Thrombosis Journal最新文献

Background: The aim of this study was to elucidate the molecular abnormalities in a four-generation Chinese family affected by congenital fibrinogen disorder (CFD).

Case presentation: The proband was a 5-year-old Chinese boy with CFD. Routine clotting tests revealed decreased plasma fibrinogen concentration in the proband and in his father and sister. Notably, the condition presented was clinically asymptomatic. Whole exome sequencing identified a heterozygous c.1299G > A mutation in exon 8 of the FGB gene, leading to p.Trp433* (TGG > TGA). Further Sanger sequencing revealed the presence of this mutation in his great-grandmother, grandfather, father, and sister as well.

Conclusion: The FGB gene variant c.1299G > A (p.Trp433*) across four consecutive generations is associated with CFD.

Background: Septic-induced coagulopathy (SIC) is a major cause of mortality in sepsis, closely associated with endothelial glycocalyx damage. Enolase 1 (Eno1), a key enzyme in glycolysis, plays a crucial role in sepsis-related systemic inflammation and the maintenance of glycocalyx integrity.

Objective: This study utilizes multi-omics analysis to investigate the Eno1-regulated network, providing a comprehensive understanding of its molecular mechanisms in SIC.

Methods: We used RNA-seq datasets to identify Eno1-related gene sets through weighted gene co-expression network analysis and validated their biological functions via gene set enrichment analysis.

Results: Through RNA-seq analysis, we identified gene sets associated with Eno1 involved in immune regulation, endothelial cell apoptosis, coagulation, and glycosaminoglycan metabolism. Immune infiltration analysis revealed that Eno1 modulates SIC pathogenesis by influencing T cells and macrophages, with significant associations with endothelial dysfunction and inflammatory markers. Additionally, we observed that Eno1 regulation of glycolysis is linked to endothelial glycocalyx degradation, contributing to microcirculatory and vascular impairments in SIC. Furthermore, preliminary studies suggest that melatonin treatment may alleviate glycocalyx damage by inhibiting Eno1-mediated glycolytic pathways, offering a potential new therapeutic avenue for intervening in endothelial injury associated with SIC.

Conclusions: This study underscores the critical role of Eno1 in promoting SIC and its potential as both a diagnostic marker and therapeutic target for glycocalyx repair. The multi-omics approach provides valuable insights into the molecular networks regulating SIC, offering new avenues for targeted interventions in sepsis management.

Background: Cystic adventitial disease (CAD) is a rare vascular condition that causes arterial stenosis due to the presence of a cyst in the adventitia (outer layer) of the artery. It is most commonly seen in young and middle-aged men, with an occurrence rate of around 0.1% among vascular diseases. Symptoms may include intermittent claudication, rest pain, and, in severe cases, ulcers or limb ischemia. CAD is often underdiagnosed due to its rarity and the broad range of differential diagnoses for arterial obstruction.

Case presentation: This case describes a 36-year-old female who presented with sudden left lower limb soreness that worsened with activity over five days, but without symptoms such as intermittent claudication or rest pain, which are typically associated with other vascular diseases. The patient had no significant history of smoking or other risk factors for peripheral arterial disease. Imaging studies, including angiography, revealed a focal filling defect and luminal narrowing in the popliteal artery (PA), which suggested the presence of an abnormality in the vessel wall. Given the findings and the patient's symptoms, surgical intervention was planned. The procedure involved the resection of the affected portion of the artery and replacement with an autologous vein graft. Pathological examination of the resected arterial segment confirmed the diagnosis of CAD, revealing a cyst in the adventitia filled with a gelatinous substance.

Conclusion: CAD is a rare but important cause of arterial obstruction and the etiology of CAD is still unclear. It should be considered in younger patients with symptoms of limb ischemia, especially without smoking history or traditional risk factors. Imaging techniques, such as ultrasound and CT/MRI angiography, are crucial for diagnosis. Surgical management, typically involving resection and autologous grafting, is often required to alleviate symptoms and prevent further vascular complications. However, it is worth mentioning that conservative treatments, such as avoiding triggering movements, are sometimes sufficient. Since CAD is rarely suspected, awareness of this condition can help in making an early diagnosis, potentially avoiding misdiagnosis and improving patient outcomes.

Background: Mycoplasma pneumoniae pneumonia complicated with arterial embolism in children is rare but progresses rapidly, potentially leading to severe limb ischemia and disability. This study reports a case of MPP complicated with upper limb arterial embolism and reviews relevant literature to explore its pathogenesis, treatment strategies, and clinical management principles.

