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Original Articles

Janus kinase inhibitors ruxolitinib and baricitinib impair glycoprotein-VI mediated platelet function

, , , , , , , , & show all
Pages 404-415 | Received 25 Jan 2021, Accepted 26 Apr 2021, Published online: 07 Jun 2021

References

  • Subramaniam PS, Torres BA, Johnson HM. So many ligands, so few transcription factors: a new paradigm for signaling through the STAT transcription factors. Cytokine 2001;15:175–187. doi:10.1006/cyto.2001.0905.
  • Kiu H, Nicholson SE. Biology and significance of the JAK/STAT signalling pathways. Growth Factors Chur Switz 2012;30:88–106. doi:10.3109/08977194.2012.660936.
  • Aaronson DS, Horvath CM. A road map for those who don’t know JAK-STAT. Science 2002;296:1653–1655. doi:10.1126/science.1071545.
  • Kontzias A, Kotlyar A, Laurence A, Changelian P, O’Shea JJ. Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol 2012;12:464–470. doi:10.1016/j.coph.2012.06.008.
  • McKeage K. Ruxolitinib: a review in polycythaemia vera. Drugs 2015;75:1773–1781. doi:10.1007/s40265-015-0470-2.
  • Plosker GL. Ruxolitinib: a review of its use in patients with myelofibrosis. Drugs 2015;75:297–308. doi:10.1007/s40265-015-0351-8.
  • Tanaka Y. Recent progress and perspective in JAK inhibitors for rheumatoid arthritis: from bench to bedside. J Biochem (Tokyo) 2015;158:173–179. doi:10.1093/jb/mvv069.
  • Genovese MC, Fleischmann R, Combe B, Hall S, Rubbert-Roth A, Zhang Y, Zhou Y, Mohamed M-EF, Meerwein S, Pangan AL, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. The Lancet 2018;391:2513–2524. doi:10.1016/S0140-6736(18)31116-4.
  • Markham A. Baricitinib: first Global Approval. Drugs 2017;77:697–704. doi:10.1007/s40265-017-0723-3.
  • Gonzales AJ, Bowman JW, Fici GJ, Zhang M, Mann DW, Mitton‐Fry M, et al. Oclacitinib (APOQUEL®) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy. J Vet Pharmacol Ther 2014;37:317–324. doi:10.1111/jvp.12101.
  • Virtanen AT, Haikarainen T, Raivola J, Silvennoinen O. Selective JAKinibs: prospects in inflammatory and autoimmune diseases. BioDrugs 2019;33:15–32. doi:10.1007/s40259-019-00333-w.
  • Rajasimhan S, Pamuk O, Katz JD. Safety of janus kinase inhibitors in older patients: a focus on the thromboembolic risk. Drugs Aging 2020;37:551–558. doi:10.1007/s40266-020-00775-w.
  • Verden A, Dimbil M, Kyle R, Overstreet B, Hoffman KB. Analysis of spontaneous postmarket case reports submitted to the FDA regarding thromboembolic adverse events and JAK inhibitors. Drug Saf 2018;41:357–361. doi:10.1007/s40264-017-0622-2.
  • Mehta P, Ciurtin C, Scully M, Levi M, Chambers RC. JAK inhibitors in COVID-19: need for vigilance regarding increased inherent thrombotic risk. Eur Respir J 2020;56:2001919. doi:10.1183/13993003.01919-2020.
  • Barraco F, Greil R, Herbrecht R, Schmidt B, Reiter A, Willenbacher W, Raymakers R, Liersch R, Wroclawska M, Pack R, et al. Real-world non-interventional long-term post-authorisation safety study of ruxolitinib in myelofibrosis. Br J Haematol 2020. doi:10.1111/bjh.16729.
  • Aslan JE. Platelet shape change. In: Gresele P, Kleiman NS, Lopez JA, Page CP, editors. Platelets in thrombotic and non-thrombotic disorders: pathophysiology, pharmacology and therapeutics: an update. Springer International Publishing; 2017. p. 321–336. doi:10.1007/978-3-319-47462-5_24.
  • Koupenova M, Clancy L, Corkrey HA, Freedman JE. Circulating platelets as mediators of immunity, inflammation, and thrombosis. Circ Res 2018;122:337–351. doi:10.1161/CIRCRESAHA.117.310795.
  • Aslan JE. Platelet proteomes, pathways, and phenotypes as informants of vascular wellness and disease. Arterioscler Thromb Vasc Biol 2021;41:999–1011. doi:10.1161/ATVBAHA.120.314647.
  • Research, C. for D. E. and. FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). FDA. 2019.
