plug formation
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2022 ◽  
Vol 934 ◽  
Author(s):  
O. Erken ◽  
F. Romanò ◽  
J.B. Grotberg ◽  
M. Muradoglu

Capillary instability of a two-layer liquid film lining a rigid tube is studied computationally as a model for liquid plug formation and closure of human airways. The two-layer liquid consists of a serous layer, also called the periciliary liquid layer, at the inner side and a mucus layer at the outer side. Together, they form the airway surface liquid lining the airway wall and surrounding an air core. Liquid plug formation occurs due to Plateau–Rayleigh instability when the liquid film thickness exceeds a critical value. Numerical simulations are performed for the entire closure process, including the pre- and post-coalescence phases. The mechanical stresses and their gradients on the airway wall are investigated for physiologically relevant ranges of the mucus-to-serous thickness ratio, the viscosity ratio, and the air–mucus and serous–mucus surface tensions encompassing healthy and pathological conditions of a typical adult human lung. The growth rate of the two-layer model is found to be higher in comparison with a one-layer equivalent configuration. This leads to a much sooner closure in the two-layer model than that in the corresponding one-layer model. Moreover, it is found that the serous layer generally provides an effective protection to the pulmonary epithelium against high shear stress excursions and their gradients. A linear stability analysis is also performed, and the results are found to be in good qualitative agreement with the simulations. Finally, a secondary coalescence that may occur during the post-closure phase is investigated.


2021 ◽  
Vol 12 ◽  
Author(s):  
Mingyan Wang ◽  
Wei Zhang ◽  
Zhi Qi

Platelets deposition at the site of vascular injury is a key event for the arrest of bleeding and for subsequent vascular repair. Therefore, the regulation of platelet deposition onto the injured site during the process of platelet plug formation is an important event. Herein, we showed that electrical signal could regulate the deposition of platelets onto the injured site. On the one hand, the area of platelet deposition was reduced when the cathode of the applied electric field was placed at the injured site beforehand, while it was increased when the anode was at the site. On the other hand, if a cathode was placed at the injured site after the injury, the electrical signal could remove the outer layer of the deposited platelets. Furthermore, an electric field could drive rapid platelet deposition onto the blood vessel wall at the site beneath the anode even in uninjured blood vessels. Platelet deposition could thus be manipulated by externally applied electric field, which might provide a mechanism to drive platelet deposition onto the wall of blood vessels.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2072-2072
Author(s):  
Sally Azer ◽  
Oluwamayokun Oshinowo ◽  
Meredith E. Fay ◽  
Yumiko Sakurai ◽  
Yongzhi Qiu ◽  
...  

