ABSTRACT
A 28-year-old woman was found to have coagulation factor â § activity (Fâ §â¶C) <1% and von Willebrand factor antigen (VWFâ¶Ag) <1% during routine prenatal examinations. No pathogenic variation was found in the exon region of the VWF gene using next-generation sequencing. The clinical presentation of this patient does not match the clinical characteristics of type â ¢ hemophilia [von Willebrand disease (VWD) ]; therefore, third-generation sequencing technology was used to perform whole-genome sequencing on the patient and her family members. Multiple members of the patient's paternal family carried a heterozygous variant of VPS33B, c.869G>C. The family members carrying this variant all had varying degrees of reduced VWF levels (39% -56% ). Moreover, the proband was detected with the heterozygous variant c.1474dupA in GP1BA. The ACMG and Clinvar databases determined that this variation was associated with platelet-type pseudo VWD. The decrease in VWF levels caused by heterozygous variations in VPS33B in families is the first international report, and no previous studies have reported cases of severe decrease in plasma VWF levels caused by double heterozygous variations in VPS33B and GP1BA.
Subject(s)
Mutation , Vesicular Transport Proteins , von Willebrand Factor , Humans , Female , Adult , von Willebrand Factor/genetics , Vesicular Transport Proteins/genetics , Heterozygote , Pedigree , von Willebrand Diseases/genetics , von Willebrand Diseases/diagnosis , Platelet Glycoprotein GPIb-IX Complex/geneticsABSTRACT
Our aim was to explore possible relationships between serum levels of biomarkers in patients with hand-arm vibration injury in relation to the severity of the vascular, i.e., Raynaud's phenomenon (RP), and neurosensory manifestations, the current exposure level, and the duration of exposure. This study was of case series design and involved 92 patients diagnosed with hand-arm vibration injury. Jonckheere's trend test was used to assess any association between serum levels of biomarkers and RP as well as neurosensory manifestations, graded by the International Consensus Criteria. Generalized linear models with adjustment for possible confounders were also used for associations between serum levels of biomarkers and; (1) severity of RP recorded as the extent of finger blanching calculated with Griffin score, (2) vibration perception thresholds, (3) magnitude of current exposure as [A(8); (m/s2)] value, and (4) the duration of exposure in years. Serum levels of thrombomodulin, von Willebrand factor, calcitonin gene related peptide (CGRP), heat shock protein 27, and caspase-3 were positively associated with severity of RP. Serum levels of CGRP were positively associated with the neurosensory component. No associations with exposure were shown for these biomarkers. For Intercellular adhesion molecule 1 and monocyte chemoattractant protein 1, no associations were found with neither severity nor exposure. Levels of serum biomarkers associated with endothelial injury or dysfunction, inflammation, vasodilation, neuroprotection, and apoptosis were positively associated with the severity of hand-arm vibration injury.
Subject(s)
Biomarkers , Hand-Arm Vibration Syndrome , Raynaud Disease , Vibration , Humans , Raynaud Disease/blood , Raynaud Disease/diagnosis , Biomarkers/blood , Male , Female , Middle Aged , Vibration/adverse effects , Adult , Hand-Arm Vibration Syndrome/blood , Hand-Arm Vibration Syndrome/diagnosis , Severity of Illness Index , von Willebrand Factor/metabolism , von Willebrand Factor/analysis , Calcitonin Gene-Related Peptide/blood , AgedABSTRACT
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening, often immune-mediated disease that affects 2-13 persons per million per year. Hemolytic anemia, thrombocytopenia, and end-organ damage due to the formation of microthrombi are characteristic of TTP. ADAMTS13 is a disintegrin, metalloproteinase, cleaving protein of von Willebrand factor (VWF) that processes the VWF multimers to prevent them from interacting with platelets and, in turn, to microvascular thrombosis. Prompt diagnosis of TTP is critical yet challenging. Thrombotic microangiopathies have similar clinical presentation. Measurement of ADAMTS13 activity helps in the differential diagnosis. Less than 10% ADAMTS13 activity is indicative of TTP. Laboratory ADAMTS13 activity assays include incubating the test plasma with the substrate (full-length VWM multimers) and detection with direct or indirect measurement of the cleavage product. The purpose of this study is to examine the diagnostic potential, advantages, and weaknesses of the ADAMTS13 potency in TTP.