  • Taylor PC, Weinblatt ME, Burmester GR, Rooney TP, Witt S, Walls CD, Issa M, Salinas CA, Saifan C, Zhang X, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol Hoboken NJ 2019;71:1042–1055. doi:10.1002/art.40841.
  • Samuelson BT, Vesely SK, Chai-Adisaksopha C, Scott BL, Crowther M, Garcia D, et al. The impact of ruxolitinib on thrombosis in patients with polycythemia vera and myelofibrosis: a meta-analysis. Blood Coagul Fibrinolysis Int J Haemost Thromb 2016;27:648–652. doi:10.1097/MBC.0000000000000446.
  • Marchetti M, Barosi G, Cervantes F, Birgegård G, Griesshammer M, Harrison C, Hehlmann R, Kiladjian -J-J, Kröger N, McMullin MF, et al. Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations. Leukemia 2017;31:882–888. doi:10.1038/leu.2016.283.
  • Harrison CN, Vannucchi AM, Platzbecker U, Cervantes F, Gupta V, Lavie D, Passamonti F, Winton EF, Dong H, Kawashima J, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol 2018;5:e73–e81. doi:10.1016/S2352-3026(17)30237-5.
  • Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger M, Miller C, Silver RT, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366:799–807. doi:10.1056/NEJMoa1110557.
  • Shatzel JJ, Olson SR, Tao DL, McCarty OJT, Danilov AV, DeLoughery TG, et al. Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies. J Thromb Haemost JTH 2017;15:835–847. doi:10.1111/jth.13651.
  • Zheng TJ, Lofurno ER, Melrose AR, Lakshmanan HHS, Pang J, Phillips KG, Fallon ME, Kohs TCL, Ngo ATP, Shatzel JJ, et al. Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. Am J Physiol Cell Physiol 2021. doi:10.1152/ajpcell.00296.2020.
  • Rigg RA, Aslan JE, Healy LD, Wallisch M, Thierheimer MLD, Loren CP, Pang J, Hinds MT, Gruber A, McCarty OJT. Oral administration of Bruton’s Tyrosine Kinase (Btk) inhibitors impairs GPVI-mediated platelet function. Am J Physiol Cell Physiol 2015. doi:10.1152/ajpcell.00325.2015.
  • Loren CP, Aslan JE, Rigg RA, Nowak MS, Healy LD, Gruber A, Druker BJ, McCarty OJT, et al. The BCR-ABL inhibitor ponatinib inhibits platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling, platelet activation and aggregate formation under shear. Thromb Res 2015;135:155–160. doi:10.1016/j.thromres.2014.11.009.
  • Lu W-J, Lin K-C, Huang S-Y, Thomas PA, Wu Y-H, Wu H-C, Lin K-H, Sheu J-R, et al. Role of a Janus kinase 2-dependent signaling pathway in platelet activation. Thromb Res 2014;133:1088–1096. doi:10.1016/j.thromres.2014.03.042.
  • Yuan H, Houck KL, Tian Y, Bharadwaj U, Hull K, Zhou Z, Zhou M, Wu X, Tweardy DJ, Romo D, et al. Piperlongumine blocks JAK2-STAT3 to inhibit collagen-induced platelet reactivity independent of reactive oxygen species†. PLOS ONE 2015;10:e0143964. doi:10.1371/journal.pone.0143964.
  • Xu Z, Xu Y-J, Hao Y-N, Ren L-J, Zhang Z-B, Xu X, Cao B-Y, Dai K-S, Zhu L, Fang Q, et al. A novel STAT3 inhibitor negatively modulates platelet activation and aggregation. Acta Pharmacol Sin 2017;38:651–659. doi:10.1038/aps.2016.155.
  • Zhou Z, Gushiken FC, Bolgiano D, Salsbery BJ, Aghakasiri N, Jing N, Wu X, Vijayan KV, Rumbaut RE, Adachi R, et al. STAT3 regulates collagen-induced platelet aggregation independent of its transcription factor activity. Circulation 2013;127:476–485. doi:10.1161/CIRCULATIONAHA.112.132126.
  • Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998;334((Pt 2)):297–314. doi:10.1042/bj3340297.
  • Houck KL, Yuan H, Tian Y, Solomon M, Cramer D, Liu K, Zhou Z, Wu X, Zhang J, Oehler V, et al. Physical proximity and functional cooperation of glycoprotein 130 and glycoprotein VI in platelet membrane lipid rafts. J Thromb Haemost 2019;17:1500–1510. doi:10.1111/jth.14525.
  • Eaton N, Subramanian M, Schulte M, Drew C, Jakab D, Haberichter S, Weiler H, Falet H. Bleeding diathesis in mice lacking JAK2 in platelets. Blood Adv. In press.
