Thrombomodulin Concentrations Research Articles

Tyrosine Kinase-2, Angiopoietin-2, and Thrombomodulin Axes in the Late-Onset Fetal Growth Restriction: A Prospective Cohort Study

OBJECTIVE: Investigating the interaction among three interconnected proteins, namely receptor Tyrosine Kinase-2 (Tie-2), the vascular remodeling cytokine Angiopoietin-2 (Ang-2), and the coagulation inhibitor Thrombomodulin (TM), may offer fresh insights into the multifactorial origins of late-onset fetal growth restriction (LFGR). STUDY DESIGN: In this prospective cohort study, we assessed the maternal serum concentrations of Tie-2, Ang-2, and TM in pregnancies that developed LFGR (n=30) and a control group (n=59) within the gestational weeks of 32-39 gestational weeks at Trakya University Hospital (January 2021-December 2021). Concentrations were quantified using ELISA, and data analysis was conducted using the SPSS 22.0 Windows software package. RESULTS: The 75th percentile concentrations of these proteins were significantly lower in cases of LFGR. Among heavy smokers, the risk of LFGR increased by 2.37-fold. A significant correlation was observed between these proteins in both LFGR and healthy pregnancies. However, the sensitivity and specificity of these proteins within the Tie-2, Ang-2, and TM axes were 51%, 56%, 51%, and 45%, 52%, and 50%, respectively. When we examined cases where all three proteins exhibited a consistent trend, LFGRs accounted for 23.33% with reduced levels and 30% with elevated levels, whereas this pattern was observed in 40.67% with reduced levels and 42.37% with elevated levels in healthy pregnancies. CONCLUSION: Although our study underscores the significance of the intricate interactions between Tie-2, Ang-2, and TM proteins in LFGR pregnancies, it is evident that a more comprehensive investigation is required to make meaningful contributions to the clinical applicability of this subject.

Plasma thrombomodulin as a candidate biomarker for the diagnosis and prognosis of HBV-related acute-on-chronic liver failure.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complicated syndrome with high short-term mortality. Effective biomarkers are required for its early diagnosis and prognosis. This study aimed to determine the diagnostic and prognostic value of thrombomodulin (TM) in patients with HBV-ACLF. The expression of TM during disease progression was evaluated through transcriptomics analysis. The plasma TM concentrations of 393 subjects with HBV-ACLF (n=213), acute-on-chronic hepatic dysfunction (ACHD, n=50), liver cirrhosis (LC, n=50) or chronic hepatitis B (CHB, n=50), and normal controls (NC, n=30) from a prospective multicenter cohort, were measured to verify the diagnostic and prognostic significance of plasma TM for HBV-ACLF patients by enzyme-linked immunosorbent assay (ELISA). TM mRNA was highly expressed in the HBV-ACLF group compared with the ACHD group (AUROC=0.710). High expression of TM predicted poor prognosis for HBV-ACLF patients at 28/90 days (AUROCs=0.823/0.788). Functional analysis showed that TM was significantly associated with complement activation and the inflammatory signaling pathway. External validation confirmed its high diagnostic accuracy for HBV-ACLF patients (AUROC=0.796). Plasma TM concentrations were correlated with organ failure, including coagulation and kidney failure. Plasma TM concentrations showed a potential prognostic value for 28-day mortality rates (AUROC=0.702). Risk stratification specifically identified HBV-ACLF patients with a high risk of death as having a plasma TM concentration of ≥8.4 ng/mL. This study reveals that the plasma TM can be a candidate biomarker for early diagnosis and prognosis of HBV-ACLF, and might play a vital role in coagulation and inflammation.

LASSO regression shows histidine and sphingosine 1 phosphate are linked to both sepsis mortality and endothelial damage

Sepsis is a major cause of death worldwide, with a mortality rate that has remained stubbornly high. The current gold standard of risk stratifying sepsis patients provides limited mechanistic insight for therapeutic targeting. An improved ability to predict sepsis mortality and to understand the risk factors would allow better treatment targeting. Sepsis causes metabolic dysregulation in patients; therefore, metabolomics offers a promising tool to study sepsis. It is also known that that in sepsis endothelial cells affecting their function regarding blood clotting and vascular permeability. We integrated metabolomics data from patients admitted to an intensive care unit for sepsis, with commonly collected clinical features of their cases and two measures of endothelial function relevant to blood vessel function, platelet endothelial cell adhesion molecule and soluble thrombomodulin concentrations in plasma. We used least absolute shrinkage and selection operator penalized regression, and pathway enrichment analysis to identify features most able to predict 30-day survival. The features important to sepsis survival include carnitines, and amino acids. Endothelial proteins in plasma also predict 30-day mortality and the levels of these proteins also correlate with a somewhat overlapping set of metabolites. Overall metabolic dysregulation, particularly in endothelial cells, may be a contributory factor to sepsis response. By exploring sepsis metabolomics data in conjunction with clinical features and endothelial proteins we have gained a better understanding of sepsis risk factors.

