Markers Of Fibrinolysis Research Articles

Good metabolic control is associated with decreased circulating factor VIIa- antithrombin complexes in type 2 diabetes: a cross-sectional study.

Diabetes is associated with a prothrombotic state that contributes to cardiovascular (CV) events in type 2 diabetes (T2DM). Activated factor VII (FVIIa)- antithrombin (AT) complexes are indicative of tissue factor (TF) exposure and have been associated with thromboembolic risk in coronary artery disease. To our knowledge there have been no reports on FVIIa-AT complexes in T2DM, therefore we assessed factors that determine FVIIa-AT complexes in this disease and the impact of higher complexes on a prothrombotic state. In 108 T2DM patients (mean age 63.8 years, 52.8% men, median HbA1c of 6.9 [interquartile range 6.1-8.2] %) and 83 age- and sex-matched non-diabetic subjects, we measured FVIIa-AT complexes. Metabolic control of T2DM involved fasting glucose, glycated hemoglobin (HbA1c), albumin/creatinine ratio (ACR), and lipid levels. To characterize a prothrombotic state, we determined thrombin generation parameters, fibrinolysis markers, and plasma fibrin clot properties. FVII-AT complexes in T2DM patients were similar to controls (73.6 [59.4-91.7] vs. 79.6 [59.2-97.1]pM, respectively, p = 0.30). The T2DM patients with FVIIa-AT in the top vs. the bottom quartile had a larger prevalence of active smoking and insulin use, along with higher fasting glucose (+ 36.4%), HbA1c (+ 27.4%), ACR (+ 72.8%), total cholesterol (+ 34.5%), and LDL-cholesterol (+ 80%). FVIIa-AT complexes showed no associations with in vitro thrombin generation potential, plasma fibrin clot properties, or fibrinolysis variables. On multivariable analysis HbA1c, ACR, and total cholesterol remained independently associated with FVIIa-AT complexes in T2DM. This is the first study to show that in T2DM higher FVIIa-AT complexes are associated with markers of dyslipidemia and glycemia control, indicating that TF-induced coagulation activation could be suppressed by achieving treatment targets.

Circulating levels of neutrophil extracellular traps reflects local neutrophil activity but not fibrinolytic activity in coronary thrombi from patients with ST-elevation myocardial infarction

Abstract Introduction Neutrophil extracellular traps (NETs) are associated with impaired fibrinolysis in ischemic stroke, while NETs degradation enhances lysis of coronary thrombi in ex vivo experiments. Whether circulating NET markers are associated with local fibrinolytic activity in patients with ST-elevation myocardial infarction (STEMI) has not been reported. Purpose We investigated associations between circulating NET markers and gene expression of fibrinolytic markers in aspirated coronary thrombi from patients with STEMI. Furthermore, we explored whether local upregulation of NET formation by peptidylarginine deiminase 4 (PAD4) was reflected in the circulation. Methods Coronary thrombi from 35 STEMI patients undergoing primary percutaneous coronary intervention (PCI) were aspirated and promptly snap-frozen to -80°C. Peripheral blood samples were collected simultaneously. Median time from start of symptoms to PCI was 152 min. Thrombus gene expression of tissue Plasminogen Activator (tPA), urinary-type Plasminogen Activator (uPA), plasminogen-activation inhibitor type 1 (PAI-1) and PAD4 were quantified with RT-PCR. Gene expression of PAD4 was also measured in circulating leukocytes. Circulating NET markers were measured by a fluorescent nucleic acid stain using fluorometry (dsDNA), an in-house ELISA technique (MPO-DNA) and commercial ELISA (H3Cit). Correlations were tested using Spearman’s rho. Results There were no correlations between any of the circulating NET markers and gene expression of the fibrinolytic markers tPA, uPA and PAI-1 in the thrombus. Of the circulating NET markers, dsDNA correlated with thrombus gene expression of PAD4 (rs=0.491 p=0.006), whereas none of the NET markers correlated with gene expression of PAD4 in circulating leukocytes. Conclusion Circulating NET markers were not associated with gene expression of fibrinolytic activity in thrombi from patients with STEMI. Local NET formation in the thrombi, measured as PAD4 expression, was associated with the circulating NET marker dsDNA. These findings suggest that circulating NET markers have limited utility for assessing local fibrinolytic activity, but might reflect PAD4-dependent NET formation in coronary thrombi.

