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1.
Artigo em Inglês | MEDLINE | ID: mdl-38457608

RESUMO

OBJECTIVE: Individuals positive for anti-cyclic-peptide-antibodies (anti-CCP) and musculoskeletal complaints (MSK-C) are at risk for developing rheumatoid arthritis (RA). In this study we aimed to investigate factors involved in arthritis progression. METHODS: Anti-CCP2-positive individuals with MSK-C referred to a rheumatologist were recruited. Individuals lacked arthritis at clinical and ultrasound examination and were followed for ≥three years or until clinical arthritis diagnosis. Blood samples from inclusion were analyzed for; nine anti-citrullinated-protein-antibody (ACPA) reactivities (citrullinated α-1-enolase, fibrinogen, filaggrin, histone, vimentin and tenascin peptides); 92 inflammation-associated proteins; and HLA-shared epitope alleles. Cox regression was applied to the data to identify independent predictors in a model. RESULTS: 267 individuals were included with median follow up of 49 months (IQR: 22-60). 101 (38%) developed arthritis after median 14 months (IQR: 6-27). The analysis identified that presence of at least one ACPA reactivity (HR 8.0, 95% CI 2.9-22), ultrasound detected tenosynovitis (HR 3.4, 95% CI 2.0-6.0), IL6 levels (HR 1.5, 95% CI 1.2-1.8) and IL15-Rα levels (HR 0.6, 95% CI 0.4-0.9) are significant independent predictors for arthritis progression in a prediction model (Harrell's C 0.76 [SE 0.02], AUC 0.82 [95% CI 0.76-0.89], cross-validated AUC 0.70 [95% CI 0.56-0.85]). CONCLUSION: We propose a high-Risk-RA phase characterized by presence of ACPA reactivity, tenosynovitis, IL6, and IL15-Rα and suggest that these factors need to be further investigated for their biological effects and clinical values, to identify individuals at particular low risk and high risk for arthritis progression.

2.
Forensic Sci Int Genet ; 71: 103033, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38522394

RESUMO

In forensic DNA analysis, evidence sampling stands as a pivotal step setting the ground for the quality of the forensic profiling. The collection of touch DNA from objects, when guidelines are scarce or absent, is usually governed by ad hoc decisions based on the available case circumstances. In our laboratory, in the context of illicit drug-related crimes, similar objects are frequently encountered, offering an opportunity for the standardization of evidence treatment. This study aims to develop an effective method for sampling touch DNA from knots on plastic bags. We examine both the exposed and hidden areas of knots, considering the latter as "protected" zones less likely to accumulate biological material during subsequent handling. The study contrasts a single sample method (whole knot surface sampling, Method 1) with dual-sample methods that separate exterior (exposed) and interior (hidden) surfaces of the knot. Notably, our study consistently reveals higher DNA yields from exterior surfaces of the knots as opposed to interior samples. Importantly, our findings demonstrate that utilizing a single sample may produce DNA profiles that are not interpretable, while employing a dual-sample approach may allow for the differentiation between the genetic contributions of the person who tied the knot, the packer, from the person who held the package, the holder. We have refined the dual-sample method to reduce holder DNA in the interior sample while maintaining it on the exterior, also allowing the packer's DNA to be detected on both surfaces. We explore four dual-sample collection methods. Method 2 involves taking the first sample from the exterior and the second from the interior of an untied knot. Method 3 visually differentiates between the original exposed and hidden surfaces for precise sampling. Method 4 employs tools to open the knot for interior sampling. Method 5 uses Diamond dye to highlight cell-free DNA on both surfaces before sampling. In conclusion, this study not only clarifies the complex dynamics of touch DNA transfer and collection on plastic bag knots, but also offers insights into standardizing evidence collection in similar cases.


Assuntos
Impressões Digitais de DNA , DNA , Manejo de Espécimes , Tato , Humanos , Impressões Digitais de DNA/métodos , Manejo de Espécimes/métodos , DNA/genética , Repetições de Microssatélites , Plásticos , Reação em Cadeia da Polimerase
3.
Int J Lab Hematol ; 46(1): 42-49, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37795549

