Arch Pharm Res Vol 35, No 10, 1693-1699, 2012 DOI 10.1007/s12272-012-1000-3
Report on Investigational Drugs
Targeting von Willebrand Factor as a Novel Anti-platelet Therapy; Application of ARC1779, an Anti-vWF Aptamer, against Thrombotic Risk Ok-Nam Bae College of Pharmacy, Hanyang University, Gyeonggi-do 426-791, Korea
Excessive activation of platelets is a causative factor for thrombotic diseases such as acute coronary syndrome or stroke, and various anti-platelet drugs were developed. Aspirin and clopidogrel have been used as gold standards for anti-platelet therapies, however, their clinical limitations including bleeding problem have increased the demand driving development of novel anti-platelet drugs with new targets. Among several activating pathways leading to platelet aggregation, the interaction between von Willebrand factor (vWF) and glycoprotein Ib, which mainly occurs under high shear stress in arterioles, is recently suggested to be a new promising target. The anti-thrombotic efficacy of anti-vWF agents, such as ARC1779, has been proved in several preclinical and clinical studies. Here, we will discuss the potential benefits of targeting vWF as a novel antiplatelet therapy, providing an insight into the role of vWF in increased thrombotic risk.
ANTI-PLATELET THERAPY
During
endothelial damage or in atherosclerotic rupture, subendothelial matrix is exposed, providing a site for multi-step platelet activation and formation of platelet-rich thrombi (Jackson and Schoenwaelder, 2003; Mackman, 2008). The initial stage is platelet adhesion mediated by the binding of von Willebrand factor (vWF) to platelet glycoprotein (GP) Ib (Sadler, 2002; Raju et al., 2008). Following vWF-GP Ib interaction, the secondary mediators such as adenosine diphosphate (ADP) and thromboxane A2 (TXA2) are released, resulting in further platelet activation (SillerMatula et al., 2010). The binding of ADP to its receptor purinergic receptor P2Y, G protein-coupled 12 (P2Y12) amplifies platelet responses to other agonists, triggering the conformational change of GP IIb/IIIa, to which
Correspondence to: Ok-Nam Bae, College of Pharmacy, Hanyang University, Ansan 426-791, Korea Tel: 82-31-400-5805, Fax: 82-31-400-5958 E-mail:
[email protected] Edited by Mi-Kyoung Kwak, College of Pharmacy (Rm 408), The Catholic University of Korea, Bucheon 420-743, Korea Tel: 82-2-2164-6532 E-mail:
[email protected]
fibrinogen and vWF bind for platelet aggregation and formation of hemostatic plug (Varga-Szabo et al., 2008; Nesbitt et al., 2009). Since platelets have a pivotal role in the pathogenesis of thrombotic diseases including acute coronary syndromes (ACS) or stroke (Davi and Patrono, 2007), antiplatelet therapies have been extensively used for patients at the risk of cardiovascular events (Barrett et al., 2008; Siller-Matula et al., 2010). Various anti-platelet agents have been developed targeting critical pathways in platelet activation (Fig. 1), either antagonizing membrane receptors such as Thromboxane/prostaglandin endoperoxide receptor (TPr), P2Y12, Proteinaseactivated receptor (PAR1), GP IIb/IIIa and GP Ib, or modulating intracellular signaling pathways including TXA2 and cyclic nucleotides. Many clinically important anti-platelet agents are designed to block the specific interaction between platelet agonists and their receptors, as exemplified with clopidogrel and prasugrel that blocks ADP receptor P2Y12. Aspirin, the most traditional anti-platelet drug, reduces TXA2 synthesis through inhibition of cyclooxygenase-1, and dipyridamole and cilostazol increase the intracellular level of cAMP and/or cGMP by inhibition of phosphodiesterases (Gresele et al., 2011). The current gold standards of
1693
1694
O.-N. Bae
Fig. 1. Molecular targets of anti-platelet agents. Following platelet tethering at the site of vascular damage, platelets are activated through various molecular mediators resulting in platelet aggregation and thrombus formation. Various antiplatelet agents have been developed targeting critical pathways in platelet activation, either antagonizing membrane receptors or modulating intracellular signaling molecules. ADP, Adenosine diphosphate; ECs, endothelial cells; GP, glycoprotein; PAR-1, Proteinase-activated receptor 1; PLTs, platelets; TPr, Thromboxane/prostaglandin endoperoxide receptor; TXA2, Thromboxane A2; vWF, von Willebrand factor.