Subject(s)
ADAMTS13 Protein , Purpura, Thrombotic Thrombocytopenic , ADAMTS13 Protein/metabolism , Humans , Purpura, Thrombotic Thrombocytopenic/diagnosis , Purpura, Thrombotic Thrombocytopenic/blood , von Willebrand Factor/metabolismABSTRACT
Introduction: Elevated ambient pollution exposure is potentially linked to thromboembolism. However, the mechanisms by which particulate matter (PM) interferes with the balance of hemostatic system remain unclear. This study investigates PM-mediated hemostatic changes in individuals across unique seasonal variations of ambient pollution. Methods: This prospective study was conducted between February and July 2020 during alterations in ambient pollution in Chiang Mai, Thailand. Blood tests from 30 healthy subjects were assessed at four-week intervals, four times in total. Various coagulation tests, including prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor (vWF), platelet count, and platelet functions, were evaluated. A mixed-effects model was used to analyze the impact of high PM2.5 and PM10 on hemostatic parameters. Results: Thirty male subjects with mean age of 38.9 ± 8.2 years, were included. High levels of PM2.5 and PM10 were significantly associated with PT shortening, with no such effect observed in aPTT. PM2.5 and PM10 values also positively correlated with vWF function, while vWF antigen levels remained unchanged. Soluble P-selectin showed a strong positive association with PM2.5 and PM10 levels. Platelet function analysis revealed no correlation with PM values. Conclusion: Short-term exposure to elevated PM2.5 and PM10 concentrations was linked to shortened PT and enhanced vWF function in healthy individuals. Exploring the impact of these changes on clinically relevant thrombosis is crucial. Additional studies on the pathogenesis of pollution-related thrombosis are warranted for maintaining good health.
Subject(s)
Air Pollution , Blood Platelets , Hemostasis , Particulate Matter , Humans , Particulate Matter/adverse effects , Male , Adult , Hemostasis/drug effects , Thailand , Prospective Studies , Air Pollution/adverse effects , Blood Platelets/drug effects , Air Pollutants/adverse effects , Middle Aged , von Willebrand Factor/metabolism , von Willebrand Factor/analysis , Platelet Count , Environmental Exposure/adverse effects , Seasons , Blood Coagulation TestsABSTRACT
BACKGROUND: Long-haul flights have been associated with a two- to four-fold increased risk of aviation-related thrombosis (ART). Several studies have investigated the extent to which hypoxic hypobaric exposure, dehydration and prolonged immobilisation during air travel induce changes in haemostasis. OBJECTIVE: To investigate the role of high altitude as a risk factor for ART. METHODS: Healthy volunteers aged ≥18 years (N=40), without risk factors for venous thromboembolism, were exposed to an exacerbated altitude of 18 000 feet (5 486 m) for 1 hour. During the flight, the oxygen (O2) levels of the participants, who received supplemental O2, were measured by pulse oximetry and maintained at >92%. Venous blood and urine samples were collected prior to departure and immediately after flying in an unpressurised twin-engine airplane. D-dimer levels, thromboelastography (TEG) parameters, von Willebrand factor (VWF) activity and urine osmolality were measured. RESULTS: The participants were 19 men and 21 women, with a mean (standard deviation) age of 46 (14) years. A significant difference in D-dimer levels, VWF activity, urine osmolality and TEG parameters (reaction (R) time, kinetic (K) time and maximum amplitude (MA)) before and after the 1-hour flight was observed (p<0.001). Urine osmolality correlated positively with VWF activity levels (r=0.469; p<0.002). CONCLUSION: Air travel at high altitude induced a hypercoagulable state in healthy volunteers. Future research should focus on whether thromboprophylaxis can significantly obviate the activation of coagulation in response to high altitude.
