Search Results (191)

Objective: Tranexamic acid (TXA) is widely used in rhinoplasty to minimize intraoperative bleeding and improve visualization; however, its effect on postoperative bleeding remains unclear. This study aimed to evaluate whether intravenous TXA reduces postoperative bleeding in patients undergoing primary or secondary rhinoplasty. Methods: A retrospective cohort study was performed using the TriNetX national research database to identify patients who underwent primary (CPT 30400, 30410, 30420) or secondary (CPT 30430, 30435, 30450) rhinoplasty from 2010 to 2023. Patients were grouped based on perioperative usage of intravenous TXA. Propensity score matching adjusted for demographics and coagulation disorders (ICD-10 D65–D69). The primary outcome was postoperative bleeding, including epistaxis, within one month of surgery. Results: Among 2586 patients who met inclusion criteria, 1293 (50%) received TXA. TXA recipients had a higher prevalence of bleeding risk factors, including prior use of antihemorrhagic medications (5.9% vs. 1.8%, p < 0.0001) and prolonged prothrombin time (20% vs. 16.1%, p = 0.032). TXA patients more frequently underwent concurrent septoplasty (29.7% vs. 21%, p < 0.0001). There were no significant differences observed in postoperative epistaxis or bleeding between cohorts. Similar postoperative bleeding rates despite these higher-risk characteristics suggest that TXA may have benefit in the mitigation of elevated bleeding risk in the treated cohort. Conclusions: TXA is preferentially administered to patients at higher risk of bleeding and during more complex, vascular procedures prone to increased blood loss. Prospective studies are needed to directly test whether TXA normalizes bleeding risk in higher-risk rhinoplasty patients. Full article

Background/Objectives: Autoimmune factor VIII deficiency (AiFVIIID) is a rare disorder that causes severe bleeding. Emicizumab has recently been found to be effective in treating AiFVIIID; however, monitoring with standard coagulation tests presents challenges. Methods: Clot waveform analysis (CWA), which involves CWA-activated partial thromboplastin time (APTT), the CWA-small amount of tissue factor activation assay (sTF/FIXa), and clotting time using a small amount of thrombin (sTT), was used to both diagnose AiFVIIID and monitor emicizumab. Results: CWA-sTT reflects the residual FVIII activity in patients with AiFVIIID. Several tests were employed, including APTT, FVIII activity, CWA, mixing tests with normal plasma, FVIII inhibitor assays, and anti-FVIII antibody activity for the diagnosis of AiFVIID in three cases. However, the sensitivity of APTT reagents to AiFVIID differed between thrombocheck-APTT and APTT-SP. Emicizumab treatment was effective for major bleeding, and anti-FVIII antibody activity could be measured using CWA-sTT. Conclusions: The sensitivity of APTT reagents to AiFVIID varies. CWA-sTT may provide utility in the diagnosis of AiFVIIID. Emicizumab is useful for the treatment of AiFVIID, and anti-FVIII antibody activity can be measured even in patients treated with emicizumab. Full article