Abstract A subset of patients with chronic bleeding remain undiagnosed even after extensive diagnostic evaluation are labeled as "bleeding of unknown cause" (BUC). The key barrier to treating these patients is that they have a clinical bleeding tendency in the presence of normal diagnostic tests, and optimal methods for monitoring and treating patients with BUC remain unknown. While patients with BUC have symptoms of a primary hemostatic disorder, there is no diagnostic test or biomarker that can accurately identify which patients are at risk for bleeding such as those with mild Von Willebrand Disease (VWD) which comprise a broad spectrum of patients with varying degrees of bleeding. In order to fill this diagnostic gap in disorders of primary hemostasis, there is a clinical need for more assays of platelet function. To that end, we have engineered multiple new biophysical assays to assess disorders of primary hemostasis and apply this panel of platelet function testing to potentially define new bleeding disorders, characterize platelet phenotypes in patients with BUC, and refine the definition of mild VWD. Our panel of platelet function tests (Fig 1) collectively enables us to simultaneously assess different facets of primary hemostasis from the microscopic level of single-platelet physiology to hemostatic plug formation, thereby capturing various aspects of platelet function with a single blood sample. Our platelet function panel ranges from platelet adhesion and bulk clot contraction assays to spatially-regulated platelet granule secretion assay, single-platelet contraction cytometry, microfluidics, and a microengineered vascularized bleeding model. As such, we are leveraging these biophysical assays to correlate platelet function with bleeding phenotype severity and establish the dynamic range of this diagnostic panel. We have now established that our assays can be utilized to study blood samples from patients with disorders including hemophilia A, Hermansky-Pudlak Syndrome, FLI-1 mutation, and sickle cell disease among others (Fig 2), demonstrating the clinical utility of our platelet function panel. Our panel can also be used to assess the effects of novel therapeutics on different aspects of platelet function simultaneously. To investigate how crizanlizumab (p-selectin inhibitor) affects hemostatic plug formation, healthy human blood was treated with crizanlizumab. Platelet α-granule secretion enables exposure of P-selectin, and with crizanlizumab we observed restricted platelet filopodial extension and diminished α-granule exocytosis, and an overall decrease in adhered platelets to the fibrinogen micropattern (Fig 3A). The adhesion assay demonstrated a decrease in spreading and adhesion of platelets to collagen and fibrinogen with treatment (Fig 3B). Using the bleeding model, hemostasis was achieved within the normal established range and platelets contracted normally. This suggests that p-selectin has a limited role in the setting of minor injury. Utilizing the bulk contraction assay, we exhibited increased contraction early in clot formation, however over time the treated platelets contracted similarly to the control (Fig 3C). Interestingly, the effect of crizanlizumab-induced restriction of filopodial extension did not correlate with impaired bulk clot contraction or time to form hemostatic plug. Our work suggests crizanlizumab affects platelet spreading at the single-cell level but does not impair platelet function in achieving primary hemostasis at the whole blood level. Here we demonstrate the translational utility of our platelet function panel in providing a deeper understanding of platelet biophysics as it relates to hematologic conditions, with implications for investigation to include pharmaceutical applications. The versatility of this novel panel in capturing platelet function from single-platelet contraction to providing in vitro models with the bleeding device provides multiple dimensions to platelet investigation for primary hemostatic disorders and BUC that have not yet been elucidated. Ongoing research is being conducted using our comprehensive platelet function panel to investigate platelet properties in BUC and mild VWD and correlate these biophysics with bleeding phenotypes. Using this approach we aim to provide novel diagnostic testing with clinical relevance for disorders that have been incompletely characterized until now. Figure 1 Figure 1. Disclosures Meeks: National Institutes of Health: Research Funding; Hemophilia of Georgia: Research Funding; National Hemophilia Foundation: Research Funding; Spark Therapeutics: Consultancy; Sangamo Therapeutics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Takeda: Consultancy. Lam: Sanguina, Inc.: Current holder of individual stocks in a privately-held company.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1000-1000
Author(s):  
Robert H Lee ◽  
Tomohiro Kawano ◽  
Vanthana Bharathi ◽  
David Martinez ◽  
Dale O Cowley ◽  
...  

Abstract Introduction: Protease-activated receptor 4 (PAR4) is expressed by a wide variety of cells, including megakaryocytes/platelets, immune cells, cardiomyocytes and lung epithelial cells, and activated by multiple ligands including thrombin and cathepsin G. Importantly, PAR4 is the only functional thrombin receptor on murine platelets. A global deficiency of PAR4 is associated with impaired hemostasis and protection from thrombosis which are attributed to loss of platelet PAR4, but this has not been specifically demonstrated in mice. Additionally, global PAR4 deficiency increases mortality after influenza A virus infection, but the cell type/s responsible for the enhanced mortality have not been determined. Here, we describe the generation of PAR4 floxed (PAR4 fl/fl) mice that can be used to delete PAR4 in a cell type-specific manner, and examine the effect of megakaryocyte/platelet-specific deletion of PAR4 on hemostasis, thrombosis and viral infection using PAR4 fl/fl;PF4Cre + mice. Methods: PAR4global knockout (PAR4 -/-), MK/platelet-specific knockout (PAR4 fl/fl;PF4Cre +) and appropriate littermate control mice were used for experiments. Platelet function was determined by light transmission aggregometry and flow cytometry. Hemostasis was assessed in the saphenous vein laser injury model. Platelet plug formation was visualized by intravital microscopy following saphenous vein laser ablation (~50 μm diameter injury), followed by 2 subsequent ablations to reinjure the same site unless on-going bleeding was occurring. Mice were treated with ibrutinib (12.5 mg/kg) to inhibit GPVI signaling, or dabigatran etexilate (chow containing 10 mg/g) or recombinant hirudin (50 mg/kg) to inhibit thrombin activity. Thrombosis was assessed in the carotid artery FeCl 3 model. The carotid artery was exposed and 8% FeCl 3 applied for 3 mins. Blood flow was observed for 30 mins and occlusion was defined as no blood flow for 2 mins. To study susceptibility to viral infection, mice were challenged intranasally with a mouse-adapted H1N1 influenza A virus (H1N1 IAV PR8; 0.02 hemagglutination assay units), which induces mortality in 20% of WT mice. Mortality was defined as body weight loss greater than 25%, which required euthanasia. Results: As expected, PAR4 fl/fl;PF4Cre + platelets were unresponsive to thrombin or PAR4-specific stimulation, while the response to other agonists was retained. In the saphenous vein laser injury hemostasis model, PAR4 fl/fl;PF4Cre + mice were able to rapidly form a hemostatic platelet plug, but the majority of plugs (7/8) were unstable and re-opened after several minutes, leading to severely prolonged total bleeding times. We observed similar findings in global PAR4 -/- mice with 8/12 plugs re-opening. To investigate the mechanism mediating initial platelet plug formation, we inhibited GPVI signaling in PAR4 fl/fl;PF4Cre + mice using the Btk inhibitor ibrutinib. Ibrutinib administration shortened time to plug re-opening in PAR4 fl/fl;PF4Cre + mice but plugs were still able to form, which is likely mediated by GPIbα/VWF. We observed a similar phenotype to PAR4 fl/fl;PF4Cre + mice in mice treated with the direct thrombin inhibitor hirudin, suggesting thrombin is the primary activator of PAR4 during hemostatic plug formation. In the FeCl 3-induced carotid artery thrombosis model, both PAR4 fl/fl;PF4Cre + and PAR4 -/- mice were significantly protected compared to controls. Finally, when challenged with the mouse-adapted H1N1 IAV PR8, PAR4 fl/fl;PF4Cre + mice demonstrated similar body weight loss and survival as littermate controls. Conclusions: Our results in mice demonstrate that 1) platelet PAR4 is not required for initial hemostatic plug formation but is necessary for maintaining hemostatic plug stability, 2) loss of platelet PAR4 protects from arterial thrombosis, and 3) platelet PAR4 does not alter the course of H1N1 IAV infection, at least at the virus dose used in this study. In summary, we generated a novel mouse line carrying a floxed PAR4 allele which can be used to investigate cell-specific roles of PAR4 in disease. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Simone Morris ◽  
Pradeep Manuneedhi Cholan ◽  
Warwick J. Britton ◽  
Stefan H. Oehlers

