ArticleJournal of thrombosis and haemostasis : JTH2024
A mouse model of the protease-activated receptor 4 Pro310Leu variant has reduced platelet reactivity.
Article in Journal of thrombosis and haemostasis : JTH, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Neutrophil cathepsin G potentiates biased signaling through protease-activated receptor 4.Blood advances · 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
- Humanized murine models of platelet function.Current opinion in hematology · 2025Review
- Serine proteases and protease-activated receptors signaling in the kidney.American journal of physiology. Cell physiology · 2025Review
- Scoring systems to predict thrombotic complications in solid tumor patients.Current opinion in hematology · 2025Review
- Mice with reduced protease-activated receptor 4 reactivity show decreased venous thrombosis and platelet procoagulant activity.Journal of thrombosis and haemostasis : JTH · 2025Article
- Endothelial protease-activated receptor 4: impotent or important?Frontiers in cardiovascular medicine · 2025Review
- Mice with Reduced PAR4 Reactivity show Decreased Venous Thrombosis and Platelet Procoagulant Activity.bioRxiv : the preprint server for biology · 2024Article
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10 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundProtease-activated receptor 4 (PAR4) mediates thrombin signaling on platelets and other cells. Our recent structural studies demonstrated that a single nucleotide polymorphism in extracellular loop 3 and PAR4-P310L (rs2227376) leads to a hyporeactive receptor.
objectivesThe goal of this study was to determine how the hyporeactive PAR4 variant in extracellular loop 3 impacts platelet function in vivo using a novel knock-in mouse model (PAR4-322L).
methodsA point mutation was introduced into the PAR4 gene F2rl3 via CRISPR/Cas9 to create PAR4-P322L, the mouse homolog to human PAR4-P310L. Platelet response to PAR4 activation peptide (AYPGKF), thrombin, ADP, and convulxin was monitored by αIIbβ3 integrin activation and P-selectin translocation using flow cytometry or platelet aggregation. In vivo responses were determined by the tail bleeding assay and the ferric chloride-induced carotid artery injury model.
resultsPAR4-P/L and PAR4-L/L platelets had a reduced response to AYPGKF and thrombin measured by P-selectin translocation or αIIbβ3 activation. The response to ADP and convulxin was unchanged among genotypes. In addition, both PAR4-P/L and PAR4-L/L platelets showed a reduced response to thrombin in aggregation studies. There was an increase in the tail bleeding time for PAR4-L/L mice. The PAR4-P/L and PAR4-L/L mice both showed an extended time to arterial thrombosis.
conclusionPAR4-322L significantly reduced platelet responsiveness to AYPGKF and thrombin, which is in agreement with our previous structural and cell signaling studies. In addition, PAR4-322L had prolonged arterial thrombosis time. Our mouse model provides a foundation to further evaluate the role of PAR4 in other pathophysiological contexts.
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