The Relationship between Plasminogen Activator Inhibitors and the Severity of COVID-19

The fibrinolysis process is assisted by plasminogen activators and inhibitors by converting plasminogen into plasmin, which later will promote the fibrinolysis process. Incomplete fibrinolysis increases the risk of thrombosis in patients with COVID-19. Plasminogen Activator Inhibitor (PAI-1) plays an important role as acute phase reactants to be used as a marker to assess the prognosis and mortality of COVID-19 patients. This study aimed to elaborate on whether fibrinolysis shutdown occurs in COVID-19 patients using PAI-1 as a marker of fibrinolysis. This was a cross-sectional analytical study from November 2022 to May 2023. This research consisted of a total of 39 patients with COVID-19, hospitalized at Haji Adam Malik General Hospital, Medan. PAI-test in COVID-19 patients was carried out with the ELISA method using Chemwell Analyzer. The severity of COVID-19 measured by clinical examination was divided into moderate, severe, and critical. The association between the two variables was subjected to a comparative test followed by a correlation test to explore the association between the two variables with an independent T-test. In this study, the median PAI-1 level was 1.77 ng/mL (0.71–11.49 ng/mL). The highest PAI-1 levels were observed in the critical severity group, followed by the severe and moderate group of 8.54 ng/mL (5.76–10.84), 2.45 ng/mL (0.71–11.49), and 1.29 ng/mL (0.73–3.77), respectively. There was a significant relationship between PAI-1 levels and the severity of COVID-19 patients (p=0.003). PAI-1 cut-off value of 1.89 ng/mL may predict the degree of COVID-19 severity with sensitivity of 88.9%, specificity of 90.5%, and accuracy of 89.7%. This study classified the severity of COVID-19 into two categories, which are moderate (n=21) and severe-critical (n=18) to obtain the AUC value of PAI-1. PAI-1 can be used to predict the severity of COVID-19 disease with a moderate level (AUC >70–80%). This phenomenon can be secondary to enhanced platelet aggregation, inflammation micro thrombosis, and impaired fibrinolysis. Fibrinolysis disorders lead to a fibrin buildup and increased levels of PAI-1 in the circulation.

The hemostatic activity and Mechanistic roles of glucosyloxybenzyl 2-isobutylmalate extract (BSCE) from Bletilla striata (Thunb.) Rchb.f. in Inhibiting pulmonary hemorrhage

BackgroundHemorrhagic events cause numerous deaths annually worldwide, highlighting the urgent need for effective hemostatic drugs. The glucosyloxybenzyl 2-isobutylmalates Control Extract (BSCE) from the orchid plant Bletilla striata (Thunb.) Rchb.f. has demonstrated significant hemostatic activity in both in vitro and in vivo studies. However, the effect and mechanism of BSCE on non-traumatic bleeding remain unclear. MethodsPulmonary hemorrhage was induced in 40 Sprague-Dawley rats by administering Zingiber officinale Roscoe. for 14 days. These rats were then randomly divided into five groups: model (Mod), positive control (YNBY), and BSCE low, medium, and high-dose groups. An additional 8 rats served as the control group (Con). The BSCE groups received different doses of BSCE for 10 days, while the YNBY group received Yunnan Baiyao suspension. The effects on body weight, food and water intake, red blood cell count (RBC), hemoglobin concentration (HGB), lung tissue pathology, platelet count, coagulation parameters, and fibrinolytic system markers were evaluated. Network pharmacology and molecular docking analyses were also conducted to identify potential targets and pathways involved in BSCE's effects. ResultsBSCE treatment significantly improved body weight, food intake, and water consumption in rats with pulmonary hemorrhage. RBC and HGB levels increased significantly in the BSCE medium and high-dose groups compared to the Mod group (P < 0.05). Pathological examination revealed that BSCE reduced lung tissue hemorrhage and inflammation, with improvements in alveolar structure. BSCE also positively affected platelet count, thrombin time (TT), activated partial thromboplastin time (APTT), fibrinogen (FIB) levels, and fibrinolytic markers (D-dimer, PAI-1, and t-PA). Network pharmacology and molecular docking identified key targets such as MMPs, CASPs, and pathways including IL-17 and TNF signaling, suggesting BSCE's involvement in hemostasis and anti-inflammatory processes. ConclusionsBSCE exhibits significant hemostatic and protective effects on Z.officinale-induced pulmonary hemorrhage in rats by improving hematological parameters, reducing lung tissue damage, and modulating the coagulation and fibrinolytic systems. The study provides evidence supporting the potential of BSCE as a therapeutic agent for hemorrhagic diseases, with its efficacy linked to multi-target and multi-pathway interactions.

Gene expression profiling of markers of inflammation, angiogenesis, coagulation and fibrinolysis in patients with coronary artery disease treated with PCSK9 inhibitors

Gene expression profiling of markers of inflammation, angiogenesis, coagulation and fibrinolysis in patients with coronary artery disease treated with PCSK9 inhibitors

Elevated lipopolysaccharide level is largely driven by time since symptom onset in acute ischemic stroke: the impact on clinical outcomes

