Busygina

Byrd

Jamasbi

Levade

Bye, A. P.

Gibbins, J. M.

Central Archive at the University of Reading

Move along, nothing to see here: Btk inhibitors stop platelets sticking to plaques  Article Published Version Creative Commons: Attribution 4.0 (CC­BY) Open Access Bye, A. P. and Gibbins, J. M. (2018) Move along, nothing to see here: Btk inhibitors stop platelets sticking to plaques. Journal of Thrombosis and Haemostasis, 16 (8). pp. 1461­1463. ISSN 1538­7933 doi: https://doi.org/10.1111/jth.14201 Available at http://centaur.reading.ac.uk/77822/ It is advisable to refer to the publisher’s version if you intend to cite from the work.  See Guidance on citing .To link to this article DOI: http://dx.doi.org/10.1111/jth.14201 Publisher: Wiley­Blackwell All outputs in CentAUR are protected by Intellectual Property Rights law, including copyright law. Copyright and IPR is retained by the creators or other copyright holders. Terms and conditions for use of this material are defined in the End User Agreement . www.reading.ac.uk/centaur CentAUR Central Archive at the University of Reading Reading’s research outputs onlineNEIGHBORHOOD WATCHMove along, nothing to see here: Btk inhibitors stop plateletssticking to plaquesA. P . BYE and J . M. G IBB INSInstitute for Cardiovascular and Metabolic Research, University of Reading, Reading, UKTo cite this article: Bye AP, Gibbins JM. Move along, nothing to see here: Btk inhibitors stop platelets sticking to plaques. J Thromb Haemost2018; 16: 1461–3.Platelets have evolved an intricate array of overlappingmechanisms to respond effectively to vessel damage byforming a clot to minimize blood loss. Unfortunately,these same responses may also be triggered by atheroscle-rotic lesions in diseased arteries. Vessels can becomeoccluded when platelets form a thrombus at the site of aruptured plaque, causing myocardial infarction (MI) orischemic stroke, depending on where the thrombus formsor where a resulting embolus becomes lodged.Current therapy following MI or ischemic strokeinvolves treatment with antiplatelet drugs to reduce therisk of recurrent events by inhibiting one or more of themechanisms that drive the formation of a platelet throm-bus. However, the overlap between the mechanisms thatdrive pathological thrombus formation and those thatfacilitate hemostasis means that patients receiving antipla-telet medication are at higher risk of hemorrhage, includ-ing intracranial hemorrhage and gastrointestinal bleeding.The benefits of current antiplatelet therapy outweigh therisks for patients, but there is still a need for safer anti-platelet therapies that do not compromise hemostasis tobetter serve this patient population, which is large andgrowing globally.In order to develop new antiplatelet drugs, researchersmust consider the similarities and differences between thepathological process of thrombosis and the physiologicalprocess of hemostasis. Platelets skim over the surfaces ofvascular endothelial cells, scanning for collagen and otherexposed subendothelial matrix proteins that serve as envi-ronmental cues indicating that vessel damage hasoccurred. The initial interaction with exposed collagenoccurs via the plasma protein von Willebrand factor,which binds to collagen and undergoes conformationalchange at high shear rates (present in arteries), enablingthe platelet protein glycoprotein (GP) Iba to bind to it.Collagen is also recognized directly by the platelet GPVIreceptor and integrin a2b1, which, together, mediate adhe-sion to collagen and trigger a cascade of intracellular sig-naling events that ultimately help the aggregate to growand become stable. Atherosclerotic plaques are rich incollagen and provide a strong environmental cue to plate-lets to adhere and form an aggregate within the lumen ofthe vessel. The intracellular signaling processes stimulatedin both scenarios are similar, and result in the plateletssynthesizing thromboxane A2 and secreting ADP, which,via paracrine and autocrine mechanisms, act as secondarymediators to recruit platelets to the growing aggregateand stabilize it. The antiplatelet drugs aspirin and P2Y12inhibitors such as clopidogrel or ticagrelor target thesepositive feedback mechanisms to limit thrombus growthand prevent vessel occlusion. The success of these drugsin providing relatively safe platelet inhibition can beunderstood in the context of the ‘core’ and ‘shell’ modelof thrombus formation, whereby a core of platelets isstrongly activated by direct contact with collagen, and issurrounded by an outer shell of weakly activated plateletsstimulated by secondary mediators. In this model, thecore is required for hemostasis, whereas the shell is par-tially redundant but serves a pathological role in throm-bosis by causing vessel occlusion. However, both aspirinand P2Y12 inhibitors are associated with increased ratesof hemorrhage, suggesting that either these drugs are notsufficiently specific in targeting the shell, or the shell isalso important for hemostasis.Although the environment of an atherosclerotic plaqueand that of a damaged blood vessel have similarities,some in vitro studies have identified differences that couldbe exploited pharmacologically