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

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

Key points

  • Btk inhibitors block specifically platelet thrombus formation onto atherosclerotic plaque but spare physiologic hemostasis.

  • Irreversible Btk inactivation in platelets incapable of enzyme resynthesis allows low intermittent drug dosing for anti-atherothrombosis.

Abstract

Interaction of Von Willebrand factor (VWF) with platelet glycoprotein (GP) Ib and of collagen with GPVI is essential for thrombus formation on ruptured or eroded atherosclerotic plaques (atherothrombosis). GPIb and GPVI signal through Bruton tyrosine kinase (Btk) which can irreversibly be blocked 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, the Btk-inhibitors prevented platelet thrombus formation onto human atherosclerotic plaque homogenate and plaque tissue sections from arterially flowing blood, whereas integrin α2β1 and VWF- dependent platelet adhesion to collagen important for physiologic hemostasis was not affected. This plaque-selective platelet inhibition was also observed in CLL patients taking 450 mg 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 onto 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 dose.

  • Submitted September 27, 2017.
  • Accepted March 14, 2018.