anti-platelet therapy are aspirin and clopidogrel, and these agents are extensively used in patients with myocardiac infarction, ACS, and stroke (Jackson and Schoenwaelder, 2003; Raju et al., 2008). Despite the established clinical efficacy, current anti-platelet agents have clinical limitations, such as escalated bleeding risk (Chen et al., 2004; Michelson, 2010; Sostres and Lanas, 2011) and high interindivisual variability (SillerMatula et al., 2010), raising an urgent need for development of a novel anti-platelet drug with improved efficacy and safety. Gastrointestinal hemorrhage following aspirin treatment or significantly increased bleeding problems after clopidogrel administration is suggested to be the major concern on their clinical usage. GP IIb/IIIa inhibitors, which showed its potent antiplatelet capacity without redundant effects on vascular system, also significantly increased the risk of bleeding proportional to the potency of anti-platelet activity (Scarborough et al., 1999). Targeting vWF-GP Ib interaction might have a potential advantage with wider margin of safety on bleeding complication, in terms that vWF-GP Ib interaction is an initial step of shearinduced platelet aggregation (SIPA), which occurs selectively under high shear stress in atherosclerotic lesion (Clemetson and Clemetson, 2008; Firbas et al., 2010; Lenting et al., 2010).
ROLE OF von WILLEBRAND FACTOR IN PLATELET ACTIVATION As represented in Fig. 2, vWF is a multimeric protein in size from 500 to 20,000 KDa, composed of a polypeptide monomer subunit with several functional domains (Ruggeri, 2007). The large multimers of vWF effectively promote its hemostatic function, through the localized abundance of the binding sites to their ligands (He et al., 2001). vWF is primarily synthesized in endothelial cells and megakaryocytes, and is present in plasma, subendothelial matrix, endothelium and platelets (Reininger, 2008). vWF was named after Dr. Erik von Willebrand, who reported a new type of bleeding disorder caused by inherited defect of vWF (von Willebrand, 1926; De Meyer et al., 2012). The central role of vWF in hemostasis and thrombosis was identified in patients with von Willebrand diseases (vWD), where vWF is impaired quantitatively (type 1 and 3) or qualitatively (type 2). Approximately 1 in 100 individuals are reported to have vWD, making vWD be one of the most frequent inherited bleeding disorders (Sadler et al., 2006). Structural abnormalities in vWF either appear to enhance or decrease its binding to platelets, as found in vWD type 2B or type 2M, respectively (Nichols et al., 2008). In
1695
Fig. 2. Representative scheme of vWF structure. vWF is produced as a prepro-protein comprising 2813 amino acids, and processed to its mature form. Further C-terminal dimerization and N-terminal multimerization yield mature vWF multimers. FVIII, coagulation factor VIII; GP, glycoprotein; RGD, Arg-Gly-Asp motif; vWF, von Willebrand factor.
