1,721,003 research outputs found
Analysis of Thrombus Composition and Architecture in a High-Shear vs Low-Shear Stress Environment
No full textIntroduction
Thrombotic diseases—including acute ischemic stroke (AIS) and venous thromboembolism (VTE)—are major global health burdens with current therapies limited by narrow time windows, bleeding risks, or infrastructure barriers. While arterial thrombi are often labeled “white clots” rich in platelets and venous thrombi as “red clots” rich in RBCs and fibrin, this dichotomy lacks thorough validation in human tissue. Understanding thrombus composition and architecture under different shear stress conditions may uncover novel and translatable therapeutic targets, especially for patients ineligible for standard thrombolytics.
Methods
Thrombi were collected from AIS and VTE patients under IRB protocol and processed for immunofluorescent staining. Markers for von Willebrand Factor (VWF), fibrin, CD42b (platelets), glycophorin A (RBCs), PAI-1, and NETs markers (Cit-H3, MPO, NE) were quantified by percent positive area using ImageJ segmentation. Morphology was classified as peripheral, clustering, diffuse, or mixed. A two-tailed unpaired T-test compared percent area, and Z-tests assessed morphological distribution differences between arterial (n=74) and venous (n=31) thrombi.
Results
RBCs had significantly greater percent area in venous thrombi (p=0.0039), while fibrin content was paradoxically lower in venous thrombi (p=0.0128). No significant differences were observed for VWF, platelets, PAI-1, or NETs markers. Morphologically, venous thrombi demonstrated decreased clustering and increased mixed morphologies across nearly all markers. NETs markers were predominantly diffuse in both thrombus types. VWF and fibrin exhibited substantial peripheral localization. Despite expectations, VWF levels were not significantly lower in venous thrombi, suggesting that shear stress alone does not dictate its distribution.
Conclusion
These results challenge the conventional “white vs red clot” model by revealing that fibrin is more abundant in arterial thrombi and that platelet content is not significantly reduced in venous thrombi. Elevated PAI-1 and a shell-like fibrin structure suggest thrombolytic resistance, while VWF and NETs may prove to be efficacious therapeutic targets due to their widespread presence in both AIS and VTE. This work underscores the need to revise simplistic thrombus classifications and supports targeted therapeutic innovation.A three-year embargo was granted for this item.Academic Major: Biomedical Scienc
Inhibition of VWF Demonstrates Thrombolysis Following ex vivo Thrombus Formation in Patients with AIS LVO
Full text linkAcute ischemic stroke (AIS) is the leading cause of combined death and disability across the world. While recombinant tissue plasminogen activator (rTPA) and its analogs are the sole approved thrombolytic for AIS, its application is constrained by its strict administration window due to lack of reversibility, and potential for hemorrhage. Von Willebrand factor (VWF) is a glycoprotein pivotal in the adhesion, aggregation, and propagation of platelets. Most notably, VWF is responsible for tethering a thrombus to the collagen within a vessel wall through interaction with the platelet glycoprotein receptor, GP-Ib. This interaction also further activates surrounding platelets and leads to deceleration in cerebral blood flow, exacerbating ischemic injury. Thus, VWF is a crucial mediator in AIS pathophysiology. BB-031 is an RNA aptamer shown to inhibit VWF-platelet interaction in in vivo and in vitro settings. The objective of this study was to determine if BB-031 will be an effective therapeutic in AIS large vessel occlusion (LVO) patients using a kinetic ex vivo microfluidic model.
A microfluidic model of arterial thrombus was used to recapitulate the constant pressure and kinetic environment found with in vivo occlusion. After thrombus formation, BB-031 was introduced to the flow at a concentration of 1692 nM. A 2-hour perfusion period was observed following treatment administration of BB-031 or vehicle control (PBS). Patency and thrombus surface area were measured throughout the perfusion.
In the kinetic model, patency was achieved in 85% (6/7) of samples in the BB-031 samples compared to 0% (0/8) of the samples in the vehicle control group. Analysis of the surface area of the thrombi showed a decrease in pre-occlusion platelets throughout the perfusion in the BB-031 treatment group compared to PBS control. Interestingly, post-occlusion platelets initially increased in surface area as new platelets were deposited and eventually decreased in the BB-031 group. The control group showed decreased post-occlusion platelet deposition.