RESUMO

INTRODUCTION: Increased levels of extracellular vesicles (EVs) are associated with haemostatic disturbances in various clinical settings. However, their role in COVID-19 patients is still not fully clear. In the present study we investigated EVs in plasma from patients with COVID-19 and neurological symptoms in relation to the activation of coagulation. METHODS: Nineteen COVID-19 patients with neurological symptoms and twenty-three aged-matched healthy individuals were included. Global coagulation assays were performed and levels of EVs were determined by flow-cytometry in plasma and cerebrospinal fluid (CSF). RESULTS: A procoagulant state characterized by significantly increased overall coagulation- (OCP) and overall haemostatic potential (OHP), diminished overall fibrinolytic potential (OFP) together with a denser fibrin structure was found in patients with COVID-19. Flow cytometry revealed elevated levels of plasma circulating EVs derived from neutrophils (MPO+) and platelets (CD61+), as well as EVs expressing phosphatidylserine (PS+) and complement component C5b-9 (TCC+) in patients with COVID-19 compared with controls. The concentrations of PS+, CD61+ and TCC+ EVs were positively correlated with OCP and OHP in COVID-19 patients. Moreover, we identified CD61+, MPO+ and endothelial cell-derived EVs, as well as EVs exposing PS and TCC in the CSF of patients suffering from neurological symptoms during COVID-19. CONCLUSION: The unique finding in this study was the presence of EVs in the CSF of COVID-19 patients with neurologic manifestations as well as higher expression of complement protein on circulating plasma EVs. EVs may indicate blood-brain barrier damage during SARS-COV-2 infection.


Assuntos
COVID-19 , Vesículas Extracelulares , Hemostáticos , Humanos , Idoso , SARS-CoV-2 , Coagulação Sanguínea
4.
Acta Chim Slov ; 70(4): 634-641, 2023 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-38124634

RESUMO

Benzodiazepines and their derivatives belong to a category of new psychoactive substances that have been introduced into the continually expanding illicit market. However, there is a notable absence of available pharmacological data for these substances. To gain a deeper understanding of their pharmacology, we employed the Monte Carlo optimization conformation-independent method as a tool for developing QSAR models. These models were built using optimal molecular descriptors derived from both SMILES notation and molecular graph representations. The resulting QSAR model demonstrated robustness and a high degree of predictability, proving to be very reliable. Moreover, we were able to identify specific molecular fragments that exerted both positive and negative effects on binding activity. This discovery paves the way for the swift prediction of binding activity for emerging benzodiazepines, offering a faster and more cost-effective alternative to traditional in vitro/in vivo analyses.


Assuntos
Benzodiazepinas , Receptores de GABA-A , Benzodiazepinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Ligação Proteica , Método de Monte Carlo
5.
Front Med (Lausanne) ; 10: 1240325, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37915326

RESUMO

Objectives: To study circulating myeloperoxidase (MPO)-positive extracellular vesicles (MPO+EVs) exposing citrullinated histone-3 (H3Cit), tissue factor (TF), and plasminogen (Plg) in association to thrombin generation in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). Methods: We have involved well-characterized patients with AAV together with population-based controls. Flow cytometry was used to assess the levels of MPO+EVs in citrated plasma. MPO+EVs were phenotyped by anti-MPO-antibodies together with anti-CD142 (anti-TF), anti-H3Cit, and anti-Plg antibodies. A modified Calibrated Automated Thrombogram (CAT) assay was utilized to measure thrombin generation in plasma initiated by EVs-enriched pellets. The activity of AAV was evaluated with the Birmingham Vasculitis Activity Score (BVAS). Results: This study comprised 46 AAV patients, 23 in the active stage of the disease and 23 in remission, as well as 23 age- and sex matched population-based controls. Augmented levels of all investigated MPO+ EVs were found in active AAV patients in comparison to the subgroup of patients in remission and controls. Thrombin generation, measured by endogenous thrombin potential (ETP) and peak of thrombin formation, was higher in plasma when triggered by EVs-enriched pellet from AAV patients. ETP and peak were associated with the levels of MPO+TF+ and MPO+H3Cit+ EVs. Additionally, MPO+TF+ EVs correlated with the disease activity evaluated with BVAS. Conclusion: Augmented thrombin generation is found in AAV patients regardless of disease activity and is associated with higher exposure of TF and H3Cit on MPO+EVs. This may contribute to the increased risk of thrombosis seen in AAV patients.

