Search Results (60)

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by excessive proliferation of one or more myeloid lineages, frequently accompanied by an elevated risk of thrombotic events. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are implicated in numerous inflammatory and vascular pathophysiological processes. In this study, we analyzed the association between selected MMP polymorphisms, rs1799750, rs243865, rs3025058, rs3918242, and rs17576, and thrombotic risk as well as clinical characteristics in patients with MPNs. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Among the polymorphisms analyzed, a statistically significant association was identified between the MMP-9 rs3918242 CT genotype and an increased risk of arterial thrombosis (OR = 4.206, CI 1.337–13.234, p = 0.014). Moreover, rs3918242 CT was associated with thrombotic events (both arterial and venous thrombosis combined), suggesting a potential contributory role in the prothrombotic phenotype observed in MPNs (OR = 3.200, CI 1.110–9.258, p = 0.031). These findings indicate that genetic variation in MMP-9, particularly rs3918242, may serve as a predictive marker for vascular complications in MPN patients. Further studies with larger cohorts are warranted to confirm these associations and to elucidate the molecular mechanisms underlying the contribution of MMP polymorphisms to thrombosis in MPNs. Full article

Background: Venous thromboembolism is more prevalent among patients with inflammatory bowel disease (IBD). This study aimed to identify prothrombotic hemorheological alterations in IBD. Methods: We conducted a case–control study with patients with ulcerative colitis, Crohn’s disease, and non-IBD control subjects. We measured hemorheological indicators including plasma viscosity (PV), whole blood viscosity (WBV), erythrocyte aggregation (EA), and erythrocyte deformability (ED). Uni- and multivariate tests were employed for analysis. Results: A total of 53 IBD patients and 77 control subjects were recruited. IBD patients showed significantly higher aggregation index (68.8% (35.3–83.5%) vs. 66.9% (35.2–83.5%), p = 0.003) and threshold shear rate (120 1/s (55–325 1/s) vs. 110 1/s (55–325 1/s), p < 0.001), with lower aggregation half-time (1.6 s (0.6–7.1 s) vs. 1.8 s (0.6–7.1 s), p = 0.004), indicating enhanced EA. However, after adjusting for covariates, including inflammatory markers, IBD no longer predicted EA. There were no significant differences in EA. PV, WBV, and ED between the groups. Fibrinogen, rather than the Crohn’s Disease Activity Index, was the strongest predictor of the outcomes. Conclusions: Our study demonstrates that IBD patients exhibit enhanced EA, predicted mainly by fibrinogen. These results confirm that inflammation plays the cardinal role in the increased tendency for venous thromboembolism in IBD. Full article

Insulin resistance is a condition wherein cells fail to adequately respond to insulin. It is a prevalent medical condition associated with several diseases, such as type 2 diabetes mellitus, metabolic syndrome, hypertension, obesity, and polycystic ovary syndrome. Insulin resistance may be involved in metabolic disturbances, such as hyperglycemia, hyperinsulinemia, dyslipidemia, hyperuricemia, endothelial dysfunction, elevated inflammatory markers, and a prothrombotic state. Severe insulin resistance syndromes are a heterogeneous group of rare disorders. These disorders are characterized by profound insulin resistance, substantial metabolic abnormalities, and different clinical manifestations and complications. They may be hereditary or acquired, caused by defects in insulin action and cellular responsiveness to insulin. Severe insulin resistance syndromes may also be due to aberrations in adipose tissue function and development. The majority of these disorders are associated with an increased risk of severe complications and mortality. This review aims to summarize the current knowledge on the epidemiology, pathophysiology, complications and prognosis of severe insulin resistance syndromes, as well as to categorize these syndromes by disease process, including defects in insulin receptor, intracellular insulin signaling defects, lipodystrophies, etc. Full article