BackgroundGut dysbiosis leading to increased intestinal barrier permeability and translocation of lipopolysaccharide (LPS) in the circulation has been demonstrated in patients with acute myocardial infarction and pulmonary embolism. ObjectivesWe investigated changes in circulating LPS concentrations in acute ischemic stroke (AIS) and their consequences, including prognosis. MethodsWe studied 98 AIS patients, aged 74 ± 12 years, including 74 (75.5%) thrombolysed individuals. We determined serum LPS and zonulin, a marker of gut permeability, along with protein carbonyl (PC), fibrin clot properties, and thrombin generation on admission, at 24 hours and 3 months. Stroke severity was assessed using the National Institutes of Health Stroke Scale. Stroke functional outcome using modified Rankin scale and stroke-related mortality were evaluated at 3 months. ResultsSerum LPS and zonulin levels on admission were associated with time since symptom onset (r = 0.57; P < .0001; and r = 0.40; P < .0001). Baseline LPS levels correlated with PC (r = 0.51; P < .0001) but not with coagulation and fibrinolysis markers. LPS levels increased at 24 hours in thrombolysed patients (P < .001) and correlated with the National Institutes of Health Stroke Scale score (r = 0.31; P = .002) and PC (r = 0.32; P = .0057). Both LPS and zonulin levels measured at 24 hours increased the odds of having unfavorable modified Rankin scale scores (odds ratio [OR], 1.22; 95% CI, 1.04-1.42; and OR, 2.36; 95% CI, 1.24-4.49 per unit). Elevated LPS level, but not zonulin, was associated with stroke-related mortality (OR, 1.26; 95% CI, 1.02-1.55 per unit). ConclusionIn AIS patients intestinal permeability is mainly driven by increasing time since the symptom onset. Our findings suggest that LPS, with a trend toward its further rise following thrombolysis, adversely affects neurologic functional outcomes and 3-month mortality.

Temporal changes in markers of coagulation and fibrinolysis in adults during extracorporeal membrane oxygenation.

Bleeding and thrombotic events (BTE) are frequent during extracorporeal membrane oxygenation (ECMO). They occur at varying timepoints and may be affected by temporal changes in coagulation and fibrinolysis. We aimed to assess various coagulation and fibrinolytic markers over time and their relationship with BTE. A single-centre prospective study was performed in 17 patients with severe respiratory failure receiving veno-venous ECMO. Blood samples were collected before and during ECMO, and around circuit decannulation. Prior to ECMO, D-Dimer, Plasmin-Antiplasmin complexes (PAP), Plasminogen-Activator Inhibitor-1 (PAI-1) and fibrinogen were elevated. There was an increase in D-Dimer and Prothrombin Fragments 1+2 (PF1+2) (729 to 1305pmol/L, p = .034) by day 1 and PAP increased by day 2 from baseline levels (median 1022 to 1797µg/L, p = .023). There was a strong positive correlation in PAP, PF1+2 and thrombin-antithrombin complexes (TAT) to D-Dimer. BTE were frequent - 18% had major extracranial haemorrhage and 24% had intracranial haemorrhage. Over time, there was a progressive elevation PAP in patients developing subsequent extracranial haemorrhage, whereas D-Dimer, PAP and PF1+2 increased after intracranial haemorrhage. There were early changes in coagulation activity during ECMO by PF1+2 followed by subsequent fibrinolysis by PAP. Changes in PAP, PF1+2 and TAT were associated with major haemorrhage.

Reduced protein carbonylation on hormone therapy is associated with improved fibrinolysis in postmenopausal women: the impact of PAI-1 and TAFI activity.

Hormone therapy (HT) has been reported to reduce protein carbonylation (PC) in postmenopausal women, in whom fibrinolysis is impaired. We investigated whether PC affects fibrinolysis and if HT modulates this effect. We enrolled 150 women aged 55.5 ± 4.7years in a randomized interventional open-label study, including 50 on standard oral HT, 50 on ultra-low-dose HT, and 50 controls. PC, along with global fibrinolysis (clot lysis time, CLT), fibrinolysis proteins, and prothrombotic markers were determined at baseline and at 24weeks. Patients with the baseline top quartile PC (> 2.07nM/mg protein) had 10.3% longer CLT, higher activity (but not antigen) of TAFI (+ 19.9%) and PAI-1 (+ 68.1%) compared to the remainder. No differences were observed in thrombin generation, factor VIII, plasminogen or α2-antiplasmin. On-treatment PC decreased by 16.4% (p < 0.0001), without differences related to the type of HT, compared to baseline and by 30% compared to controls, in whom PC and fibrinolysis markers remained unchanged. Patients with PC > 2.07nM/mg had shortened CLT during HT compared to baseline, along with lower PAI-1 (-69%) and TAFI (-26%) activity. In this subgroup CLT was 5.8% shorter compared to controls with the highest PC. In postmenopausal women with increased PC, HT was accompanied by PC reduction and faster clot lysis together with decreased PAI-1 and TAFI activity.

