Platelet/von Willebrand Factor Inhibitors to the Rescue of Ischemic Stroke
2010; Lippincott Williams & Wilkins; Volume: 30; Issue: 10 Linguagem: Inglês
10.1161/atvbaha.110.212316
ISSN1524-4636
Autores Tópico(s)Platelet Disorders and Treatments
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 30, No. 10Platelet/von Willebrand Factor Inhibitors to the Rescue of Ischemic Stroke Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPlatelet/von Willebrand Factor Inhibitors to the Rescue of Ischemic Stroke Pier Mannuccio Mannucci Pier Mannuccio MannucciPier Mannuccio Mannucci From Scientific Direction, IRCCS Cà Granda Foundation Maggiore Policlinico Hospital, Milan, Italy. Originally published1 Oct 2010https://doi.org/10.1161/ATVBAHA.110.212316Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30:1882–1884In the last few decades, there have been dramatic advances in the treatment of acute coronary syndromes, leading to a substantial reduction in the actual mortality and disability of the most frequent atherothrombotic diseases. To make brief a long story of clinical success, coronary care units initially managed to reduce mortality by controlling severe arrhythmias and heart failure. Further reduction of major adverse cardiac events was subsequently achieved through early coronary artery reperfusion by means of pharmacological thrombolysis and percutaneous coronary intervention with stent deployment. The development and improved use of anticoagulant and antiplatelet drugs has also been crucial for further clinical progress.See accompanying article on page 1949Clinicians are well aware that progress was much smaller for ischemic stroke, the second most frequent atherothrombotic disease. Specialized intensive care units are helpful, but their impact on stroke mortality and disability is not as great as that of cardiac care units. Pharmacological thrombolysis is only effective in the limited therapeutic window of 3 to 4.5 hours after the onset of symptoms of cerebral ischemia (the sooner the treatment, the higher the efficacy), and the risk of intracerebral bleeding looms large. Moreover, antiplatelet and anticoagulant drugs are of more limited efficacy in the acute phase of ischemic stroke than in acute coronary syndromes, but at the same time they carry a high risk of bleeding in the central nervous system. These limitations warrant a fresh look into the pathogenetic mechanisms of thrombus formation in acute ischemic stroke,1 an essential step to foster treatment.Von Willebrand factor (VWF)—a huge multimeric glycoprotein contained in plasma, vascular endothelial cells, and platelets—is essential for platelet tethering/adhesion and subsequent activation/aggregation under vascular conditions of subendothelial collagen exposure and high shear stress. These properties of VWF explain its central role not only in primary hemostasis but also in arterial thrombogenesis. There is more and more evidence, at least from animal models, that a heightened interaction between platelets and VWF is an important mechanistic culprit in ischemic stroke, and hence a potential new target for treatment, because none of the currently available antiplatelet agents (aspirin, P2Y12, and platelet glycoprotein IIb/IIIa inhibitors) is directly targeting VWF. In this issue, De Meyer et al2 first confirm their own previous findings3 that mice made VWF deficient by means of gene abrogation are protected from ischemic brain injury, with a dramatic reduction in the size of thrombus formation and fibrin accumulation in the infarcted brain hemisphere. The novel findings of their elegant experiments are that reconstitution of plasma VWF deficiency by the transfer of genes encoding VWF variants defective in the binding sites