title: Rapidly regulating platelet activity in vivo with an antidote controlled platelet inhibitor.
abstract: Millions of individuals are prescribed platelet inhibitors, such as aspirin and clopidogrel, to reduce their risk of thrombosis-related clinical events. Unfortunately many platelet inhibitors are contraindicated in surgical settings because of their inherent bleeding risk complicating the treatment of patients who require surgery. We describe the development of a potent antiplatelet agent, an RNA aptamer-termed Ch-9.14-T10 that binds von Willebrand factor (VWF) with high affinity and inhibits thrombosis in a murine carotid artery damage model. As expected, when this potent antiplatelet agent is administered, it greatly increases bleeding from animals that are surgically challenged. To improve this antiplatelet agent's safety profile, we describe the generation of antidotes that can rapidly reverse the activity of Ch-9.14-T10 and limit blood loss from surgically challenged animals. Our work represents the first antidote controllable antiplatelet agent, which could conceivably lead to improved medical management of patients requiring antiplatelet medication who also need surgery.
authors.affiliation: Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Nimjee
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lohrmann
authors.forename: Haichen
authors.initials: H
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Snyder
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cummings
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.forename: Sabah
authors.initials: S
authors.lastname: Oney
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Sullenger
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology; D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001483:Base Sequence; D002482:Cellulose / Q000494:pharmacology; D003505:Cyclodextrins / Q000494:pharmacology; D006470:Hemorrhage / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013927:Thrombosis / Q000188:drug therapy; D014841:von Willebrand Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000931:Antidotes; D052157:Aptamers, Nucleotide; D003505:Cyclodextrins; D009841:Oligonucleotides; D010975:Platelet Aggregation Inhibitors; C041953:cyclodextrin polymer; D014841:von Willebrand Factor; D002482:Cellulose
references.citation: Curr Opin Mol Ther. 2009 Jun;11(3):322-8
references.pmid: 19479665
references.citation: Circulation. 2001 Jan 30;103(4):576-83
references.pmid: 11157725
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9524-9
references.pmid: 9689113
references.citation: Nat Biotechnol. 2004 Nov;22(11):1423-8
references.pmid: 15502817
references.citation: Blood. 2006 Aug 1;108(3):862-9
references.pmid: 16638935
references.citation: Thromb Haemost. 1998 Jan;79(1):202-10
references.pmid: 9459348
references.citation: Transfusion. 2010 May;50(5):1079-87
references.pmid: 20070617
references.citation: Nat Med. 2009 Oct;15(10):1224-8
references.pmid: 19801990
references.citation: Blood. 1999 Jul 1;94(1):172-8
references.pmid: 10381510
references.citation: Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5428-32
references.pmid: 8516284
references.citation: Surg Neurol. 2004 Oct;62(4):304-11
references.pmid: 15451272
references.citation: Nat Rev Drug Discov. 2003 Oct;2(10):775-89
references.pmid: 14526381
references.citation: Circulation. 2007 Dec 4;116(23):2678-86
references.pmid: 18025536
references.citation: Curr Opin Hematol. 2003 Mar;10(2):142-9
references.pmid: 12579041
references.citation: N Engl J Med. 1998 Aug 13;339(7):436-43
references.pmid: 9705684
references.citation: Lancet. 1999 Jan 16;353(9148):227-31
references.pmid: 9923894
references.citation: Arterioscler Thromb Vasc Biol. 2007 Oct;27(10):2079-93
references.pmid: 17600224
references.citation: Blood. 2002 May 15;99(10):3623-8
references.pmid: 11986216
references.citation: Circulation. 1999 Jul 27;100(4):437-44
references.pmid: 10421606
references.citation: J Thromb Haemost. 2009 Jul;7(7):1155-62
references.pmid: 19422452
references.citation: Curr Treat Options Cardiovasc Med. 2007 Apr;9(2):99-108
references.pmid: 17484812
references.citation: Arterioscler Thromb Vasc Biol. 2001 May;21(5):731-8
references.pmid: 11348867
references.citation: Oligonucleotides. 2007 Fall;17(3):265-74
references.pmid: 17854267
references.citation: Circulation. 2003 Jul 1;107(25):3141-5
references.pmid: 12796127
references.citation: Blood Rev. 2005 Mar;19(2):111-23
references.pmid: 15603914
references.citation: Blood. 1999 Mar 15;93(6):1825-30
references.pmid: 10068653
references.citation: Neurosurgery. 2006 Nov;59(5 Suppl 3):S77-92; discussion S3-13
references.pmid: 17053621
references.citation: Platelets. 2009 Aug;20(5):334-40
references.pmid: 19637097
references.citation: Blood. 1994 Jun 1;83(11):3218-24
references.pmid: 8193356