Subject(s)
Altitude , Fibrin Fibrinogen Degradation Products , Humans , Male , Female , Middle Aged , Adult , Fibrin Fibrinogen Degradation Products/analysis , Fibrin Fibrinogen Degradation Products/metabolism , Thrombelastography , Risk Factors , von Willebrand Factor/analysis , von Willebrand Factor/metabolism , Thrombosis/prevention & control , Thrombosis/etiology , Healthy Volunteers , Air Travel , OximetryABSTRACT
von Willebrand disease (VWD) is the most common inherited bleeding disorder. The disorder is characterized by excessive mucocutaneous bleeding. The most common bleeding manifestations of this condition include nosebleeds, bruising, bleeding from minor wounds, menorrhagia or postpartum bleeding in women as well as bleeding after surgery. Other less frequent symptoms include gastrointestinal bleeding, haematomas or haemarthroses. VWD pathophysiology is complex and results from defects in von Willebrand factor (VWF) glycoprotein. Quantitative deficiencies are responsible for type 1 VWD with a partial decrease of VWF and type 3 with the complete absence of VWF. Qualitative abnormalities cause type 2 VWD, being further divided into types 2A, 2B, 2M and 2N. Although common, VWD is at risk of misdiagnosis, overdiagnosis and underdiagnosis owing to several factors, including complex diagnosis, variability of bleeding symptoms, presence of external variables (blood groups and other physiological modifiers such as exercise, thyroid hormones, oestrogens, and ageing), and lack of disease awareness among non-specialist health-care providers. Establishing the correct VWD diagnosis requires an array of specialized phenotypic assays and/or molecular genetic testing of the VWF gene. The management of bleeding includes increasing endogenous VWF levels with desmopressin or infusion of exogenous VWF concentrates (plasma-derived or recombinant). Fibrinolytic inhibitors, topical haemostatic agents and hormonal therapies are used as effective adjunctive measures.
Subject(s)
von Willebrand Diseases , von Willebrand Factor , Humans , von Willebrand Diseases/diagnosis , von Willebrand Diseases/physiopathology , von Willebrand Factor/analysis , Deamino Arginine Vasopressin/therapeutic use , Female , Hemostatics/therapeutic use , Hemorrhage/physiopathology , Hemorrhage/etiology , Hemorrhage/diagnosisABSTRACT
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) can potentially cure malignant blood disorders and benign conditions such as haemoglobinopathies and immunologic diseases. However, allo-HSCT is associated with significant complications. The most common and debilitating among them is graft-versus-host disease (GVHD). In GVHD, donor-derived T cells mount an alloimmune response against the recipient. The alloimmune response involves several steps, including recognition of recipient antigens, activation and proliferation of T cells in secondary lymphoid organs, and homing into GVHD-targeted organs. Adhesion molecules on T cells and endothelial cells mediate homing of T cells into lymphoid and non-lymphoid tissues. In this study, we showed that Von Willebrand factor (VWF), an adhesion molecule secreted by activated endothelial cells, plays an important role in mouse models of GVHD. We investigated the effect of the VWF-cleaving protease ADAMTS13 on GVHD. We found that ADAMTS13 reduced the severity of GVHD after bone marrow transplantation from C57BL6 donor to BALB/C recipient mice. A recombinant VWF-A2 domain peptide also reduced GVHD in mice. We showed that ADAMTS13 and recombinant VWF-A2 reduced the binding of T cells to endothelial cells and VWF in vitro, and reduced the number of T cells in lymph nodes, Peyer's patches and GVHD-targeted organs in vivo. We identified LFA-1 (αLß2) as the binding site of VWF on T cells. Our results showed that blocking T-cell homing by ADAMTS13 or VWF-A2 peptide reduced the severity of the GVHD after allo-HSCT, a potentially novel method for treating and preventing GVHD.