Background/Objectives: Alcohol Use Disorder (AUD) and Substance Use Disorders (SUDs) can affect both the liver, where clotting factors are synthesized, and the coagulation system, which prevents acute bleeding. Methods: This study included 451 inpatients undergoing addiction detoxification and 150 healthy controls. Patients were stratified by substance type: Alcohol (n = 110), Cannabinoid (n = 71), Methamphetamine (n = 110), Multiple-Substance (Methamphetamine + Cannabinoid, n = 110), and Opioid (n = 50) users. Age-matched control groups (mean ages 45, n = 50; 30, n = 100) were used. Serum levels of Ca, INR, PT, APTT, PLT, AST, and ALT, alongside sociodemographic variables, were assessed. Results: Significant group differences were observed in ALT, AST, PT, APTT, and PLT (p < 0.001). Notably, PT was lower in Multiple Substance and Methamphetamine users; APTT was elevated in Cannabinoid users; AST was higher in Alcohol users; and Methamphetamine and Opioid users exhibited both decreased AST and ALT. Post hoc analyses confirmed substance-specific effects (p < 0.001). Regular cigarette use was significantly more prevalent among alcohol and substance user groups compared to controls; however, smoking did not exert a significant effect on the evaluated biochemical or coagulation parameters. Conclusions: These findings demonstrate that liver enzymes and coagulation parameters can vary significantly by substance type. Observed alterations in AST, ALT, PT, APTT, and PLT suggest that substance use may exert substance-specific effects on hepatic and haemostatic function, highlighting potential risks for bleeding or thrombotic complications. Monitoring these parameters in AUD and SUD patients could provide valuable clinical insights, allowing for more tailored and proactive management strategies. While the underlying mechanisms remain to be fully elucidated, these results emphasize the importance of considering substance-specific physiological impacts when assessing liver and coagulation health in addicted populations. Full article

The liver is a primary metabolic hub and a pivotal target for gene therapy, owing to its capacity for protein secretion, role in metabolic homeostasis and immune tolerance. Liver-directed gene therapies are used to treat numerous inherited metabolic disorders and coagulation factor deficiencies including hemophilia (A and B), Crigler–Najjar syndrome, mucopolysaccharidoses, phenylketonuria, Fabry, Gaucher, Wilson and Pompe diseases. The efficacy and safety of liver-directed gene therapy rely on the use of strong tissue-specific promoters. To date, there are many different liver-specific promoters used in preclinical and clinical studies, including novel completely synthetic promoters. This review provides a comprehensive analysis of the design, engineering and application of liver-specific promoters. Furthermore, we discuss fundamental principles of gene expression regulation in the liver and the physiological and immunological characteristics that make it a suitable target organ for gene therapy delivery. Full article

p17, the human immunodeficiency virus type 1 (HIV-1) matrix protein traditionally associated with viral assembly, has been recently investigated for its extracellular functions linked to vascular damage. This review examines the molecular and pathogenic signatures by which p17 and its variants (vp17s) contribute to endothelial activation, aberrant angiogenesis, and vascular inflammation, highlighting their relevance even under effective antiretroviral therapy (ART). Specifically, p17 exerts chemokine-like activities by binding to chemokine (C-X-C motif) receptor-1 and 2 (CXCR-1/2) on endothelial cells (ECs). This interaction triggers key signaling cascades, including the protein kinase B (Akt)-dependent extracellular signal-regulated kinase (ERK) pathway and endothelin-1/endothelin receptor B axis, driving EC motility, capillary formation, and lymphangiogenesis. Variants such as S75X demonstrate enhanced lymphangiogenic potency, associating them with tumorigenic processes involved in non-Hodgkin lymphoma (NHL) pathogenesis. Importantly, p17 promotes endothelial von Willebrand factor (vWF) storage and secretion, implicating a pro-coagulant state that may trigger the increased thromboembolic risks observed in HIV-positive patients. Furthermore, p17 crosses the blood–brain barrier (BBB) via CXCR-2-mediated pathways, contributing to neuroinflammation by activating microglia and astrocytes and amplifying monocyte chemoattractant protein-1 (MCP-1) levels, therefore playing a critical role in the development of HIV-associated neurocognitive disorders. Hence, the elaboration of potential therapeutic strategies finalized at inhibiting p17/vp17s’ interaction with their receptors could complement ART by addressing HIV-related neurovascular morbidity. Full article

