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  1. Article ; Online: Effects of inflammation on thrombosis and outcomes in COVID-19: secondary analysis of the ATTACC/ACTIV-4a trial.

    Walborn, Amanda T / Heath, Anna / Neal, Matthew D / Zarychanski, Ryan / Kornblith, Lucy Z / Hunt, Beverley J / Castellucci, Lana A / Hochman, Judith S / Lawler, Patrick R / Paul, Jonathan D

    Research and practice in thrombosis and haemostasis

    2023  Volume 7, Issue 7, Page(s) 102203

    Abstract: Background: Patients hospitalized for COVID-19 are at high risk of thrombotic complications and organ failure, and often exhibit severe inflammation, which may contribute to hypercoagulability.: Objectives: To determine whether patients hospitalized ... ...

    Abstract Background: Patients hospitalized for COVID-19 are at high risk of thrombotic complications and organ failure, and often exhibit severe inflammation, which may contribute to hypercoagulability.
    Objectives: To determine whether patients hospitalized for COVID-19 experience differing frequencies of thrombotic and organ failure complications and derive variable benefits from therapeutic-dose heparin dependent on the extent of systemic inflammation and whether observed benefit from therapeutic-dose anticoagulation varies depending on the degree of systemic inflammation.
    Methods: We analyzed data from 1346 patients hospitalized for COVID-19 enrolled in the ATTACC and ACTIV-4a platforms who were randomized to therapeutic-dose heparin or usual care for whom levels of C-reactive protein (CRP) were reported at baseline.
    Results: Increased CRP was associated with worse patient outcomes, including a >98% posterior probability of increased organ support requirement, hospital length of stay, risk of 28-day mortality, and incidence of major thrombotic events or death (patients with CRP 40-100 mg/L or ≥100 mg/L compared to patients with CRP <40 mg/L). Patients with CRP 40 to 100 mg/L experienced the greatest degree of benefit from treatment with therapeutic doses of unfractionated or low molecular weight heparin compared with usual-care prophylactic doses. This was most significant for an increase in organ support-free days (odds ratio: 1.63; 95% confidence interval, 1.09-2.40; 97.9% posterior probability of beneficial effect), with trends toward benefit for other evaluated outcomes.
    Conclusion: Moderately ill patients hospitalized for COVID-19 with CRP between 40 mg/L and 100 mg/L derived the greatest benefit from treatment with therapeutic-dose heparin.
    Language English
    Publishing date 2023-09-16
    Publishing country United States
    Document type Journal Article
    ISSN 2475-0379
    ISSN (online) 2475-0379
    DOI 10.1016/j.rpth.2023.102203
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Regulation of valve endothelial cell vasculogenic network architectures with ROCK and Rac inhibitors.

    Arevalos, C Alexander / Walborn, Amanda T / Rupert, Amanda A / Berg, Jonathan M / Godfrey, Elizabeth L / Nguyen, Jacqueline M V / Grande-Allen, K Jane

    Microvascular research

    2015  Volume 98, Page(s) 108–118

    Abstract: Objective: The age- and disease-dependent presence of microvessels within heart valves is an understudied characteristic of these tissues. Neovascularization involves endothelial cell (EC) migration and cytoskeletal reorientation, which are heavily ... ...

    Abstract Objective: The age- and disease-dependent presence of microvessels within heart valves is an understudied characteristic of these tissues. Neovascularization involves endothelial cell (EC) migration and cytoskeletal reorientation, which are heavily regulated by the Rho family of GTPases. Given that valve ECs demonstrate unique mesenchymal transdifferentiation and cytoskeletal mechanoresponsiveness, compared to vascular ECs, this study quantified the effect of inhibiting two members of the Rho family on vasculogenic network formation by valve ECs.
    Approach and results: A tubule-like structure vasculogenesis assay (assessing lacunarity, junction density, and vessel density) was performed with porcine aortic valve ECs treated with small molecule inhibitors of Rho-associated serine-threonine protein kinase (ROCK), Y-27632, or the Rac1 inhibitor, NSC-23766. Actin coordination, cell number, and cell migration were assessed through immunocytochemistry, MTT assay, and scratch wound healing assay. ROCK inhibition reduced network lacunarity and interrupted proper cell-cell adhesion and actin coordination. Rac1 inhibition increased lacunarity and delayed actin-mediated network formation. ROCK inhibition alone significantly inhibited migration, whereas both ROCK and Rac1 inhibition significantly reduced cell number over time compared to controls. Compared to a vascular EC line, the valve ECs generated a network with larger total vessel length, but a less smooth appearance.
    Conclusions: Both ROCK and Rac1 inhibition interfered with key processes in vascular network formation by valve ECs. This is the first report of manipulation of valve EC vasculogenic organization in response to small molecule inhibitors. Further study is warranted to comprehend this facet of valvular cell biology and pathology and how it differs from vascular biology.
    MeSH term(s) Actins/metabolism ; Amides/chemistry ; Aminoquinolines/chemistry ; Animals ; Aortic Valve/metabolism ; Cell Communication ; Cell Movement ; Cell Transdifferentiation ; Endothelial Cells/cytology ; Endothelial Cells/metabolism ; Image Processing, Computer-Assisted ; Immunohistochemistry ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Protein Kinase Inhibitors/chemistry ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Pyridines/chemistry ; Pyrimidines/chemistry ; Swine ; Wound Healing ; rho-Associated Kinases/antagonists & inhibitors
    Chemical Substances Actins ; Amides ; Aminoquinolines ; NSC 23766 ; Platelet Endothelial Cell Adhesion Molecule-1 ; Protein Kinase Inhibitors ; Pyridines ; Pyrimidines ; Y 27632 (138381-45-0) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; rho-Associated Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2015-02-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80307-8
    ISSN 1095-9319 ; 0026-2862
    ISSN (online) 1095-9319
    ISSN 0026-2862
    DOI 10.1016/j.mvr.2015.01.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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