to fibrillar collagen or platelet glycoprotein Ibα (GPIbα) conferred protection from stroke to mice, whereas reconstitution with transgenes encoding variants lacking the VWF binding site to platelet glycoprotein IIb/IIIa (GPIIb/IIIa) did restore susceptibility to stroke to a degree similar to that seen in wild-type mice.2What are the potential clinical implications of these experimental findings? Pharmacological agents that block the interactions between VWF and platelet GPIIb/IIIa have improved the treatment of acute coronary syndromes, but they are of little value in the treatment of acute ischemic stroke in animals and humans,4,5 in agreement with the experimental data obtained in mice by De Meyer et al.2 Pertaining to antithrombotic agents blocking VWF-collagen or VWF-GPIbα interactions, no phase III clinical trial designed to tackle ischemic stroke in humans is ongoing at the moment, so no drug has yet achieved regulation approval for marketing. However, there are some promising agents6–8 that have been tested in experimental studies and, to a lesser extent, in preclinical studies in healthy volunteers and phase I and II trials in patients with coronary artery disease or thrombotic thrombocytopenic purpura, ie, the epitome of the clinical conditions caused by a heightened interaction between VWF and platelet GPIbα. Examples of these novel therapeutic approaches are DNA aptamers, which act like chemical antibodies by binding with high affinity to VWF, and an array of monoclonal antibodies targeting VWF or its receptor GPIbα on platelets. The Table summarizes the mechanisms of action of these agents and the main preclinical and clinical studies, at least for those most widely investigated so far.9–22Table Inhibitors of the Interactions Between von Willebrand Factor (VWF) and Platelet Glycoprotein Ibα (GPIbα) in Arterial ThrombogenesisInhibitorTargets and Mechanisms of ActionPreclinical StudiesClinical StudiesReferencesAJW200Humanized monoclonal Ab, targeting human VWF.Inhibits shear-stress induced platelet aggregation in vitro in humans and ex-vivo in monkeys, with a moderate prolongation of the bleeding time.Pharmacokinetic/pharmacodynamic study in healthy volunteers: no clinical adverse effects or immunogenicity.9,10ARC1779Nuclease-resistant, PEG-conjugated aptamer. Binds to the activated VWF A1 domain, preventing GPIbα-VWF interactions.Inhibits shear-stress induced platelet function (PF-100) in blood from human volunteers and ACS patients.Improves thrombocytopenia in critically ill patients with congenital or acquired TTP. Prevents desmopressin-induced thrombocytopenia in type 2 von Willebrand disease.11 through 15ALX-0081Humanized anti-VWF nanobody, targeting the GPIbα-binding site.Inhibits in vitro platelet adhesion in blood from ACS patients. Greater therapeutic window compared to aspirin, clopidogrel and abciximab in baboons and cynomolgus monkeys.Inhibits VWF-mediated platelet aggregation induced by ristocetin in patients with stable angina undergoing PCI. Administered safely in combination with heparin, aspirin, clopidogrel. Ongoing phase 2 study in PCI.16,1782D6A3Monoclonal anti-VWF Ab. Inhibits VWF-collagen interactions.Inhibits VWF binding to collagen in a model of stent stenosis in baboons treated also with aspirin, clopidogrel and heparin. No thrombocytopenia or prolongation of the bleeding time. Lack of effect of neointima formation in the stent.None as yet.20,21h6B4-FabHumanized monoclonal Ab targeting GPIbα. Neutralizes the binding site of the VWF-A1 domain.Inhibits ex vivo the VWF-mediated platelet aggregation induced by ristocetin in baboons. Full antithrombotic effect with no prolongation of the bleeding time in the frame of a model of injured and stenosed