Hemophilia B is a hereditary bleeding disorder caused by mutations localized throughout the F9 gene. Existing gene therapy products containing AAV vectors have significant limitations. Replacement therapy with coagulation factor FIX infusions is not an optimal way of treatment, as patients still have periodic bleeding and require frequent transfusions. Moreover, approximately 5% of adult patients with hemophilia B develop inhibitory antibodies to recombinant forms of FIX. Therefore, it is important to develop universal CRISPR/Cas gene therapy approaches for F9 editing using non-viral delivery systems to enable gene reversion to a functional sequence at an early stage of disease development and establishment of the patients’ immune system. In this study, a unique approach of F9 prime-editing was tested for the first time. This method is estimated to edit 7.3% of pathogenic F9 mutation types. Specifically, it targets the gene region encoding amino acids 374 V to 408 Q, which accounts for approximately 9.35% of patients with hemophilia B. An advantage of this gene therapy approach is the absence of the need to change Primer Binding Site (PBS) or Reverse Transcriptase Template (RTT) sequences until going from preclinical to clinical trials, as well as the introduction of gain of function mutations in order to compensate for the low prime-editing frequencies and enhance the effect of treatment in vivo. Full article

Snake venoms are rich sources of bioactive molecules that modulate hemostasis and, among these, anticoagulant snake venom phospholipases A₂ (sPLA₂) are found in a range of snake venoms. Crotoxin (CTX), from the Crotalus durissus rattlesnake, is a heterodimeric PLA₂ complex, and literature has reported its mechanisms in anticoagulant activity. The present review revisits the biological roles of anticoagulant sPLA₂ and critically examines evidence on CTX in hemostatic regulation, aiming to clarify its mechanisms and therapeutic promise. CTX exerts anticoagulant activity via enzymatic hydrolysis of procoagulant phospholipids and direct interaction with coagulation factors, disrupting key complex assembly. It also counteracts inflammation-induced coagulation by modulating leukocyte- and endothelial-derived mediators, restoring balance among anticoagulant, procoagulant, and fibrinolytic pathways. Effects on platelet function appear comparatively modest, ranging from less potent pro-aggregatory activity to negligible aggregation. The dual anticoagulant and anti-inflammatory properties of CTX highlight its potential as a model for novel antithrombotic agents in hypercoagulable and inflammation-driven disorders, despite toxicological concerns that necessitate cautious pharmacological exploration. Full article

With the increasing global burden of major depressive disorder (MDD), identifying modifiable environmental risk factors has become a critical priority. Per- and polyfluoroalkyl substances (PFASs), characterized by environmental persistence and bioaccumulation, have been linked to elevated mental health risks. However, the potential neurotoxicity of GenX—a novel PFAS developed to replace perfluorooctanoic acid (PFOA)—and its molecular association with MDD remain unclear. In this study, peripheral blood serum transcriptomic data from the Gene Expression Omnibus (GEO) were integrated with multidimensional bioinformatics analyses to elucidate molecular mechanisms connecting GenX exposure with MDD. Four hub genes (UCP2, AKR1B1, TP53, and F5) were identified, showing strong combined diagnostic performance (AUC = 0.925). Functional enrichment and immune infiltration analyses revealed their involvement in energy metabolism, oxidative stress, and immune-coagulation regulation. Molecular docking and dynamics simulations further confirmed stable interactions between GenX and these proteins, providing structural support for their mechanistic roles. Although classical dopaminergic markers (TH, SLC6A3, DRD1–5) were not detected in the serum-derived transcriptomes, the identified hub genes may still affect dopaminergic function indirectly by modulating metabolic, oxidative stress, and inflammatory/coagulation pathways, thereby influencing MDD susceptibility. This study provides the first integrated transcriptomic and structural evidence linking GenX to psychiatric risk, proposing a novel “GenX-dopamine-MDD” framework for understanding pollutant-mediated neuropsychiatric mechanisms. Full article