Inflammation contributes to myocardial injury in ST-elevation myocardial infarction (STEMI). Interleukin-6 receptor (IL-6R) inhibition has been shown to mitigate myocardial injury and reduce levels of the prothrombotic and inflammatory mediator, neutrophil extracellular traps (NETs). The enzyme peptidylarginine deiminase 4 (PAD4) is central in NET formation. We hypothesized that PAD4 links IL-6R activation and NET formation. Methods: We conducted thrombus aspiration and peripheral blood sampling in 33 STEMI patients. In thrombi and leukocytes, we quantified the mRNA of IL-6, IL-6R, and PAD4. In peripheral blood, the protein levels of IL-6, IL-6R, PAD4, dsDNA, H3Cit, MPO-DNA, and troponin T were quantified. Results: In thrombi and circulating leukocytes, PAD4 mRNA was associated with IL-6R mRNA (thrombi: β = 0.34, 95% CI [0.16–0.53], p = 0.001, circulating leukocytes: β = 0.92, 95% CI [0.07–1.77], p = 0.036). There were no correlations between PAD4 and IL-6 in thrombi and leukocytes. The protein levels of IL-6R were associated with the NET marker H3Cit (r_s = 0.40, p = 0.02). In thrombi, PAD4 mRNA was associated with high levels of troponin T (β = 1.15 95% CI [0.27–2.04], p = 0.013). Conclusion: We demonstrate an association between PAD4, IL-6R, and troponin release in STEMI patients. Our findings indicate a PAD4-mediated connection between IL-6R and NET formation and highlight PAD4 as a potential treatment target for mitigating inflammation and myocardial injury in STEMI. Full article

Background/Objectives: Tranexamic acid (TXA) reduces mortality in patients with massive hemorrhage by inhibiting fibrinolysis. However, it is associated with an increased risk of thrombosis. The activation of neutrophil extracellular traps (NETs) has been implicated in the formation of thrombosis. This study investigated the effects of tranexamic acid on circulating and localized NETs, neutrophils, platelets, and the vascular endothelium in a mouse model of thrombosis. Methods: A ferric chloride-induced thrombosis mouse model was used and divided into five groups: a Control group that received intraperitoneal phosphate-buffered saline (PBS), and four experimental groups that received intraperitoneal tranexamic acid at doses of 5 mg/kg, 10 mg/kg, 20 mg/kg, and 30 mg/kg, respectively. To evaluate the expression of circulating and localized NETs, neutrophils, platelets, vascular endothelial cells, fibrinogen, and D-dimer, the following markers were analyzed: myeloperoxidase (MPO), neutrophil marker, cluster of differentiation (CD)31, CD34, fibrinogen α-chain, and D-dimer. These markers were assessed using flow cytometry, immunohistofluorescence staining, and Western blot analysis. The primary endpoint was the differential expression of anti-MPO antibody among the groups. Results: In total, data from 20 thrombosis mouse models were analyzed. For each group, four samples were assessed by flow cytometry, and three samples by immunohistofluorescence staining and Western blot analysis, respectively. In the flow cytometric analysis, circulating anti-MPO antibody expression was significantly higher in the TXA 20 and TXA 30 groups compared to the Control group (p = 0.001 and p = 0.001, respectively). Immunohistofluorescence staining revealed that D-dimer expression in the thrombotic femoral artery was significantly lower in the TXA 5, TXA 10, and TXA 20 groups compared to the Control group (p = 0.005; p = 0.018; p = 0.004, respectively), but significantly higher in the TXA 30 group than in the Control group (p = 0.044). Similarly, the expression of anti-fibrinogen antibody was significantly lower in the TXA 5, TXA 10, and TXA 20 groups compared to the Control group (p = 0.038; p = 0.003; p = 0.041, respectively). Western blot analysis showed no significant differences in the expression of anti-Ly6B.2, anti-fibrinogen, and anti-CD31 antibodies among the groups. Conclusions: The present study suggests that high-dose tranexamic acid (30 mg/kg) administration may increase circulating NETs and localized D-dimer levels, indicating a higher potential for thrombosis in a thrombosis mouse model. These findings imply that the prothrombotic effects of tranexamic acid may be dose-dependent and could vary based on underlying disease conditions. Therefore, the careful dosage adjustment of tranexamic acid may be necessary, particularly in patients at risk of thrombosis. Full article

