Improved coagulation in bleeding disorders by Non-Anticoagulant Sulfated Polysaccharides (NASP)

Tongyao Liu; Ciaran D. Scallan; George J. Broze Jr.; Susanna Patarroyo-White; Glenn F. Pierce; Kirk W. Johnson

doi:10.1160/TH05-05-0361

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(01): 68-76
DOI: 10.1160/TH05-05-0361

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Improved coagulation in bleeding disorders by Non-Anticoagulant Sulfated Polysaccharides (NASP)

Authors

Tongyao Liu

¹Avigen, Inc., Alameda, California
Ciaran D. Scallan

¹Avigen, Inc., Alameda, California
George J. Broze Jr.

²Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, Missouri, USA
Susanna Patarroyo-White

¹Avigen, Inc., Alameda, California
Glenn F. Pierce

¹Avigen, Inc., Alameda, California
Kirk W. Johnson

¹Avigen, Inc., Alameda, California

Abstract

Summary

Additional therapeutic options are needed for patients with bleeding disorders such as hemophilia A, hemophilia B, severe von Willebrand disease, and other rare factor deficiencies. A novel approach to improve coagulation in such clotting disorders has been identified that, parodoxically, involves heparinlike sulfated polysaccharides.Select molecules of this broad class are largely devoid of anticoagulant activity and are here denoted Non-Anticoagulant Sulfated Polysaccharides (NASPs).A mechanism involving blockade of the extrinsic pathway downregulator,Tissue Factor Pathway Inhibitor (TFPI) by NASPs, was conceived as an approach for improving procoagulant behavior in hemophilic settings.A subset of NASPs, including pentosan polysulfate (PPS) and fucoidan inhibited both full-length and Kunitz 1 and 2 (K1K2) TFPI and, at concentrations from 4-500 nM, improved (i.e. accelerated) the clotting time of human hemophilia A and hemophilia B plasmas or plasma with reduced factor VII levels when tested in dilute prothrombin time (dPT) assays. Fucoidan did not reduce normal plasma APTT times implying specificity for extrinsic pathway control. Improved hemostasis in vivo was observed in mice with hemophilias A orB following low dose subcutaneous administration of PPS or fucoidan, or a combination of NASP plus factor supplement. Increased survival of factor deficient mice following a bleeding challenge was observed. Accordingly, administration of select NASP(s), via mechanism(s) not fully understood, represents a unique means of improving coagulation in bleeding disorders.