Value of novel thrombotic markers for predicting occurrence of the malignant cerebral artery infarction: a prospective clinical study

ObjectiveThis study investigated the diagnostic performance of thrombin–antithrombin complex (TAT), plasmin–α2 plasmin inhibitor complex (PIC), tissue plasminogen activator–plasminogen activator inhibitor complex (t-PAIC), and thrombomodulin (TM) in predicting the progression of massive cerebral infarction to the malignant cerebral artery infarction.MethodA total of 71 patients with massive cerebral infarction confirmed by imaging examination were divided into malignant cerebral artery infarction group (MCAI) and non-malignant cerebral artery infarction group (NMCAI) based on whether they progressed to MCAI after admission. TAT, PIC, t-PAIC, and TM were measured immediately after admission. The predictive performance was analyzed by the receiver characteristic operating curve (ROC).ResultThe median plasma concentrations of TM, PIC, TAT, and t-PAIC in the MCAI patients at admission were 10.65 IU/mL, 1.17 μg/mL, 12.25 ng/mL, and 13.85 ng/mL, respectively, which were higher than those in the NMCAI patients (9.00 IU/mL, 1.07 μg/mL, 4.60 ng/mL, and 8.70 ng/mL), and the difference was statistically significant (p = 0.045, p = 0.035, p = 0.004, and p = 0.003). Elevated plasma t-PAIC concentration was shown to be an independent risk factor for progression of massive cerebral infarction to MCAI (OR = 1.131) by multivariate logistic regression analysis. ROC curve analysis showed that t-PAIC was the best predictor of MCAI (AUC = 74.7%), with a sensitivity of 75.0% and specificity of 75.9% when t-PAIC concentration was ≥12.4 ng/mL; TAT had the highest specificity in predicting MCAI, with a specificity of 90.7% when the TAT concentration was ≥13.5 ng/mL.ConclusionThe detection of PIC, TAT, t-PAIC, and TM is a comprehensive assessment of vascular endothelial damage and activation of the coagulation and fibrinolytic systems and has predictive value for poor prognosis in patients with MCAI. The widespread use of these tests will likely greatly improve the early diagnosis rate of MCAI.

АНАЛИЗ МАРКЕРОВ СИСТЕМЫ ГЕМОСТАЗА У ПАЦИЕНТОВ С ФИБРИЛЛЯЦИЕЙ ПРЕДСЕРДИЙ НЕКЛАПАННОГО ГЕНЕЗА С ТРОМБОЭМБОЛИЧЕСКИМИ ОСЛОЖНЕНИЯМИ

Introduction. Atrial fibrillation (AF) is one of the most common heart rhythm disorders. The risk of developing thromboembolic complications, including ischemic stroke, in patients with AF is 5 times higher than that in patients with sinus rhythm; therefore, one of the main directions in the treatment of patients with this rhythm disorder is the prevention of thromboembolic complications. Objective: to study the markers of monitoring the blood coagulation system in the blood serum of patients with non-valvular AF receiving anticoagulant therapy and having a history of thrombotic and thromboembolic complications. Materials and methods. The study included 31 healthy volunteers (without a history of AF, thrombosis) and 31 patients over 18 years of age with a diagnosis of AF (mean age 66.2±8.1), receiving anticoagulant therapy and having a history of thrombotic and thromboembolic events. complications. Therapy taken by patients at the time of inclusion in the study was in line with current recommendations and included standard conventional antiarrhythmic and anticoagulant therapy, as well as therapy for the underlying cardiovascular disease. Biomarkers of thrombus formation and pro-inflammatory activation (L-selectin, thrombomodulin) were determined by enzyme immunoassay using diagnostic kits from BiomedicaGmbH, Austria. Results. During the screening of 2820 patients treated in the Department of CHLSRS&EX for the nosology of AF in the period 01.2020-01.2023, 31 patients were included in the study, who were diagnosed with thrombotic and thromboembolic complications (0.01% of the total number of screened patients) against the background of regular anticoagulant therapy . Among all patients included in the study, thrombotic complications in AF were as follows: thrombosis of the left atrial appendage was noted in 17 patients (54%), spontaneous echo contrast of grade II or more in 5 patients (16%), cardioembolic stroke - in 3 patients (10%) , thrombosis of peripheral arteries (2 (6%)), thrombosis on EKS electrodes (2 (6%)). The concentration of soluble thrombomodulin in the blood serum of patients with thrombotic and thromboembolic complications was reduced compared with the group of healthy volunteers (2073.0±548.6 vs. 2845.3±726.4 pg/ml; p=0.004). Serum levels of L-selectin in patients with thrombotic and thromboembolic complications were reduced compared to healthy volunteers (1.5±0.6 vs. 2.4±1.3 µg/mL; p=0.04). Conclusion. In patients with thrombotic and thromboembolic complications that occurred against the background of adequate anticoagulant therapy, there was a decrease in serum soluble thrombomodulin and L-selectin, which may indicate damage to the endothelium, activation of thrombus formation and inflammation.