Subject(s)
ADAMTS13 Protein , Graft vs Host Disease , Mice, Inbred BALB C , Mice, Inbred C57BL , T-Lymphocytes , von Willebrand Factor , Graft vs Host Disease/etiology , Graft vs Host Disease/immunology , Animals , ADAMTS13 Protein/metabolism , Mice , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , von Willebrand Factor/metabolism , Humans , Transplantation, Homologous , Hematopoietic Stem Cell Transplantation/adverse effects , Disease Models, Animal , Bone Marrow Transplantation , Endothelial Cells/metabolismABSTRACT
OBJECTIVES: To derive systematic review informed, modified Delphi consensus regarding monitoring and replacement of specific coagulation factors during pediatric extracorporeal membrane oxygenation (ECMO) support for the Pediatric ECMO Anticoagulation CollaborativE. DATA SOURCES: A structured literature search was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2020, with an update in May 2021. STUDY SELECTION: Included studies assessed monitoring and replacement of antithrombin, fibrinogen, and von Willebrand factor in pediatric ECMO support. DATA EXTRACTION: Two authors reviewed all citations independently, with conflicts resolved by a third reviewer if required. Twenty-nine references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. A panel of 48 experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. We developed one weak recommendation and four expert consensus statements. CONCLUSIONS: There is insufficient evidence to formulate recommendations on monitoring and replacement of antithrombin, fibrinogen, and von Willebrand factor in pediatric patients on ECMO. Optimal monitoring and parameters for replacement of key hemostasis parameters is largely unknown.
Subject(s)
Antithrombins , Delphi Technique , Extracorporeal Membrane Oxygenation , Fibrinogen , von Willebrand Factor , Extracorporeal Membrane Oxygenation/methods , Humans , Fibrinogen/analysis , Antithrombins/therapeutic use , Child , von Willebrand Factor/analysis , Anticoagulants/administration & dosage , Anticoagulants/therapeutic useABSTRACT
Portal vein thrombosis (PVT) is divided into cirrhotic and non-cirrhotic PVTs. The incidence rate of PVT varies greatly among different clinical stages of cirrhosis, with an overall incidence rate of about 13.92%, and the prevalence of cirrhotic PVT following splenectomy is as high as 60%. The pathogenesis of cirrhotic PVT is still unclear. However, the activation of Janus kinase/signal transduction and activator transcription signaling pathways, the rise in the expression of von Willebrand factor, and the gut microbiota along with its metabolite trimethylamine-N-oxide play an important role in the injury of vascular endothelial cells and the formation of PVT in cirrhosis. Therefore, these could be a new target for cirrhotic PVT prevention and treatment.
Subject(s)
Liver Cirrhosis , Portal Vein , Venous Thrombosis , Humans , Venous Thrombosis/etiology , Venous Thrombosis/prevention & control , Liver Cirrhosis/complications , Signal Transduction , Methylamines/metabolism , Gastrointestinal Microbiome , von Willebrand Factor/metabolism , Janus Kinases/metabolismABSTRACT
Trauma is the leading cause of death in individuals up to 45 years of age. Alterations in platelet function are a critical component of trauma-induced coagulopathy (TIC), yet these changes and the potential resulting dysfunction is incompletely understood. The lack of clinical assays available to explore platelet function in this patient population has hindered detailed understanding of the role of platelets in TIC. The objective of this study was to assess trauma patient ex vivo flow-dependent platelet hemostatic capacity in a microfluidic model. We hypothesized that trauma patients would have flow-regime dependent alterations in platelet function. Blood was collected from trauma patients with level I activations (N = 34) within 60 min of hospital arrival, as well as healthy volunteer controls (N = 10). Samples were perfused through a microfluidic model of injury at venous and arterial shear rates, and a subset of experiments were performed after incubation with fluorescent anti-CD41 to quantify platelets. Complete blood counts were performed as well as plasma-based assays to quantify coagulation times, fibrinogen, and von Willebrand factor (VWF). Exploratory correlation analyses were employed to identify relationships with microfluidic hemostatic parameters. Trauma patients had increased microfluidic bleeding times compared to healthy controls. While