type 2B vWD patients, thrombocytopenia is frequently observed due to the spontaneous binding of vWF to platelets, but thrombotic events are hardly achieved as these aggregates are easily degraded by ADAMTS13 that inactivates vWF via proteolytic cleavage (Rayes et al., 2007; Yago et al., 2008). Representative symptoms of vWD include spontaneous bleeding and blood loss after wounds or surgical intervention (Firbas et al., 2010). Thrombotic thrombocytopenic purpura (TTP), is another critical disease related to vWF, where thrombocytopenia along with thrombotic microangiopathy is observed (Noris and Balduini, 2011). Owing to the defect of ADAMTS13, ultra large vWF multimers could not undergo the normal processing, resulting in the persistence of vWF in its active form. Beside the evidence from vWF-related inherited disorders, the clinical observations under thrombotic risk are also demonstrating the potential role of vWF in hemostasis and thrombosis (Vischer, 2006). The correlation between high plasma levels of vWF and development of cardiovascular diseases (CVD) were found in ACS, stroke and chronic coronary artery diseases (CAD; also known as coronary heart disease (CHD)) (He et al., 2001; Bongers et al., 2006). Increased vWF levels are considered to be a predictive marker for acti-
vation of endothelial cells, however, it is also suggested that vWF is not only a marker but also an important player in the pathogenesis of thrombotic events (Vischer, 2006). As described earlier, vWF mediates platelet tethering at the site of vascular damage as a bridging component between subendothelium and platelets (Kiefer and Becker, 2009). A3 and A1 domain in vWF interact with collagen in subendothelium and GP Ib in platelets, respectively. In regular sized vWF, the binding site in A1 domain is cryptic, preventing spontaneous binding to GP Ib. High shear stress (>1000/s) induces the conformation change of vWF exposing A1 domain, thus vWFGP Ib association usually occurs under high shear in atherosclerotic arteries or stenotic area (Blann, 2006; Lenting et al., 2010). Adhered platelets can be further activated outside-in signaling from GP Ib, as well as from GP IV following collagen-GP IV interaction of tethered platelets as previously described (Fig. 1). Beside the initiation of platelet adhesion, vWF involves in further platelet aggregation via vWF-GP IIb/IIIa interaction (Gawaz et al., 2005). Contribution of vWF to inflammation and the development of atherogenic plaque are also noted (Wagner and Burger, 2003), making anti-vWF agents be promising anti-thrombotic
1696
O.-N. Bae
Table I. Pharmacological modulators of vWF-related platelet adhesion Type
Agent
Target
Mode of action
Development stage
Antibody
AJW200
vWF
Antibody against vWF A1 domain; Inhibits binding of vWF to GP Ib
Clinical
Antibody
82D6A3
vWF
Antibody against vWF A3 domain; Inhibits binding of vWF to collagen
Preclinical
Antibody
6B4
GP Ib
Antibody against GP Ibα; Inhibits binding of vWF to GP Ib
Preclinical
Chimeric recombinant protein
GPG 290
vWF
Chimeric protein containing gain-of-function GP Ibα; Binds to vWF inhibiting vWF-GP Ib interaction
Preclinical
vWF
Recombinant ADAMTS13;Cleavages vWF A2 domain and degrades vWF multimer
Preclinical
Recombinant protein rADAMTS13 Aptamer
ARC1779
vWF
Aptamer against vWF A1 domain; Inhibits binding of vWF to GP Ib
Clinical
Nanobody®
ALX-0081 /ALX-0681
vWF
Nanobody against vWF A1 domain; Inhibits binding of vWF to GP Ib
Clinical
therapeutic options. Despite the role of vWF in excessive platelet activation and thrombus formation, pharmacological agents targeting vWF are limited and none of anti-vWF agents has achieved regulatory approval for pharmaceutical marketing. Recent studies have suggested that vWFGP Ib interaction be the most promising target in antiplatelet therapy (Barrett et al., 2008; Firbas et al., 2010), and an emerging interest in the development of anti-vWF agents is now expanding. As listed in Table I, several agents targeting vWF-mediated platelet activation are currently under developments. Among several candidates, ARC1779, an aptamer interfering vWF A1 domain, has been paid a special attention due to its novel benefit as an aptamer that can be inactivated by complementary antidotes if an adverse effect occurs. We will further discuss the safety and efficacy of ARC1779, based on the preclinical and clinical evidences.
EFFICACY AND SAFETY OF ARC 1779 ARC1779 Aptamers, often called as chemical antibodies, are novel therapeutic class of RNA or DNA oligonucleotides that binds target molecules through specific, high-affinity interaction (Keefe and Schaub, 2008; Bouchard et al., 2010). They have little immunogenicity, and can be simply modified to improve their bioavailability or pharmacokinetic, demonstrating the advantages as therapeutic agents. ARC1779, a 40-mer aptamer conjugated to polyethylene glycol, specifically binds to vWF A1 domain with high affinity (Kd~2 nM). It is a second generation agent derived from ARC1172 to improve its resistance to nuclease (Cosmi, 2009; Huang et al., 2009). The efficacy of ARC1779 in platelet inhibition has been demonstrated in several preclinical and clinical
trials.
