Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis

Vandendries, Erik; Hamilton, Justin Raymond; Coughlin, Shaun R.; Furie, Bruce; Furie, Barbara C.

doi:10.1073/pnas.0610188104

Cited by 159 publications

(187 citation statements)

References 21 publications

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“…Additionally, genetic inactivation of the principal thrombin receptor on mouse platelets (PAR-4, which corresponds to PAR-1 on human platelets) does not result in spontaneous bleeding 22) . These data collectively suggest that inhibition/inactivation of the principal platelet thrombin receptor pathway may not increase the risk for bleeding complications.…”

Section: Discussionmentioning

confidence: 99%

“…First, genetic inactivation of the principal thrombin receptor on mouse platelets does not interfere with either the initial platelet deposition or fibrin generation required for normal hemostasis and healing in response to vascular injury 22) . Additionally, PAR-1 inhibition does not interfere with platelet binding to and activation by collagen 15,23) , which is important for normal hemostasis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

Goto

Yamaguchi

Ikeda

et al. 2010

JAT

103

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Aim: A previous phase 2 study of patients undergoing non-urgent PCI treated with SCH530348 plus aspirin and clopidogrel tended to reduce MACE without increased bleeding. This study evaluated the safety of SCH530348 in Japanese patients with NSTE ACS. Methods: Subjects (117), in whom PCI was planned, received standard-of-care (aspirin, ticlopidine, and heparin) and were randomized 4:1 to receive either SCH530348 (20 or 40 mg loading dose followed by 1 mg/d or 2.5 mg/d for 60 days) or placebo. The key safety endpoint was TIMI major and minor bleeding in the PCI cohort (n 92). The key exploratory efficacy endpoint was MACE and death within 60 days. Addition of SCH530348 to standard-of-care did not significantly increase the rate of TIMI major and minor bleeding (or non-TIMI bleeding) in the primary cohort. Results: Incidence (non-MACE) and discontinuation of AEs were similar across groups. PCI subjects treated with SCH530348 plus standard-of-care experienced a significant reduction in periprocedural MI compared with standard-of-care alone (16.9% vs 42.9%, respectively; p 0.013). There were no deaths or any other MACE. Conclusion: SCH530348 added to standard-of-care did not result in excess bleeding in Japanese subjects with NSTE ACS but significantly reduced the incidence of periprocedural MI in subjects undergoing urgent PCI. J Atheroscler Thromb, 2010; 17:156-164.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

Goto

Yamaguchi

Ikeda

et al. 2010

JAT

103

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“…To investigate whether the primary effect of thrombin on leukocyte migration was related to platelet stimulation, we performed studies on PAR4 À / À mice, as platelets from these mice are completely unresponsive to thrombin stimulation 33 . Compatible with a reduction in thrombin-induced platelet activation, thrombus stability in mesenteric veins was markedly decreased in PAR4 À / À mice following needle injury (Fig.…”

Section: Thrombin-activated Platelets Promote Leukocyte Traffickingmentioning

confidence: 99%

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

et al. 2015

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Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIba and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIba, as seen in mice with abrogated thrombin-platelet GPIba binding (hGPIba D277N ). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct 'checkpoint' mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIba and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.

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“…For instance, mice deficient in the PAR-4 thrombin receptor, refractory to thrombin-induced platelet activation, do not develop a significant platelet thrombus but generate normal amounts of fibrin around the vessel injury. 60 This invites the question as to whether the required procoagulant surfaces come from other sources such as endothelial cells or microparticles instead of platelets. In vivo, experiments also show that thrombin activity is distributed throughout the platelet thrombus and not only at the thrombus-blood interface, indicating that the arterial thrombi are porous and allow the flow of agonists within.…”

confidence: 99%

Platelet receptors and signaling in the dynamics of thrombus formation

Rivera¹,

Lozano²,

et al. 2009

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Hemostasis and pathological thrombus formation are dynamic processes that require a co-ordinated series of events involving platelet membrane receptors, bidirectional intracellular signals, and release of platelet proteins and inflammatory substances. This review aims to summarize current knowledge in the key steps in the dynamics of thrombus formation, with special emphasis on the crucial participation of platelet receptors and signaling in this process. Initial tethering and firm adhesion of platelets to the exposed subendothelium is mediated by glycoprotein (GP) Ib/IX/V complex and collagen receptors, GP VI and α2β1 integrin, in the platelet surface, and by VWF and fibrillar collagen in the vascular site. Interactions between these elements are largely influenced by flow and trigger signaling events that reinforce adhesion and promote platelet activation. Thereafter, soluble agonists, ADP, thrombin, TxA2, produced/released at the site of vascular injury act in autocrine and paracrine mode to amplify platelet activation and to recruit circulating platelets to the developing thrombus. Specific interactions of these agonists with their G-protein coupled receptors generate inside-out signaling leading to conformational activation of integrins, in particular αIIbβ3, increasing their ligand affinity. Binding of αIIbβ3 to its ligands, mainly fibrinogen, supports processes such as clot retraction and platelet aggregation. Stabilization of thrombi is supported by the late wave of signaling events promoted by close contact between aggregated platelets. The best known contact-dependent signaling is outside-in signaling through αIIbβ3, but new ones are being clarified such as those mediated by interaction of Eph receptors with ephrins, or by Sema 4D and Gas-6 binding to their receptors. Finally, newly identified mechanisms appear to control thrombus growth, including back-shifting of activated integrins and actuation of compensatory molecules such as ESAM or PECAM-1. The expanding knowledge of thrombotic disease is expected to translate into the development of new drugs to help management and prevention of thrombosis.Key words: platelet, receptors, thrombus formation.Citation: Rivera J, Lozano ML, Navarro-Núñez L, Vicente V. Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 2009; 94:700-711. doi:10.3324/haematol.2008 This is an open-access paper. ABSTRACT Platelet receptors and signaling in the dynamics of thrombus formationJosé Rivera, María Luisa Lozano, Leyre Navarro-Núñez, and Vicente Vicente Unit of Hematology and Clinical Oncology, Centro Regional de Hemodonación, University of Murcia, Spain © F e r r a t a S t o r t i F o u n d a t i o nand metastasis, or immunological host defense. 1Internally, platelets contain a cytoskeleton, a dense tubular system, few mitochondrias, glycogen granules, dense (δ) and α storage granules and peroxisomes. The α-granules retain relevant proteins for the hemostatic function of platelets, such as von Willebrand factor (VWF), fibrinogen, P-selectin,...

show abstract

Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis

Cited by 159 publications

References 21 publications

Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

Platelet receptors and signaling in the dynamics of thrombus formation

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