trauma patient samples were able to deposit a substantial amount of clot in the model injury site, the platelet contribution to microfluidic hemostasis was attenuated. Trauma patients had largely normal hematology and plasma-based coagulation times, yet had elevated D-Dimer and VWF. Venous microfluidic bleeding time negatively correlated with VWF, D-Dimer, and mean platelet volume (MPV), while arterial microfluidic bleeding time positively correlated with oxygenation. Arterial clot growth rate negatively correlated with red cell count, and positively with mean corpuscular volume (MCV). We observed changes in clot composition in trauma patient samples reflected by significantly diminished platelet contribution, which resulted in reduced hemostatic function in a microfluidic model of vessel injury. We observed a reduction in platelet clot contribution under both venous and arterial flow ex vivo in trauma patient samples. While our population was heterogenous and had relatively mild injury severity, microfluidic hemostatic parameters correlated with different patient-specific data depending on the flow setting, indicating potentially differential mechanistic pathways contributing to platelet hemostatic capacity in the context of TIC. These data were generated with the goal of identifying key features of platelet dysfunction in bleeding trauma patients under conditions of flow and to determine if these features correlate with clinically available metrics, thus providing preliminary surrogate markers of physiological platelet dysfunction to be further studied across larger cohorts. Future studies will continue to explore those relationships and further define mechanisms of TIC and their relationship with patient outcomes.
Subject(s)
Blood Platelets , Hemostasis , Microfluidics , Wounds and Injuries , Humans , Blood Platelets/metabolism , Male , Female , Adult , Wounds and Injuries/blood , Wounds and Injuries/complications , Microfluidics/methods , Middle Aged , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/blood , von Willebrand Factor/metabolism , Fibrinogen/metabolism , Case-Control Studies , Bleeding TimeABSTRACT
Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration-time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration-time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week.
Subject(s)
Factor VIII , Hemophilia A , von Willebrand Factor , Humans , Factor VIII/pharmacokinetics , Factor VIII/administration & dosage , Hemophilia A/drug therapy , Hemophilia A/blood , von Willebrand Factor/pharmacokinetics , von Willebrand Factor/administration & dosage , Models, Biological , Adult , Male , Young Adult , Kinetics , Polyethylene Glycols/pharmacokinetics , Polyethylene Glycols/administration & dosage , AdolescentABSTRACT
Normally, von Willebrand factor (VWF) remains inactive unless its A1A2 domains undergo a shear stress-triggered conformational change. We demonstrated the capacity of a recombinant A2 domain of VWF to bind and to affect fibrin formation, altering the fibrin clot structure. The data indicated that VWF contains an additional binding site for fibrin in the A2 domain that plays a role in the incorporation of VWF to the polymerizing fibrin. This study is to examine the hypothesis that active plasma VWF directly influence fibrin polymerization and the structure of fibrin clots. The study used healthy and type 3 von Willebrand disease (VWD) plasma, purified plasma VWF, fibrin polymerization assays, confocal microscopy and scanning electron microscopy. The exposed A2 domain in active VWF harbors additional binding sites for fibrinogen, and significantly potentiates fibrin formation (Pâ<â0.02). Antibody against the A2 domain of VWF significantly decreased the initial rate of change of fibrin formation (Pâ<â0.002). Clot analyses revealed a significant difference in porosity between normal and type 3 VWD plasma (Pâ<â0.008), further supported by scanning electron microscopy, which demonstrated thicker fibrin fibers in the presence of plasma VWF (Pâ<â0.0003). Confocal immunofluorescence microscopy showed punctate VWF staining along fibrin fibrils, providing visual evidence of the integration of plasma VWF into the fibrin matrix. The study with type 3 VWD plasma supports the hypothesis that plasma VWF directly influences fibrin polymerization and clot structure. In addition, a conformational change in the A1A2 domains exposes a hidden fibrin(ogen) binding site, indicating that plasma VWF determines the fibrin clot structure.