Results from preclinical studies ARC1779 inhibited vWF-dependent or shear stressinduced platelet aggregation, and platelet adhesion to collagen-coated matrices (Diener et al., 2009). ARC1779 reduced thrombus formation on injured porcine arteries, and inhibited carotid artery thrombosis in nonhuman primates (Diener et al., 2009). When ARC1779 was treated to platelets isolated from patients with CAD, shear stress-induced platelet adhesion was significantly reduced, while aggregation induced by physiological agonists such as ADP or AA was not affected (Arzamendi et al., 2011). These ex vivo effects of ARC1779 on shearinduced platelet activation and vWF activity were also observed in patients with acute myocardial infarction, who displayed increased activity of plasma vWF (Spiel et al., 2009). Clinical outcomes Since Gilbert et al. (2007) reported the first-in-human phase 1 clinical study regarding the safety and tolerability of ARC1779 in healthy subjects, several phase II studies were conducted to investigate the clinical efficacy of ARC1779 in human patients. In patients undergoing carotid endarterectomy, intravenous treatment of ARC1779 demonstrated its efficacy in reducing cerebral embolization (Markus et al., 2011). The clinical efficacy of ARC1779 was intensively evaluated in patients with congenital defects of vWF, providing evidence that ARC1779 is a potent inhibitor of vWF in humans. Treatment of ARC1779 in patients with TTP significantly inhibited vWF activity and vWF-dependent platelet activation, and raised platelet counts (Knöbl et al., 2009; Mayr et al., 2010; Jilma-Stohlawetz et al, 2011a, 2011b). Cataland et al. (2012) reported the effi-
1697
cacy and safety of ARC1779 treatment to patients with TTP. While patients from ARC1779 treated group showed improved clinical symptoms, no safety issue including bleeding was found. Pharmacokinetics and pharmacodynamics of ARC1779 in patients with TTP were found to be in agreement with those observed in healthy volunteers (Jilma-Stohlawetz et al., 2011b). ARC1779 also prevented thrombocytopenia in patients with type 2B vWD (Jilma et al., 2010; Jilma-Stohlawetz et al., 2012). Further phase II and III trials will be necessary to establish the therapeutic potential of ARC-1779 as an anti-platelet and anti-thrombotic agent.
LIMITATIONS vWF antagonists offer intrinsic advantages over other types of anti-platelet agent in regards to reduced bleeding risk, since vWF plays a key role in platelet activation selectively under high shear stress in pathological environments. Although this concept has been proved in previous experimental and clinical settings, there still remain concerns regarding bleeding problem. The clinical observations of vWD patients including spontaneous bleeding, skin bruise, and gastrointestinal bleeding demonstrate that vWF also partly contributes to normal hemostasis. Actually, the template bleeding time in cynomolgus macaques is actually prolonged by ARC1779 treatment in a dose-dependent manner (Diener et al., 2009). Since platelets involves in normal hemostasis as well as abnormal thrombosis, it may be intrinsically impossible to develop anti-platelet agents without bleeding risk. Although anti-vWF agents have demonstrated their superior safety over other types of anti-platelet drugs, detailed elucidation of balance between pharmacokinetic and anti-platelet activities following anti-vWF agents should be required for the determination of therapeutic dose window. Absence of orally active form of anti-vWF agent is another factor limiting its clinical application. Oral bioavailability is a critical factor for long-term therapy of anti-platelet agents for reduction of thrombotic risk, and many of anti-platelet drugs under development are orally active (Weitz et al., 2008). Up to now, all of the clinical trials on ARC1779 demonstrated its efficacy following intravenous administration. There are few studies regarding bioavailability and efficacy of antivWF agents, including ARC1779, after treatment in different administration routes. Jilma-Stohlawetz et al. (2011a) showed that the daily subcutaneous injections of ARC1779 did not correct the clinical features of TTP, demonstrating low bioavailability of ARC1779 after subcutaneous injection. Intensive studies are required to improve oral bioavailability of anti-vWF agents.
CONCLUDING REMARK There is growing evidence that demonstrate the anti-platelet potential of agents targeting vWF. Fewer bleeding complications are expected due to the specific interaction of vWF-GP Ib under high shear stress in arterial system. Although vWF inhibitors have not yet received the regulatory authorization, we expect that anti-vWF agents will be a therapeutic alternative in thrombotic diseases, through further preclinical and clinical investigation.
ACKNOWLEDGEMENTS This work is supported by a grant from Hanyang University (201200000000204).