femoral artery in baboons.None as yet.18,19GPG-290Recombinant chimeric protein linked to human Fc, containing the N-terminal 290 amino acids of GPIbα.Inhibits VWF-GPIbα interactions and thrombus formation in a canine model of coronary artery thrombosis, with no increase of bleeding. The prolonged template bleeding time caused by larger doses of GPG-290 was prevented by i.v. desmopressin (potential antidote).None as yet.22Of course, a still unresolved but very cogent issue is whether or not pharmacological targeting of the VWF-platelet GPIbα axis would cause fewer bleeding complications than the currently available antiplatelet agents. There are reasons to surmise that inhibitors of VWF-dependent platelet tethering/adhesion and subsequent activation/aggregation may reduce arterial thrombus formation without impinging on primary hemostasis, because these drugs should only be active under settings of high fluid shear stress (shear rates greater than 1500/s), such as those that develop in large arteries rendered stenotic by atherosclerotic plaques. At the moment, this optimistic view is supported mainly by animal studies demonstrating that inhibition of various models of arterial thrombosis is associated with minimal bleeding (Table). For instance, in healthy volunteers, the aptamer ARC1779 caused no excessive bleeding in spite of an adequate block of ex vivo platelet aggregation.11 In thrombocytopenic patients with thrombotic thrombocytopenic purpura, the same agent was given without mishap.14 The nanobody ALX-0081 was infused safely to healthy male volunteers and patients with coronary artery disease undergoing percutaneous intervention.16,17 It is hoped that these early results, promising as they are as far as safety, will soon be confirmed by larger clinical trials designed to assess efficacy, particularly in a disease such as ischemic stroke that currently lacks valid antiplatelet drugs. The Finnish pediatrician Erik von Willebrand will smile in his grave realizing that his seminal description of the inherited bleeding disorder in the Åland Islands may ultimately help to rescue patients with stroke.23FootnotesCorrespondence to Pier Mannuccio Mannucci, Scientific Direction, Istituto di Ricovero e Cura Carattere Scientifico Cà Granda Foundation Maggiore Policlinico Hospital, Via Pace 9, Milan 20122, Italy. E-mail [email protected] References 1 Stoll G, Kleinschnitz C, Nieswandt B. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood. 2008; 112: 3555–3562.CrossrefMedlineGoogle Scholar2 De Meyer SF, Schwarz T, Deckmyn H, Denis CV, Nieswandt B, Stoll G, Vanhoorelbeke K, Kleinschnitz C. Binding of von Willebrand factor to collagen and GPIbα, but not to GPIIb/IIIa, contributes to ischemic stroke in mice [epub ahead of print]. Arterioscler Thromb Vasc Biol. 2010; PMID: 20616311.Google Scholar3 Kleinschnitz C, De Meyer SF, Schwarz T, Austinat M, Vanhoorelbeke K, Nieswandt B, Deckmyn H. Deficiency of von Willebrand factor protects mice from ischemic stroke. Blood. 2009; 113: 3600–3603.CrossrefMedlineGoogle Scholar4 Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation. 2007; 115: 2323–2330.LinkGoogle Scholar5 Adams HP Jr, Effron MB, Torner J, Dávalos A, Frayne J, Teal P, Leclerc J, Oemar B, Padgett L, Barnathan ES, Hacke W; AbESTT-II Investigators. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke. 2008; 39: 87–99.LinkGoogle Scholar6 De Meyer SF, Vanhoorelbeke K, Broos K, Salles II, Deckmyn H. Antiplatelet drugs. Br J Hematol. 2008; 142: 515–528.CrossrefMedlineGoogle Scholar7 Keefe AD, Schaub RG. Aptamers as candidate therapeutics for cardiovascular indications. Curr Opin Pharmacol. 2008; 8: 147–152.CrossrefMedlineGoogle Scholar8 Spiel AO, Gilbert JC, Jilma B. von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation. 