Inflammatory and coagulant responses after acute respiratory failure in children of different body habitus

BackgroundEndothelial injury and systemic inflammation are key determinants of acute respiratory failure (ARF) outcome. We sought to determine if childhood obesity alters the degree of injury and inflammation in (ARF) patients with and without sepsis.MethodsPlasma markers of endothelial injury (thrombomodulin), thrombosis (plasminogen activator inhibitor, PAI-1), and inflammation (IL-8 and IL-1ra) were measured over 3 days in children with ARF. Weight classification (healthy, overweight, and obesity) was determined by body mass index or weight‐for‐height z scores. Daily biomarker concentration and concentration change over time were compared among weight groups. Secondarily, we stratified by sepsis versus non-sepsis ARF.ResultsTwenty-six percent of the 229 children had obesity. Obesity was associated with longer duration of mechanical ventilation (median of 12 days compared to 7 days in the healthy weight, p = 0.006) and ICU stay (median of 18 days compared to 10 days in the healthy weight, p = 0.01 and compared to 11 days in the overweight, p = 0.02). Thrombomodulin levels were significantly higher in the obesity group on study days 1 and 2. In those with sepsis-associated ARF, thrombomodulin change over time increased most significantly in the obesity group (p = 0.015 for the interaction term of weight group and day on thrombomodulin concentration). There were no weight-based differences for IL-8, IL-1ra, or PAI-1.ConclusionsObesity was associated with elevated thrombomodulin, most notably in children with sepsis-associated ARF. This may denote worse endothelial injury in children with obesity and ARF. We found no difference in biomarkers of systemic inflammation among the weight groups.

Peripheral artery disease and markers of endothelial dysfunction and platelet activation in people with HIV.

People with HIV (PWH) have increased risk of peripheral artery disease (PAD), but the pathogenesis is unknown. We aimed to determine associations between markers of endothelial dysfunction and platelet activation and both PAD at baseline and de novo PAD in PWH. 1012 PWH from the longitudinal Copenhagen Comorbidity in HIV Infection (COCOMO) study and 57 age- and sex-matched population controls were included. Plasma samples were collected at baseline and analyzed for soluble thrombomodulin, syndecan-1 and CD40 ligand (sCD40L). Ankle-brachial index was measured at baseline and two-year follow-up in PWH. Logistic and Poisson regression models were used to test associations. PWH had higher concentrations of soluble thrombomodulin (P=0.03) and syndecan-1 (P<0.001), and lower concentrations of sCD40L (P<0.001) compared to controls. High concentration of soluble thrombomodulin, but not syndecan-1 or sCD40L, was associated with lower odds of PAD in PWH at baseline after adjustments (adjusted odds ratio: 0.50 [0.28, 0.90], P=0.02). None of the markers were associated with de novo PAD. PWH had higher concentrations of soluble thrombomodulin and syndecan-1 and lower concentration of sCD40L compared to controls. Soluble thrombomodulin was associated with lower odds of PAD at baseline. Further studies are needed to elucidate the pathogenesis of PAD in people with HIV.

Value of Serum Thrombomodulin as a Marker and Predictor in Patients with Sepsis-Associated Acute Kidney Injury.