Coagulation and fibrinolytic markers offer utility when distinguishing between benign and malignant gallbladder tumors: A cross-sectional study

BackgroundThe metabolic or proliferative abnormalities that are characteristic of tumor cells can lead to abnormal fibrinolysis or coagulation system activity, with certain tumors exhibiting hypercoagulability or existing in a fibrinolytic state. However, the utility of biomarkers of coagulation and fibrinolysis when seeking to differentiate between benign gallbladder disease and malignant gallbladder tumors remains uncertain. MethodsThis study included a total of 81 patients with benign gallbladder polyps and 94 patients with malignant gallbladder tumors. Pre-biopsy or pretreatment levels of PT, APTT, FIB, D-dimer, FDP, PLT, PIC, TAT, TM, and t-PAIC from these patients were compared using Mann-Whitney tests. The baseline data of the patients were analyzed using chi-square tests, and the diagnostic utility of these biomarkers in distinguishing between benign and malignant gallbladder lesions was evaluated using ROC curves, and Spearman correlation analysis was employed to assess the correlation between these indicators and tumor parameters. ResultsThe average age of malignant gallbladder tumor group was higher than benign gallbladder polyp group. And the base line analysis showed that there was a statistic difference in age, history of smoking, drinking, biliary tract disease, BMI of over weight between these two groups. In patients with malignant gallbladder tumors, FIB, D-dimer, FDP, PIC, TAT, TM, and t-PAIC levels were significantly elevated relative to those in patients affected by benign gallbladder polyp. The AUC for FIB, D-dimer, and FDP was 0.8469, 0.6514, 0.5950, while for PIC, TAT, TM, t-PAIC and four biomarker combined diagnosed was 0.8455, 0.6554, 0.7130, 0.6806, and 0.8859. Among these, TM was associated with the vascular invasion of tumor patients; TAT and t-PAIC were associated with neural invasion; D-dimer and FDP were related to the maximum tumor diameter; and FDP had a certain correlation with the tumor stage. ConclusionsIn gallbladder tumor patients, conventional coagulation metrics like FIB, D-dimer, and FDP, as well as newer thrombotic indicators such as PIC, TAT, TM, and t-PAIC, were obviously increased. Correlations with tumor parameters suggested their potential as biomarkers to distinguish benign from malignant gallbladder growths.

Impaired fibrinolysis in patients with atrial fibrillation and elevated circulating lipopolysaccharide

It is unknown whether elevated gut-derived serum lipopolysaccharide (LPS) can affect thrombin generation, fibrinolysis, and fibrin clot properties in atrial fibrillation (AF). We aimed to evaluate associations of circulating LPS with prothrombotic markers in AF patients. A total of 157 (women, 57.3%) ambulatory anticoagulant-naïve AF patients aged from 42 to 86 years were recruited. Clinical data together with serum LPS, inflammation, endothelial injury, coagulation and fibrinolysis markers, including fibrin clot permeability (Ks) and clot lysis time (CLT), were analyzed. A median LPS concentration was 73.0 (58.0-100.0) pg/mL and it showed association with CLT (r = 0.31, p < 0.001) and plasminogen activator inhibitor-1 (PAI-1, r = 0.57, p < 0.001), but not other fibrinolysis proteins, thrombin generation, inflammatory markers, or Ks. There were weak associations of LPS with von Willebrand factor (vWF, r = 0.2, p = 0.013), cardiac troponin I (r = 0.16, p = 0.045), and growth differentiation factor-15 (r = 0.27, p < 0.001). No associations of LPS and CHA2DS2-VASc or other clinical variables were observed. Multivariable regression adjusted for potential confounders showed that serum LPS ≥ 100 pg/mL was an independent predictor of prolonged CLT. This study is the first to demonstrate antifibrinolytic effects of elevated LPS in AF patients largely driven by enhanced PAI-1 release.

Clinical significance of elevated D-dimer in emergency department patients: a retrospective single-center analysis

IntroductionD-dimer is a marker of coagulation and fibrinolysis widely used in clinical practice for assessing thrombotic activity. While it is commonly ordered in the Emergency Department (ED) for suspected venous thromboembolism (VTE), elevated D-dimer levels can occur due to various other disorders. The aim of this study was to find out the causes of elevated D-dimer in patients presenting to a large ED in Saudi Arabia and evaluate the accuracy of D-dimer in diagnosing these conditions.MethodsData was collected from an electronic hospital information system of patients who visited the ED from January 2016 to December 2022. Demographic information, comorbidities, D-dimer levels, and diagnoses were analyzed. Statistical analysis was performed using the SPSS software. The different diagnoses associated with D-dimer levels were analyzed by plotting the median D-dimer levels for each diagnosis category and their interquartile ranges (IQR). The receiver operating characteristic (ROC) curves were calculated and their area under the curve (AUC) values were demonstrated. The optimal cut-off points for specific diseases were determined based on the ROC analysis, along with their corresponding sensitivities and specificities.ResultsA total of 19,258 patients with D-dimer results were included in the study. The mean age of the participants was 50 years with a standard deviation of ± 18. Of the patients, 66% were female and 21.2% were aged 65 or above. Additionally, 21% had diabetes mellitus, 20.4% were hypertensive, and 15.1% had been diagnosed with dyslipidemia. The median D-dimer levels varied across different diagnoses, with the highest level observed in aortic aneurysm 5.46 g/L. Pulmonary embolism (PE) and deep vein thrombosis (DVT) were found in 729 patients (3.8%) of our study population and their median D-dimer levels 3.07 g/L (IQR: 1.35–7.05 g/L) and 3.36 g/L (IQR: 1.06–8.38 g/L) respectively. On the other hand, 1767 patients (9.2%) were diagnosed with respiratory infections and 936 patients (4.9%) were diagnosed with shortness of breath (not specified) with median D-dimer levels of 0.76 g/L (IQR: 0.40–1.47 g/L) and 0.51 g/L (IQR: 0.29–1.06 g/L), respectively. D-dimer levels showed superior or excellent discrimination for PE (AUC = 0.844), leukemia (AUC = 0.848), and aortic aneurysm (AUC = 0.963). DVT and aortic dissection demonstrated acceptable discrimination, with AUC values of 0.795 and 0.737, respectively. D-dimer levels in respiratory infections and shortness of breath (not specified) exhibited poor to discriminatory performance.ConclusionThis is the first paper to identify multiple causes of elevated D-dimer levels in Saudi Arabia population within the ED and it clearly highlights their accurate and diagnostic values. These findings draw attention to the importance of considering the specific clinical context and utilizing additional diagnostic tools when evaluating patients with elevated D-dimer levels.

