Thrombosis Journal最新文献

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.

Background: Deep venous thrombosis (DVT) is part of a spectrum of venous thromboembolism, which also includes pulmonary embolism. Up to 50% of hospitalized individuals who develop pulmonary embolism have DVT. Pulmonary embolism is responsible for up to 10% of hospital deaths. However, the burden and specific risk factors for DVT among inpatients living with HIV in our setting are not well established. Thromboprophylaxis, which reduces the risk of DVT, is not routinely administered to all inpatients. Understanding the burden and risk factors for DVT in this population can guide the implementation of preventive measures, identify high-risk individuals, and inform guidelines for thromboprophylaxis.

Methods: This cross-sectional study was conducted between October 2023 and April 2024 in two National Referral hospitals among hospitalized people living with HIV. A total of 186 participants were consecutively sampled and enrolled in the study. All adult inpatients living with HIV who fulfilled the eligibility criteria had a bedside Doppler ultrasound scan of the lower limbs for DVT. Relevant demographic, clinical, laboratory, and HIV-related data were obtained. Both bivariable and multivariable analyses were performed via R software.

Results: Up to 186 participants were enrolled, with a median age of 40 years (interquartile range (IQR): 34-52). The prevalence of lower limb DVT was 18.3% (34/186). The participants with DVT had a median age of 49 years (IQR: 39-56, p-value 0.045). Up to 53% (99/186) of the participants were male. The median duration of hospitalization was 5.0 days (IQR: 4.0-7.8) among those with DVT. A positive history of cigarette smoking was identified in 6.5% (12/34) of the participants and was significantly associated with the development of DVT (P-value = 0.004). TB coinfection was significantly associated with DVT, with a prevalence ratio (PR) of 2.22 (P-value = 0.007). A low CD4 (< 200) was also significantly associated with lower limb DVT (PR = 2.70, P-value = 0.003).

Conclusion: The prevalence of lower limb DVT among hospitalized people living with HIV is high (18.3%) in our setting. Older age, a positive history of smoking, a low CD4 count (< 200), and TB coinfection are significant risk factors for DVT in HIV-positive inpatients.

Background: Lower extremity deep vein thrombosis (LEDVT) is a common vascular disease, with its pathogenesis mainly involving inflammatory responses and oxidative stress. Liquiritin (LIQ) is a flavonoid that exhibits pharmacological effects such as anti-inflammatory and antioxidant properties. This study aimed to investigate the role of LIQ in LEDVT and its potential mechanisms.

Methods: We established an LEDVT model in mice by ligating the inferior vena cava (IVC) and performed in vitro experiments by stimulating human umbilical vein endothelial cells (HUVECs) with IL-1β (10 ng/mL) to simulate endothelial cell injury.

Results: We found that LIQ significantly reduced the size and weight of thrombi and decreased the concentrations of inflammatory factors TNF-α and IL-6 in the IVC of LEDVT mice. Furthermore, LIQ inhibited the secretion of prothrombotic mediators such as tissue factor (TF) and vascular cell adhesion molecule-1 (VCAM-1). Administration of LIQ resulted in a notable reduction in immune inflammatory cells in the IVC of LEDVT mice. LIQ also demonstrated antioxidant properties, as the treatment of LIQ enhanced SOD activity and restored ROS levels to normal in the IVC. Similarly, LIQ reduced the formation of inflammatory factors and the secretion of prothrombotic mediators by HUVECs while inhibiting oxidative stress in HUVECs. Finally, LIQ effectively suppressed the levels of phosphorylated p65 in both the IVC and HUVECs.

Conclusions: LIQ reduces inflammatory responses and oxidative stress in LEDVT by inhibiting the NF-κB signaling pathway. This finding provides new insights into the prevention and treatment of LEDVT.

Introduction: Peripheral Artery Disease (PAD) is a common cardiovascular condition marked by peripheral artery stenosis or occlusion. Despite treatment advancements, patients will still face vascular complications, highlighting the need for innovative therapies. Human proteins play crucial roles in biology and drug research. Mendelian randomization (MR) analysis, a gene-based method, is increasingly used in drug target identification. This study aims to identify PAD-associated plasma proteins through MR analysis for potential therapies.

Methods: We first used GWAS data and seven pQTL datasets to identify plasma proteins causally linked to PAD through MR analysis. Then, we performed KEGG pathway enrichment analysis, Bayesian colocalization analysis, and MR-BMA analysis were carried out to investigate mechanisms and prioritize these proteins. Finally, we assessed the druggability of the target proteins using the DrugBank database.