AbstractHyperglycaemia damages the microvasculature in part through the reduced recruitment of immune cells and interference with platelet signalling, leading to poor wound healing and accelerated lipid deposition in mammals. We investigated the utility of zebrafish larvae to model the effect of exogenous glucose on neutrophil and macrophage recruitment to a tail wound, wound-induced haemostasis, and chicken egg yolk feed challenge-induced hyperlipidaemia by supplementing larvae with exogenous glucose by immersion or injection. Neither method of glucose supplementation affected the recruitment of neutrophils and macrophages following tail transection. Glucose injection reduced thrombocyte retention and fibrin plug formation while only thrombocyte retention was reduced by glucose immersion following tail transection. We observed accelerated lipid accumulation in glucose-injected larvae challenged with high fat chicken egg yolk feeding. Our study identifies conserved and divergent effects of high glucose on inflammation, haemostasis, and hyperlipidaemia in zebrafish larvae compared to mammals.


2021 ◽  
Vol 22 (15) ◽  
pp. 7876
Author(s):  
Chenshuang Li ◽  
Zhong Zheng

Osteoarthritis (OA) is a major public health challenge that imposes a remarkable burden on the affected individuals and the healthcare system. Based on the clinical observation, males and females have different prevalence rates and severity levels of OA. Thus, sex-based differences may play essential roles in OA’s prognosis and treatment outcomes. To date, the comprehensive understanding of the relationship between sex and OA is still largely lacking. In the current study, we analyzed a published transcriptome dataset of knee articular cartilage (GSE114007) from 18 healthy (five females, 13 males) and 20 OA (11 females, nine males) donors to provide a slight insight into this important but complex issue. First, comparing female healthy cartilage samples with those of males revealed 36 differential expression genes (DEGs), indicating the fundamental sex-related differences at the molecular level. Meanwhile, 923 DEGs were distinguished between OA and healthy female cartilage, which can be enriched to 15 Reactome pathways. On the other hand, when comparing OA and healthy male cartilage, there are only 419 DEGs were identified, and only six pathways were enriched against the Reactome database. The different signaling response to OA in the male and female cartilage was further enforced by recognizing 50 genes with significantly different OA-responsive expression fold changes in males and females. Particularly, 14 Reactome pathways, such as “Extracellular matrix organization”, “Collagen biosynthesis and modifying enzymes”, “Dissolution of fibrin clot”, and “Platelet Aggregation (Plug formation)”, can be noted from these 50 sex-dependent OA-responsive genes. Overall, the current study explores the Sex as a Biological Variable (SABV) at the transcriptomic level in the knee articular cartilage in both healthy status and OA event, which could help predict the differential OA prognosis and treatment outcome of males and female patients.