Subject(s)
Fibrin , von Willebrand Factor , von Willebrand Factor/metabolism , Humans , Fibrin/metabolism , Fibrin/ultrastructure , von Willebrand Disease, Type 3/blood , Binding Sites , Microscopy, Electron, Scanning/methodsABSTRACT
BACKGROUND: SARS-CoV-2 is a systemic disease that affects endothelial function and leads to coagulation disorders, increasing the risk of mortality. Blood levels of endothelial biomarkers such as Von Willebrand Factor (VWF), Thrombomodulin or Blood Dendritic Cell Antigen-3 (BDCA3), and uUokinase (uPA) increase in patients with severe disease and can be prognostic indicators for mortality. Therefore, the aim of this study was to determine the effect of VWF, BDCA3, and uPA levels on mortality. METHODS: From May 2020 to January 2021, we studied a prospective cohort of hospitalized adult patients with polymerase chain reaction (PCR)-confirmed COVID-19 with a SaO2 ≤ 93% and a PaO2/FiO2 ratio < 300. In-hospital survival was evaluated from admission to death or to a maximum of 60 days of follow-up with Kaplan-Meier survival curves and Cox proportional hazard models as independent predictor measures of endothelial dysfunction. RESULTS: We recruited a total of 165 subjects (73% men) with a median age of 57.3 ± 12.9 years. The most common comorbidities were obesity (39.7%), hypertension (35.4%) and diabetes (30.3%). Endothelial biomarkers were increased in non-survivors compared to survivors. According to the multivariate Cox proportional hazard model, those with an elevated VWF concentration ≥ 4870 pg/ml had a hazard ratio (HR) of 4.06 (95% CI: 1.32-12.5) compared to those with a lower VWF concentration adjusted for age, cerebrovascular events, enoxaparin dose, lactate dehydrogenase (LDH) level, and bilirubin level. uPA and BDCA3 also increased mortality in patients with levels ≥ 460 pg/ml and ≥ 3600 pg/ml, respectively. CONCLUSION: The risk of mortality in those with elevated levels of endothelial biomarkers was observable in this study.
Subject(s)
Biomarkers , COVID-19 , Thrombomodulin , Urokinase-Type Plasminogen Activator , von Willebrand Factor , Humans , COVID-19/mortality , COVID-19/blood , Male , von Willebrand Factor/metabolism , von Willebrand Factor/analysis , Middle Aged , Female , Biomarkers/blood , Aged , Urokinase-Type Plasminogen Activator/blood , Thrombomodulin/blood , Prospective Studies , Prognosis , SARS-CoV-2 , Adult , Endothelium, Vascular/physiopathology , Hospital Mortality , Proportional Hazards ModelsABSTRACT
Von Willebrand factor (VWF) is a multimer with a variable number of protomers, each of which is a head-to-head dimer of two multi-domain monomers. VWF responds to shear through the unfolding and extension of distinct domains, thereby mediating platelet adhesion and aggregation to the injured blood vessel wall. VWF's C1-6 segment uncoils and then the A2 domain unfolds and extends in a hierarchical and sequential manner. However, it is unclear whether there is any reservoir of further extensibility. Here, we explored the presence of cryptic extensibility in VWF by nanodissecting individual, pre-stretched multimers with atomic force microscopy (AFM). The AFM cantilever tip was pressed into the surface and moved in a direction perpendicular to the VWF axis. It was possible to pull out protein loops from VWF, which resulted in a mean contour length gain of 217 nm. In some cases, the loop became cleaved, and a gap was present along the contour. Frequently, small nodules appeared in the loops, indicating that parts of the nanodissected VWF segment remained folded. After analyzing the nodal structure, we conclude that the cryptic extensibility lies within the C1-6 and A1-3 regions. Cryptic extensibility may play a role in maintaining VWF's functionality in extreme shear conditions.