Abstract 7652: Plasma markers of hemostasis, fibrinolysis, and angiogenesis prior to androgen deprivation therapy (ADT) in progressive prostate cancer (PC) and associations with long-term thrombotic events and survival

Abstract Background: PC is the third most common malignancy associated with thrombosis, procoagulants may play a role in tumorigenesis and progression, and patients (pts) with PC may have activation of the hemostatic system evident in plasma. The prognostic significance of these markers and their relationship to thrombotic events and overall survival (OS) are under-explored. Methods: Patients &amp;gt;18 years were included if they had progressive PC planned to start ADT, were &amp;gt;6 months from surgery or RT, with no history of prior VTE, unexplained bleeding, current or planned anticoagulation, or an additional active malignancy. Plasma samples were obtained via peripheral venipuncture in tubes containing 3.2% sodium citrate and immediately placed on ice. Samples were analyzed for D-dimer, thrombin-antithrombin complex (TAT), IL-6, IL-8, VEGF, and tissue factor (TF) levels by ELISA. Patients had markers drawn at baseline (prior to initiation of ADT), 1 month, and 6 months after initiation. Results: 40 patients were accrued with a median age of 68 years. At baseline, 29 (73%) had presence of metastases. Baseline median PSA was 15 and median PSA doubling time was 0.32. Baseline median hemoglobin was 13.85, platelets were 218, D-dimer was 322 ng/dL, IL-6 was 0 pg/mL, IL-8 was 0 pg/mL, TAT was 3 ug/L, VEGF was 21 pg/mL, and TF was 26 pg/mL. Median follow-up was 78 months. During follow up, 35 (87.5%) had metastases. 10 (25%) had thrombotic events (6 [15%] venous, 4 [10%] arterial) at median 37 months follow up. Median baseline age of pts with subsequent thrombotic events was 74, vs 67 in those without a thrombotic event. While there was no significant difference in baseline PSA between groups with and without clotting events, pretreatment PSA doubling time was significantly lower in pts with subsequent thrombosis (0.27 vs 0.35, p=0.047). Median baseline D-dimer and TF were higher in patients with subsequent thrombosis (D-dimer: 516 vs 282, p=0.10; TF: 36 vs 24, p=0.12). In univariate analysis, baseline IL-6 and VEGF were associated with OS (IL-6: HR=1.05, 95% CI [1.01,1.09], p=0.025; VEGF: HR=1.02, 95% CI [1.00,1.03], p=0.028). When controlling for presence of metastasis, baseline TAT was associated with OS (HR=1.05, 95% CI [1.00,1.11], p=0.055). Conclusions: Plasma markers of hemostatic activation, fibrinolysis, and angiogenesis prior to initiation of ADT are associated with subsequent thrombotic events and overall survival years later. Further analysis will examine how these markers change over time with hormonal therapy. Citation Format: Jessica S. Palmer, Charlene Thomas, Nicole Jacobs, David Nanus, Scott T. Tagawa. Plasma markers of hemostasis, fibrinolysis, and angiogenesis prior to androgen deprivation therapy (ADT) in progressive prostate cancer (PC) and associations with long-term thrombotic events and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7652.

Fibrinolysis as a Causative Mechanism for Bleeding Complications on Extracorporeal Membrane Oxygenation: A Pilot Observational Prospective Study.

