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Bioscience Reports May 2024During inflammation and situations of cellular stress protein disulfide isomerase (PDI) is released in the blood plasma from the platelet and endothelial cells to...
During inflammation and situations of cellular stress protein disulfide isomerase (PDI) is released in the blood plasma from the platelet and endothelial cells to influence thrombosis. The addition of exogenous PDI makes the environment pro-thrombotic by inducing disulfide bond formation in specific plasma protein targets like vitronectin, factor V, and factor XI. However, the mechanistic details of PDI interaction with its target remain largely unknown. A decrease in the coagulation time was detected in activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) on addition of the purified recombinant PDI (175 nM). The coagulation time can be controlled using an activator (quercetin penta sulfate, QPS) or an inhibitor (quercetin 3-rutinoside, Q3R) of PDI activity. Likewise, the PDI variants that increase the PDI activity (H399R) decrease, and the variant with low activity (C53A) increases the blood coagulation time. An SDS-PAGE and Western blot analysis showed that the PDI does not form a stable complex with either thrombin or antithrombin (ATIII) but it uses the ATIII-thrombin complex as a template to bind and maintain its activity. A complete inhibition of thrombin activity on the formation of ATIII-thrombin-PDI complex, and the complex-bound PDI-catalyzed disulfide bond formation of the target proteins may control the pro- and anti-thrombotic role of PDI.
Topics: Humans; Protein Disulfide-Isomerases; Thrombin; Blood Coagulation; Antithrombin III; Protein Binding; Antithrombins; Quercetin
PubMed: 38660763
DOI: 10.1042/BSR20231540 -
Frontiers in Pediatrics 2024Direct Oral Anticoagulants (DOACs) typically exhibit a predictable pharmacokinetic and pharmacodynamic response at a fixed dose, not necessitating monitoring under...
Direct Oral Anticoagulants (DOACs) typically exhibit a predictable pharmacokinetic and pharmacodynamic response at a fixed dose, not necessitating monitoring under standard conditions. Yet, in specific clinical scenarios that can impair it, like Congenital Nephrotic Syndrome (CNS) or Short Bowel Syndrome (SBS) due to absorption issues, anti-thrombin III (AT-III) deficiency and non-selective proteinuria, adjusting the dosage to achieve appropriate plasma concentrations could prove beneficial. We report a 3-month-old female with catheter-related jugular thrombosis affected by CNS concomitant to SBS and failure of both treatments with heparin and warfarin, that was switched to dose-adjusted pediatric rivaroxaban. Rivaroxaban was adjusted to reach peak levels between 189 and 419 ng/ml and the lower trough levels between 6 and 87 ng/ml. Increasing doses were needed due to SBS related malabsorption but a complete permeabilization of the vein was achieved without bleeding complications. The use of anti-Xa adjusted rivaroxaban could be an alternative to improve anticoagulation and secondary thromboprophylaxis in pediatric patients SBS and an option to children with CNS.
PubMed: 38633324
DOI: 10.3389/fped.2024.1385065 -
Respiratory Research Apr 2024Sarcoidosis is a systemic granulomatous disease of unknown etiology primarily affecting the lungs. Treatment is needed when disease symptoms worsen and organ function...
BACKGROUND
Sarcoidosis is a systemic granulomatous disease of unknown etiology primarily affecting the lungs. Treatment is needed when disease symptoms worsen and organ function deteriorates. In pulmonary sarcoidosis, prednisone and methotrexate (MTX) are the most common anti-inflammatory therapies. However, there is large inter-patient variability in response to treatment, and predictive response markers are currently lacking.
OBJECTIVE
In this study, we investigated the predictive potential of biomarkers in extracellular vesicles (EVs) isolated from biobanked serum of patients with pulmonary sarcoidosis stored prior to start of therapy.