Background: Thrombophilia is a prothrombotic disorder that can affect pregnancy outcomes, potentially leading to maternal complications, fetal growth restriction, and adverse perinatal events. However, the precise relationship between thrombophilia and these outcomes remains under investigation, and the impact of hematological, renal, hepatic, and coagulation alterations in thrombophilic pregnancies is not yet fully understood. This study aims to examine the maternal and neonatal consequences of thrombophilia by analyzing key laboratory parameters and perinatal outcomes in affected pregnancies. Methods: A retrospective observational study was conducted on 251 pregnant women, divided into thrombophilic (n = 226) and non-thrombophilic (n = 25) groups. Data on maternal demographics, laboratory parameters (hematological, metabolic, renal, hepatic, and coagulation markers), obstetric outcomes, and neonatal characteristics were extracted from medical records. Statistical analysis included t-tests, chi-square tests, and Pearson correlation analysis to assess the association between thrombophilia and clinical outcomes. Results: Thrombophilic pregnancies were associated with significantly lower fibrinogen levels (p = 0.036) and decreased INR (p = 0.006), suggesting a hypercoagulable state. Renal function was affected, as evidenced by elevated urea (p = 0.012) and creatinine (p = 0.009), indicating a predisposition to kidney dysfunction. Neonates from thrombophilic pregnancies exhibited slightly lower Apgar scores at 1 and 5 min, though the differences were not statistically significant (p = 0.101, p = 0.131). NICU admission rates were comparable between groups (p = 0.317), suggesting that thrombophilia may not be a major determinant of neonatal intensive care needs. However, gestational age and birth weight remained the strongest predictors of neonatal vitality (p < 0.001), while coagulation abnormalities and renal dysfunction correlated with poorer perinatal outcomes. Conclusions: Thrombophilia is associated with altered coagulation profiles, renal dysfunction, and potential risks for maternal complications. While neonatal outcomes were not significantly different, the observed trends suggest the need for enhanced monitoring in thrombophilic pregnancies. Early intervention, thromboprophylaxis, and individualized management strategies may improve maternal and neonatal prognosis. Further research is needed to refine preventive strategies and optimize therapeutic approaches in high-risk pregnancies. Full article

Multisystem inflammatory syndrome in children (MIS-C) is a rare, delayed hyperinflammatory response, which occurs 2–6 weeks after SARS-CoV-2 infection. Main symptoms include fever, involvement of at least two organ systems, elevated inflammatory markers and evidence of infection with or exposure to SARS-CoV-2. While the prognosis is generally favorable, complications—such as myocardial dysfunction, coronary aneurysms, and coagulation disorders—can lead to severe outcomes, including death. Immunomodulatory and antithrombotic therapies are key components of treatment. We report a clinical case of a 3-year-old boy who developed MIS-C, initially presenting with fever, multiorgan involvement, and confirmed SARS-CoV-2 infection, along with a coinfection caused by group A β-hemolytic Streptococcus (GAS) isolated from throat culture. On the ninth day of illness, thrombosis of the right subclavian vein was detected. Subsequent genetic testing for thrombophilia revealed that the patient was a heterozygous carrier of Factor V Leiden, Factor V HR2, and PAI-1 4G/5G polymorphisms. Thromboembolic events (TEs) are serious and potentially life-threatening complications of MIS-C. This case highlights the occurrence of TE in a 3-year-old boy, an age group younger than typically observed, emphasizing the need for heightened awareness, early detection, and prompt intervention. Additionally, it underscores the importance of careful monitoring of thrombotic risks in MIS-C patients, particularly those with underlying prothrombotic conditions, to prevent severe outcomes. Full article

