RSS-Feed abonnieren
DOI: 10.1160/TH06-11-0658
Resolution of venous thrombosis using a novel oral small-molecule inhibitor of P-selectin (PSI-697) without anticoagulation
Financial support: This work was supported by NIH ROI HL 70766 (TWW) and Wyeth Research (PSI-697 compound and partial funding for research supplies).Publikationsverlauf
Received
22. November 2006
Accepted after revision
02. Januar 2007
Publikationsdatum:
28. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200703/lookinside/thumbnails/10-1160-th06-11-0658-1.jpg)
Summary
P-selectin inhibition has been shown to decrease thrombogenesis in multiple animal species. In this study, we show that a novel oral small-molecule inhibitor of P-selectin, PSI-697, promotes thrombus resolution and decreases inflammation in a baboon model of venous thrombosis. Experimental groups consisted of the following: 1) primates receiving a single oral dose of PSI-697 (30 mg/kg) daily starting three days pre-iliac vein balloon occlusion, and continued for six days; 2) primates receiving a single treatment dose of a low-molecular-weight-heparin (LMVVH) (1.5 mg/kg) daily starting one day pre-iliac balloon occlusion, and continued for six days; and 3) primates receiving a single oral dose of a vehicle control daily starting three days pre-iliac vein balloon occlusion, and continued for six days. Animals receiving PSI-697, although thrombosed after balloon deflation, demonstrated greater than 80% vein lumen opening over time, with no opening (0%) for vehicle control (p<0.01). LMVVH opening evident after balloon deflation slightly deteriorated overtime compared to PSI-697. PSI-697 therapy also significantly decreased vein wall inflammation determined by magnetic resonance venography (MRV). Importantly, this beneficial opening occurred without measured anticoagulation. Animals receiving PSI-697 demonstrated significantly increased plasma D-dimer levels versus LMVVH and control animals six hours post thrombus induction (p<0.01). This study is the first to demonstrate the effectiveness of oral P-selectin inhibition to modify venous thrombogenesis, increase vein lumen opening, and decrease inflammation in a large animal model.
Keywords
Deep venous thrombosis - thrombus resolution - small-molecule inhibitor of p-selectin - inflammation - animal modelsFootnote: Presented in part as an oral presentation at The XXth Congress of the International Society on Thrombosis and Haemostasis and 51st Annual SCC Meeting, Tuesday August 9, 2005, Sydney Australia, and the 51st Clinical Meeting of the Frederick A. Coller Surgical Society, Friday October 21, 2005, Santa Barbara, California, USA.
-
References
- 1 Proctor MC, Greenfield LJ. Pulmonary embolism: diagnosis, incidence and implications. Cardiovasc Surg (London) 1997; 5: 77-81.
- 2 Silverstein MD, Heit JA, Mohr DN. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585-593.
- 3 Goldhaber SZ. Pulmonary embolism. Lancet 2004; 363: 1295-1305.
- 4 Anderson Jr FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933-938.
- 5 Coon WW. Epidemiology of venous thromboembolism. Ann Surg 1977; 186: 149-164.
- 6 Deatrick KB, Eliason JL, Lynch EM. et al. Vein wall remodeling after deep vein thrombosis involves matrix metalloproteinases and late fibrosis in a mouse model. J Vasc Surg 2005; 42: 140-148.
- 7 Delis KT, Bountouroglou D, Mansfield AO. Venous claudication in iliofemoral thrombosis: long-term effects on venous hemodynamics, clinical status, and quality of life. Ann Surg 2004; 239: 118-126.
- 8 Heit JA. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost 2005; 3: 1611-1617.
- 9 Heit JA, Silverstein MD, Mohr DN. et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001; 86: 452-463.
- 10 Hull RD, Pineo GF, Raskob GE. The economic impact of treating deep vein thrombosis with low-molecular- weight heparin: outcome of therapy and health economy aspects. Haemostasis 1998; 28 (Suppl. 03) (Suppl) 8-16.
- 11 Nicolaides AN, Breddin HK, Fareed J. et al. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. Int Angiol 2001; 20: 1-37.
- 12 Virchow R. Gesammelte Abhandlungen zur wissenschaftlichen Medicin Meidinger U Comp, Frankfurt am Main; 1856
- 13 Schaub RG, Simmons CA, Koets MH. et al. Early events in the formation of a venous thrombus following local trauma and stasis. Laboratory Invest 1984; 51: 218-224.
- 14 Stewart GJ, Ritchie WG, Lynch PR. Venous endothelial damage produced by massive sticking and emigration of leukocytes. Am J Pathol 1974; 74: 507-532.
- 15 Eppihimer MJ, Schaub RG. P-Selectin-dependent inhibition of thrombosis during venous stasis. Arterioscl Thromb Vasc Biol 2000; 20: 2483-2488.
- 16 Kumar A, Villani MP, Patel UK. et al. Recombinant soluble form of PSGL-1 accelerates thrombolysis and prevents reocclusion in a porcine model. Circulation 1999; 99: 1363-1369.
- 17 Myers Jr D, Farris D, Hawley A. et al. Selectins influence thrombosis in a mouse model of experimental deep venous thrombosis. J Surg Res 2002; 108: 212-221.
- 18 Myers Jr DD, Henke PK, Wrobleski SK. et al. P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a rat model. J Vasc Surg 2002; 36: 928-938.
- 19 Myers Jr DD, Schaub R, Wrobleski SK. et al. P-selectin antagonism causes dose-dependent venous thrombosis inhibition. Thromb Haemost 2001; 85: 423-429.
- 20 Myers Jr DD, Wrobleski SK, Londy FJ. et al. New and effective treatment of experimentally induced venous thrombosis with anti-inflammatory rPSGL-Ig. Thromb Haemost 2002; 87: 374-382.