METHODS
Protein concentrations of a four-protein test panel of inflammatory proteins were measured in a discovery (n = 16) and replication (n = 129) cohort of patients with sarcoidosis and 47 healthy controls. Response to therapy was defined as an improvement of the absolute score of > 5% forced vital capacity (FVC) and/or > 10% diffusion lung of carbon monoxide (DLCO) after 24 weeks compared to baseline (before treatment).
RESULTS
Serum protein levels differed between EV fractions and serum, and between sarcoidosis cases and controls. Serpin C1 concentrations in the low density lipid particle EV fraction were lower at baseline in the group of patients with a good response to MTX treatment in both the discovery cohort (p = 0.059) and in the replication cohort (p = 0.032). EV Serpin C1 showed to be a significant predictor for response to treatment with MTX (OR 0.4; p = 0.032).
CONCLUSION
This study shows that proteins isolated from EVs harbor a distinct signal and have potential as new predictive therapy response biomarkers in sarcoidosis.
Topics: Humans; Sarcoidosis, Pulmonary; Methotrexate; Antithrombin III; Sarcoidosis; Biomarkers; Extracellular Vesicles
PubMed: 38627696
DOI: 10.1186/s12931-024-02809-y -
Proteomics Apr 2024Mild cognitive impairment (MCI) is an early stage of memory loss that affects cognitive abilities with the aging of individuals, such as language or visual/spatial...
Mild cognitive impairment (MCI) is an early stage of memory loss that affects cognitive abilities with the aging of individuals, such as language or visual/spatial comprehension. MCI is considered a prodromal phase of more complicated neurodegenerative diseases such as Alzheimer's. Therefore, accurate diagnosis and better understanding of the disease prognosis will facilitate prevention of neurodegeneration. However, the existing diagnostic methods fail to provide precise and well-timed diagnoses, and the pathophysiology of MCI is not fully understood. Alterations of the serum N-glycoproteome expression could represent an essential contributor to the overall pathophysiology of neurodegenerative diseases and be used as a potential marker to assess MCI diagnosis using less invasive procedures. In this approach, we identified N-glycopeptides with different expressions between healthy and MCI patients from serum glycoproteins. Seven of the N-glycopeptides showed outstanding AUC values, among them the antithrombin-III Asn224 + 4-5-0-2 with an AUC value of 1.00 and a p value of 0.0004. According to proteomics and ingenuity pathway analysis (IPA), our data is in line with recent publications, and the glycoproteins carrying the identified N-sites play an important role in neurodegeneration.
PubMed: 38602241
DOI: 10.1002/pmic.202300620 -
Chemistry & Biodiversity Jun 2024Thromboembolism is the culprit of cardiovascular diseases, leading to the highest global mortality rate. Anticoagulation emerges as the primary approach for managing... (Review)
Review
Thromboembolism is the culprit of cardiovascular diseases, leading to the highest global mortality rate. Anticoagulation emerges as the primary approach for managing thrombotic conditions. Notably, sulfated polysaccharides exhibit favorable anticoagulant efficacy with reduced side effects. This review focuses on the structure-anticoagulant activity relationship of sulfated polysaccharides and the underlying action mechanisms. It is concluded that chlorosulfonicacid-pyridine method serves as the preferred technique to synthesize sulfated polysaccharides. The anticoagulant activity of sulfated polysaccharides is linked to the substitution site of sulfate groups, degree of substitution, molecular weight, main side chain structure, and glycosidic bond conformation. Moreover, sulfated polysaccharides exert anticoagulant activity via various pathways, including the inhibition of blood coagulation factors, activation of antithrombin III and heparin cofactor II, antiplatelet aggregation, and promotion of the fibrinolytic system.
Topics: Anticoagulants; Polysaccharides; Structure-Activity Relationship; Humans; Sulfates; Animals
PubMed: 38600639
DOI: 10.1002/cbdv.202400152 -
Medicine Apr 2024White matter lesions (WMLs) are structural changes in the brain that manifest as demyelination in the central nervous system pathologically. Vasogenic WMLs are the most...