Background/Objectives: Obesity is a global health challenge linked to a higher risk of metabolic and cardiovascular complications. This study investigates the role of cardiovascular markers in predicting metabolic crises in obese patients, focusing on the prevalence and clinical implications of these markers. Methods: This retrospective cohort study included 433 patients presenting with metabolic crises at the Emergency Department of Timișoara Municipal Emergency Hospital between 2019 and 2024. Patients were classified into obese (n = 161) and non-obese (n = 272) groups, with obesity further stratified into four grades based on body mass index (BMI). Cardiovascular markers, including NT-proBNP, troponin I, CRP, CK-MB, and D-dimer, alongside metabolic parameters, were analyzed. Results: Metabolic crises were significantly more prevalent in obese patients in all metabolic emergencies: hyperglycemia (27.9% vs. 11.0%, p < 0.001), electrolyte imbalance (23.6% vs. 9.2%, p < 0.001), and acute kidney injury (AKI) (12.4% vs. 5.5%, p = 0.01). NT-proBNP levels independently predicted AKI in obese patients (adjusted OR: 1.14 per 1000 pg/mL, 95% CI: 1.10–1.19, p < 0.001), with excellent discriminatory power (AUC: 0.88). Troponin I and D-dimer were higher in hyperglycemia and electrolyte imbalance, respectively, emphasizing the role of cardiac stress and pro-thrombotic states. Inflammatory markers such as CRP were significantly associated with metabolic disturbances, supporting the contribution of systemic inflammation. Comorbidities, particularly heart failure and atrial fibrillation, further increased the risk of metabolic crises. Conclusions: Cardiovascular markers suggest potential utility for early risk stratification of metabolic crises in obese patients. However, further studies are needed to validate their clinical applicability and to establish standardized approaches for integrating these biomarkers into routine practice, especially in patients with advanced obesity grades. Full article

Background: Normal pregnancy and the postpartum period are characterized by thrombotic predisposition. Consequently, monitoring coagulation markers and conducting risk assessments are essential in preventing thrombotic events that negatively impact both the mother and the child. In medical practice, fibrinogen/fibrin degradation products (FDPs) are the main coagulation markers currently investigated in pregnancy. Methods: We investigated proteins C and S, antiphospholipid antibodies (APLs), human factor V, and beta-2-glycoprotein 1 or apolipoprotein H (APOH) levels to determine whether there is any difference between normal third-trimester pregnancies and pregnant women in late pregnancy who end up developing deep vein thrombosis (DVT). Results: Our data show a significant correlation between protein C levels and the number of weeks of pregnancy, as well as statistically significant differences between healthy pregnant women and pregnant women with DVT in terms of the values of FDP, protein S, and APL. The DVT group had higher FDP levels but lower AFL and protein S values. Conclusions: Given the significant prothrombotic correlation that exists between proteins C and S, we propose that variations in their levels can serve as valuable markers in the evaluation of thrombotic risk during the final stages of pregnancy. Full article

COVID-19 and post-COVID (long COVID) are associated with thromboembolic complications; however, it is still not clear whether platelets play a leading role in this phenomenon. The platelet hyperreactivity could result from the direct interaction between platelets and viral elements or the response to inflammatory and prothrombotic factors released from blood and vessel cells following infection. The existing literature does not provide clear-cut answers, as the results determining platelet status vary according to methodology. Elevated levels of soluble markers of platelet activation (P selectin, PF4), increased platelet aggregates, and platelet-derived microparticles suggest the activation of platelets circulating in the bloodstream of COVID-19 patients. Similarly, platelets isolated from COVID-19 patients demonstrate increased reactivity in response to collagen, thrombin, and ADP. By contrast, an analysis of whole blood from COVID-19 patients indicates the reduced activation of the fibrinogen receptor. Similarly, some in vitro studies report potential targets for SARS-CoV-2 in platelets, whereas others do not indicate any direct effect of the virus on platelets. The aim of this work is to review and evaluate the reliability of the methodology for testing platelet function after contact with SARS-CoV-2. Despite the diversity of methods yielding varying results and the influence of plasma components or blood cells, it can be concluded that platelets play an important role in the development of thrombotic complications after exposure to SARS-CoV-2. Full article