To investigate the serum soluble thrombomodulin (sTM) concentration in patients with sepsis-associated acute kidney injury (AKI) and to determine the value of sTM in predicting AKI and mortality in sepsis patients. This prospective observational study was conducted on 71 patients diagnosed with sepsis according to Sepsis 3 at the Intensive Care Unit, Hue Central Hospital, Vietnam, from September 2021 to February 2023. Among 71 sepsis patients, there were 38 (53.5%) AKI cases, including 16 (22.5%) cases of stage 1 AKI, 14 (19.7%) cases of stage 2 AKI, 8 (11.3%) cases of stage 3 AKI, 16 (22.5%) cases of renal replacement therapy, 28 (39.4%) cases of septic shock, and 21 (29.6%) cases of mortality within 28 days. The concentrations of lactate and IL-6 in the AKI and mortality groups were statistically significantly greater than those in the non-AKI and survival groups (p < 0.05). The serum sTM concentration was 4.33 ng/mL, the serum sTM level in the AKI group was statistically significantly higher than that in the non-AKI group (sTM [4.71 vs 2.54 ng/mL, p < 0.001]), and the serum sTM level in the mortality group was statistically significantly higher than the survival group (sTM [4.78 vs 3.87 ng/mL, p < 0.001]). The AUC of sTM for predicting AKI was 0.864; the AUCs of sTM, IL-6, SOFA, and APACHE II for predicting mortality were 0.811, 0.671, 0.816, and 0.705, respectively. AKI was a prevalent complication among sepsis patients at the ICU. In the AKI and mortality groups, sTM concentration was statistically significantly higher than that in the non-AKI and survival groups. sTM was the predictor of acute kidney injury and mortality in patients with sepsis.

Prothrombotic state, endothelial injury, and echocardiographic changes in non-active sarcoidosis patients.

Sarcoidosis is a multisystem inflammatory granulomatous disease of unknown cause that most commonly affects lungs and lymph nodes, with frequent yet asymptomatic cardiac involvement. The epidemiologically associated cardiovascular risk suggests an underlying prothrombotic state and endothelial dysfunction, currently understudied in the available literature. Therefore, we aimed to investigate prothrombotic plasma properties together with selected echocardiographic and laboratory biomarkers of cardiovascular injury in that disease. N = 53 patients with pulmonary sarcoidosis in clinical remission and N = 66 matched controls were assessed for inflammatory and endothelial injury biomarkers, plasma thrombin generation profile, and echocardiographic and lung function parameters. Sarcoidosis cases had impaired systolic and diastolic left ventricular function, higher concentrations of inflammatory markers, D-dimer and factor VIII activity compared to the controls. The coexistence of extrapulmonary disease was associated with elevated circulating vascular cell adhesion molecule 1, while cases with hypercalcemia had higher thrombomodulin concentration. Sarcoidosis was characterized by the unfavorably altered thrombin generation profile, reflected by the 16% higher endogenous thrombin potential (ETP), 24% increased peak thrombin concentration, and 12% shorter time to thrombin peak in comparison to the control group. ETP was higher in cases with proxies of pulmonary restriction, extrapulmonary-extracutaneous manifestation, and need for corticosteroids use. Despite the clinical remission, sarcoidosis is related to prothrombotic plasma properties and signs of endothelial injury, likely contributing to the higher risk of cardiovascular events. In addition, subclinical cardiac involvement may play an additional role, although further clinical and experimental studies are needed to verify these findings.

Circulating concentrations of glycocalyx degradation products in preeclampsia.

Background and Objectives: Preeclampsia is a multisystem disorder that affects maternal endothelium. The glycocalyx lines and protects the endothelial surface. In severe systemic diseases, like sepsis, it is shed and glycocalyx degradation products can be detected in increased concentrations in plasma. The aim of this study was to compare circulating concentrations of glycocalyx degradation products in degrees of preeclampsia severity. Study design: In this observational study, we included women from the South African PROVE biobank. Women were divided into normotensive controls, women with preeclampsia without end-organ complications, women with a single end-organ complication and women with multiple end-organ complications. Plasma samples taken at inclusion after diagnosis (preeclampsia cases) or at admission for delivery (normotensive controls) were analyzed with ELISA for syndecan-1, hyaluronic acid and thrombomodulin and compared between groups. Results: Women with preeclampsia (n = 47) had increased plasma concentrations of hyaluronic acid (100.3 ng/ml IQR 54.2–204 vs. 27.0 ng/ml IQR (13.5–66.6), p < 0,001) and thrombomodulin (4.22 ng/ml IQR 3.55–5.17 vs. 3.49 ng/ml IQR 3.01–3.68, p = 0.007) but not syndecan-1 compared with normotensive women (n = 10). There were no differences in plasma concentration in any of these biomarkers in women with preeclampsia with no end-organ complications (n = 10) compared with women with preeclampsia and one end-organ complication (n = 24). Women with preeclampsia with two or more end-organ complications (n = 13) had increased plasma concentrations of thrombomodulin (5.46 ng/ml, IQR 4.85–7.83 vs. 4.66 ng/ml, IQR 3.45–4.88, p = 0.042) compared with women with preeclampsia and no end-organ complications. Conclusion: Thrombomodulin was associated with disease severity and may be valuable for risk-stratifying women with preeclampsia.