Case presentation: On January 9, 2025, Hebei Provincial Hospital of Traditional Chinese Medicine admitted an Asian male pediatric patient with upper limb arterial embolism. The patient developed acute limb ischemia secondary to Mycoplasma pneumoniae pneumonia and was diagnosed with upper limb arterial embolism. Endovascular thrombectomy was performed, followed by postoperative anticoagulation, anti-infective therapy, and traditional Chinese medicine treatment. After comprehensive management, the ischemic condition of the affected limb significantly improved, with no obvious functional impairment, achieving satisfactory therapeutic outcomes.

Conclusion: The risk of thrombosis in children with Mycoplasma pneumoniae pneumonia is often overlooked by clinicians. Due to its rapid progression and potentially severe consequences, early identification of thrombotic risk is crucial. A multidisciplinary approach should be adopted to determine the most appropriate treatment strategy for each patient, aiming to improve prognosis and reduce the risk of disability.

Background: Severe acute respiratory syndrome coronavirus 2 infection causes systemic immune overresponse (cytokine storm), which can lead to microthrombi and dysfunction of coagulation such as disseminated intravascular coagulation (DIC) of sepsis. Coronavirus disease 2019 (COVID-19) coagulopathy is known to occur mainly in the pulmonary microcirculation. We aimed to investigate hematological differences in coagulopathy between COVID-19 pneumonia and bacterial pneumonia.

Methods: We performed an observational cohort study using the Japanese REsearch of COVID-19 by assEmbling Real-world data (J-RECOVER) study database for COVID-19 patients and the Japan Medical Data Center (JMDC) database for bacterial pneumonia patients. The J-RECOVER database includes data from patients discharged between January 1 and September 31, 2020. The JMDC database covers patients emergently hospitalized from 2014 to 2022. We analyzed the association between hematological coagulopathy, systematic inflammation, and organ dysfunction in both groups after one-to-one propensity score matching.

Results: We enrolled 572 COVID-19 patients and 2,413 bacterial pneumonia patients who required mechanical ventilation. The COVID-19 group was younger, had higher intensive care unit admission rates, and lower mortality in comparison to the bacterial group (p < 0.05). On day 1, the two groups showed no significant differences in JAAM-2 and sepsis-induced coagulopathy criteria. After matching, platelet counts, antithrombin activity, and prothrombin time-international normalized ratio were consistently maintained within normal ranges in the COVID-19 group. However, trends in D-dimer and fibrin degradation products in the COVID-19 group were similar to those in the bacterial pneumonia group.

Conclusions: COVID-19 coagulopathy differs from bacterial septic DIC by exhibiting lower platelet consumption and minimal vascular hyperpermeability. Consequently, management strategies for COVID-19 coagulopathy should be distinct from those for septic DIC.

Background: Locally acting antiplatelet and anticoagulant (APAC) is developed as an antithrombotic agent for administration during vascular interventions and in thrombo-inflammatory conditions. APAC has entered human studies as a dual inhibitor of von Willebrand factor-mediated platelet recruitment on collagen and thrombin generation. We aimed to assess safety and escalating intravenous (i.v.) doses of APAC on hemostasis using a large animal model.

Methods: We studied escalating APAC boluses (0.15-1.5 mg/kg; n = 11) and their reversal in anesthetized pigs for pharmacodynamics using functional coagulation testing. In some experiments, aspirin (500 mg) was co-administered with APAC, and protamine sulfate for reversal. Blood was repeatedly sampled for blood cell counts (CBC), activated partial thromboplastin time (APTT), prothrombin and thrombin time (PT, TT), thrombin generation (TG), activated clotting time (ACT), rotational thromboelastometry (ROTEM), and collagen-induced platelet aggregation (CIPA).

Results: APAC was well-tolerated, and CBC remained stable. APAC modestly inhibited CIPA at high doses, while APTT, TT and ACT, unlike PT, prolonged dose-dependently. The anticoagulant ED₅₀ doses of APAC and UFH showed similar range (0.54 vs. 0.43 mg/kg), but UFH lasted longer and was less reversible by protamine. At 0.75 mg/kg of APAC, TG was abolished, InTEM coagulation and clot formation times were prolonged ≥ 2.8-fold, maximum clot firmness was reduced to 8-45%, and amplitude to 35-80%. APAC effects were transient (T_1/2 APAC = 30 min), and reversible by protamine.

Conclusions: Escalating i.v. doses of APAC were safe and provided modest platelet inhibition.Our results indicate that the dose-dependent anticoagulation effects of APAC can be monitored using conventional laboratory assays.

Background: The elevated prevalence of venous thromboembolism (VTE) among individuals diagnosed with inflammatory bowel disease (IBD) necessitates thorough investigation. Analyzing the genetic association mechanisms between these conditions is essential for comprehending their concurrent manifestation.