Endometriosis (EM), a chronic inflammatory condition predominantly affecting women of reproductive age, has been linked to an elevated risk of thrombosis, though its underlying molecular mechanisms remain incompletely understood. In this case-control study, involving 71 EM patients and 71 matched controls, we explored the structural and functional changes in fibrinogen and their potential role in thrombosis. Key oxidative stress markers, such as reactive oxygen species (ROS) levels in blood lymphocytes, monocytes, and granulocytes, along with plasma lipid peroxidation markers and total antioxidant capacity, were measured. Fibrinogen structure was examined using circular dichroism spectroscopy and intrinsic fluorescence, while functional properties were evaluated by analyzing thrombin-mediated polymerization and plasmin-induced lysis. Compared to controls, EM patients exhibited elevated ROS production and systemic oxidative stress, leading to notable fibrinogen oxidation and structural alterations. These changes were associated with impaired fibrin polymerization and enhanced resistance to plasmin-induced lysis, which are indicative of a pro-thrombotic state. These findings suggest that oxidative stress-driven fibrinogen modifications may contribute to the heightened thrombotic risk in women with EM, highlighting a potential therapeutic target to mitigate cardiovascular complications. Full article

In end-stage heart failure, which is characterized by persistent or progressive ventricular dysfunction despite optimal medical therapy, a left ventricular assist device (LVAD) can be beneficial. Congestive heart failure provokes inflammatory and prothrombotic activation. The aim of this study was to evaluate the serum concentration of citrullinated histone 3 (CH3) representing neutrophil extracellular trap (NET) formation in patients referred for LVAD implantation. There were 10 patients with a median age of 61 (57–65) years enrolled in a prospective single-center analysis who underwent LVAD implantation. The CH3 plasma concentration was measured preoperatively and on the 1st and 7th postoperative days, followed by control measurements on the median (Q1–3) 88th (49–143) day. The preoperative CH3 concentration strongly correlated with brain natriuretic peptide (r = 0.879, p < 0.001). Significant differences in CH3 serum concentration were observed between pre- and postoperative measurements, including an increase on the first postoperative day (p < 0.001), as well as a decrease on the seventh day (p = 0.016) and in follow-up (p < 0.001). CH3 concentration, as a marker of NET formation, decreases after LVAD implantation. Full article

Sepsis-associated coagulopathy increases risk of mortality. Impairment of the anticoagulant protein C (PC) pathway may contribute to the thrombotic phenotype in coronavirus disease 2019 (COVID-19) sepsis. This study assessed the functionality of this pathway in COVID-19 and non-COVID sepsis by measuring its key enzymes, thrombin and activated PC (APC). The study population included 30 patients with COVID-19, 47 patients with non-COVID sepsis, and 40 healthy controls. In healthy controls, coagulation activation and subsequent APC formation was induced by 15 µg/kg recombinant activated factor VII one hour before blood sampling. APC and thrombin in plasma were measured using oligonucleotide-based enzyme capture assays. The indirect thrombin markers prothrombin-fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) were also measured. Compared with stimulated healthy controls, median thrombin, F1+2, and TAT levels were higher in patients with COVID-19 (up to 6-fold, p < 2 × 10⁻⁶) and non-COVID sepsis (up to 4.7-fold, p < 0.010). APC levels were 2.4-fold higher in patients with COVID-19 (7.44 pmol/L, p = 0.011) and 3.4-fold higher in non-COVID sepsis patients (10.45 pmol/L, p = 2 × 10⁻⁴) than in controls (3.08 pmol/L). Thrombin markers and APC showed correlation in both COVID-19 (r = 0.364–0.661) and non-COVID sepsis patients (r = 0.535–0.711). After adjustment for PC levels, median APC/thrombin, APC/F1+2, and APC/TAT ratios were 2-fold (p = 0.036), 6-fold (p = 3 × 10⁻⁷) and 3-fold (p = 8 × 10⁻⁴) lower in the COVID-19 group than in the non-COVID sepsis group, and the latter two were also lower in the COVID-19 group than in stimulated healthy controls. In conclusion, it was found that a comparatively lower anticoagulant APC response in COVID-19 patients as compared to non-COVID sepsis patients, potentially linked to endothelial dysfunction, contributes to the prothrombotic phenotype of COVID-19 sepsis. Full article