RATIONALE
White matter lesions (WMLs) are structural changes in the brain that manifest as demyelination in the central nervous system pathologically. Vasogenic WMLs are the most prevalent type, primarily associated with advanced age and cerebrovascular risk factors. Conversely, immunogenic WMLs, typified by multiple sclerosis (MS), are more frequently observed in younger patients. It is crucial to distinguish between these 2 etiologies. Furthermore, in cases where multiple individuals exhibit WMLs within 1 family, genetic testing may offer a significant diagnostic perspective.
PATIENT CONCERNS
A 25-year-old male presented to the Department of Neurology with recurrent headaches. He was healthy previously and the neurological examination was negative. Brain magnetic resonance imaging (MRI) showed widespread white matter hyperintensity lesions surrounding the ventricles and subcortical regions on T2-weighted and T2 fluid-attenuated inversion recovery images, mimicking immunogenic disease-MS.
DIAGNOSES
The patient was diagnosed with a patent foramen ovale, which could explain his headache syndrome. Genetic testing unveiled a previously unidentified missense mutation in the SERPINC1 gene in the patient and his father. The specific abnormal laboratory finding was a reduction in antithrombin III activity, and the decrease may serve as the underlying cause for the presence of multiple intracranial WMLs observed in both the patient and his father.
INTERVENTIONS
The patient received percutaneous patent foramen ovale closure surgery and took antiplatelet drug recommended by cardiologists and was followed up for 1 month and 6 months after operation.
OUTCOMES
While the lesions on MRI remain unchanging during follow-up, the patient reported a significant relief in headaches compared to the initial presentation.
LESSONS
This case introduces a novel perspective on the etiology of cerebral WMLs, suggesting that hereditary antithrombin deficiency (ATD) could contribute to altered blood composition and may serve as an underlying cause in certain individuals with asymptomatic WMLs.
Topics: Male; Humans; Adult; White Matter; Foramen Ovale, Patent; Antithrombin III; Antithrombin III Deficiency; Brain; Magnetic Resonance Imaging; Vascular Diseases; Nervous System Diseases; Multiple Sclerosis; Headache; Mutation; Antithrombins
PubMed: 38579030
DOI: 10.1097/MD.0000000000037721 -
Journal of Applied Physiology... May 2024Despite the prognostic effect of physical activity, acute bouts of high-volume endurance exercise can induce cardiac stress and postexercise hypercoagulation associated...
Despite the prognostic effect of physical activity, acute bouts of high-volume endurance exercise can induce cardiac stress and postexercise hypercoagulation associated with increased thrombotic risk. The aim of this study was to explore the effect of high-volume endurance exercise on coagulation and thrombotic activity in recreational cyclists. Thirty-four recreational cyclists completed 4.8 ± 0.3 h of cycling at 45 ± 5% of maximal power output on a bicycle ergometer. Intravenous blood samples were collected preexercise, immediately postexercise, 24 and 48 h postexercise, and analyzed for brain natriuretic peptide (BNP), cardiac troponin (cTn), C-reactive protein (CRP), D-dimer, thrombin-antithrombin (TAT) complex, tissue factor (TF), tissue factor pathway inhibitor (TFPI), and TF-to-TFPI ratio (TF:TFPI). An increase in cTn was observed postexercise ( < 0.001). CRP concentrations were increased at 24 and 48 h postexercise compared with preexercise concentrations ( ≤ 0.001). TF was elevated at 24 h postexercise ( < 0.031) and TFPI was higher immediately postexercise ( < 0.044) compared with all other time points. TF:TFPI was increased at 24 and 48 h postexercise compared with preexercise ( < 0.025). TAT complex was reduced at 48 h postexercise compared with preexercise ( = 0.015), D-dimer was higher immediately postexercise compared with all other time points ( ≤ 0.013). No significant differences were observed in BNP ( > 0.05). High-volume endurance cycling induced markers of cardiac stress among recreational cyclists. However, plasma coagulation and fibrinolytic activity suggest no increase in thrombotic risk after high-volume endurance exercise. In this study, a high-volume endurance exercise protocol induced markers of cardiac stress and altered plasma coagulation and fibrinolytic activity for up to 48 h in recreationally active cyclists. However, analysis of coagulation biomarkers indicates no increase in thrombotic risk when appropriate hydration and rest protocols are implemented.