  • Izquierdo I, Barrachina MN, Hermida-Nogueira L, Casas V, Morán LA, Lacerenza S, Pinto-Llorente R, Eble JA, de los Ríos V, Domínguez E, et al. A Comprehensive tyrosine phosphoproteomic analysis reveals novel components of the platelet CLEC-2 signaling cascade. Thromb Haemost 2020;120:262–276. doi:10.1055/s-0039-3400295.
  • Babur Ö, Melrose AR, Cunliffe JM, Klimek J, Pang J, Sepp A-LI, Zilberman-Rudenko J, Tassi Yunga S, Zheng T, Parra-Izquierdo I, et al. Phosphoproteomic quantitation and causal analysis reveal pathways in GPVI/ITAM-mediated platelet activation programs. Blood 2020;136:2346–2358. doi:10.1182/blood.2020005496.
  • Rodríguez-Liñares B, Watson SP. Phosphorylation of JAK2 in thrombin-stimulated human platelets. FEBS Lett 1994;352:335–338. doi:10.1016/0014-5793(94)00983-X.
  • Tibbles HE, Vassilev A, Wendorf H, Schonhoff D, Zhu D, Lorenz D, Waurzyniak B, Liu X-P, Uckun FM, et al. Role of a JAK3-dependent biochemical signaling pathway in platelet activation and aggregation. J Biol Chem 2001;276:17815–17822. doi:10.1074/jbc.M011405200.
  • Ezumi Y, Takayama H, Okuma M. Thrombopoietin, c-Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists-induced aggregation in platelets in vitro. FEBS Lett 1995;374:48–52. doi:10.1016/0014-5793(95)01072-M.
  • Miyakawa Y, Oda A, Druker BJ, Miyazaki H, Handa M, Ohashi H, Ikeda Y, et al. Thrombopoietin induces tyrosine phosphorylation of Stat3 and Stat5 in human blood platelets. Blood 1996;87:439–446. doi:10.1182/blood.V87.2.439.bloodjournal872439.
  • Moore SF, Smith NR, Blair TA, Durrant TN, Hers I. Critical roles for the phosphatidylinositide 3-kinase isoforms p110β and p110γ in thrombopoietin-mediated priming of platelet function. Sci Rep 2019;9:1468. doi:10.1038/s41598-018-37012-9.
  • Hobbs CM, Manning H, Bennett C, Vasquez L, Severin S, Brain L, Mazharian A, Guerrero JA, Li J, Soranzo N, et al. JAK2V617F leads to intrinsic changes in platelet formation and reactivity in a knock-in mouse model of essential thrombocythemia. Blood 2013;122:3787–3797. doi:10.1182/blood-2013-06-501452.
  • Matsuura S, Thompson CR, Belghasem ME, Bekendam RH, Piasecki A, Leiva O, Ray A, Italiano J, Yang M, Merill-Skoloff G, et al. Platelet Dysfunction and thrombosis in JAK2 V617F -mutated primary myelofibrotic mice. Arterioscler Thromb Vasc Biol 2020;40:e262–e272. doi:10.1161/ATVBAHA.120.314760.
  • Dellas C, Schäfer K, Rohm I, Lankeit M, Leifheit M, Loskutoff D, Hasenfuss G, Konstantinides S, et al. Leptin signalling and leptin-mediated activation of human platelets: importance of JAK2 and the phospholipases Cgamma2 and A2. Thromb Haemost 2007;98:1063–1071. doi:10.1160/TH07-03-0213.
  • Bye AP, Unsworth AJ, Gibbins JM. Platelet signaling: a complex interplay between inhibitory and activatory networks. J Thromb Haemost 2016;14:918–930. doi:10.1111/jth.13302.
  • Stalker TJ, Newman DK, Ma P, Wannemacher KM, Brass LF. Platelet signaling. Handb Exp Pharmacol 2012:59–85. doi:10.1007/978-3-642-29423-5_3.
  • Kehrel B, Wierwille S, Clemetson KJ, Anders O, Steiner M, Graham Knight C, Farndale RW, Okuma M, Barnes MJ, et al. Glycoprotein VI is a major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not. Blood 1998;91:491–499. doi:10.1182/blood.V91.2.491.
  • Tt Z, Li H, Cheung SM, Costantini JL, Hou S, Al-Alwan M, Marshall AJ, et al. Phosphoinositide 3-kinase-regulated adapters in lymphocyte activation. Immunol Rev 2009;232:255–272. doi:10.1111/j.1600-065X.2009.00838.x.