2008; 117: 1449–1459.LinkGoogle Scholar9 Kageyama S, Matsushita J, Yamamoto H. Effect of a humanized monoclonal antibody to von Willebrand factor in a canine model of coronary arterial thrombosis. Eur J Pharmacol. 2002; 443: 143–149.CrossrefMedlineGoogle Scholar10 Kageyama S, Yamamoto H, Nakazawa H, Matsushita J, Kouyama T, Gonsho A, Ikeda Y, Yoshimoto R. Pharmacokinetics and pharmacodynamics of AJW200, a humanized monoclonal antibody to von Willebrand factor, in monkeys. Arterioscler Thromb Vasc Biol. 2002; 22: 187–192.CrossrefMedlineGoogle Scholar11 Gilbert JC, DeFeo-Fraulini T, Hutabarat RM, Horvath CJ, Merlino PG, Marsh HN, Healy JM, Boufakhreddine S, Holohan TV, Schaub RG. First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers. Circulation. 2007; 116: 2678–2686.LinkGoogle Scholar12 Spiel AO, Mayr FB, Ladani N, Wagner PG, Schaub RG, Gilbert JC, Jilma B. The aptamer ARC1779 is a potent and specific inhibitor of von Willebrand factor mediated ex vivo platelet function in acute myocardial infarction. Platelets. 2009; 20: 334–340.CrossrefMedlineGoogle Scholar13 Diener JL, Daniel Lagassé HA, Duerschmied D, Merhi Y, Tanguay JF, Hutabarat R, Gilbert J, Wagner DD, Schaub R. Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779. J Thromb Hemost. 2009; 7: 1155–1162.CrossrefMedlineGoogle Scholar14 Knöbl P, Jilma B, Gilbert JC, Hutabarat RM, Wagner PG, Jilma-Stohlawetz P. Anti-von Willebrand factor aptamer ARC1779 for refractory thrombotic thrombocytopenic purpura. Transfusion. 2009; 49: 2181–2185.CrossrefMedlineGoogle Scholar15 Jilma B, Paulinska P, Jilma-Stohlawetz P, Gilbert JC, Hutabarat R, Knöbl P. A randomized pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease [epub ahead of print]. Thromb Hemost. 2010; 104: PMID: 20589313 .Google Scholar16 Ulrichts H, Schoolmeester A, Hoefman S, Lauwereys M, Casteels P, Stanssens P, Baumeister J, Roodt J, de Jaegere PPT, Holz J. Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared to current marketed antiplatelet drugs. J Thromb Hemost. 2009; (suppl): AS-Th-024.Google Scholar17 Holz J, Bartunek J, Barbato E, Vercruysse K, Pullan S, Heydrickxs G. ALX-0081 a novel anti-thrombotic: first results of a multiple dose phase I study in patients with stable angina undergoing PCI. J Thromb Hemost. 2009; (suppl): PP-WE-416.Google Scholar18 Fontayne A, Vanhoorelbeke K, Pareyn I, Van Rompaey I, Meiring M, Lamprecht S, Roodt J, Desmet J, Deckmyn H. Rational humanization of the powerful antithrombotic anti-GPIbalpha antibody: 6B4. Thromb Hemost. 2006; 96: 671–684.CrossrefMedlineGoogle Scholar19 Wu D, Vanhoorelbeke K, Cauwenberghs N, Meiring M, Depraetere H, Kotze HF, Deckmyn H. Inhibition of the von Willebrand (VWF)-collagen interaction by an antihuman VWF monoclonal antibody results in abolition of in vivo arterial platelet thrombus formation in baboons. Blood. 2002; 99: 3623–3628.CrossrefMedlineGoogle Scholar20 Vanhoorelbeke K, Depraetere H, Romijn RA, Huizinga EG, De Maeyer M, Deckmyn H. A consensus tetrapeptide selected by phage display adopts the conformation of a dominant discontinuous epitope of a monoclonal anti-VWF antibody that inhibits the von Willebrand factor-collagen interaction. J Biol Chem. 2003; 278: 37815–37821.CrossrefMedlineGoogle Scholar21 De Meyer SF, Staelens S, Badenhorst PN, Pieters H, Lamprecht S, Roodt J, Janssens S, Meiring M, Vanhoorelbeke K, Bruwer A, Brown S, Deckmyn H. Coronary artery in-stent stenosis persists despite inhibition of the von Willebrand factor–collagen interaction in baboons. Thromb Hemost. 2007; 98: 1343–1349.CrossrefMedlineGoogle Scholar22 Wadanoli M, Sako D, Shaw GD, Schaub RG, Wang Q, Tchernychev B, Xu J, Porter TJ, Huang Q. The von Willebrand factor antagonist (GPG-290) prevents coronary thrombosis without prolongation of bleeding time. Thromb Hemost. 