Topics: Humans; Bicycling; Male; Blood Coagulation; Adult; Thrombosis; Physical Endurance; Thromboplastin; C-Reactive Protein; Fibrin Fibrinogen Degradation Products; Exercise; Natriuretic Peptide, Brain; Young Adult; Lipoproteins; Biomarkers; Antithrombin III; Risk Factors; Peptide Hydrolases
PubMed: 38572538
DOI: 10.1152/japplphysiol.00824.2023 -
Pediatric Blood & Cancer Jun 2024
Topics: Humans; Antithrombin III; Frameshift Mutation; Antithrombin III Deficiency; Heterozygote; Male; Female
PubMed: 38563157
DOI: 10.1002/pbc.30986 -
Thrombosis Journal Mar 2024Thromboembolic complications are well known in the treatment of childhood acute lymphoblastic leukemia. Over the years it has not been possible to reach a consensus on a...
BACKGROUND
Thromboembolic complications are well known in the treatment of childhood acute lymphoblastic leukemia. Over the years it has not been possible to reach a consensus on a possible prophylaxis of thromboembolic events during intensive therapy. Only the administration of enoxaparin was able to achieve evidence in the literature to date.
METHODS
In this retrospective study, 173 childhood leukemia patients were treated over 20 years with a thromboembolic prophylaxis including enoxaparin and AT III during induction therapy with L-asparaginase and cortisone.
RESULTS
We here report the effectiveness of administration of enoxaparin and AT III in childhood leukemia, showing a strikingly low prevalence of deep vein thrombosis (2.9%). Especially in adolescent patients, a particularly great need for AT III was demonstrated.
CONCLUSIONS
We recommend thromboembolic prophylaxis with enoxaparin and AT III substitution during induction/reinduction therapy with L-asparaginase and glucocorticosteroids, especially from adolescence onwards.
PubMed: 38539225
DOI: 10.1186/s12959-024-00602-x -
Clinical and Applied... 2024To investigate the effect of reduced early-pregnancy activated partial thrombin time (APTT), prothrombin time (PT), and international standardized ratio (INR) on the...
To investigate the effect of reduced early-pregnancy activated partial thrombin time (APTT), prothrombin time (PT), and international standardized ratio (INR) on the risk of preeclampsia. A total of 8549 pregnant women with singleton births were included. Early pregnancy APTT, PT, and INR levels, with age, birth, prepregnancy body mass index, fibrinogen (FBG), thrombin time (TT), D-dimer (DD2), antithrombin III (ATIII), fibrin degradation products (FDP) as confounders, generalized linear model of APTT, the relative risk of PT and INR when INR reduction. After adequate adjustment for confounders, the relative risk of preeclampsia was 0.703 for every 1 s increase in plasma PT results in early pregnancy, and for every 0.1 increase in plasma INR results, the relative risk of preeclampsia was 0.767. With a PT less than the P25 quantile (<11 s), the relative risk of preeclampsia was 1.328. The relative risk of preeclampsia at an INR less than the P25 quantile (<0.92) was 1.24. There was no statistical association between APTT on the risk of preeclampsia. The relative risk of preeclampsia is strongly associated with a decrease in PT and INR in early pregnancy. PT and INR in early pregnancy were a potential marker in the risk stratification of preeclampsia. Focusing on reduced PT and INR levels in early pregnancy can help to identify early pregnancies at risk for preeclampsia.
Topics: Humans; Female; Pregnancy; International Normalized Ratio; Pre-Eclampsia; Retrospective Studies; Blood Coagulation Tests; Prothrombin Time; Partial Thromboplastin Time
PubMed: 38529627
DOI: 10.1177/10760296241238015