This study demonstrates the potential of BB-031 as a therapeutic intervention for large vessel occlusion acute ischemic stroke, exhibiting encouraging trends in enhancing patency and modulating thrombus formation. These results offer promising for those affected by this lethal disease and more work must be done to further strengthen the thrombolytic replacement of rTPA with BB-031 or at least, efficacy for those patients not eligible for therapeutic treatment.No embargoAcademic Major: Biomedical Scienc
Inhibition of the Glycoprotein Von Willebrand Factor via an RNA Aptamer in a Large Animal Model of Middle Cerebral Arterial Occlusion Stroke
Full text linkEvery three and a half minutes an individual dies from a stroke. Approximately 85% of strokes are ischemic, and over half of all ischemic strokes originate in the middle cerebral artery (MCA)1-2,6. Currently, standard stroke treatment includes intravenous infusion of recombinant tissue plasminogen activator (rTPA), a serine protease that's primary function is to eliminate occlusion caused by blood clots via thrombolysis3. This method is only marginally effective at thrombolysis, cannot be reversed, and must be given within a timeframe of 3-4.5 hours of stroke onset, due to increased hemorrhage risk. Knowing that von Willebrand Factor (vWF), a known glycoprotein mediator in platelet adhesion and aggregation, plays a major role in vessel injury hemostasis, the Nimjee Lab developed a vWF-inhibiting aptamer, DTRI-031 (REF Oney, Nimjee et al. Oligonucleotides 2007; Nimjee et al. Molecular Therapy 2012 and Nimjee et al. Molecular Therapy 2019). Aptamers are RNA or DNA oligonucleotides which bind to and inhibit specific target molecules (REF Nimjee et al. Annual Reviews of Medicine 2005).
In this study, we tested the hypothesis that DTRI-031 can lyse a blood clot 6 hours after it is placed in the MCA of canine hounds4. Furthermore, DTRI-031 can be rapidly reversed by another single-stranded RNA ligand, DTRI-025, to mitigate hemorrhage risk induced by the activity of DTRI-031. This study aims to demonstrate the efficacy of DTRI-031 to thrombolyse an occlusive thrombus in a large animal MCA occlusion (MCAO) model by measuring functional differences at different aptamer concentrations, like reperfusion rate, infarct volume, and inhibition of platelet activity and aggregation. Additionally, this study aims to demonstrate the reversibility of DTRI-031 by DTRI-025 using a point-of-care platelet activity assay (PFA-100) and platelet aggregometry. We anticipate that higher concentrations of DTRI-031 will result in improved cerebral perfusion, decreased infarct size, and lower platelet aggregation. Moreover, DTRI-025 will rapidly and durably reverse DTRI-031 functionality in both platelet activity and aggregation assays.Undergraduate Research ScholarshipNo embargoAcademic Major: Biomedical Engineerin
Aptamer-Based von Willebrand Factor Inhibition Mediates Platelet and Neutrophil Activation in Canine Middle Cerebral Artery Occlusion
Full text linkAcute ischemic stroke (AIS) is a leading cause of combined death and disability that has seen a 70% increase in incidence since 19901. Current treatment includes mechanical thrombectomy or administration of recombinant tissue plasminogen activator (rTPA). rTPA activates plasminogen, recruiting plasmin to break down fibrin within a clot2. However, rTPA is limited due to its short administration window and risk of hemorrhage, leaving around 85% of AIS patients without sufficient treatment3.
Von Willebrand Factor (VWF) is a glycoprotein highly implicated in pathological thrombosis following vascular injury. Due to its role in platelet adhesion, aggregation, and clot contraction, VWF is a compelling target for AIS treatment. BB-031 is an aptamer targeted to inhibit VWF with high specificity (Oney et al. 2007, Nimjee et al. 2012, Nimjee et al. 2019). Additionally, the effects of BB-031 can be rapidly reversed upon administration of its targeted antidote, BB-025, minimizing the hemorrhage risk characteristic of rTPA (Oney et al. 2007, Nimjee et al 2012).
In the following studies, we simulated middle cerebral artery occlusion (MCAO) over a period of 6 hours in canine hounds to assess the efficacy of varied dosages of BB- 031, as the MCA is the most prevalent location for clinical stroke4. Performance was assessed from multiple parameters including platelet inhibition, infarct volume, and cerebral reperfusion, resulting in 0.5 mg/kg as an optimal concentration. We also assessed the ability of BB-025 to reverse BB-031 activity. More recent studies aim to further understand the inflammatory profile of MCAO in the presence of BB-031, as long- term inflammation remains a pervasive challenge in stroke care. We expect 0.5 mg/kg of BB-031 will significantly reduce inflammatory markers implicated in AIS due to its role in attenuating platelet activation and aggregation.No embargoAcademic Major: Neuroscienc
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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