Altered platelet reactivity, coagulation, endothelial and inflammatory markers early after smoking cessation verified with cotinine plasma concentration

Abstract Background/Introduction Cigarette smoking is a potent modifiable risk factor for coronary artery disease (CAD) including patients after percutaneous coronary interventions (PCI). Cigarette smoking is associated with major changes in platelet, endothelial, inflammatory, and coagulation responses. The early period after PCI witnesses the highest risk of thrombotic events. However, data regarding alterations of prothrombotic state and platelet reactivity early after smoking cessation are scarce. Purpose We investigated alterations to platelet reactivity, coagulation and markers of platelet, endothelial and neutrophil activation in clopidogrel-treated patients with CAD after PCI before and after smoking cessation. Methods Patients aged 18 years or older, who smoked at least 10 cigarettes per day, at least 30 days after successful PCI with stent placement, and those treated with 75 mg clopidogrel and 75 mg acetylsalicylic acid (ASA) once daily, were included in the study and were encouraged to quit the habit. Platelet reactivity was measured with VerifyNow system and the concentrations of cotinine, thrombomodulin, P-selectin, platelet factor 4 (CXCL4/PF4), citrullinated histone H3 (H3cit), were assessed in blood samples at baseline and at the 30-day follow-up visit. Smoking cessation was defined as cotinine concentrations of &amp;lt;50 ng/ml. Results Among 117 patients, being current smokers, who attended the baseline visit, 84 patients completed a 30-day follow-up. The median [interquartile range] age of patients was 50 [55–65] years, median body mass index was 27.55 [25.2–30.9] kg/m2, and a median load of smoking was 40 [30–47] pack-years. At the follow-up visit, 30 patients stopped smoking as confirmed by cotinine concentrations (study group) and 54 patients continued smoking (control group). Baseline characteristics were similar in both groups. In the study group as compared to the control group, at day 30 a change in platelet reactivity was larger (Δ platelet reactivity units (PRU) 19 [2, 43] vs −6 [−32, 37], p=0.018), along with a change in P-selectin concentration (−11.82 [−23.62, 1.34] vs 7.19 [−14.24, 17.19] ng/ml), p=0.005). The change in the concentrations of thrombomodulin, CXCL4/PF4, and citH3 did not differ significantly between groups. Conclusion In the early period after smoking cessation in coronary artery disease patients following PCI treated with clopidogrel and ASA, an increase in platelet reactivity with a decrease in P-selectin levels was observed. No significant changes in other markers were noticed. It might be speculated that the risk of thrombotic complications might be paradoxically enhanced among such patients after smoking cessation despite dual antiplatelet therapy. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Centre of Postgraduate Medical Education

Вміст тригерних компонентів системи протеолізу та їхніх регуляторів при розвитку патологій підшлункової залози

The content of the plasminogen activation system components (plasminogen, plasminogen tissue activator, and its inhibitor PAI-1) was investigated as well as the concentration of thrombomodulin, protein C, matrix metalproteinases (MMP -1, -2, -3, -8, -9, -10) and their inhibitor TIMP, growth factors content (such as transforming growth factor-β1, insulin-like growth factor-1, fibroblasts growth factor-2) and cytokine profile (interleukines IL-1β, -4, -6, -8, -10, tumor necrosis factor, interferon-γ in patients with chronic pancreatitis (CP) and pancreatic cancer (PC) were established. Khmelnitsky Regional Clinical Hospital patients aged 28-89 were selected for this study: 20 people with chronic pancreatitis (group CP); 20 people with pancreatic cancer (group PC); 20 conditionally healthy persons (control). Blood plasma samples and pancreatic tissue homogenates were obtained from all the patients. The studied indicators’ content in the experimental materials was determined by the enzyme-linked immunosorbent assay using appropriate antibodies. At the level of systemic circulation, a statistically significant increase was found in most of the studied parameters under the CP conditions. However, PC was characterized by an increase of two blood plasma indications only (thrombomodulin and protein C). In contrast, the pancreatic sample tissue examination for both aforementioned pathologies revealed significant changes in the content of most metalloproteinases and cytokines under PC. This indicates the development of metastasis, angiogenesis, and immunomodulation-aimed local biochemical processes in the affected organ.

Thrombomodulin and von willebrand factor as markers of endothelial dysfunction in patients with chronic kidney disease

The aim of research was to study the levels of thrombomodulin (TM) and von Willebrand factor (VWF) in the serum and urine of patients with chronic kidney disease (CKD)as diagnostic markers of endothelial dysfunction. The study involved 140 patients with CKD. The clinical diagnosis was determined based on standard methods of patients examination according to the kidney diseases classification and protocols of CKD patients management. The concentrations of TM and VWF in serum and urine were quantified by ELISA. A generalized endothelial dysfunction in the vessels of the whole body, including the kidneys and high concentration of TM and FVF in the serum and urine of patients with a diabetic nephropathy have been found. The concentration of TM and VWF in the serum of patients with a chronic glomerulonephritis was at the same level as in the serum of healthy individuals, while those in urine significantly exceeded the control values, indicating endothelial damage in the glomeruli of the kidneys due to exposure to pro-inflammatory cytokines. In our opinion, the studied markers will contribute to the timely diagnosis of endothelial dysfunction in patients with CKD and to the development of criteria for prescribing antiplatelet agents in glomerular kidney disease.