  • Kiwanuka KN, Motunrayo Kolawole E, Mcleod JJA, Baker B, Paez PA, Zellner MP, Haque TT, Paranjape A, Jackson K, Kee SA, et al. Stat5B is required for IgE-mediated mast cell function in vitro and in vivo. Cell Immunol 2021;364:104344. doi:10.1016/j.cellimm.2021.104344.
  • Durrant TN, Hutchinson JL, Heesom KJ, Anderson KE, Stephens LR, Hawkins PT, Marshall AJ, Moore SF, Hers I, et al. In-depth PtdIns(3,4,5)P3 signalosome analysis identifies DAPP1 as a negative regulator of GPVI-driven platelet function. Blood Adv 2017;1:918–932. doi:10.1182/bloodadvances.2017005173.
  • Zhou Z, Gushiken FC, Bergeron A, Vijayan VK, Rumbaut R, Lopez JA, Dong J-F, et al. STAT3 regulates collagen-induced platelet aggregation independent of its transcription factor activity. Blood 2010;116:157–157. doi:10.1182/blood.V116.21.157.157.
  • Müller J, Sperl B, Reindl W, Kiessling A, Berg T. Discovery of chromone-based inhibitors of the transcription factor STAT5. Chembiochem Eur J Chem Biol 2008;9:723–727. doi:10.1002/cbic.200700701.
  • Margraf A, Zarbock A. Platelets in Inflammation and Resolution. J Immunol 2019;203:2357–2367. doi:10.4049/jimmunol.1900899.
  • Gear ARL, Camerini D. Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. Microcirc N Y N 1994 2003;10:335–350.
  • D’ Atri LP, Schattner M. Platelet toll-like receptors in thromboinflammation. Front Biosci Landmark Ed 2017;22:1867–1883. doi:10.2741/4576.
  • Fragoulis GE, McInnes IB, Siebert S. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology 2019;58:i43–i54. doi:10.1093/rheumatology/key276.
  • Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK–STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs 2017;77:521–546. doi:10.1007/s40265-017-0701-9.
  • Haines E, Minoo P, Feng Z, Resalatpanah N, Nie X-M, Campiglio M, Alvarez L, Cocolakis E, Ridha M, Di Fulvio M, et al. Tyrosine phosphorylation of Grb2: role in prolactin/epidermal growth factor cross talk in mammary epithelial cell growth and differentiation. Mol Cell Biol 2009;29:2505–2520. doi:10.1128/MCB.00034-09.
  • Abell K, Watson CJ. The Jak/Stat pathway: a novel way to regulate PI3K activity. Cell Cycle Georget Tex 2005;4:897–900. doi:10.4161/cc.4.7.1837.
  • Lu Y, Zhou J, Xu C, Lin H, Xiao J, Wang Z, Yang B, et al. JAK/STAT and PI3K/AKT pathways form a mutual transactivation loop and afford resistance to oxidative stress-induced apoptosis in cardiomyocytes. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 2008;21:305–314. doi:10.1159/000129389.
  • Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, Anania FA, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 2007;67:2497–2507. doi:10.1158/0008-5472.CAN-06-3075.
  • Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, Rawling M, Savory E, Stebbing J, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. The Lancet 2020;395:e30–e31. doi:10.1016/S0140-6736(20)30304-4.
  • Parra-Izquierdo I, Aslan JE. Perspectives on platelet heterogeneity and host immune response in coronavirus disease 2019 (COVID-19). Semin Thromb Hemost 2020;46:826–830. doi:10.1055/s-0040-1715093.
  • Blair TA, Moore SF, Walsh TG, Hutchinson JL, Durrant TN, Anderson KE, Poole AW, Hers I, et al. Phosphoinositide 3-kinase p110α negatively regulates thrombopoietin-mediated platelet activation and thrombus formation. Cell Signal 2018;50:111–120. doi:10.1016/j.cellsig.2018.05.005.
  • Grimley PM, Dong F, Rui H. Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation. Cytokine Growth Factor Rev 1999;10:131–157.
  • Kollmann S, Grundschober E, Maurer B, Warsch W, Grausenburger R, Edlinger L, Huuhtanen J, Lagger S, Hennighausen L, Valent P, et al. Twins with different personalities: STAT5B—but not STAT5A—has a key role in BCR/ABL-induced leukemia. Leukemia 2019;33:1583–1597. doi:10.1038/s41375-018-0369-5.
  • Drayer AL, Boer A-K, Los EL, Esselink MT, Vellenga E. Stem cell factor synergistically enhances thrombopoietin-induced STAT5 signaling in megakaryocyte progenitors through JAK2 and Src kinase. Stem Cells Dayt Ohio 2005;23:240–251. doi:10.1634/stemcells.2004-0153.

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