- 21 Shebuski RJ, Kilgore KS. Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Therap 2002; 300: 729-735.
- 22 Wakefield TW, Strieter RM, Schaub R. et al. Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation therapy. J Vasc Surg 2000; 31: 309-324.
- 23 Wakefield TW, Strieter RM, Wilke CA. et al. Venous thrombosis-associated inflammation and attenuation with neutralizing antibodies to cytokines and adhesion molecules. Arterioscl Thromb Vasc Biol 1995; 15: 258-268.
- 24 Hsu-Lin S, Berman CL, Furie BC. et al. A platelet membrane protein expressed during platelet activation and secretion. Studies using a monoclonal antibody specific for thrombin-activated platelets. J Biol Chem 1984; 259: 9121-9126.
- 25 Bonfanti R, Furie BC, Furie B. et al. PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells. Blood 1989; 73: 1109-1112.
- 26 Larsen E, Celi A, Gilbert GE. et al. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell 1989; 59: 305-312.
- 27 Andre P. P-selectin in haemostasis. Br J Haematol 2004; 126: 298-306.
- 28 Furie B, Furie BC, Flaumenhaft R. A journey with platelet P-selectin: the molecular basis of granule secretion, signalling and cell adhesion. Thromb Haemost 2001; 86: 214-221.
- 29 Vandendries ER, Furie BC, Furie B. Role of P-selectin and PSGL-1 in coagulation and thrombosis. Thromb Haemost 2004; 92: 459-466.
- 30 Yang J, Furie BC, Furie B. The biology of P-selectin glycoprotein ligand-1: its role as a selectin counterreceptor in leukocyte-endothelial and leukocyte-platelet interaction. Thromb Haemost 1999; 81: 1-7.
- 31 Moore KL. Structure and function of P-selectin glycoprotein ligand-1. Leuk Lymphoma 1998; 29: 1-15.
- 32 Celi A, Lorenzet R, Furie BC. et al. Microparticles and a P-selectin-mediated pathway of blood coagulation. Dis Markers 2004; 20: 347-352.
- 33 Furie B, Furie BC. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med 2004; 10: 171-178.
- 34 Polgar J, Matuskova J, Wagner DD. The P-selectin, tissue factor, coagulation triad. J Thromb Haemost 2005; 3: 1590-1596.
- 35 McGregor L, Martin J, McGregor JL. Platelet-leukocyte aggregates and derived microparticles in inflammation, vascular remodelling and thrombosis. Front Biosci 2006; 11: 830-837.
- 36 Bedard PW, Clerin V, Sushkova N. et al. Novel P-selectin inhibitor, PSI-697, demonstrates positive activity following oral administration in rodent models of vascular inflammation. J Thromb Haemost 2005; 3 (Suppl. 01) (Suppl) OR390
- 37 Kaila N, Janz K, Huang A. et al. 2-(4-Chlorobenzyl)- 3-hydroxy-7,8,9,10-tetrahydrobenzo[H ]quinoline- 4-carboxylic acid (PSI-697): Identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists. J Med Chem 2007; 50: 40-64.
- 38 Myers Jr DD, Henke PK, Bedard PW. et al. Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis. J Vasc Surg 2006; 44: 625-632.
- 39 Myers Jr DD, Rectenwald JE, Bedard PW. et al. Decreased venous thrombosis with an oral inhibitor of P selectin. J Vasc Surg 2005; 42: 329-336.
- 40 Myers Jr DD, Wrobleski SK, Henke PK. et al. Coagulation Biology. In: Surgical Research. Academic Press, San Diego; 2001
- 41 Hernandez RJ, Strouse PJ, Londy FJ. et al. Gadolinium- enhanced MR angiography (Gd-MRA) of thoracic vasculature in an animal model using double-dose gadolinium and quiet breathing. Pediatr Radiol 2001; 31: 589-593.
- 42 Rectenwald JE, Myers Jr DD, Hawley AE. et al. D-dimer, P-selectin, and microparticles: novel markers to predict deep venous thrombosis. A pilot study. Thromb Haemost 2005; 94: 1312-1317.
- 43 Feingold HM, Pivacek LE, Melaragno AJ. et al. Coagulation assays and platelet aggregation patterns in human, baboon, and canine blood. Am J Vet Res 1986; 47: 2197-2199.
- 44 Kelly CA, Gleiser CA. Selected coagulation reference values for adult and juvenile baboons. Lab Anim Sci 1986; 36: 173-175.
- 45 Hrachovinova I, Cambien B, Hafezi-Moghadam A. et al. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nature Med 2003; 9: 1020-1025.
- 46 Sullivan VV, Hawley AE, Farris DM. et al. Decrease in fibrin content of venous thrombi in selectin-deficient mice. J Surg Res 2003; 109: 1-7.
- 47 Thanaporn P, Myers DD, Wrobleski SK. et al. P-selectin inhibition decreases post-thrombotic vein wall fibrosis in a rat model. Surgery 2003; 134: 365-371.
- 48 Falati S, Liu Q, Gross P. et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 2003; 197: 1585-1598.
- 49 Ten Cate-Hoek AJ, Prins MH. Management studies using a combination of D-dimer test result and clinical probability to rule out venous thromboembolism: a systematic review. J Thromb Haemost 2005; 3: 2465-2470.
- 50 Stein PD, Hull RD, Patel KC. et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med 2004; 140: 589-602.
- 51 Wells PS, Anderson DR, Rodger M. et al. Evaluation of D-dimer in the diagnosis of suspected deepvein thrombosis. N Engl J Med 2003; 349: 1227-1235.
- 52 Myers Jr DD, Hawley AE, Farris DM. et al. P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 2003; 38: 1075-1089.