Extracorporeal membrane oxygenation (ECMO) is associated with a high risk of bleeding complications. The specific impact of ECMO on fibrinolysis remains unexplored. The objective of the current pilot observational prospective study was to investigate the longitudinal dynamics of fibrinolytic markers-i.e., changes over time-in the context of bleeding events in patients on ECMO. Longitudinal dynamics of contact phase components (kininogen and bradykinin) and fibrinolysis markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1], their complexes [tPA•PAI-1], plasmin-antiplasmin complexes, plasminogen, and D-dimer) were measured in patients undergoing venovenous and venoarterial ECMO, before implantation, at 0, 6, and 12 h after implantation, and daily thereafter. The cohort consisted of 30 patients (214 ECMO days). The concentrations of tPA, D-dimer, plasmin-antiplasmin complexes, PAI-1, and tPA•PAI-1 complexes were increased, whereas plasminogen decreased compared to normal values. A noteworthy divergence was observed between hemorrhagic and nonhemorrhagic patients: in bleeding patients, D-dimer, plasmin-antiplasmin, tPA, PAI-1, and tPA•PAI-1 followed an increasing kinetics before hemorrhage and then decreased to their baseline level; conversely, nonbleeding patients showed a decreasing kinetics in these markers. Also, D-dimer and tPA followed an increasing kinetics in bleeding patients compared to nonbleeding patients (median values for D-dimer dynamics: 1,080 vs. -440 ng/ml, P = 0.05; tPA dynamics: 0.130 vs. 0.100 nM, P = 0.038), and both markers significantly increased the day before hemorrhage. A tPA concentration above 0.304 nM was associated with bleeding events (odds ratio, 4.92; 95% CI, 1.01 to 24.08; P = 0.049). Contact activation induces fibrinolysis in ECMO patients, especially in patients experiencing bleeding. This finding supports the role of this mechanism as a possible causal factor for hemorrhages during ECMO and open new avenues for novel therapeutic perspectives.

Correction of endothelial dysfunction in patients with type 2 diabetes mellitus, diabetic kidney disease and non-alcoholic steatohepatitis

Background. Non-alcoholic fatty liver disease and chronic kidney disease are public health concerns worldwide due to their increasing prevalence, adverse prognosis, and health care burden. The purpose of the study was to determine the probable effect of a combination of metformin, rosuvastatin, essential phospholipids and quercetin on the blood lipids, endothelial function, fibrinolysis system and platelet hemostasis, which are factors for the progression of nonalcoholic steatohepatitis. Materials and methods. Studies were performed on the dynamics of treatment in 60 patients with non-alcoholic fatty liver disease, type 2 diabetes mellitus and diabetic kidney disease (stage I–III). Depending on the prescribed treatment at random, the examined patients were divided into 2 groups. Twenty-eight persons of the first group received a low-calorie diet with dietary restrictions, essential phospholipids, metformin hydrochloride, rosuvastatin. Thirty-two patients from the second group received quercetin in addition to similar dietary recommendations, essential phospholipids, hypoglycemic and hypolipidemic therapy. The mean age of patients was 53.80 ± 3.52 years. The comparison group consisted of 30 healthy individuals of the corresponding age. Results. To evaluate the degree of endothelial-protective effect of quercetin on the background of the recommended protocol therapy, markers of endothelial dysfunction, fibrinolysis and platelet hemostasis were studied. NO content significantly reduced (1.7 times) in patients of group 2 before treatment, increased by 1.5 times (p &lt; 0.05). This can be explained by the effect of quercetin, as well as the use of metformin, which reduces the degree of insulin resistance and the level of hyperlipidemia. Conclusions. The effectiveness of a combination therapy for non-alcoholic steatohepatitis and type 2 diabetes mellitus with diabetic kidney disease using essential phospholi­pids, statins and metformin with the addition of quercetin is higher than that of traditional therapy, as it significantly restores the functional state of the endothelium, eliminates the phenomena of hypercoagulation syndrome without the additional prescription of antiplatelet agents.

Exercise testing unmasks exaggerated blood pressure independent of fibrinolytic response in Black but not White postmenopausal females.

Exercise testing unmasks more exaggerated systolic blood pressure responses (SBP) in Black compared with White male adults. Such responses, if translatable to females, may detect racial disparities particularly relevant during menopause. Given the endothelial involvement in BP regulation and as a source of fibrinolytic markers, it follows that fibrinolytic and BP response to exercise could be linked. Thus, we examined BP and fibrinolytic responses to exercise testing in Black and White postmenopausal females. Postmenopausal females (Black = 40; White = 41; 51-70 yr) performed maximal treadmill exercise. BP and blood draws were conducted before and immediately after exercise. Plasma samples, using minimal stasis, were analyzed for tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) activity and antigen, respectively. Resting SBP and fibrinolytic potential were similar between races. Black females exhibited greater increases in SBP during exercise [change (d)=75, 95% CI: 64-86 mmHg, P < 0.001] than White females (d = 60, 95% CI: 48-71 mmHg, P < 0.001). Black compared with White females had smaller changes in tPA (d = 3.27, 95% CI: 2.28-4.27 IU/mL, P < 0.001 vs. d = 5.55, 95% CI: 4.58-6.53, P < 0.001) and PAI-1 (d = -2.89, 95% CI: -4.39 to -1.40 IU/mL, P < 0.001 vs. d = -5.08, 95% CI: -6.59 to -3.61, P < 0.001) activities after exercise. SBP exercise-induced changes were not associated with tPA (r = -0.10, P = 0.42) or PAI-1 (r = 0.13, P = 0.30), without any influence of race (P > 0.05). Our findings show that maximal exercise unmasks risk factors for cardiovascular disease in Black postmenopausal females.NEW & NOTEWORTHY Exaggerated SBP responses to exercise testing are more frequent in Black than in White male adults. Such responses, if translatable to females, may detect early racial disparities arriving during menopause. Because the endothelium regulates BP and fibrinolytic responses, these could be linked during exercise. At peak exercise, Black but not White postmenopausal females had more exaggerated SPB responses regardless of reduced fibrinolytic potential. Maximal exercise unmasked risk factors for cardiovascular disease in Black postmenopausal females.