Diabetes mellitus type 2 (DM2) is a hypercoagulable state with enhanced platelet (PLT) activation and increased clotting factor production. Simultaneously, the fibrinolytic cell system is inhibited due to the formation of clots with high fibrinolysis resistance. The stages of PLT “activation” have been well characterized microscopically, morphometrically, and nanomechanically using a light microscope, transmission electron microscope (TEM), scanning electron microscope (SEM), and atomic force microscope (AFM). Thrombocytes in an “activated” (procoagulant) state play a central role in two main biological processes: hemostasis and vascular vessel repair. Enhanced PLT reactivity in diabetic patients is considered a “pro-thrombotic” state. PLT hematometric indices are higher in retrospective and prospective studies, such as PLTs (count), MPV (mean platelet volume), PDW (platelet distribution width), PCR (platelet crit), and the PLTs/Ly ratio. The platelet indices MPV and PDW are higher in people with diabetes who have chronic vascular complications, and are statistically significant. PLT parameters/indices are useful biomarkers in the early diagnosis and prognosis of DM2. Precise studies of PLT activation state during DM2 may be useful for new diabetes (DM2) treatment strategies and effective therapeutic agents. Researchers have observed an association between MPV and medications such as insulin, metformin, and sulfonylureas using the blood glucose concentration attached to hemoglobin (HbA1c values) as markers of glycemic control in patients with diabetes. Computational modeling of PLT activation in DM2 is also a controlling factor for thrombocyte distribution and margination in blood vessels, both of which are associated with micro- and macrovascular disease in DM2. PLT-derived microRNAs (miRNAs) are novel molecular biomarkers for the diagnosis and prognosis of DM2, insulin resistance, and diabetes complications. Anti-platelet agents and natural plant products may also be effective in the prevention and secondary treatment of micro- and macrovascular complications in type 2 diabetes mellitus. To determine new ways of diagnosing, treating, predicting, and managing DM2 and its related vascular complications, we propose monitoring a combination of hematological, hemorheological, and hemostatic parameters (indices), which merit future studies. Full article

The pathologic consequences of Coronavirus Disease-2019 (COVID-19) include elevated inflammation and dysregulated vascular functions associated with thrombosis. In general, disruption of vascular homeostasis and ensuing prothrombotic events are driven by activated platelets, monocytes, and macrophages, which form aggregates (thrombi) attached to the endothelium lining of vessel walls. However, molecular pathways underpinning the pathological interactions between myeloid cells and endothelium during COVID-19 remain undefined. Here, we tested the hypothesis that modulations in the expression of cellular receptors angiotensin-converting enzyme 2 (ACE2), CD147, and glucose-regulated protein 78 (GRP78), which are involved in homeostasis and endothelial performance, are the hallmark responses induced by SARS-CoV-2 infection. Cultured macrophages and lungs of hamster model systems were used to test this hypothesis. The results indicate that while macrophages and endothelial cells are less likely to support SARS-CoV-2 proliferation, these cells may readily respond to inflammatory stimuli generated by the infected lung epithelium. SARS-CoV-2 induced modulations of tested cellular receptors correlated with corresponding changes in the mRNA expression of coagulation cascade regulators and endothelial integrity components in infected hamster lungs. Among these markers, tissue factor (TF) had the best correlation for prothrombotic events during SARS-CoV-2 infection. Furthermore, the single-molecule fluorescence in situ hybridization (smFISH) method alone was sufficient to determine the peak and resolution phases of SARS-CoV-2 infection and enabled screening for cellular markers co-expressed with the virus. These findings suggest possible molecular pathways for exploration of novel drugs capable of blocking the prothrombotic shift events that exacerbate COVID-19 pathophysiology and control the disease. Full article