6.
Artigo em Inglês | MEDLINE | ID: mdl-37822066

RESUMO

BACKGROUND: Some variations of the cerebral arterial circle (CAC) are associated with an increased risk for the development of various pathological conditions. This paper aimed to determine the prevalence of hypoplastic arteries of CAC and to emphasize the limited possibility of their visualization by computed tomography angiography (CTA). MATERIALS AND METHODS: The research was performed on 400 adult cadavers by macro- and microdissection of the cerebral arteries. Each case was photographed and the diameter of the arteries was measured digitally, by analyzing photographs of the bases of the brain in the ImageJ program. RESULTS: The largest prevalence of artery diameter <1mm (<0.6mm) in CAC had the posterior communicating artery (PCoA). PCoA on the left side was hypoplastic in 44.9% (11.4%) of cases, while the same artery on the right side was hypoplastic in 44.3% (6.6%) of cases. The posterior cerebral artery was hypoplastic on the left side in 3% (0.6%) and on the right side in 4.2% (0.6%) of cases. The anterior cerebral artery had a hypoplastic caliber only on the right side in 2.4% (0.6%) of the cases, while the internal carotid arteries did not have a diameter <1mm in any case. The anterior communicating artery showed the greatest variability in morphology. Studies on CTA describe the occurrence of aplasia in a statistically significantly higher percentage, and the occurrence of hypoplastic arteries in a statistically significantly lower percentage compared to studies on cadavers. CONCLUSIONS: Due to significant differences between cadaveric and radiological studies, it is necessary to analyze their results regarding arterial hypoplasia and aplasia separately. A diameter of less than 1 mm has been suggested as a criterion for arterial hypoplasia.

8.
Vaccines (Basel) ; 10(12)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36560456

RESUMO

Acute hemorrhagic encephalomyelitis (AHEM) is a rare hyperacute form of acute disseminated encephalomyelitis (ADEM). The disease is characterized by fulminant inflammation and demyelination in the brain and spinal cord and is often preceded by an infection or vaccination. This case report presents a 53-year-old male with rheumatoid arthritis and ongoing treatment with methotrexate and etanercept who developed fatal AHEM following the second dose of the COVID-19 vaccine. The disease course was complicated by multiorgan thromboembolic disease and the presence of high/moderate levels of cardiolipin IgG antibodies and anti-beta-2 glycoprotein 1 IgG antibodies suggesting a possible antiphospholipid syndrome. Treatment with immunosuppressive therapies failed to improve the course. The report comprises comprehensive clinical, neuroimaging, and neuropathological findings. The case highlights diagnostic challenges in a patient with several preceding risk factors, including autoimmune disease, immunotherapy, and vaccination, with possible pathophysiological implications. The temporal association with the COVID-19 vaccination may suggest possible causality although evidence cannot be ascertained. Reporting possible adverse events following COVID-19 vaccination is important to identify at-risk populations and to accomplish control of the current pandemic.

10.
J Rheumatol ; 49(6): 598-606, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35169064

RESUMO

OBJECTIVE: To assess thrombin generation, fibrin formation, and structure together with the fibrinolytic status in patients with systemic sclerosis (SSc) in relation to the occurrence of digital ulcers (DUs) during the course of disease. METHODS: We studied variables of endothelial dysfunction, thrombin generation, overall hemostatic potential, and fibrin clot turbidity in plasma from 58 patients with SSc (39 with DU history and 19 DU-naïve) and 46 matched healthy controls (HCs). Fibrin structure was visualized using scanning electron microscopy (SEM). Finally, 39 patients with a history of DUs were followed for 1.5 years and the predictive value of all investigated markers for new DU onset was explored. RESULTS: Significantly enhanced endogenous thrombin potential (ETP) and prolonged clot lysis time (CLT) were found in patients with DUs compared to HCs. CLT was prolonged in patients with DUs compared to those without, showing good validity in identifying DUs with an area under the curve of 0.7 (95% CI 0.6-0.8). The levels of ETP and intercellular adhesion molecule 1 were independently associated with CLT. Over the follow-up period, 20 patients developed new DUs. CLT was prolonged (P < 0.001) in patients with new DU episodes, especially those with recurrent DUs. Regression analysis showed that the Raynaud phenomenon visual analog scale and CLT were predictors of new DUs (OR 1.1, 95% CI 1.0-1.1 and OR 1.2, 95% CI 1.1-1.3, respectively). SEM confirmed denser fibrin clots in patients with new DUs. CONCLUSION: Our results suggest that impaired fibrinolysis might have an emerging role in underlying digital vasculopathy and its progression in SSc.