Author(s):  
Sangbin Han

When tissue injury results to breakage, platelets are not only involved in plug formation and wound sealing, but they also play an important role throughout the tissue recovery process. Specifically, platelets accumulate at the site of injury and release a large number of biologically active mediators at injury sites, which initiate or modulate damaged tissue regeneration. Moreover, extensive experimental evidence has elucidated the involvement of platelets in tumor growth and metastasis. As such, this mini-review aimed to highlight the relatively lesser known functions of platelets.


Author(s):  
M.P. Doubrovsky ◽  
◽  
V.O. Dubravina ◽  

Modern marine structures (berths, breakwaters, offshore platforms, etc.) often include steel tubular piles of essential length (80-100 m and more) that should provide high bearing capacity in case of external axial loads application. Interaction between elements of the system “piled structure – soil media” is not studied sufficiently yet. It relates also to the bearing capacity of the long steel tubular piles of large diameter. One of the interesting peculiarities of long tubular piles behavior is the formation of soil plug at the piles tip. There are a lot of suggestion and methods aimed to increase piles bearing capacity under static pressing load. One of them relates to use of the additional structural element, i.e., the internal diaphragm welded to the internal surface of the pile shaft. Such approach has been applied in some practical cases of marine construction and demonstrated its effectiveness. At the moment there are no researches focused on study of the peculiarities of internal diaphragm application. So proposed research aimed to study two connected processes during steel tubular pile driving: soil plug formation at the tip of the open-end pile and soil behavior under the internal diaphragm fixed inside the tubular pile shaft. To study mentioned processes we provided several series of laboratory experiments fulfilled at the Geotechnical laboratory of the Department “Sea, River Ports and Waterways” in Odessa National Maritime University. In these experiments the model of steel tubular pile has been driven (pressed) into fine sand by mechanical jack. The first series was devoted to determination of the conditions related to the soil plug formation at the pile tip. The next series were aimed to study the influence of the flat rigid diaphragm inside the pile shaft. Obtained experimental results allow to conclude that (a) in the fine sand the plug is formatted at the comparatively early stage of pile installation (in case of our modeling – at the penetration depth of some 4-5 pile diameter); (b) our empirical assessment of the conditions of soil plug formation corresponds to the approaches based on PLR and IFR characteristics; (c) formation of soil plug at the pile tip is followed by decreasing of soil level in the pile shaft relatively its initial value (on completing the plug formation the soil level in the shaft become stable); (d) regarding above mentioned, we may note that in case of use of internal diaphragm on the recommended depth (5-7 pile diameters) there may be no contact between diaphragm and the soil inside the pile (e) application of the diaphragm may lead to increasing of the pile’s bearing capacity. It was proposed (and checked by our tests) the technological improvement based on sand filling into space under the internal diaphragm to provide constant diaphragm-soil contact and related soil resistance.


2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110155
Author(s):  
Qiuli Yan ◽  
Wensi Niu ◽  
Wujun Jiang ◽  
Chuangli Hao ◽  
Meiyuan Chen ◽  
...  

Objective To determine the risk factors for delayed radiographic resolution in children with refractory Mycoplasma pneumoniae pneumonia (RMPP) and explore the most suitable time for interventional bronchoscopy. Methods This retrospective study involved 142 children with RMPP who were admitted to our hospital from 1 January 2015 to 31 December 2017. They were divided into a common resolution group and a delayed resolution group based on their chest radiograph series. Results Among the 142 patients, 67 showed common resolution on chest radiographs and 75 showed delayed resolution. Independent risk factors for delayed resolution were a clinical course of ≥11.5 days before the performance of interventional bronchoscopy, mucus plug formation, corticosteroid resistance, and atelectasis. When bronchoscopy was performed before the disease had been present for <11.5 days, the length of hospitalization, total fever duration, and duration of time until disappearance of coughing were shorter than those in children who underwent bronchoscopy after the disease had been present for ≥11.5 days. Conclusions Corticosteroid resistance, the time to interventional bronchoscopy, atelectasis, and mucus plug formation were associated with delayed resolution on chest radiographs. Performance of interventional bronchoscopy before the clinical course has reached 11.5 days may help alleviate clinical symptoms and improve radiographic resolution.


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