to provide platelet inhibi-tion specifically in the context of atherothrombosis whilesparing normal hemostasis. One such difference concernsthe morphologically distinct forms of type I and type IIIcollagen present in atherosclerotic plaques, which triggerCorrespondence: Alexander Paul Bye, Institute for Cardiovascularand Metabolic Research, School of Biological Sciences, HarborneBuilding, University of Reading, Whiteknights, Reading RG6 6AS,UKTel.: +44 (0)118 378 4562E-mail: a.bye@reading.ac.ukReceived: 30 May 2018Manuscript handled by: T. LismanFinal decision: P.H. Reitsma, 6 June 2018© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Throm-bosis and Haemostasis.This is an open access article under the terms of the Creative Commons Attribution License,which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Journal of Thrombosis and Haemostasis, 16: 1461–1463 DOI: 10.1111/jth.14201thrombus formation via GPVI but not via integrin a2b1[1]. The traditional model of the interaction of plateletswith collagen involves complementary roles for integrina2b1 in mediating adhesion, and GPVI in stimulatingintracellular signaling and full platelet activation. How-ever, patients who are genetically deficient in plateletGPVI do not suffer from severe bleeding, suggesting thatthe role of GPVI is not as critical for hemostasis as itsrole as the primary mediator of collagen-evoked plateletactivation might suggest. The observations that GPVI iscritical for thrombus formation on atherosclerotic plaquesbut partially redundant for normal hemostasis promptedthe development of GPVI inhibitors for antiplatelet ther-apy, which are currently undergoing clinical trials (e.g.clinicaltrials.gov NCT03312855). Meanwhile, the first clin-ical Bruton’s tyrosine kinase (Btk) inhibitor, ibrutinib,has been approved for the treatment of chronic lympho-cytic leukemia and mantle cell lymphoma, and has beenfound to cause GPVI-specific platelet dysfunction inpatients. Btk is targeted for the treatment of B-cell lym-phomas because of its central role in the signaling pathwaythat promotes the development of B cells and contributestowards malignancy. The role of Btk in platelets hadalready been established in studies of mice deficient in Btkand in humans with X-linked gammaglobulinemia wholack functional Btk; these studies reported that GPVI sig-naling was at least partially dependent on the presence offunctional Btk. Btk and its family member Tec are knownto couple the GPVI receptor to phospholipase Cc activa-tion and the release of Ca2+ from intracellular stores intothe cytosol, which is a critical step in collagen-evokedplatelet activation. Like GPVI inhibitors, ibrutinib doesnot abolish adhesion to collagen under flow, suggestingthat other receptors and pathways are able to compen-sate for the loss of Btk activity downstream of GPVI.However, unlike the absence of severe bleeding inpatients with GPVI or Btk deficiencies, ibrutinib doesincrease the risk of major bleeding, suggesting that theeffects of ibrutinib on platelet function cannot be fullyattributable to loss of Btk or GPVI signaling. In supportof this, ibrutinib was found to inhibit platelet functiondownstream of other adhesion receptors, including GPIband integrin aIIbb3, and to inhibit other platelet kinases,most importantly Tec and Src family kinases [2,3]. Trialsof the more specific, second-generation Btk inhibitoracalabrutinib showed no incidents of major bleeding,and, although the drug was found to inhibit GPVI-mediated aggregation, it did not inhibit thrombus forma-tion on native type I collagen [4].The growing body of evidence surrounding Btk inhibi-tors and their effects on platelets begs the question oftheir potential efficacy in the prevention of atherothrom-bosis. The recent study by Busygina et al. sought toaddress this idea directly by studying the effects of Btkinhibitors in vitro and ex vivo on the interactions of plate-lets with atherosclerotic plaque tissue derived fromcarotid endarterectomy specimens [5]. Thrombus forma-tion on homogenized plaque or tissue sections under flowwas abolished by treatment of whole blood with the Btkinhibitors ibrutinib, acalabrutinib, and ONO/GS-4059 (anew-generation Btk inhibitor, also referred to as tirabruti-nib). However, thrombi forming on native type I collagenwere unaffected by acalabrutinib or ONO/GS-4059, andonly partially inhibited by higher concentrations of ibruti-nib. The finding that ibrutinib abolished thrombus forma-tion on plaque tissue, but only partially inhibitedthrombus formation on type I collagen, was recapitulatedwith blood samples from patients receiving ibrutiniborally (420 mg daily). The authors argue that the use ofplaque tissue and the use of native type I collagen repre-sent the pathological process of atherothrombosis and thephysiological process of hemostasis, respectively, andtherefore that Btk inhibitors preferentially target thepathological processes while sparing hemostasis. If thismodel is correct, Btk inhibitors could represent anentirely new approach to antiplatelet therapy, wherebythe interaction of platelets with the culprit lesion thattriggers vascular events is selectively prevented, while theability