2007; 98: 397–405.CrossrefMedlineGoogle Scholar23 Mannucci PM. Treatment of von Willebrand's disease. N Engl J Med. 2004; 351: 683–694.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited BySabater-Lleal M, Huffman J, de Vries P, Marten J, Mastrangelo M, Song C, Pankratz N, Ward-Caviness C, Yanek L, Trompet S, Delgado G, Guo X, Bartz T, Martinez-Perez A, Germain M, de Haan H, Ozel A, Polasek O, Smith A, Eicher J, Reiner A, Tang W, Davies N, Stott D, Rotter J, Tofler G, Boerwinkle E, de Maat M, Kleber M, Welsh P, Brody J, Chen M, Vaidya D, Soria J, Suchon P, van Hylckama Vlieg A, Desch K, Kolcic I, Joshi P, Launer L, Harris T, Campbell H, Rudan I, Becker D, Li J, Rivadeneira F, Uitterlinden A, Hofman A, Franco O, Cushman M, Psaty B, Morange P, McKnight B, Chong M, Fernandez-Cadenas I, Rosand J, Lindgren A, Gudnason V, Wilson J, Hayward C, Ginsburg D, Fornage M, Rosendaal F, Souto J, Becker L, Jenny N, März W, Jukema J, Dehghan A, Trégouët D, Morrison A, Johnson A, O'Donnell C, Strachan D, Lowenstein C and Smith N (2018) Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels, Circulation, 139:5, (620-635), Online publication date: 29-Jan-2019. Agostini S and Lionetti V (2017) New insights into the non-hemostatic role of von Willebrand factor in endothelial protection, Canadian Journal of Physiology and Pharmacology, 10.1139/cjpp-2017-0126, 95:10, (1183-1189), Online publication date: 1-Oct-2017. Wu M, Atkinson T and Lindner J (2017) Platelets and von Willebrand factor in atherogenesis, Blood, 10.1182/blood-2016-07-692673, 129:11, (1415-1419), Online publication date: 16-Mar-2017. Pavlova J, Fasano A and Sequeira A (2016) Numerical simulations of a reduced model for blood coagulation, Zeitschrift für angewandte Mathematik und Physik, 10.1007/s00033-015-0610-2, 67:2, Online publication date: 1-Apr-2016. Verhenne S, Denorme F, Libbrecht S, Vandenbulcke A, Pareyn I, Deckmyn H, Lambrecht A, Nieswandt B, Kleinschnitz C, Vanhoorelbeke K and De Meyer S (2015) Platelet-derived VWF is not essential for normal thrombosis and hemostasis but fosters ischemic stroke injury in mice, Blood, 10.1182/blood-2015-03-632901, 126:14, (1715-1722), Online publication date: 1-Oct-2015. Rutten B, Maseri A, Cianflone D, Laricchia A, Cristell N, Durante A, Spartera M, Ancona F, Limite L, Hu D, Li H, Uren N, de Groot P, Mannucci P and Roest M (2014) Plasma levels of active Von Willebrand factor are increased in patients with first ST-segment elevation myocardial infarction: A multicenter and multiethnic study, European Heart Journal: Acute Cardiovascular Care, 10.1177/2048872614534388, 4:1, (64-74), Online publication date: 1-Feb-2015. Arslan Y, Yoldaş T and Zorlu Y (2013) Interaction Between vWF Levels and Aspirin Resistance in Ischemic Stroke Patients, Translational Stroke Research, 10.1007/s12975-013-0259-0, 4:5, (484-487), Online publication date: 1-Oct-2013. Golwala H, Dib C, Abu-Fadel M and Tafur A (2012) A New Era of Antithrombotic Therapy in Patients With Atrial Fibrillation, The American Journal of the Medical Sciences, 10.1097/MAJ.0b013e3182429b1e, 344:2, (128-135), Online publication date: 1-Aug-2012. Nichols T, Bellinger D, Merricks E, Raymer R, Kloos M, DeFriess N, Ragni M and Griggs T (2010) Porcine and Canine von Willebrand Factor and von Willebrand Disease: Hemostasis, Thrombosis, and Atherosclerosis Studies, Thrombosis, 10.1155/2010/461238, 2010, (1-11), Online publication date: 7-Feb-2010. October 2010Vol 30, Issue 10 Advertisement Article Information Metrics https://doi.org/10.1161/ATVBAHA.110.212316PMID: 20844269 Originally publishedOctober 1, 2010 PDF download Advertisement
Referência(s)