Impact of Laparoscopic Sleeve Gastrectomy on Thrombomodulin Concentration and Early Markers of Atherosclerosis.

Background Thrombomodulin, an integral membrane protein functioning as a cofactor in the anticoagulant pathways, has recently emerged as a marker of endothelial dysfunction. This study aimed to investigate the impact of laparoscopic sleeve gastrectomy (LSG) on thrombomodulin concentration and early markers of atherosclerosis. Methods Forty-four subjects undergoing LSG were prospectively examined. The change in thrombomodulin concentration from baseline (preoperative) to the sixth postoperative month following the LSG and the relationship between the change in thrombomodulin concentration and BMI, CIMT, ABI, and blood lipids were examined. Results The medical records were available for 44 patients (mean age: 37.2 ± 10.9 years, 65.9% male). LSG led to significant reductions in total body weight and body mass index (BMI) at postoperative six months (37.0 ± 5.6 kg/m2 vs. 47.1 ± 5.8 kg/m2, p < 0.001). Markers of early atherosclerotic events, including carotid intima-media thickness (CIMT) and ABI, improved. The change in thrombomodulin concentration (Δ TMD) was significantly correlated with the change in Δ BMI (r = 0.500, p=0.011), Δ LDL (r = 0.389, p=0.032), Δ systolic blood pressure (r = 0.384, p=0.012), and Δ CIMT (r = 0.327, p=0.012) and was negatively correlated with Δ HDL (r = −0.344, p=0.020) and Δ ABI (r = −0.357, p=0.020). Conclusion LSG leads to significant improvements in blood lipids, systolic and diastolic blood pressure, and in surrogate markers of atherosclerotic burden and endothelial function, including thrombomodulin, ABI, and CIMT, at postoperative six months. LSG might prevent or reduce atherogenesis in the early stages by stopping endothelial dysfunction.

Thrombin antithrombin complex concentration as an early predictor of deep vein thrombosis after total hip arthroplasty and total knee arthroplasty

AimEarly predictive markers of venous thromboembolism (VTE) after total hip arthroplasty (THA)/total knee arthroplasty (TKA) remain unclear. Our study identified early predictive markers for VTE after THA/TKA.MethodsA single-institution retrospective review study was conducted between May 2020 and April 2022 (n = 256). All patients underwent Doppler ultrasounds exam in preoperation and seventh day after surgery. Deep vein thrombosis (DVT) was defined by Doppler ultrasound of the lower extremities, which revealed thrombosis. Thrombin-antithrombin complex (TAT), thrombomodulin (TM), and plasmin-antiplasmin complex (PIC) concentration were tested from each patient’s preoperative and postoperative days 1, 4, 7, 14. These values were then accessed via receiver operating characteristic (ROC) curve analysis and further quantified the level of this risk by concentration.ResultsOn postoperative day 1 (pod-1), all patients’ TAT and PIC concentrations were significantly higher than those preoperatively (p < 0.05). The levels of TAT and PIC in patients in the DVT group on pod-1 were significantly higher than those in the non-DVT group (p < 0.05). At pod-1, the TAT concentration for DVT patients was 49.47 ng/mL compared to 20.70 ng/mL for non-DVT patients, PIC was 3.72μg/mL compared to 1.65μg/mL. ROC curve analysis demonstrated that a TAT concentration of 24.3 ng/mL had a sensitivity of 87.9% and a specificity of 69.1%.ConclusionTAT levels on pod-1 may predict DVT early after THA/TKA, which makes it possible for early intervention to decrease the incidence of DVT.

Relationship Between Endothelial and Angiogenesis Biomarkers Envisage Mortality in a Prospective Cohort of COVID-19 Patients Requiring Respiratory Support.