Results: MR analysis found four plasma proteins causally linked to PAD: MMP3 positively correlated with PAD, while CASS4, ISG15, and MMP1 exhibited negative associations. Bayesian colocalization analysis confirmed these relationships, and the MR-BMA analysis prioritized MMP1 as the main target. KEGG pathway enrichment analysis highlighted lipid metabolism and atherosclerosis pathways as central to these drug targets. The druggability evaluation indicated that drugs targeting these proteins are either in development or already in clinical use.

Conclusion: This study integrates genetic and proteomic data to identify therapeutic targets for PAD and evaluate their potential for drug development. The prioritization of MMP1 and ISG15 as key targets shows promise for PAD treatment, but further validation and clinical exploration of these findings are needed.

Background: Thrombotic thrombocytopenic purpura (TTP) is an uncommon and life-threatening disorder caused by a deficiency of ADAMTS-13, and eventually leads to microangiopathic hemolytic anemia, severe thrombocytopenia, and organ damages. Acute TTP events could be triggered by infections, or inflammations in the context of ADAMTS-13 deficiency. Recently, several case reports have indicated an association between diabetic ketoacidosis (DKA) and TTP. Here, we present a case with the concomitant presentation of DKA and TTP.

Case presentation: A 37-year-old male with diabetes mellitus presented with typical symptoms of diabetic ketoacidosis. He was managed with an insulin pump and intravenous fluids. However, he developed seizure and progressed to coma, his rapidly deteriorating condition necessitated continuous renal replacement therapy, intubation, and inotropic support. Laboratory data indicated hemolytic anemia and thrombocytopenia, and a blood smear revealed schistocytes. The PLASMIC score was 5, and ADAMTS-13 activity was 2%. The patient was diagnosed with TTP and treated with therapeutic plasma exchange, steroids, and rituximab. His platelet count stabilized above 150,000/µL, and ADAMTS-13 activity progressively improved.

Conclusions: This case report emphasizes the concurrence of DKA and iTTP, presenting the rare complication of acute renal failure in TTP. TTP is a rare and serious disease that requires prompt recognition and management. Concurrent conditions should be considered when calculating prediction scores such as the PLASMIC and French scores.

Background: The National Early Warning Score (NEWS2) predicts clinical deterioration in hospitalized patients. Its role in pulmonary embolism (PE) risk stratification remains underexplored. This study assessed the association of initial NEWS2 with clinical deterioration and advanced interventions during hospitalization.

Methods: We retrospectively analyzed a PE response team (PERT) registry of adults with submassive and massive PE from 11 emergency departments (2016-2024). Initial NEWS2 was calculated for each registry patient. The primary outcome was in-hospital PE-related clinical deterioration (death, cardiac arrest, vasoactive medications for hypotension, or emergent respiratory interventions). The secondary outcome was advanced intervention use. We calculated odds ratios (OR) for different NEWS2 cut-offs. We used multivariable analysis to assess the association of NEWS2 and study outcomes, and decision curve analysis to determine net benefit of clinical deterioration.

Results: Among 2119 patients (mean age 62.2 [16.8], 51.2% female, 168 [7.9%] with massive PE, and 1951 [92.1%] with submassive PE), 309 patients (14.6%) experienced clinical deterioration and 488 (23.0%) required advanced interventions. Mean NEWS2 was higher in patients with vs. without clinical deterioration (6.0 ± 3.3 vs. 3.0 ± 2.4; p < 0.001) and in those with vs. without advanced interventions (4.8 ± 3.1 vs. 3.0 ± 2.5; p < 0.001). NEWS2 cut-off of ≥ 3 identified patients at risk of clinical deterioration: sensitivity 87% (82-90%), OR 6.1 (95% CI: 4.3-8.5), and negative predictive value (NPV) 96% (94-97%). NEWS2 cut-off ≥ 4 had specificity of 62% (60-65%), OR of 5.1 (95% CI: 3.9-6.7), and NPV of 94% (92-95%). As a continuous variable, NEWS2 had an OR of 1.2 (95% CI: 1.1-1.3). NEWS2 cut-offs from 3 to 5 showed an improved net benefit (0.08, 0.16, and 0.34) compared with treating all patients as high risk for clinical deterioration.

Conclusion: Patients with PE and initial NEWS2 scores ≥ 3 had a four-fold to eight-fold higher odds of clinical deterioration than those with NEWS2 < 3. NEWS2 is useful for predicting clinical deterioration and guiding intervention strategies in PE.