ArticleProceedings of the National Academy of Sciences of the United States of America2001
Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
100 citing papers in PubMed, 299 citations in OpenAlex.
- A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome.BMC pulmonary medicine · 2012Trial
- Advances in Brain Tumor Biomarkers: From Molecular Profiling to Liquid Biopsy and AI-Driven Detection.Cancers · 2026Review
- Rivaroxaban suppresses factor Xa-Driven PAR-2-ERK inflammatory, catabolic, osteoclastogenic, and mitochondrial dysfunction signaling in osteoarthritis-relevant chondrocytes: a drug-repurposing strategy for joint inflammation.Frontiers in pharmacology · 2026Article
- Protease-activated receptor 4 deficiency increases mortality, intracranial bleeding, and blood-brain barrier impairment following traumatic brain injury in mice.Research and practice in thrombosis and haemostasis · 2025Article
- Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development.Blood · 2024Article
- Article
- Peripheral blood mononuclear cell tissue factor (F3 gene) transcript levels and circulating extracellular vesicles are elevated in severe coronavirus 2019 (COVID-19) disease.Journal of thrombosis and haemostasis : JTH · 2023Article
- Cancer-related stroke: Exploring personalized therapy strategies.Brain and behavior · 2022Review
- Tissue factor: a neglected role in cancer biology.Journal of thrombosis and thrombolysis · 2022Review
- Alboserpin, the Main Salivary Anticoagulant from the Disease VectorImmunoHorizons · 2022Article
- Manipulation of tissue factor-mediated basal PAR-2 signalling on macrophages determines sensitivity for IFNγ responsiveness and significantly modifies the phenotype of murine DTH.Frontiers in immunology · 2022Article
- Uncovering Membrane-Bound Models of Coagulation Factors by Combined Experimental and Computational Approaches.Thrombosis and haemostasis · 2021Review
- Factor VIIa Regulates the Level of Cell-Surface Tissue Factor through Separate but Cooperative Mechanisms.Cancers · 2021Article
- Coagulation Signaling through PAR1 as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma.International journal of molecular sciences · 2021Review
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- Accumulation of tissue factor in endothelial cells promotes cellular apoptosis through over-activation of Src1 and involves β1-integrin signalling.Apoptosis : an international journal on programmed cell death · 2020Article
- Platelet Membrane Receptor Proteolysis: Implications for Platelet Function.Frontiers in cardiovascular medicine · 2020Review
- SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress.Frontiers in physiology · 2020Review
- The Ratio of Factor VIIa:Tissue Factor Content within Microvesicles Determines the Differential Influence on Endothelial Cells.TH open : companion journal to thrombosis and haemostasis · 2019Article
- Roles of Coagulation Proteases and PARs (Protease-Activated Receptors) in Mouse Models of Inflammatory Diseases.Arteriosclerosis, thrombosis, and vascular biology · 2019Review
40 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
The crucial role of cell signaling in hemostasis is clearly established by the action of the downstream coagulation protease thrombin that cleaves platelet-expressed G-protein-coupled protease activated receptors (PARs). Certain PARs are cleaved by the upstream coagulation proteases factor Xa (Xa) and the tissue factor (TF)--factor VIIa (VIIa) complex, but these enzymes are required at high nonphysiological concentrations and show limited recognition specificity for the scissile bond of target PARs. However, defining a physiological mechanism of PAR activation by upstream proteases is highly relevant because of the potent anti-inflammatory in vivo effects of inhibitors of the TF initiation complex. Activation of substrate factor X (X) by the TF--VIIa complex is here shown to produce enhanced cell signaling in comparison to the TF--VIIa complex alone, free Xa, or Xa that is generated in situ by the intrinsic activation complex. Macromolecular assembly of X into a ternary complex of TF--VIIa--X is required for proteolytic conversion to Xa, and product Xa remains transiently associated in a TF--VIIa--Xa complex. By trapping this complex with a unique inhibitor that preserves Xa activity, we directly show that Xa in this ternary complex efficiently activates PAR-1 and -2. These experiments support the concept that proinflammatory upstream coagulation protease signaling is mechanistically coupled and thus an integrated part of the TF--VIIa-initiated coagulation pathway, rather than a late event during excessive activation of coagulation and systemic generation of proteolytic activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.