Assuntos
Escleroderma Sistêmico , Úlcera Cutânea , Trombose , Fibrina , Tempo de Lise do Coágulo de Fibrina , Fibrinólise , Humanos , Escleroderma Sistêmico/complicações , Úlcera Cutânea/complicações , Trombina , Úlcera
11.
Front Med (Lausanne) ; 8: 761453, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34805227

RESUMO

Background: Pre-eclampsia (P-EC) is associated with systemic inflammation, endothelial dysfunction and hypercoagulability. The role of extracellular vesicles (EVs) in coagulation disturbances affecting the development and severity of P-EC remains elusive. We aimed to evaluate the concentration of EVs expressing phosphatidylserine (PS) and specific markers in relation to the thrombin and fibrin formation as well as fibrin clot properties, in pregnant women with P-EC in comparison to healthy pregnant women of similar gestational age. Methods: Blood samples of 30 pregnant women diagnosed with P-EC were collected on the morning following admission to hospital and after delivery (mean duration 5 days). The concentration of the PS-exposing EVs (PS+ EVs) from platelets (CD42a+, endothelial cells (CD62E+), and PS+ EVs expressing tissue factor (TF) and vascular cell adhesion molecule 1 (VCAM-1) were measured by flow cytometry. Further phenotyping of EVs also included expression of PlGF. Markers of maternal haemostasis were correlated with EVs concentration in plasma. Results: Preeclamptic pregnancy was associated with significantly higher plasma levels of PS+ CD42a+ EVs and PS+ VCAM-1+ EVs in comparison with normotensive pregnancy. P-EC patients after delivery had markedly elevated concentration of PS+ CD42a+ EVs, CD62E+ EVs, TF+ EVs, and VCAM-1+ EVs compared to those before delivery. Inverse correlation was observed between EVs concentrations (PS+, PS+ TF+, and PlGF+) and parameters of overall haemostatic potential (OHP) and fibrin formation, while PS+ VCAM-1+ EVs directly correlated with FVIII activity in plasma. Conclusion: Increased levels of PS+ EVs subpopulations in P-EC and their association with global haemostatic parameters, as well as with fibrin clot properties may suggest EVs involvement in intravascular fibrin deposition leading to subsequent microcirculation disorders.

12.
Front Immunol ; 12: 718845, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394126

RESUMO

This study sought to identify different subpopulations of extracellular vesicles (EVs) in plasma from female patients with established rheumatoid arthritis (RA) in relation to the activation of coagulation and fibrin formation in these patients. Forty women were included in the study, 20 patients and 20 age-matched healthy controls. The mean disease duration in patients was 13.0 (5.0-25.0) years, with medium to high disease activity despite ongoing treatment with low-dose prednisolone and methotrexate. There were no differences between the investigated groups regarding the presence of traditional cardiovascular risk factors. The concentration of phosphatidylserine-positive (PS+) EVs; platelet (CD42a+), leucocyte (CD45+), monocyte (CD14+), and endothelial (CD144+)-derived EVs; and EVs-expressing tissue factor (CD142+), P-selectin (CD62P+), and E-selectin (CD62E+) were determined by flow cytometry analysis. Overall hemostasis potential (OHP) was assessed to follow the hemostatic disturbances, including the parameters for overall coagulation potential (OCP) and overall fibrinolytic potential (OFP). Fibrin clot turbidity was measured together with clot lysis time, and scanning electron microscopy was performed. Increased concentrations of PS+, CD42a+, CD142+, CD45+, CD14+, and CD62P+ EVs were found in plasma from patients with RA compared to healthy controls, and the concentrations of PS+, CD42a+, CD14+, and CD62P+ EVs were positively correlated with the inflammatory parameters in RA patients. Positive correlations were also found between the levels of PS+ and CD42a+ EVs and OCP as well as between the levels of PS+, CD42a+, and CD62P+EVs and OHP. The levels of PS+, CD42a+, CD14+, CD62P+, and CD62E+ EVs were negatively correlated with OFP. Elevated levels of circulating EVs of different cell origins were found in patients with established RA, in relation to the inflammatory burden and coagulation activation in the disease.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Biomarcadores , Coagulação Sanguínea , Vesículas Extracelulares/metabolismo , Expressão Gênica , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Testes de Coagulação Sanguínea , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Fibrina/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/patologia
13.
Semin Thromb Hemost ; 47(5): 506-511, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33878780

