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Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque-triggered thrombus formation in humans.
Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque-triggered thrombus formation in humans.
- Source :
-
Blood [Blood] 2018 Jun 14; Vol. 131 (24), pp. 2605-2616. Date of Electronic Publication: 2018 Mar 20. - Publication Year :
- 2018
-
Abstract
- Interaction of von Willebrand factor (VWF) with platelet glycoprotein Ib (GPIb) and interaction of collagen with GPVI are essential for thrombus formation on ruptured or eroded atherosclerotic plaques (atherothrombosis). GPIb and GPVI signal through Bruton tyrosine kinase (Btk), which can be blocked irreversibly by oral application of ibrutinib, an established therapy for chronic lymphocytic leukemia (CLL) with long-term safety. We found that ibrutinib and the novel Btk inhibitors acalabrutinib and ONO/GS-4059 block GPVI-dependent static platelet aggregation in blood exposed to human plaque homogenate and collagen but not to ADP or arachidonic acid. Moreover, Btk inhibitors prevented platelet thrombus formation on human atherosclerotic plaque homogenate and plaque tissue sections from arterially flowing blood, whereas integrin α <subscript>2</subscript> β <subscript>1</subscript> and VWF-dependent platelet adhesion to collagen, which is important for physiologic hemostasis, was not affected. This plaque-selective platelet inhibition was also observed in CLL patients taking 450 mg of ibrutinib and in volunteers after much lower and intermittent dosing of the drug. We conclude that Btk inhibitors, by targeting GPIb and GPVI signal transduction, suppress platelet thrombus accretion from flowing blood on atherosclerotic plaque but spare hemostatic platelet function. Btk inhibitors hold promise as the first culprit lesion-focused oral antiplatelet drugs and are effective at low doses.<br /> (© 2018 by The American Society of Hematology.)
- Subjects :
- Adenine analogs & derivatives
Administration, Oral
Adult
Agammaglobulinaemia Tyrosine Kinase metabolism
Aged
Benzamides administration & dosage
Humans
Imidazoles administration & dosage
Male
Middle Aged
Piperidines
Plaque, Atherosclerotic drug therapy
Plaque, Atherosclerotic metabolism
Plaque, Atherosclerotic pathology
Platelet Aggregation drug effects
Platelet Aggregation Inhibitors administration & dosage
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors therapeutic use
Pyrazines administration & dosage
Pyrazoles administration & dosage
Pyrimidines administration & dosage
Thrombosis metabolism
Thrombosis pathology
Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors
Benzamides therapeutic use
Imidazoles therapeutic use
Plaque, Atherosclerotic complications
Platelet Aggregation Inhibitors therapeutic use
Pyrazines therapeutic use
Pyrazoles therapeutic use
Pyrimidines therapeutic use
Thrombosis etiology
Thrombosis prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 131
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 29559479
- Full Text :
- https://doi.org/10.1182/blood-2017-09-808808