PurposeEndothelial damage and angiogenesis are fundamental elements of neovascularisation and fibrosis observed in patients with coronavirus disease 2019 (COVID-19). Here, we aimed to evaluate whether early endothelial and angiogenic biomarkers detection predicts mortality and major cardiovascular events in patients with COVID-19 requiring respiratory support.MethodsChanges in serum syndecan-1, thrombomodulin, and angiogenic factor concentrations were analysed during the first 24 h and 10 days after COVID-19 hospitalisation in patients with high-flow nasal oxygen or mechanical ventilation. Also, we performed an exploratory evaluation of the endothelial migration process induced by COVID-19 in the patients' serum using an endothelial cell culture model.ResultsIn 43 patients, mean syndecan-1 concentration was 40.96 ± 106.9 ng/mL with a 33.9% increase (49.96 ± 58.1 ng/mL) at day 10. Both increases were significant compared to healthy controls (Kruskal–Wallis p < 0.0001). We observed an increase in thrombomodulin, Angiopoietin-2, human vascular endothelial growth factor (VEGF), and human hepatocyte growth factor (HGF) concentrations during the first 24 h, with a decrease in human tissue inhibitor of metalloproteinases-2 (TIMP-2) that remained after 10 days. An increase in human Interleukin-8 (IL-8) on the 10th day accompanied by high HGF was also noted. The incidence of myocardial injury and pulmonary thromboembolism was 55.8 and 20%, respectively. The incidence of in-hospital deaths was 16.3%. Biomarkers showed differences in severity of COVID-19. Syndecan-1, human platelet-derived growth factor (PDGF), VEGF, and Ang-2 predicted mortality. A multiple logistic regression model with TIMP-2 and PDGF had positive and negative predictive powers of 80.9 and 70%, respectively, for mortality. None of the biomarkers predicted myocardial injury or pulmonary thromboembolism. A proteome profiler array found changes in concentration in a large number of biomarkers of angiogenesis and chemoattractants. Finally, the serum samples from COVID-19 patients increased cell migration compared to that from healthy individuals.ConclusionWe observed that early endothelial and angiogenic biomarkers predicted mortality in patients with COVID-19. Chemoattractants from patients with COVID-19 increase the migration of endothelial cells. Trials are needed for confirmation, as this poses a therapeutic target for SARS-CoV-2.

Supra-Physiological Concentrations of C1 Esterase Inhibitor Enhance Thrombin Generation in the Presence of Thrombomodulin

Introduction. Human C1-esterase inhibitor (C1INH) is a multifunctional plasma glycoprotein with a broad spectrum biological activities, best known for its role in regulation of the classical complement pathway, contact activation system and its essential roles in the coagulation and fibrinolytic cascades [1,2]. The main targets of C1INH are C1 esterase, Factors XIa and XIIa, kallikrein, thrombin and plasmin. Low levels of functional C1INH in plasma are considered to be the primary cause for hereditary angioedema (HAE) with symptoms of swelling in the face, throat, hands, feet and abdomen. HAE patients receive replacement therapy with plasma-derived C1INH products recently licensed in the US and EU for prophylactic and acute treatment of HAE [1]. Studies suggest that supra-physiological doses of C1INH can promote thrombotic events.. To date the use of C1INH at plasma concentrations exceeding normal have been proposed in a range of disease states including renal transplant, myocardial infarction and acute lung injury. However, the mechanism and concentration required to augment the risk of thromboembolic events remains unclear and therefore raises questions about the safety of high dose C1INH therapy. We evaluated all possible sites of the C1INH concentration-dependent interaction with the coagulation system and here we focus on a hypothesis that supra-physiological concentrations of C1INH alter the anticoagulant protein C system. To study the interactive role of C1INH and the protein C pathway we performed thrombin generation assays (TGA) on plasmas from both male and female healthy donors in the presence of supra-physiologic concentrations of C1INH and increasing concentrations of thrombomodulin (TM).Methods. Platelet poor plasma (PPP) was isolated by centrifugation from blood of 20 healthy donors and mixed with 16 IU/ml of C1INH or with the same volume of buffer. The used C1INH concentration was 16 times bigger than normal values. Concentrations of TM added to the plasma samples were equal to 3, 6, 9, 12 and 15 nM. 4.5 pm tissue factor-induced thrombin generation was performed by continuous measurement of thrombin proteolytic activity of thrombin-specific substrate Z-Gly-Gly-Arg-AMC added to PPP before induction of coagulation. Thrombin peak was calculated using Origin software. Wilcoxon and sign paired tests with P=0.05 were used to obtain statistics.Results and conclusions. C1INH significantly reduced thrombin peak up to 2 times in the absence and at the lowest concentrations of TM (3 and 6 nM). Addition of 9 nM TM caused disappearance of the difference between the samples with and without C1INH. Finally, in the presence of 12 and 15 nM of TM, C1INH significantly enhanced thrombin peak (Figure 1A, B). Figure 1B demonstrates that reducing C1INH concentration can bring the thrombin peak back to the values obtained without C1INH presence. These results indicate that presence of TM crucially change the action of C1INH on coagulation and explains how supra-physiological concentrations of coagulation inhibitor may cause thrombosis in certain clinical situations.Figure 1. A: Effect of elevation of C1INH concentration on thrombin peak. Statistics was obtained using Wilcoxon (*) and Sign (**) paired tests with P value equal to 0.05 from 20 healthy donors. B: Representative dependence of thrombin peak on TM concentration with and without the presence of 16 IU/ml C1INH. C: representative dependence of Thrombin peak on C1INH concentration in the presence of TM.