REFERENCES Arzamendi, D., Dandachli, F., Théorêt, J. F., Ducrocq, G., Chan, M., Mourad, W., Gilbert, J. C., Schaub, R. G., Tanguay, J. F., and Merhi, Y., An anti-von Willebrand factor aptamer reduces platelet adhesion among patients receiving aspirin and clopidogrel in an ex vivo shear-induced arterial thrombosis. Clin. Appl. Thromb. Hemost., 17, E70-E78 (2011). Barrett, N. E., Holbrook, L., Jones, S., Kaiser, W. J., Moraes, L. A., Rana, R., Sage, T., Stanley, R. G., Tucker, K. L., Wright, B., and Gibbins, J. M., Future innovations in anti-platelet therapies. Br. J. Pharmacol., 154, 918-939 (2008). Blann, A. D., Plasma von Willebrand factor, thrombosis, and the endothelium: the first 30 years. Thromb. Haemost., 95, 49-55 (2006). Bongers, T. N., de Maat, M. P., van Goor, M. L., Bhagwanbali, V., van Vliet, H. H., Gómez García, E. B., Dippel, D. W., and Leebeek, F. W., High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability. Stroke, 37, 26722677 (2006). Bouchard, P. R., Hutabarat, R. M., and Thompson, K. M., Discovery and development of therapeutic aptamers. Annu. Rev. Pharmacol. Toxicol., 50, 237-257 (2010). Cataland, S. R., Peyvandi, F., Mannucci, P. M., Lämmle, B., Kremer Hovinga, J. A., Machin, S. J., Scully, M., Rock, G., Gilbert, J. C., Yang, S., Wu, H., Jilma, B., and Knoebl, P., Initial experience from a double-blind, placebo-controlled, clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura. Am. J. Hematol., 87, 430-432 (2012). Cauwenberghs, N., Meiring, M., Vauterin, S., van Wyk, V., Lamprecht, S., Roodt, J. P., Novák, L., Harsfalvi, J., Deckmyn, H., and Kotzé, H. F., Antithrombotic effect of platelet glycoprotein Ib-blocking monoclonal antibody Fab fragments in nonhuman primates. Arterioscler. Thromb. Vasc. Biol., 20, 1347-1353 (2000). Chen, L., Bracey, A. W., Radovancevic, R., Cooper, J. R., Jr.,
1698
Collard, C. D., Vaughn, W. K., and Nussmeier, N. A., Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting. J. Thorac. Cardiovasc. Surg., 128, 425-431 (2004). Clemetson, K. J. and Clemetson, J. M., Platelet GPIb complex as a target for anti-thrombotic drug development. Thromb. Haemost., 99, 473-479 (2008). Cosmi, B., ARC-1779, a PEGylated aptamer antagonist of von Willebrand factor for potential use as an anticoagulant or antithrombotic agent. Curr. Opin. Mol. Ther., 11, 322-328 (2009). Davi, G. and Patrono, C., Platelet activation and atherothrombosis. N. Engl. J. Med., 357, 2482-2494 (2007). De Meyer, S. F., Stoll, G., Wagner, D. D., Kleinschnitz, C., De Meyer, S. F., Stoll, G., Wagner, D. D., and Kleinschnitz, C., Stroke, 43, 599-606 (2012). Diener, J. L., Daniel Lagassé, H. A., Duerschmied, D., Merhi, Y., Tanguay, J. F., Hutabarat, R., Gilbert, J., Wagner, D. D., and Schaub, R., Inhibition of von Willebrand factormediated platelet activation and thrombosis by the antivon Willebrand factor A1-domain aptamer ARC1779. J. Thromb. Haemost., 7, 1155-1162 (2009). Firbas, C., Siller-Matula, J. M., and Jilma, B., Targeting von Willebrand factor and platelet glycoprotein Ib receptor. Expert Rev. Cardiovasc. Ther., 8, 1689-1701 (2010). Gawaz, M., Langer, H., and May, A. E., Platelets in inflammation and atherogenesis. J. Clin. Invest., 115, 3378-3384 (2005). Gilbert, J. C., DeFeo-Fraulini, T., Hutabarat, R. M., Horvath, C. J., Merlino, P. G., Marsh, H. N., Healy, J. M., Boufakhreddine, S., Holohan, T. V., and Schaub, R. G., First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers. Circulation, 