of platelets to trigger clotting in response to dam-aged, non-diseased tissue is spared. This view requiresacceptance of the simplified models of hemostasis andthrombosis used in the study, which cannot fully incorpo-rate rheological considerations, the contribution of coagu-lation or extracellular Ca2+ entry, and numerous otherfactors that contribute to these processes. However, shortof utilizing a more complex animal model in whichthrombosis is triggered by atherosclerotic plaque ruptureor erosion, it would be difficult to improve on theapproach taken by Busygina et al.Busygina et al. also theorized that the irreversible modeof action of ibrutinib could be exploited to achieve inhibi-tion with low or intermittent dosing, owing to the lack ofprotein turnover in the anucleate platelet. Antiplatelettherapy with the irreversible cyclooxygenase 1 inhibitoraspirin exploits the lack of platelet protein turnover toprovide effective platelet inhibition at low doses whileminimizing off-target effects. Utilizing this approach, theauthors were able to selectively block thrombus formationon plaque material by orally dosing healthy volunteerswith 120 mg of ibrutinib every day or every other day,and achieve similar levels of inhibition as observed inpatients receiving 420 mg daily. The use of low-dose ibru-tinib for antiplatelet therapy could reduce adverse eventsand avoid the off-target inhibition of Src family kinasesthat is likely to underpin severe platelet dysfunction andbleeding caused by higher concentrations of ibrutinib [6].This strategy could be even more effective with the morespecific Btk inhibitor acalabrutinib, which was only uti-lized in the in vitro part of the study, but may be associ-ated with fewer adverse events [4].Overall, the study provides a compelling basis forthinking of Btk inhibitors as potential antiplatelet drugs.© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Throm-bosis and Haemostasis.1462 Neighborhood WatchNo other kinase inhibitor has been approved for antipla-telet therapy, and the mode of action of ibrutinib andother Btk inhibitors in targeting signaling evoked byadhesion receptors rather than the conventional approachof preventing interactions of platelet receptors with theirligands is highly novel. Although existing approved Btkinhibitors may have potential as antiplatelet drugs, clini-cal trials to compare their efficacy with that of currenttherapies could still be an expensive and risky undertak-ing for the pharmaceutical industry. The authors suggesta highly targeted approach for the therapeutic use of Btkinhibitors as antiplatelet drugs by incorporating them intoprophylactic antithrombotic treatment prior to electivepercutaneous coronary interventions, which can exposeplaque material within the vascular system. Clinical evi-dence that the interaction between platelets and plaquematerial can be pharmacologically targeted would be avery important development, not only in the context ofBtk inhibitors, but also for antiplatelet drug developmentmore generally.AddendumA. P. Bye and J. M. Gibbins prepared the manuscript.Disclosure of Conflict of InterestsThe authors state that they have no conflict of interest.References1 Jamasbi J, Megens RT, Bianchini M, Munch G, Ungerer M,Faussner A, Sherman S, Walker A, Goyal P, Jung S, Brandl R,Weber C, Lorenz R, Farndale R, Elia N, Siess W. Differentialinhibition of human atherosclerotic plaque-induced platelet activa-tion by dimeric GPVI-Fc and anti-GPVI antibodies: functionaland imaging studies. J Am Coll Cardiol 2015; 65: 2404–15.2 Bye AP, Unsworth AJ, Vaiyapuri S, Stainer AR, Fry MJ, GibbinsJM. Ibrutinib inhibits platelet integrin alphaIIbbeta3 outside-insignaling and thrombus stability but not adhesion to collagen.Arterioscler Thromb Vasc Biol 2015; 35: 2326–35.3 Levade M, David E, Garcia C, Laurent PA, Cadot S, MichalletAS, Bordet JC, Tam C, Sie P, Ysebaert L, Payrastre B. Ibrutinibtreatment affects collagen and von Willebrand factor-dependentplatelet functions. Blood 2014; 124: 3991–5.4 Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S,Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, StephensDM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, HuangJ, Wang X, Kaptein A, et al. Acalabrutinib (ACP-196) in relapsedchronic lymphocytic leukemia. N Engl J Med 2016; 374: 323–32.5 Busygina K, Jamasbi J, Seiler T, Deckmyn H, Weber C, BrandlR, Lorenz R, Siess W. Oral Bruton tyrosine kinase inhibitorsselectively block atherosclerotic plaque-triggered thrombus forma-tion. Blood 2018; 24: 2605–16. in press.6 Bye AP, Unsworth AJ, Desborough MJ, Hildyard CAT, ApplebyN, Bruce D, Kriek N, Nock SH, Sage T, Hughes CE, GibbinsJM. Severe platelet dysfunction in NHL patients receiving ibruti-nib is absent in patients receiving acalabrutinib. Blood Adv 2017;1: 2610–23.© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Throm-bosis and Haemostasis.Neighborhood Watch 1463

Move along, nothing to see here: Btk inhibitors stop platelets sticking to plaques

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Move along, nothing to see here: Btk inhibitors stop platelets sticking to plaques

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