Impact of Estetrol Combined with Drospirenone on Blood Coagulation and Fibrinolysis in Patients with Endometriosis: A Multicenter, Randomized, Open-Label, Active-Controlled, Parallel-Group Study.

Venous thromboembolism is a serious safety concern in women using combined oral contraceptives; ethinyl estradiol (EE) is widely used as an estrogen. Estetrol (E4) is a native estrogen with selective tissue activity and exclusively produced by the fetal liver. This study used a multicenter, randomized, open-label, active-controlled, parallel-group design to evaluate the effects of E4 combined with drospirenone (DRSP) on coagulation and fibrinolysis in Japanese patients with endometriosis. Participants were randomized to receive either E4 15 mg/DRSP 3 mg or EE 20 µg/DRSP 3 mg for 12 weeks. E4/DRSP and EE/DRSP were administered orally once a day in a cyclic regimen, ie, 24-day active use followed by a 4-day hormone-free period, and a flexible extended regimen, respectively, and blood coagulation and fibrinolysis markers were measured. The effect on coagulation and fibrinolysis was considerably less in the E4/DRSP group than in the EE/DRSP group. Major anticoagulant proteins, protein S (free, total) and tissue factor pathway inhibitor (free), were reduced following EE/DRSP treatment. Consequently, thrombin generation determined by the activated protein C sensitivity ratio was increased by approximately 4-fold in the EE/DRSP group than in the E4/DRSP group. Eventually, the fibrinolysis cascade was triggered to compensate for disturbed coagulation, and D-dimer levels were 4.7-fold higher in the EE/DRSP group than in the E4/DRSP group. This study demonstrated that the effect of E4/DRSP on the blood coagulation and fibrinolysis cascades was significantly less than that of EE/DRSP in participants with endometriosis, a disease of women of advanced and reproductive age (jRCT2080225090, https://jrct.niph.go.jp/en-latest-detail/jRCT2080225090).

D-dimer variation in diabetic and non-diabetic patients of COVID-19

Diabetes mellitus is one of the serious comorbidities in patients with COVID-19. D-dimer which is a marker of fibrinolysis, the levels of which were quite different between the diabetic and nondiabetic groups. Hence, it is important to assess the levels of D-dimer in COVID-19 patients. The present study aimed to assess the variability of D-dimer in diabetic and non-diabetic patients with COVID-19 and its association with the severity of COVID-19 illness with glycemic control of diabetic patients. All the hospitalized patients of COVID-19 were included and diabetic and non-diabetic populations were differentiated based on their previous history, fasting blood sugar, random blood sugar and glycated hemoglobin (HbA1c). Outcomes were assessed based on evaluation of HbA1c levels with D-Dimer values and assessing the severity of illness by Computed tomography severity index (CTSI) and duration of hospital stay. Also, D-dimer variation in the two groups of COVID-19 with outcomes was observed. The D-dimer levels, CTSI and hospital stay of the diabetic patients were significantly higher than non-diabetic patients. Association for patients with D-dimer values and HbA1c of class interval 6.5–7.5 %, 7.6–9 % and > 9 % was highly significant, suggesting that patients having higher levels of D-dimer were associated with uncontrolled glycemic values. Poor glycemic control was associated with higher D-dimer values and higher CT severity Index. All COVID-19 patients with diabetes be followed closely to detect complications at early stage as the disease is more severe in diabetics as compared to non-diabetics.