RESUMO

The pathogenesis of the antiphospholipid syndrome (APS) is complex and involves the persistent presence of antiphospholipid antibodies (aPL) in the bloodstream causing a prothrombotic condition. aPL induce excessive activation of the endothelium, monocytes, and platelets in consort with aberrations in hemostasis/clotting, fibrinolytic system, and complement activation. Impaired fibrinolysis has been found in APS patients with thrombotic as well as obstetric manifestations. Increased levels of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor, together with the presence of aPL against annexin-2, tissue-type plasminogen activator, and plasminogen contribute to the compromised fibrinolytic activity in these patients. Furthermore, unfavorably altered fibrin morphology, less amenable to fibrinolysis, has been proposed as a novel prothrombotic mechanism in APS. This review aims to summarize the present knowledge of the mechanisms involved in impaired fibrinolysis in APS patients. We also present a case from clinical practice as an illustration of fibrinolysis impairment in APS patients from a real-life setting.


Assuntos
Síndrome Antifosfolipídica , Anticorpos Antifosfolipídeos , Coagulação Sanguínea , Feminino , Fibrina , Fibrinólise , Humanos , Gravidez
14.
Oxid Med Cell Longev ; 2021: 9458587, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33505593

RESUMO

Although oxidative stress is considered to be one of the key pathogenic factors in rheumatoid arthritis (RA), there is insufficient knowledge regarding the impact of menopause on redox status in this population. Thus, this study is aimed at assessing the influence of menopause within healthy women and within RA patients as well as the impact of RA in premenopausal and postmenopausal women on redox status, with special reference to bone mineral density (BMD). A total of 90 women were included in the study, 42 with RA and 48 age-matched healthy controls. They were divided into subgroups according to the presence of menopause. Following oxidative stress parameters were measured spectrophotometrically: index of lipid peroxidation (measured as TBARS), nitrites (NO2 -), superoxide anion radical (O2 -), hydrogen peroxide (H2O2), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH). BMD was assessed by using a dual-energy X-ray absorptiometry scanner. Comorbidities and drug history were recorded. The levels of H2O2 and TBARS were elevated in patients with RA, while NO2 - and O2 - increased in healthy women, both in premenopausal and postmenopausal groups. SOD activity decreased in postmenopausal RA patients. BMD was reduced in postmenopausal RA women. There was a correlation between NO2 - and O2 - with Health Assessment Questionnaire (HAQ) index in RA patients. Given that postmenopausal state was associated with elevated oxidative stress within healthy women and that menopausal state did not affect redox homeostasis within RA patients, but the redox homeostasis was altered in both RA groups compared to healthy women, it can be presumed that impaired redox status in RA occurred due to presence of the disease, irrespective of age. Moreover, menopause attenuates BMD reduction in women with RA. These results may indicate the need for therapeutic use of antioxidants in the form of supplements in women with RA, regardless of age.


Assuntos
Artrite Reumatoide/patologia , Densidade Óssea , Inflamação/complicações , Menopausa , Osteoporose Pós-Menopausa/patologia , Artrite Reumatoide/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Peroxidação de Lipídeos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/etiologia , Oxirredução , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
15.
Thromb Haemost ; 121(10): 1299-1309, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33412597

RESUMO

BACKGROUND: Low levels of total C4b-binding protein (C4BPt), a circulating inhibitor of the classical/lectin complement pathways, were observed in patients with antiphospholipid antibodies (aPLs) and during warfarin treatment. OBJECTIVES: To investigate the associations between aPL and C4BPt in patients with persistently positive (++) aPL, with/without clinical manifestations and systemic lupus erythematosus (SLE), and in controls. Furthermore, we explored the impact of anticoagulation on C4BPt and in relation to complement activation. METHODS: In a cross-sectional design we investigated defined subgroups: primary (p) antiphospholipid syndrome (APS, N = 67), aPL++ individuals without clinical manifestations (aPL carriers, N = 15), SLE-aPL++ (N = 118, among them, secondary [s] APS, N = 56), aPL negative (-) SLE (SLE-aPL-, N = 291), and 322 controls. Clinical characteristics, including treatment, were tabulated. C4BPt was determined with a magnetic bead method. Complement proteins (C1q, C2, C3, C4, C3a, C3dg, sC5b-9, factor I [FI]) were measured. A mediation analysis was performed to decompose the total effect of aPL++ on C4BPt into the direct and indirect effects of aPL++ through warfarin. RESULTS: Overall, C4BPt is 20% decreased in aPL++ patients, regardless of SLE, APS, clinical manifestations, and aPL profile. C4BPt levels associate positively with complement proteins C1q, C2, C3, and C4, and negatively with complement activation product C3dg. In the SLE group, warfarin treatment contributes to approximately half of the C4BPt reduction (9%) CONCLUSION: Both aPLs and warfarin are associated with C4BPt reduction. Complement activation in aPL++ patients may partly be explained by impaired inhibition through depressed C4BPt levels. Further studies are needed to understand the clinical implications.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Proteína de Ligação ao Complemento C4b/metabolismo , Varfarina/uso terapêutico , Adulto , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Regulação para Baixo , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade
16.
Rheumatol Adv Pract ; 4(2): rkaa056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33215056