Preliminary study of microparticle coagulation properties in septic patients with disseminated intravascular coagulation.

BackgroundSepsis typically results in enhanced coagulation system activation and microthrombus formation. Microparticle (MP) production promotes coagulation and enhances pro-coagulation. This study investigated how circulating MP levels and tissue factor-bearing MP (TF+-MP) activity caused coagulation in patients with septic disseminated intravascular coagulation (DIC).MethodsThirty patients with septic DIC and 30 healthy controls were studied from December 2017 to March 2019. Patient blood samples were collected at enrolment (day 1) and on days 3 and 5; DIC scores and Sequential Organ Failure Assessment (SOFA) scores were recorded. TF+-MP activity was measured using TF-dependent factor Xa generation experiments. Circulating MP concentrations were determined by MP capture assay. Clotting factor activity, antithrombin level, soluble thrombomodulin, and serum tissue factor pathway inhibitor (TFPI) concentrations were measured.ResultsPatients with septic DIC had lower circulating MP levels than healthy control patients. Circulating MP levels in patients with septic DIC were positively correlated with DIC scores and negatively correlated with coagulation factors, but TF+-MP activity did not correlate with clotting factor levels and TFPI.ConclusionsIn patients with septic DIC, circulating MP levels are important in promoting coagulation activation and increasing clotting factor consumption. TF+-MP activity may not be the main form of active TF.

Endothelial Markers: Thrombomodulin and Von Willebrand Factor and Risk of Kidney Thrombosis After Transplantation

Endothelial disturbance is well known as one of the causes of thrombosis. This study measured von Willebrand factor (vWF) and soluble thrombomodulin (sTM) in renal vein blood to evaluate for the risk of thrombosis after kidney transplantation. A cross-sectional study that included 61 consecutive recipients of kidney transplant. The sTM and activity of vWF were evaluated in blood of the renal vein at the time of reperfusion. The renal vein blood had higher values of vWF activity and sTM concentration than the peripheral blood. In the first minutes of reperfusion, the concentration of thrombomodulin was the highest but activity of vWF was the lowest. As the reperfusion continued, thrombomodulin gradually decreased, but vWF increased. The strong correlations of TMs and vWF with warm ischemia were observed (r=0.5577 and r=0.3429, respectively). Thrombosis was found in about 10% of all recipients. However, other complications, such as delayed graft function or ureter necrosis, were associated with high values of vWF and sTM. They were correlated with increased sTM concentration and activity of vWF (P < .006 and P < .05, respectively). This was confirmed by analysis of the receiver operator characteristic curve. The area under the curve values for TMs and vWF were 0.762 and 0.602, respectively (P < .0001 and P < .015, respectively). The cutoff points for sTM and vWF were 14.89 ng/mL and 129.89%, respectively. Positive prediction value sTM and vWF were 76% and 66% and negative prediction value 69% and 59%, respectively. The endothelium of a transplanted kidney could be involved in the pathogenesis of renal thrombosis. Endothelial protection during harvesting can greatly contribute to the improvement of transplantation outcomes. The renal pool of sTM and vWF could be a useful marker of the risk of renal thrombosis.

ABO blood types and sepsis mortality

BackgroundWe aimed to determine if the ABO blood types carry different risks of 30-day mortality, acute kidney injury (AKI), and endothelial damage in critically ill patients with sepsis. This was a retrospective cohort study of three independent cohorts of critically ill patients from the United States and Scandinavia consisting of adults with septic shock. We compared the 30-day mortality across the blood types within each cohort and pooled the results in a meta-analysis. We also estimated the incidence of AKI and degree of endothelial damage, as measured by blood concentrations of soluble thrombomodulin and syndecan-1.ResultsWe included 12,342 patients with severe sepsis. In a pooled analysis blood type B carried a slightly lower risk of 30-day all-cause mortality compared to non-blood type B (adjusted HR 0.88; 95%-CI 0.79–0.98; p = 0.02). There was no difference in the risk of AKI. Soluble thrombomodulin and syndecan-1 concentrations were lower in patients with blood type B and O compared to blood type A, suggesting less endothelial damage.ConclusionSeptic patients with blood type B had less endothelial damage, and a small reduction in mortality. The exposure is, however, unmodifiable.