Validation of the time to attain maximal clot amplitude after reaching maximal clot formation velocity parameter as a measure of fibrinolysis using rotational thromboelastometry and its application in the assessment of fibrinolytic resistance in septic patients: a prospective observational study: communication from the ISTH SSC Subcommittee on Fibrinolysis

BackgroundIn sepsis, fibrinolysis resistance correlates with worse outcomes. Practically, rotational thromboelastometry (ROTEM) is used to report residual clot amplitude relative to maximum amplitude at specified times after clot formation clot lysis indices (CLIs). However, healthy individuals can exhibit similar CLIs, thus making it challenging to solely diagnose the low fibrinolytic state. Furthermore, CLI does not include the kinetics of clot formation, which can affect overall fibrinolysis. Therefore, a more nuanced analysis, such as time to attain maximal clot amplitude after reaching maximal clot formation velocity (t-AUCi), is needed to better identify fibrinolysis resistance in sepsis. ObjectivesTo evaluate the correlation between the degree of fibrinolytic activation and t-AUCi in healthy or septic individuals. MethodsWhole blood (n = 60) from septic or healthy donors was analyzed using tissue factor–activated (EXTEM) and nonactivated (NATEM) ROTEM assays. Lysis was initiated with tissue-type plasminogen activator, and CLI and t-AUCi were calculated. Standard coagulation tests and plasma fibrinolysis markers (D-dimer, plasmin-α2-antiplasmin complex, plasminogen activator inhibitor type 1, and plasminogen) were also measured. Resultst-AUCi values decreased with increasing fibrinolytic activity and correlated positively with CLI for different degrees of clot lysis both in EXTEM and NATEM. t-AUCi cutoff value of 1962.0 seconds in EXTEM predicted low fibrinolytic activity with 81.8% sensitivity and 83.7% specificity. In addition, t-AUCi is not influenced by clot retraction. ConclusionWhole-blood point-of-care ROTEM analyses with t-AUCi offers a more rapid and parametric evaluation of fibrinolytic potential compared with CLI, which can be used for a more rapid and accurate diagnosis of fibrinolysis resistance in sepsis.

Platelet Microvesicles, Inflammation, and Coagulation Markers: A Pilot Study.

Platelet "Microvesicles" (MVs) are studied for their role in blood coagulation and inflammation. The study aimed to establish if MVs are related to age, plasma levels of inflammation, coagulation, and fibrinolysis markers in healthy individuals. We prospectively enrolled volunteers aged over 18 years. MVs, plasma levels of C-reactive protein (CRP), Interleukin 6 (IL-6), Interleukin 10 (IL-10), Interleukin 17 (IL-17), and transforming growth factor β (TGF-β), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF), homocysteine, factor VII (FVII), thrombin activatable fibrinolysis inhibitor (TAFI), and Protein S were tested. A total of 246 individuals (median age 65 years ("IQR"54-72)) were evaluated. Both univariate analysis and logistic regression models showed that MVs positively correlate with age, CRP, IL-6, IL-10, IL-17, TGF-β, fibrinogen, PAI-1, VWF, FVII, and homocysteine, while inversely correlating with TAFI and Protein S. The ROC curve analysis performed to identify a cut off for MV values (700 kMP) showed a good accuracy with over-range cytokines fibrinolysis factor and coagulation markers. To the best of our knowledge, this study is the first to correlate MVs with an entire panel of cardiovascular risk factors in healthy individuals. A future possible role of MVs in screening exams is suggested.

Elevated plasma and bile levels of corisin, a microbiota-derived proapoptotic peptide, in patients with severe acute cholangitis

BackgroundAcute cholangitis is a severe, life-threatening infection of the biliary system that requires early diagnosis and treatment. The Tokyo Guidelines recommend a combination of clinical, laboratory, and imaging findings for diagnosis and severity assessment, but there are still challenges in identifying severe cases that need immediate intervention. The microbiota and its derived products have been implicated in the pathogenesis of acute cholangitis. Corisin is a microbiome-derived peptide that induces cell apoptosis, acute tissue injury, and inflammation. This study aimed to evaluate the potential of plasma and bile corisin as a biomarker of acute cholangitis.MethodsForty patients with acute cholangitis associated with choledocholithiasis or malignant disease were enrolled. Nine patients without acute cholangitis were used as controls. Corisin was measured by enzyme immunoassays in plasma and bile samples. Patients were classified into severe and non-severe groups. The associations of plasma and bile corisin with the clinical grade of acute cholangitis and other parameters were analyzed by univariate and multivariate regression analysis.ResultsPlasma and bile corisin levels were significantly higher in patients with acute cholangitis than in controls. Patients with severe acute cholangitis had significantly higher plasma and bile corisin levels than those with non-severe form of the disease. Bile corisin level was significantly correlated with markers of inflammation, coagulation, fibrinolysis, and renal function. Univariate analysis revealed a significant association of bile corisin but a weak association of plasma corisin with the clinical grade of acute cholangitis. In contrast, multivariate analysis showed a significant relationship between plasma corisin level and the disease clinical grade. The receiver operating characteristic curve analysis showed low sensitivity but high specificity for plasma and bile corisin to detect the severity of acute cholangitis. The plasma and bile corisin sensitivity was increased when serum C-reactive protein level was included in the receiver operating characteristic curve analysis.ConclusionsOverall, these findings suggest that plasma and bile corisin levels may be useful biomarkers for diagnosing and monitoring acute cholangitis and that corisin may play a role in the pathophysiology of the disease by modulating inflammatory, coagulation and renal pathways.