Methods: Using genome-wide association study (GWAS) datasets for IBD and VTE, we applied a comprehensive approach to explore the genetic connections between these two diseases. The analysis was conducted in four steps: first, we assessed the overall genetic correlation between IBD and VTE using linkage disequilibrium score regression and genetic covariance analysis; next, we analyzed specific chromosomal regions to understand the genetic characteristics in these areas; then, we used the conditional/conjunctional false discovery rate (cond/conjFDR) method to better identify and quantify the shared genetic loci that contribute to both diseases' development.

Results: The genome-wide analysis revealed a strong genetic correlation between IBD, especially ulcerative colitis (UC), and VTE, while the correlation between Crohn's disease (CD) and VTE was weaker. A detailed regional analysis identified specific chromosomal areas with genetic links to both diseases. Using the conjFDR method, we confirmed the shared genetic components between these conditions and identified key genetic variants that influence the development of both diseases.

Conclusion: This study provides genetic-level statistical evidence into the comorbidity mechanisms of IBD and VTE from a genetic standpoint, thereby enhancing the understanding of the underlying genetic basis contributing to their concurrent occurrence.

Background: Coagulation defects, including purpura and other haemorrhagic conditions, are a critical area of medical research because of their significant health effects worldwide. Understanding the metabolic basis of these conditions may improve therapeutic strategies.

Methods: A two-sample Mendelian randomization (MR) approach was employed to evaluate the causal relationships between the levels of 1,400 metabolites and coagulation defects. Colocalization analysis confirmed significant shared genetic influences. Pathway and protein‒protein interaction (PPI) analyses identified rate-limiting enzymes and drug targets. The impacts of lifestyle factors on metabolite levels were also explored through MR.

Results: MR analysis revealed four metabolites whose abundance was significantly associated with coagulation defects: docosapentaenoate n3 DPA 22:5n3 (DPA) (OR: 1.594, 95% CI: 1.263-2.011, P < 0.001), 1-palmitoyl-2-stearoyl-gpc (PSPC) (16:0/18:0) (OR: 1.294, 95% CI: 1.134-1.477, P < 0.001), 1-stearoyl-2-docosahexaenoyl-gpc (SDPC) (18:0/22:6) (OR: 1.232, 95% CI: 1.101-1.380, P < 0.001) and hydroxypalmitoyl sphingomyelin (HPSM) (d18:1/16:0 (OH)) (OR: 0.803, 95% CI: 0.719-0.896, P < 0.001). Colocalization analysis provided robust evidence for shared genetic loci. Pathway analysis highlighted the importance of lipid metabolism, identifying key enzymes such as FADS1, FADS2 and TCP1. PPI analysis revealed an interaction between TCP1 and plasminogen, indicating potential therapeutic synergy. Further analysis revealed that lifestyle factors, including dried fruit and oily fish intake, were linked to the abundance of metabolites associated with coagulation risk.

Conclusions: This study identifies specific metabolites and metabolic pathways involved in coagulation defects, proposes novel therapeutic targets and highlights the roles of dietary and lifestyle interventions in the management of these conditions. These findings pave the way for personalized strategies to manage coagulation-related conditions.

Background: Venous thromboembolism (VTE) is a significant global health issue, yet effective therapeutic targets for its prevention and treatment remain elusive. This study aimed to identify plasma proteins causally associated with VTE risk using proteome-wide Mendelian randomization (MR) and colocalization analyses.

Methods: We utilized genome-wide association study (GWAS) data from the UK Biobank and FinnGen cohorts, encompassing 38,573 VTE cases and 946,373 controls. Plasma protein levels were quantified using Olink technology in the UK Biobank Pharma Proteomics Project (UKB-PPP) and SomaScan in the deCODE Health study. MR analysis was performed to assess causal relationships, followed by colocalization analysis to evaluate shared genetic variants. Functional enrichment analyses and molecular docking were conducted to explore biological mechanisms and predict potential therapeutic compounds.

Results: Eight proteins showed significant associations with VTE risk after Bonferroni correction (p < 3.19 × 10^-5). Odds ratios ranged from 0.98 (95% CI: 0.98-0.99) for PLEK to 1.03 (95% CI: 1.02-1.04) for LRP12. Strong colocalization evidence (PH4 ≥ 0.8) was found for LRP12, F11, PLCG2, and ABO. Molecular docking identified promising drug candidates including valine, folic acid, ibrutinib, and simvastatin, with valine showing the strongest binding energy (-32.057 kcal/mol).

Conclusions: This study highlights novel therapeutic targets for VTE and provides insights into potential drug candidates. These findings offer a foundation for future research and drug development aimed at reducing VTE risk.