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November 15, 2014Blood

Platelet PI3Kβ and GSK3 regulate thrombus stability at a high shear rate

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Key result

Deletion or pharmacological inhibition of platelet PI3Kβ caused thrombus instability and embolization at high shear rates, which was restored by GSK3 inhibition.

Why the study?

Does PI3Kβ inhibition affect thrombus stability at high shear rates in preclinical models?

Population

Mice with selective p110β deletion in the megakaryocyte lineage and human blood samples

Comparison

Genetic deletion of p110β or pharmacologic… vs Wild-type mice or untreated human blood (implied)

Design

Preclinical

Authors

PLPierre LaurentSSSonia SéverinBHBéatrice Hechler

Discussion

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Member takes

Overview

May promote embolization with PI3Kβ inhibition at high shear; leaves open clinical relevance for antithrombotic development.

Structured PICO

Does PI3Kβ inhibition affect thrombus stability at high shear rates in preclinical models?

P
Population
Mice with selective p110β deletion in the megakaryocyte lineage and human blood samples
I
Intervention
Genetic deletion of p110β or pharmacologic inhibition with AZD6482 (selective PI3Kβ inhibitor)
C
Comparator
Wild-type mice or untreated human blood (implied)
O
Outcome
Thrombus stability at high shear ratesurrogate

PI3Kβ plays a critical role in maintaining thrombus integrity at high arterial shear rates, suggesting that PI3Kβ inhibitors may carry a risk of embolization.

Cite This Study

Laurent et al. (2014) studied Arterial thrombosis. PI3Kβ deletion or inhibition (AZD6482) vs. Wild-type or untreated control was evaluated on Thrombus stability at high shear rate. Deletion or pharmacological inhibition of platelet PI3Kβ caused thrombus instability and embolization at high shear rates, which was restored by GSK3 inhibition.

synapsesocial.com/papers/6a992bfc13e19562d9f0d5afhttps://doi.org/10.1182/blood-2014-07-588335
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Impact of PI3Kα (Phosphoinositide 3-Kinase Alpha) Inhibition on Hemostasis and Thrombosis2018 · 30 citations
  2. 2Continuous signaling via PI3K isoforms β and γ is required for platelet ADP receptor function in dynamic thrombus stabilization2006 · 150 citations
  3. 3Disrupting the platelet internal membrane via PI3KC2α inhibition impairs thrombosis independently of canonical platelet activation2020 · 34 citations
  4. 4Role of Tyrosine Kinase Syk in Thrombus Stabilisation at High Shear2022 · 14 citations
  5. 5Platelet PI3Kγ Contributes to Carotid Intima-Media Thickening under Severely Reduced Flow Conditions2015 · 7 citations