RESUMO

OBJECTIVES: We investigated the incidence and potential underlying risk factors of venous thromboembolism (VTE) in patients with AAV. We assessed haemostatic disturbances and factors that might contribute to the risk of development of VTE. METHODS: ANCA-positive AAV patients (n = 187) were included. Previously identified risk factors for VTE and current medication were retrieved from the medical records. We assessed haemostasis using different methods [endogenous thrombin potential (ETP), overall haemostatic potential (OHP), overall coagulation potential (OCP) and overall fibrinolysis potential (OFP)] in patients with active AAV (n = 19), inactive AAV (n = 15) and healthy controls (n = 15). RESULTS: Twenty-eight VTEs occurred in 24 patients over a total follow-up time of 1020 person-years. A majority of VTEs occurred within the first year after diagnosis. Old age (P < 0.01), ongoing prednisolone treatment and recent rituximab administration were more common in the VTE group (P < 0.05 for all). ETP and OHP were significantly increased and OFP significantly decreased in plasma from active compared with inactive AAV patients (P < 0.05, P < 0.01 and P < 0.05, respectively) and healthy controls (P < 0.001). We could not confirm previously reported risk factors for VTE development. CONCLUSION: A high prevalence of VTE in AAV patients was seen within the first year after diagnosis, suggesting that disease activity contributes to development of VTE. Old age and concurrent treatment should also be taken into account when estimating VTE risk. The results also indicate disturbances in the haemostatic balance towards pro-thrombotic conditions in AAV patients, where ETP and OHP might be useful markers for identifying patients at high risk.

17.
Tissue Cell ; 66: 101389, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32933712

RESUMO

The aim of this research is to perform an analysis of the epineurial and endoneurial blood vessels in relation to aging. The research is conducted on samples of the human sciatic nerve of 12 case (age from 27 to 89). The histological sections are stained by streptavidin-biotin method of detecting the presence of Type IV collagen. After morphometric analysis the following stereological parameters have been calculated: the number of blood vessels per unit of area, the volume density of the blood vessels and the surface density of the blood vessels of the epineurium and endoneurium. An additional diameter measurement is performed for the endoneural blood vessels. In order to perform a more detailed analysis, the cases were classified into three age groups, the first (27-48 years), the second (49-70 years) and, the third (over 70 years). The bivariate correlation analysis showed that the number of blood vessels of the endoneurium, their volume and surface densities in relation to age produced a statistically significant positive correlation. One Way ANOVA test demonstrated a statistically significant increase in the number of endoneurial blood vessels in the age group III when compared the age group I and, in addition, it showed a significant decrease in the diameter of the age group II when compared to the age group I. Paired t - test shows a statistically significant higher number of endoneurial blood vessels in relation to the epineurial, namely, in the age group III. The volume and surface density of the epineurial blood vessels is significantly higher than the endoneurial in both the I and II age group. Age brings about significant changes of the endoneurial vascular network of the sciatic nerve due to the increase in density of the endoneurial blood vessels, their volume and surface densities. Consequently, in the cases older than 70 years, the number of endoneurial blood vessels significantly exceeds the number of epineurial blood vessels.