Subject(s)
Microscopy, Atomic Force , von Willebrand Factor , von Willebrand Factor/chemistry , von Willebrand Factor/metabolism , Humans , Protein Multimerization , Protein DomainsABSTRACT
OBJECTIVE: To review relevant literature regarding the role of metformin in angiogenesis among diabetic patients. METHODS: The systematic review and meta-analysis conducted from May to September 2022, and comprised search on Medline, ScienceDirect, ProQuest, Web of Science, EBSCOhost and Cochrane Library databases. The studies included were published in the English language and were human studies having angiogenesis endothelial markers as the outcomes of interest among patients of type 2 diabetes mellitus undergoing metformin therapy. Endothelial markers, including vascular endothelial growth factor, von-Willebrand-factor, plasminogen activator inhibitor-1, soluble vascular adhesion molecule- 1, intercellular adhesion molecule-1, soluble endothelialselectin, tissue plasminogen activator, urinary albumin excretion, platelet endothelial cell adhesion molecule-1 and thrombin-activatable fibrinolysis inhibitor, were assessed as angiogenesis outcomes. Data was statistically analysed using Review Manager 5.4. RESULTS: Of the 413 studies identified, 8(1.9%) were included; 5(62.5%) randomised control trials, 2(25.0%) cross-sectional, and 1(12.5%) cohort studies, with overall 1199 patients. Among the outcomes, von-Willebrandfactor (p=0.01), soluble vascular adhesion molecule-1 (p<0.00001), intercellular adhesion molecule-1 (p=0.0003), soluble endothelial-selectin (p=0.007), and tissue plasminogen activator (p<0.00001) showed significantly lower levels after metformin treatment using the random effect methods. CONCLUSIONS: Metformin was found to have an additional effect of endothelial function improvement.
Subject(s)
Diabetes Mellitus, Type 2 , Hypoglycemic Agents , Metformin , Humans , Metformin/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Plasminogen Activator Inhibitor 1/blood , Plasminogen Activator Inhibitor 1/metabolism , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/blood , E-Selectin/blood , Vascular Cell Adhesion Molecule-1/blood , Tissue Plasminogen Activator , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/metabolism , von Willebrand Factor/metabolism , AngiogenesisABSTRACT
OBJECTIVES: Acute pancreatitis (AP) is an inflammatory disease of the pancreas, and the prognosis of severe AP (SAP) is poor. The study aimed to identify promising biomarkers for predicting the occurrence and survival outcome of SAP patients. MATERIALS AND METHODS: Two hundred and forty AP patients were retrospectively recruited, in which 72 cases with SAP. Blood test was done for collection of laboratory indicators. After treatment, the mortality of patients was recorded. RESULTS: Patients in the SAP group had higher intensive care unit admissions and longer hospital stays (p < .001). Among laboratory parameters, significantly high values of C-reactive protein (CRP), triglycerides and glucose (TyG) index, Von willebrand factor antigen (vWF:Ag) and D-dimer were found in SAP groups relative to non-SAP ones. Receiver operating characteristic curve indicated the good performance of CRP, TyG index, vWF:Ag and D-dimer in SAP diagnosis. Among all SAP cases, 51 survived while 21 died. TyG index (odds ratio [OR] = 6.914, 95% confidence interval [CI] = 1.193-40.068, p = .028), vWF:Ag (OR = 7.441, 95% CI = 1.236-244.815, p = .028), and D-dimer (OR = 7.987, 95% CI = 1.251-50.997, p = .028) were significantly related to survival outcome of SAP patients by multiple logistic regression analysis. Both TyG index and vWF showed favorable efficiency in predicting overall prognosis. The area under the curve for the multivariate model (PRE = -35.908 + 2.764 × TyG + 0.021 × vWF:Ag) was 0.909 which was greater than 0.9, indicating its excellent performance in prognosis prediction. CONCLUSION: CRP, TyG index, vWF:Ag, and D-dimer values on admission may be potential clinical predictors of the development of SAP. Moreover, TyG index and vWF:Ag may be helpful to predict survival outcome.