Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque-triggered thrombus formation in humans

Kristina Busygina, Janina Jamasbi, Till Seiler, Hans Deckmyn, Christian Weber, Richard Brandl, Reinhard Lorenz, Wolfgang Siess*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Interaction of von Willebrand factor (VWF) with platelet glycoprotein lb (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 alpha(2)beta(1) 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.
Original languageEnglish
Pages (from-to)2605-2616
Number of pages12
JournalBlood
Volume131
Issue number24
DOIs
Publication statusPublished - 14 Jun 2018

Keywords

  • MULTIPLE ELECTRODE AGGREGOMETRY
  • PLATELET GLYCOPROTEIN-VI
  • SINGLE-AGENT IBRUTINIB
  • TERM-FOLLOW-UP
  • IN-VIVO
  • ACALABRUTINIB ACP-196
  • COMPLEMENTARY ROLES
  • CORONARY-ARTERIES
  • WHOLE-BLOOD
  • COLLAGEN

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