Assuntos
Envelhecimento/fisiologia , Vasos Sanguíneos/anatomia & histologia , Nervo Isquiático/anatomia & histologia , Nervo Isquiático/irrigação sanguínea , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
TH Open ; 4(3): e178-e188, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32844145

RESUMO

Introduction For acute venous thromboembolism (VTE), a biomarker with higher specificity than D-dimer would be of great clinical use. Thrombin generation and overall hemostatic potential (OHP) reflect the hemostatic balance by globally assessing multiple coagulation factors and inhibitors. These tests discriminate between healthy controls and patients with a prothrombotic tendency but have yet to be established as clinical biomarkers of VTE. Objective This study compares endogenous thrombin potential (ETP) and OHP to D-dimer and fibrin monomers (FM) in outpatients with suspected VTE. Methods A cross-sectional diagnostic study where 954 patients with suspected pulmonary embolism or deep venous thrombosis were recruited consecutively from the medical emergency department at Karolinska University Hospital. D-dimer, FM, OHP, and ETP were analyzed in a subpopulation of 60 patients with VTE and 98 matched controls without VTE. VTE was verified either by ultrasonography or computed tomography and clinical data were collected from medical records. Results Compared with healthy controls, both VTE and non-VTE patients displayed prothrombotic profiles in OHP and ETP. D-dimer, FM, ETP area under the curve (AUC), and ETP T lag were significantly different between patients with VTE and non-VTE. The largest receiver-operating characteristic AUCs for discrimination between VTE and non-VTE, were found in D-dimer with 0.94, FM 0.77, and ETP AUC 0.65. No useful cutoff could be identified for the ETP or the OHP assay. Conclusion Compared with D-dimer, neither ETP nor OHP were clinically viable biomarkers of acute venous thrombosis. The data indicated that a large portion of the emergency patients with suspected VTE were in a prothrombotic state.

19.
TH Open ; 4(2): e94-e103, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32704613

RESUMO

Development of inhibitors to factor VIII (FVIII) occurs in approximately 30% of severe hemophilia A (HA) patients. These patients are treated with bypassing agents (activated prothrombin complex concentrate [aPCC] and recombinant activated FVII-rFVIIa). Recently, a bispecific FIX/FIXa- and FX/FXa-directed antibody (emicizumab) has been approved for the treatment of HA patients with inhibitors. However, the data from clinical studies imply that coadministration of emicizumab and bypassing agents, especially aPCC, could have a thrombotic effect. This study was aimed to address the question of potential hypercoagulability of emicizumab and bypassing agents' coadministration, we have investigated fibrin clot formation and structure in the in vitro model of severe HA after adding sequence-identical analogue (SIA) of emicizumab and bypassing agents. Combined overall hemostasis potential (OHP) and fibrin clot turbidity assay was performed in FVIII-deficient plasma after addition of different concentrations of SIA, rFVIIa, and aPCC. Pooled normal plasma was used as control. The fibrin clots were analyzed by scanning electron microscopy (SEM). OHP and turbidity parameters improved with the addition of aPCC, while therapeutic concentrations of rFVIIa did not show substantial improvement. SIA alone and in combination with rFVIIa or low aPCC concentration improved OHP and turbidity parameters and stabilized fibrin network, while in combination with higher concentrations of aPCC expressed hypercoagulable pattern and generated denser clots. Our in vitro model suggests that combination of SIA and aPCC could potentially be prothrombotic, due to hypercoagulable changes in fibrin clot turbidity and morphology. Additionally, combination of SIA and rFVIIa leads to the formation of stable clots similar to normal fibrin clots.

20.
Sci Rep ; 10(1): 7871, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398812

RESUMO

Circulating microparticles (MPs) are procoagulant due to the surface containing phosphatidylserine (PS), which facilitates coagulation. We investigated if MPs improve hemostasis in HA plasma models. MPs isolated from pooled normal human plasma were added to severe, moderate and mild HA plasma models (0%, 2.5%, 20% FVIII). The MPs' effect on hemostasis was evaluated by calibrated automated thrombogram (CAT) and overall hemostasis potential (OHP) assays, while fibrin structure was imaged by standard confocal, stimulated emission depletion (STED) microscopy and scanning electron microscopy (SEM). MPs partially restored thrombin generation and fibrin formation in all HA plasma models. The procoagulant effect of MPs requires PS exposure, to a less extent of contact pathway activation, but not tissue factor exposure or in vitro stimulation of MPs. MPs partially normalized the fibrin structure, and using super-resolution STED, MPs attached to fibrin were clearly resolved. In summary, our results demonstrate that PS positive MPs could improve hemostasis in HA plasma models.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Fator VIII/análise , Hemofilia A/sangue , Hemostasia , Fosfatidilserinas/metabolismo , Coagulação Sanguínea , Micropartículas Derivadas de Células/ultraestrutura , Fibrina/metabolismo , Humanos , Microscopia Confocal , Microscopia Eletrônica de Varredura , Trombina/metabolismo , Tromboplastina/metabolismo
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