We carried out a comprehensive literature search for publications on the range of vascular events that have been linked to adenomyosis. This covered vascular diseases, blood coagulation disorders, thrombosis, hypercoagulation, stroke (embolic, ischemic, thrombotic, hemorrhagic), cerebrovascular episodes, cerebral infarction, cerebral hemorrhage) and renal disease. This review covers 63 articles. Nineteen articles reported clinical manifestations of intravascular thrombosis in women with adenomyosis. Eleven publications were identified that reported on cerebral involvement and adenomyosis, including cases of ischemic stroke or infarction. Dysregulation primarily seems to occur via local factors leading to altered angiogenesis. Five case reports were identified that reported on various vascular complications attributed to the presence of adenomyosis. The search also identified reports of cerebral complications in women with adenomyosis. Through a secondary search, we identified publications dealing with a possible connection between cardiac complications and renal pathology, which the authors attributed to adenomyosis. Vascular involvement in adenomyosis is documented in rare cases by the presence of endometrial tissue in myometrial vessels both in menstrual and non-menstrual uteri. Women with adenomyosis have a higher platelet count, a shorter thrombin and prothrombin time and an activated partial thromboplastin time. These findings has been applied to attempts to identify therapies for adenomyosis based on targeting the vasculature, but the existence of a link between the two conditions is under question for several reasons: only case reports (or very small series) have been published; all published cases come from one region of the world (the Far East); the published literature does not contain objective proof of a causal relationship between the two pathologies, except for the elevation of some markers. In summary, it is not possible to conclude that the presence of adenomyosis has a pathogenetic role in causing vascular events, first and foremost because available evidence consists mostly of case reports. Full article

Background/Objectives: Machine learning is an extremely important issue, considering the potential to prevent the onset of long-term complications from coronavirus disease or to ensure timely detection and effective treatment. The aim of our study was to develop an algorithm and mathematical model to predict the risk of developing long COVID in children who have had acute SARS-CoV-2 viral infection, taking into account a wide range of demographic, clinical, and laboratory parameters. Methods: We conducted a cross-sectional study involving 305 pediatric patients aged from 1 month to 18 years who had recovered from acute SARS-CoV-2 infection. To perform a detailed analysis of the factors influencing the development of long-term consequences of coronavirus disease in children, two models were created. The first model included basic demographic and clinical characteristics of the acute SARS-CoV-2 infection, as well as serum levels of vitamin D and zinc for all patients from both groups. The second model, in addition to the aforementioned parameters, also incorporated laboratory test results and included only hospitalized patients. Results: Among 265 children, 138 patients (52.0%) developed long COVID, and the remaining 127 (48.0%) fully recovered. We included 36 risk factors of developing long COVID in children (DLCC) in model 1, including non-hospitalized patients, and 58 predictors in model 2, excluding them. These included demographic characteristics of the children, major comorbid conditions, main symptoms and course of acute SARS-CoV-2 infection, and main parameters of complete blood count and coagulation profile. In the first model, which accounted for non-hospitalized patients, multivariate regression analysis identified obesity, a history of allergic disorders, and serum vitamin D deficiency as significant predictors of long COVID development. In the second model, limited to hospitalized patients, significant risk factors for long-term sequelae of acute SARS-CoV-2 infection included fever and the presence of ≥3 symptoms during the acute phase, a history of allergic conditions, thrombocytosis, neutrophilia, and altered prothrombin time, as determined by multivariate regression analysis. To assess the acceptability of the model as a whole, an ANOVA analysis was performed. Based on this method, it can be concluded that the model for predicting the risk of developing long COVID in children is highly acceptable, since the significance level is p < 0.001, and the model itself will perform better than a simple prediction using average values. Conclusions: The results of multivariate regression analysis demonstrated that the presence of a burdened comorbid background—specifically obesity and allergic pathology—fever during the acute phase of the disease or the presence of three or more symptoms, as well as laboratory abnormalities including thrombocytosis, neutrophilia, alterations in prothrombin time (either shortened or prolonged), and reduced serum vitamin D levels, are predictors of long COVID development among pediatric patients. Full article

