title: P-selectin inhibition therapeutically promotes thrombus resolution and prevents vein wall fibrosis better than enoxaparin and an inhibitor to von Willebrand factor.
abstract: OBJECTIVE
  Aptamers are oligonucleotides targeting protein-protein interactions with pharmacokinetic profiles and activity reversal options. Although P-selectin and von Willebrand factor (vWF) have been implicated in the development of venous thrombosis (VT), no studies have directly compared aptamer efficacy with standard of care in VT. In this study, ARC5692, an anti-P-selectin aptamer, and ARC15105, an anti-vWF aptamer, were compared with low-molecular-weight heparin, enoxaparin, to test the efficacy of P-selectin or vWF inhibition in promoting thrombus resolution and preventing vein wall fibrosis, in a baboon model of VT.
  
  
  RESULTS
  Groups were as follows: treatment arm: animals received P-selectin or vWF aptamer inhibitors or enoxaparin (n=3 per group). Controls received no treatment (n=3). Prophylactic arm: animals received P-selectin inhibitor (n=4) or vWF inhibitor (n=3). Treatment arm: P-selectin-inhibitor demonstrated a significant improvement in vein recanalization by magnetic resonance venography (73% at day 21), and significantly decreased vein wall collagen, compared with all groups. Anti-P-selectin equaled enoxaparin in maintaining valve competency by ultrasound. All control animals had compromised valve competency post thrombosis. Prophylactic arm: animals receiving P-selectin and vWF inhibitors demonstrated improved vein recanalization by magnetic resonance venography versus controls (80% and 85%, respectively, at day 21). Anti-P-selectin protected iliac valve function better than anti-vWF, and both improved valve function versus controls. No adverse bleeding events were observed.
  
  
  CONCLUSIONS
  The P-selectin inhibitor aptamer promoted iliac vein recanalization, preserved valve competency, and decreased vein wall fibrosis. The results of this work suggest that P-selectin inhibition maybe an ideal target in the treatment and prophylaxis of deep VT, warranting clinical trials.
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.). josediaz@med.umich.edu.
authors: Jose A
authors: JA
authors: Diaz
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Shirley K
authors: SK
authors: Wrobleski
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Christine M
authors: CM
authors: Alvarado
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Angela E
authors: AE
authors: Hawley
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Nichole K
authors: NK
authors: Doornbos
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Patrick A
authors: PA
authors: Lester
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Suzan E
authors: SE
authors: Lowe
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Joy E
authors: JE
authors: Gabriel
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Karen J
authors: KJ
authors: Roelofs
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Peter K
authors: PK
authors: Henke
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Robert G
authors: RG
authors: Schaub
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Thomas W
authors: TW
authors: Wakefield
authors: From the Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories (J.A.D., S.K.W., C.M.A., A.E.H., N.K.D., J.E.G., K.J.R., P.K.H., T.W.W., D.D.M.), Unit for Laboratory Animal Medicine (C.M.A., P.A.L., D.D.M.), and Department of Radiology (S.E.L.), University of Michigan, Ann Arbor; and Research and Development, Archemix Corporation, Cambridge, MA (R.G.S.).
authors: Daniel D
authors: DD
authors: Myers
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D017984:Enoxaparin / Q000494:pharmacology*; D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005355:Fibrosis; D007084:Iliac Vein / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D018810:Magnetic Resonance Angiography; D019007:P-Selectin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010215:Papio; D010690:Phlebography / Q000379:methods; D010974:Platelet Aggregation / Q000187:drug effects; D013997:Time Factors; D014463:Ultrasonography; D020246:Venous Thrombosis / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D055422:Venous Valves / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C572071:ARC15105; C000598203:ARC5692; D052157:Aptamers, Nucleotide; D017984:Enoxaparin; D005343:Fibrinolytic Agents; D019007:P-Selectin; D014841:von Willebrand Factor; D005337:Fibrin; D003094:Collagen
keywords: P-selectin; animal models; inflammation; venous thromboembolism; venous thrombosis
references: Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8767-71
references: 7522321
references: Int J Angiol. 2009 Winter;18(4):184-6
references: 22477550
references: J Med Primatol. 1982;11(2):91-105
references: 6290663
references: Blood. 2011 Jan 27;117(4):1106-7
references: 21273329
references: Thromb Haemost. 2008 Feb;99(2):343-51
references: 18278184
references: Thromb Haemost. 2007 Mar;97(3):400-7
references: 17334507
references: Best Pract Res Clin Haematol. 2012 Sep;25(3):235-42
references: 22959540
references: Lab Anim Sci. 1986 Apr;36(2):173-5
references: 3702336
references: J Surg Res. 2003 Jan;109(1):1-7
references: 12591228
references: J Vasc Surg. 2000 Feb;31(2):309-24
references: 10664500
references: Blood. 2008 Oct 1;112(7):2703-8
references: 18539899
references: Ann Intern Med. 1996 Jul 1;125(1):1-7
references: 8644983
references: Br Heart J. 1995 Jun;73(6):527-33
references: 7626351
references: Thromb Haemost. 2002 Mar;87(3):374-82
references: 11916067
references: Blood. 2011 Jan 27;117(4):1400-7
references: 20959603
references: Clin Chim Acta. 2011 Mar 18;412(7-8):614-8
references: 21167826
references: Chest. 2004 Sep;126(3 Suppl):338S-400S
references: 15383478
references: N Engl J Med. 2002 Sep 26;347(13):1019-22
references: 12324559
references: Thromb Haemost. 2001 Mar;85(3):423-9
references: 11307808
references: Curr Med Chem Cardiovasc Hematol Agents. 2004 Apr;2(2):149-56
references: 15320797
references: Best Pract Res Clin Haematol. 2003 Jun;16(2):261-78
references: 12763491
references: J Vasc Surg Venous Lymphat Disord. 2013 Oct 1;1(4):null
references: 24187669
references: J Exp Med. 2001 Sep 17;194(6):809-21
references: 11560996
references: J Vasc Surg. 2009 Jun;49(6):1620-3
references: 19497526
references: Thromb Haemost. 2001 Jul;86(1):214-21
references: 11487009
references: Am J Vet Res. 1986 Oct;47(10):2197-9
references: 3096173
references: Ann Intern Med. 2003 Dec 2;139(11):893-900
references: 14644891
references: N Engl J Med. 1991 May 30;324(22):1565-74
references: 2027360
references: Nature. 1992 Oct 29;359(6398):848-51
references: 1279433
references: Cryobiology. 1981 Oct;18(5):445-52
references: 7326942
references: Ann Vasc Surg. 2011 Feb;25(2):229-39
references: 21131172
references: Thromb Res. 2012 May;129 Suppl 2:S65-9
references: 22409831