Keywords

Hemophilia - sulfated polysaccharides - fucoidan - TFPI - coagulation

Full Text

References

References
1 Bishop P, Lawson J. Recombinant biologics for treatment of bleeding disorders. Nat Rev Drug Discov 2004; 03: 684-94.
2 Carcao MD, Aledort L. Prophylactic factor replacement in hemophilia. Blood Rev 2004; 18: 101-13.
3 Roberts HR, Monroe DM, Escobar MA. Current concepts of hemostasis: implications for therapy. Anesthesiology 2004; 100: 722-30.
4 Lee JW. Von Willebrand disease, hemophilia A and B, and other factor deficiencies. Int Anesthesiol Clin 2004; 42: 59-76.
5 Bohn RL, Schramm W, Bullinger M. et al. Outcome measures in haemophilia: more than just factor levels. Haemophilia 2004; 10 (Suppl. 01) 2-8.
6 Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 1991; 30: 10363-70.
7 Mann KG. Thrombin: can’t live without it; probably die from it. Chest 2003; 124 (Suppl) 1S-3S.
8 Rapaport SI, Rao LV. The tissue factor pathway: how it has become a „prima ballerina”. Thromb Haemost 1995; 74: 7-17.
9 Broze Jr GJ. The role of tissue factor pathway inhibitor in a revised coagulation cascade. Semin Hematol 1992; 29: 159-69.
10 Broze Jr GJ. The rediscovery and isolation of TFPI. J Thromb Haemost 2003; 01: 1671-5.
11 Johnson K, Hung D. Novel anticoagulants based on inhibition of the factor VIIa/tissue factor pathway. Coron Artery Dis 1998; 09: 83-7.
12 Westrick RJ, Bodary PF, Xu Z. et al. Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice. Circulation 2001; 103: 3044-6.
13 Kleesiek K, Schmidt M, Gotting C. et al. The 536C-->T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosis. Thromb Haemost 1999; 82: 1-5.
14 Nordfang O, Valentin S, Beck TC. et al. Inhibition of extrinsic pathway inhibitor shortens the coagulation time of normal plasma and of hemophilia plasma. Thromb Haemost 1991; 66: 464-7.
15 Welsch DJ, Novotny WF, Wun TC. Effect of lipoprotein-associated coagulation inhibitor (LACI) on thromboplastin-induced coagulation of normal and hemophiliac plasmas. Thromb Res 1991; 64: 213-22.
16 Erhardtsen E, Ezban M, Madsen MT. et al. Blocking of tissue factor pathway inhibitor (TFPI) shortens the bleeding time in rabbits with antibody induced haemophilia A. Blood Coagul Fibrinolysis 1995; 06: 388-94.
17 Toida TC, Chaidedgumjorn A, Linhardt RJ. Structure and bioactivity of sulfated polysaccharides. Trends in Glycoscience and Glycotechnology 2003; 15: 29-46.
18 Sinay P. Sugars slide into heparin activity. Nature 1999; 398: 377-8.
19 Bates SM, Weitz JI. The new heparins. Coron Artery Dis 1998; 09: 65-74.
20 Orgueira HA, Bartolozzi A, Schell P. et al. Modular synthesis of heparin oligosaccharides. Chemistry 2003; 09: 140-69.
21 McAuliffe JC. Carbohydrate drugs - An ongoing challenge. Chemical Industry Magazine 1997; 03: 170-4.
22 Williams PD, Ye H, Cheng FC. et al. Comparative effects of heparin and the sulfatoid GM1474 on coagulation parameters in plasma and blood from various species. Gen Pharmacol 1998; 30: 337-41.
23 Wan JG, Mu JS, Zhu HS. et al. N-desulfated nonanticoagulant heparin inhibits leukocyte adhesion and transmigration in vitro and attenuates acute peritonitis and ischemia and reperfusion injury in vivo . Inflamm Res 2002; 51: 435-43.
24 Bourin MC, Lindahl U. Glycosaminoglycans and the regulation of blood coagulation. Biochem J 1993; 289 ( Pt 2): 313-30.
25 McCaffrey TA, Falcone DJ, Borth W. et al. Fucoidan is a non-anticoagulant inhibitor of intimal hyperplasia. Biochem Biophys Res Commun 1992; 184: 773-81.
26 Luyt CE, Meddahi-Pelle A, Ho-Tin-Noe B. et al. Low-molecular-weight fucoidan promotes therapeutic revascularization in a rat model of critical hindlimb ischemia. J Pharmacol Exp Ther 2003; 305: 24-30.
27 Novotny WF, Palmier M, Wun TC. et al. Purification and properties of heparin-releasable lipoproteinassociated coagulation inhibitor. Blood 1991; 78: 394-400.
28 Broze Jr GJ, Lange GW, Duffin KL. et al. Heterogeneity of plasma tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 1994; 05: 551-9.
29 Wesselschmidt R, Likert K, Huang Z, MacPhail L, Broze Jr GJ. Structural requirements for tissue factor pathway inhibitor interactions with factor Xa and heparin. Blood Coagul Fibrinolysis 1993; 04: 661-9.
30 Anderson L, Barrowcliffe TW, Holmer E. et al. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin III and by gel filtration. Thromb Res 1976; 09: 575-83.
31 PDR Staff. Physicians’ Desk Reference. Thomson PDR. 2004
32 National Research Council. Guide for the care and use of laboratory animals. Washington, D. C: National Academy Press; 1996
33 Broze Jr GJ, Yin ZF, Lasky N. A tail vein bleeding time model and delayed bleeding in hemophiliac mice. Thromb Haemost 2001; 85: 747-8.
34 MacGregor IR, Dawes J, Pepper DS. et al. Metabolism of sodium pentosan polysulphate in man measured by a new competitive binding assay for sulphated polysaccharides--comparison with effects upon anticoagulant activity, lipolysis and platelet alpha-granule proteins. Thromb Haemost 1985; 53: 411-4.
35 Millet J, Jouault SC, Mauray S. et al. Antithrombotic and anticoagulant activities ofa low molecular weight fucoidan by the subcutaneous route. Thromb Haemost 1999; 81: 391-5.
36 Joffe S. Drug prevention of postoperative deep vein thrombosis A compararative study of calcium heparinate and sodium pentosan polysulfate. Arch Surg 1976; 111: 37-40.
37 Lush RM, Figg WD, Pluda JM. et al. A phase I study of pentosan polysulfate sodium in patients with advanced malignancies. Ann Oncol 1996; 07: 939-44.
38 Hwang P, Auclair B, Beechinor D. et al. Efficacy of pentosan polysulfate in the treatment of interstitial cystitis:a meta-analysis. Urology 1997; 50: 39-43.
39 Berteau O, Mulloy B. Sulfated fucans, fresh perspectives: structures, functions, and biological properties of sulfated fucans and an overview of enzymes active toward this class of polysaccharide. Glycobiology 2003; 13: 29R-40R.
40 Church FC, Meade JB, Treanor RE. et al. Antithrombin activity of fucoidan The interaction of fucoidan with heparin cofactor II, antithrombin III, and thrombin. J Biol Chem 1989; 264: 3618-23.
41 Giedrojc J, Klimiuk M, Radziwon P. et al. Comparative study on the in vitro and in vivo activities of heparinoids derivative investigated on the animal model. J Cardiovasc Pharmacol 1999; 34: 340-5.
42 Granert C, Raud J, Waage A. et al. Effects of polysaccharide fucoidin on cerebrospinal fluid interleukin-1 and tumor necrosis factor alpha in pneumococcal meningitis in the rabbit. Infect Immun 1999; 67: 2071-4.
43 Sweeney EA, Lortat-Jacob H, Priestley GV. et al. Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. Blood 2002; 99: 44-51.
44 Deux JF, Meddahi-Pelle A, Le Blanche AF. et al. Low molecular weight fucoidan prevents neointimal hyperplasia in rabbit iliac artery in-stent restenosis model. Arterioscler Thromb Vasc Biol 2002; 22: 1604-9.
45 Dunn F, Soria J, Soria C. et al. Fibrinogen binding on human platelets Influence of different heparins and of pentosane polysulfate. Thromb Res 1983; 29: 141-8.
46 Klocking HP, Markwardt F. Release of plasminogen activator by pentosan polysulphate. Thromb Res 1986; 41: 739-44.
47 Durig J, Bruhn T, Zurborn KH. et al. Anticoagulant fucoidan fractions from Fucus vesiculosus induce platelet activation in vitro . Thromb Res 1997; 85: 479-91.
48 Brummel Ziedins K, Rivard GE, Pouliot RL. et al. Factor VIIa replacement therapy in factor VII deficiency. J Thromb Haemost 2004; 02: 1735-44.