Background/Objectives: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease, in which multiple genetic and environmental factors may contribute. This study aimed to identify potential genetic determinants in patients with CTEPH and to compare their occurrence to a control group, which included patients with pulmonary embolism who had not developed CTEPH. Methods: Tier 1 and 2 genes related to coagulation, fibrinolysis and platelet disorders—as recommended by the International Society on Thrombosis and Haemostasis—and genes associated with vascular conditions were analyzed in n = 15 patients with CTEPH and n = 17 controls using next-generation sequencing. Non-synonymous, rare variants were collected and interpreted. Results: As expected, no single gene or variant was consistently present among CTEPH patients. Instead, individuals carried different mutations and combinations of variants. We identified several variants that were not found in the control group. Candidate variants were detected in F12, F13A1, F13B, F5, KNG1, SERPIND1, THBD, ADAMTS13, VWF, STIM1, ETV6, THPO, MPL, SERPINA1, ENG, RASA1, ACVRL1, GDF2, NFE2, SOX17 and RNF213. We did not detect exclusive variants in FGA, CPB2, and BMPR2 although they were suggested as candidates in previous studies. Elevated factor VIII and von Willebrand factor in CTEPH could not be explained by mutations in VWF and F8. Conclusions: Our study supports the hypothesis of heterogeneous genetic background in CTEPH, involving multiple pathways such as coagulation, altered fibrinolysis and impaired angiogenesis. These results provide a basis for more detailed investigations into specific genes and variants potentially associated with CTEPH in larger cohorts. Full article

Conventional whole-blood flow assays for quantifying thrombus formation are typically performed at room temperature and are technically demanding, which limits their translational applicability. We engineered a novel, disposable, mountable, and single-channel microfluidic chip (MC-2S), which is based on the Maastricht chamber (MC) and designed for automated evaluation of platelet function, coagulation and fibrinolysis under physiological conditions. The MC-2S chip allows customizable choices of thrombogenic surfaces, such as collagen and tissue factor. The chip was used in combination with an adapted, 1.3 kg brightfield/fluorescence microscope, operating at physiological temperature (37 °C), and with scripts for automated multicolor analysis of image features. The integrated system enables a robust, rapid, and high-content quantification of the kinetics of thrombus formation and dissolution. In platelet-sensitive mode, MC-2S demonstrated high sensitivity to antiplatelet therapy with aspirin or cangrelor. In coagulation-sensitive mode, it detected the anticoagulant effect of rivaroxaban plus its reversal by andexanet-α. In fibrinolysis-sensitive mode, it monitored tissue-type plasminogen activator-induced thrombus dissolution, inhibited by tranexamic acid. Collectively, the MC-2S platform was found to provide a versatile, physiologically relevant tool for functional hemostasis testing, with high potential for the acute and subacute evaluation of patient blood samples in the context of bleeding disorders, thrombosis risk, and drug monitoring. Full article

Both primary and secondary hemostasis consist of finely regulated pathways, forming a blood clot to stop bleeding. These orchestrated mechanisms involve multiple plasma- and platelet/endothelial-derived receptors, factors, enzymes, and proteins, such as the von Willebrand factor (vWF), fibrinogen, and thrombin. Over-activation or improper resolution of the coagulation cascade leads to severe pathological disorders, arterial and venous. Despite the fact that the genetic etiology of thrombophilia has gained the main research interest, there is growing evidence that the disturbed redox network of key hemostatic pathways signals thrombus formation. Oxidized LDL in dyslipidemias and many endogenous and exogenous compounds act as pro-oxidant stimuli that lead to post-translational modifications of proteins, such as sulfenylation, nitrosation, disulfide formation, glutathionylation, etc. Oxidation of cysteine and methionine residues of vWF, fibrinogen, and thrombomodulin has been detected at thrombotic episodes. Increased homocysteine levels due to, but not restricted to, methylenetetrahydrofolate reductase gene (MTHFR) mutations have been incriminated as a causative factor for oxidative stress, leading to a pro-thrombotic phenotype. Alterations in the vascular architecture, impaired vascular relaxation through decreased bioavailability of NO, accumulation of Nε-homocysteinylated proteins, ER stress, and endothelial cells’ apoptosis are among the pro-oxidant mechanisms of homocysteine. This review article focuses on describing key concepts on the oxidant-based molecular pathways that contribute to thrombotic episodes, with emphasis on the endogenous compound, homocysteine, aiming to promote further molecular, clinical, and pharmacological research in this field. Full article

