting with UEDVT, so many conclusions are drawn from smaller, single-center studies or from LEDVT research. In this article, the authors describe the evidence for the currently available treatment options and an approach to a patient with acute UEDVT.
| S-EPMC5334483 | biostudies-other
Project description:Deep vein thrombosis (DVT) is a common clinical problem, but its cellular and molecular mechanisms remain incompletely understood. We performed single-cell RNA sequencing (scRNA-seq) on the vein wall of mouse inferior vena cava (IVC) ligation model of deep vein thrombosis (DVT), to analyze the transcriptomic changes in the vein wall during acute venous thrombosis.
2023-02-10 | GSE221978 | GEO
Project description:Health-related quality of life (HRQoL) is known to be impaired in patients who develop post-thrombotic syndrome (PTS) following deep vein thrombosis (DVT). However, there is limited knowledge of the long-term HRQoL after DVT compared to controls without DVT. The objectives of this study were to evaluate long-term HRQoL following DVT and to compare that with age and sex matched control group and to population norms as well as to investigate possible predictors for reduced HRQoL.HRQoL was evaluated in 254 patients with confirmed DVT using the generic EQ-5D and the diseases specific VEINES-QOL/Sym questionnaire, whereas PTS was assessed by the Villalta scale. Patients were asked to give the EQ-5D questionnaire to two friends of same age- (±5 years) and sex (buddy controls).Patients scored significantly lower on all dimensions of EQ-5D compared to controls. EQ-5D index value was lower in patients compared with buddy controls; mean 0.79 (SD 0.17; IQR 0.72-1.00) versus 0.9 (SD 0.12; IQR 0.80-1.00), p < 0.001. EQ-5D index value was also significantly lower than age- and sex-adjusted population norms (p < 0.001). PTS and obesity (BMI >30/m(2)) were significantly associated with impaired HRQoL assessed by EQ-5D index value (odds ratio [OR] 11.0: 95 % confidence interval [CI] 4.6-29.7; and 2.3: 95 % CI 1.1-4.8, respectively) and VEINES-QOL (OR 28.2: 95 % CI 10.6-75.0; and OR 4.1: 95 % CI 1.7-9.7, respectively).Long-term HRQoL was significantly impaired in DVT patients compared with buddy controls and population norms. PTS and obesity were independently associated with impaired HRQoL.
| S-EPMC4977231 | biostudies-other
Project description:Background Overall, 30 to 50% of lower-limb deep-vein thrombosis (DVT) cases are isolated distal DVT (IDDVT). The recurrent venous thromboembolism (VTE) risk is unclear, leaving uncertainty over optimal IDDVT treatment. We present data on patients with IDDVT and proximal DVT (PDVT) from the prospective, noninterventional XALIA study of rivaroxaban for acute and extended VTE treatment. Methods Patients aged ≥18 years scheduled to receive ≥3 months' anticoagulation with rivaroxaban or standard anticoagulation were eligible, with follow-up for ≥12 months. We describe baseline characteristics, management strategies, and incidence proportions of VTE recurrence, major bleeding, and all-cause mortality in patients with IDDVT or PDVT, with or without distal vein involvement. Findings Overall, 1,004 patients with IDDVT and 3,098 with PDVT were enrolled; 641 (63.8%) and 1,683 (54.3%) received rivaroxaban, respectively. Patients with IDDVT were younger and had lower incidences of renal impairment, cancer, and unprovoked VTE than those with PDVT. On-treatment recurrence incidences for IDDVT versus PDVT were 1.0 versus 2.4% (adjusted hazard ratio [HR]: 0.56; 95% confidence interval [CI]: 0.29-1.08), and incidences posttreatment cessation were 1.1 versus 2.1% (adjusted HR: 0.65; 95% CI: 0.32-1.35), respectively. On-treatment major bleeding incidences were 0.9 versus 1.4% and mortality was 0.8 versus 2.2%, respectively. Median treatment duration in patients with IDDVT was shorter than in those with PDVT (102 vs. 192 days, respectively). Interpretation Patients with IDDVT had fewer comorbidities and were more frequently treated with rivaroxaban than those with PDVT. On-treatment and posttreatment recurrences were less frequent in patients with IDDVT. Trial registration number: NCT01619007.
| S-EPMC6524913 | biostudies-literature
Project description:BACKGROUND: We recently reported the association between the Malmö sequence variant in F9 (rs6048) and deep vein thrombosis. DESIGN AND METHODS: We aimed to study whether the association between F9 Malmö and deep vein thrombosis is explained by linkage disequilibrium with nearby single-nucleotide polymorphisms, and whether the association is explained biologically by F9 Malmö affecting factor IX antigen levels or activation of factor IX. We investigated the association of F9 Malmö and 28 nearby single-nucleotide polymorphisms with deep vein thrombosis in men from two case-control studies, LETS (n=380) and MEGA (n=1,469). We assessed the association of F9 Malmö with factor IX antigen level in male control subjects from LETS (n=191) and two subsets of MEGA (n=823 and n=484) and the association with endogenous thrombin potential in LETS control men. We studied the association between F9 Malmö and factor IX activation peptide in 1,199 healthy middle-aged men from the NPHS-II cohort. RESULTS: In the combined LETS and MEGA studies, the odds ratio (95% confidence interval) for the G allele of F9 Malmö, compared with the A allele, was 0.80 (0.69-0.93). One single-nucleotide polymorphism in F9, rs422187, was strongly linked to F9 Malmö (r(2)=0.94) and was similarly associated with deep vein thrombosis. No other single-nucleotide polymorphism or haplotype tested was more strongly associated. Factor IX antigen level, factor IX activation peptide levels and endogenous thrombin potential did not differ between F9 Malmö genotypes. CONCLUSIONS: The F9 Malmö sequence variant was the most strongly associated with deep vein thrombosis among common single-nucleotide polymorphisms in the region. However, the biological mechanism by which F9 Malmö affects risk remains unknown.
| S-EPMC2675682 | biostudies-literature