Inherited platelet function disorders (IPFD) are characterized by normal platelet count and morphology but impaired function due to pathogenic variants in genes encoding membrane receptors, granule constituents, or intracellular signaling proteins. Glanzmann’s thrombasthenia, the most representative IPFD, results from ITGA2B or ITGB3 mutations that disrupt the αIIbβ3 integrin complex, producing severe mucocutaneous bleeding. Advances in molecular genetics have expanded the IPFDs landscape to include defects in other platelet receptors (Glycoprotein (GP)-VI, P2Y₁₂, and thromboxane A₂[TxA₂]-R), signaling mediators (RASGRP2, FERMT3, G-protein regulators, PLC, and TxA₂ pathway enzymes), and granule biogenesis disorders such as Hermansky–Pudlak and Chediak–Higashi syndromes. High-throughput sequencing technologies, including long-read approaches, have greatly improved diagnostic yield and clarified genotype–phenotype correlations. Clinically, bleeding severity varies from mild to life-threatening, and management relies on antifibrinolytics, desmopressin, or platelet transfusion; recombinant activated factor VII and hematopoietic stem cell transplantation are reserved for selected cases. Emerging strategies such as gene therapy and bispecific antibodies that link platelets and coagulation factors represent promising advances toward targeted and preventive treatment. A better knowledge of the clinical features and understanding molecular pathogenesis of IPFDs not only enhances diagnostic precision and therapeutic options but also provides key insights into platelet biology, intracellular signaling, and the broader mechanisms of human hemostasis. Full article

Platelets play a pivotal role in coagulation, traditionally recognized for their involvement in thrombin generation via the prothrombinase complex and for regulating thrombopoietin (TPO) synthesis through platelet-mediated TPO uptake. However, recent studies suggest that TPO homeostasis involves more dynamic, feedback-driven mechanisms, though these interactions remain incompletely described and experimentally confirmed. The interplay between platelet activating factor (PAF) secretion, fibrinolysis, interleukin-6 (IL-6) signalling, hepatic TPO synthesis, as well as the complexity of platelet subpopulations, emphasises platelets’ multifaceted role in haemostasis and haematopoiesis. Our article investigates novel pathways by which fibrinogen degradation products (FgDPs) influence plasminogen and TPO synthesis, focusing on the interconnection between procoagulant platelets, platelet-derived messengers, and fibrinolytic processes. In this work several intermediary mechanisms are hypothesised, including the FgDP-IL-6-plasminogen pathway, the PAF-IL-6-TPO pathway, and the thrombin-FgDP-IL-6-TPO pathway, which may link FgDP and plasminogen biosynthesis with platelet activation, cytokine release, and thrombopoiesis regulation. The proposed mechanisms involve secretion of PAF by procoagulant platelets, inducing IL-6 synthesis in endothelial cells, fibroblasts, and vascular smooth muscle cells. Subsequently, IL-6 stimulates hepatocyte-driven TPO production, potentially serving as a feedback mechanism to restore platelet counts following coagulation. Furthermore, fibrinolysis-generated FgDPs may further enhance IL-6 release, implying alternative routes for TPO regulation. Our hypotheses challenge the prevailing view that platelet numbers alone dictate TPO homeostasis. Therefore, we propose that inflammatory and fibrinolytic signals actively regulate TPO homeostasis, challenging the platelet-count-centric paradigm. These insights provide a new perspective on haematopoiesis and suggest novel therapeutic targets for thrombocytopenia and coagulation disorders, highlighting the need for further experimental validation. Full article