116, 2678-2686 (2007). Gresele, P., Momi, S., and Falcinelli, E., Anti-platelet therapy: phosphodiesterase inhibitors. Br. J. Clin. Pharmacol., 72, 634-646 (2011). He, S., Cao, H., Magnusson, C. G., Eriksson-Berg, M., Mehrkash, M., Schenck-Gustafsson, K., and Blombäck, M., Are increased levels of von Willebrand factor in chronic coronary heart disease caused by decrease in von Willebrand factor cleaving protease activity? A study by an immunoassay with antibody against intact bond 842Tyr843Met of the von Willebrand factor protein. Thromb. Res., 103, 241-248 (2001). Huang, R. H., Fremont, D. H., Diener, J. L., Schaub, R. G., and Sadler, J. E., A structural explanation for the antithrombotic activity of ARC1172, a DNA aptamer that binds von Willebrand factor domain A1. Structure, 17, 1476-1484 (2009). Jackson, S. P. and Schoenwaelder, S. M., Anti-platelet therapy: in search of the 'magic bullet'. Nat. Rev. Drug Discov., 2, 775-789 (2003). Jilma, B., Paulinska, P., Jilma-Stohlawetz, P., Gilbert, J. C., Hutabarat, R., and Knöbl, P., A randomised pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease. Thromb. Haemost.,
O.-N. Bae
104, 563-570 (2010). Jilma-Stohlawetz, P., Gilbert, J. C., Gorczyca, M. E., Knöbl, P., and Jilma, B., A dose ranging phase I/II trial of the von Willebrand factor inhibiting aptamer ARC1779 in patients with congenital thrombotic thrombocytopenic purpura. Thromb. Haemost., 106, 539-547 (2011a). Jilma-Stohlawetz, P., Gorczyca, M. E., Jilma, B., SillerMatula, J., Gilbert, J. C., and Knöbl, P.., Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura. Thromb. Haemost., 105, 545-552 (2011b). Jilma-Stohlawetz, P., Knöbl, P., Gilbert, J. C., and Jilma, B. B., The anti-von Willebrand factor aptamer ARC1779 increases von Willebrand factor levels and platelet counts in patients with type 2B von Willebrand disease. Thromb. Haemost., 108, 284-290 (2012). Keefe, A. D. and Schaub, R. G., Aptamers as candidate therapeutics for cardiovascular indications. Curr. Opin. Pharmacol., 8, 147-152 (2008). Kiefer, T. L. and Becker, R. C., Inhibitors of platelet adhesion. Circulation, 120, 2488-2495 (2009). Knöbl, P., Jilma, B., Gilbert, J. C., Hutabarat, R. M., Wagner, P. G., and Jilma-Stohlawetz, P., Anti-von Willebrand factor aptamer ARC1779 for refractory thrombotic thrombocytopenic purpura. Transfusion, 49, 2181-2185 (2009). Lenting, P. J., Pegon, J. N., Groot, E., and de Groot, P. G., Regulation of von Willebrand factor-platelet interactions. Thromb. Haemost., 104, 449-455 (2010). Mackman, N., Triggers, targets and treatments for thrombosis. Nature. 45, 914-918 (2008). Markus, H. S., McCollum, C., Imray, C., Goulder, M. A., Gilbert, J., and King, A., The von Willebrand inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy: a randomized trial. Stroke, 42, 2149-2153 (2011). Mayr, F. B., Knobl, P., Jilma, B., Siller-Matula, J. M., Wagner, P. G., Schaub, R. G., Gilbert, J. C. and JilmaStohlawetz, P., The aptamer ARC1779 blocks von Willebrand factor-dependent platelet function in patients with thrombotic thrombocytopenic purpura ex vivo. Transfusion, 50, 1079-1087 (2010). Michelson, A. D., Anti-platelet therapies for the treatment of cardiovascular disease. Nat. Rev. Drug Discov., 9, 154-169 (2010). Nesbitt, W. S., Westein, E., Tovar-Lopez, F. J., Tolouei, E., Mitchell, A., Fu, J., Carberry, J., Fouras, A. and Jackson, S. P., A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat. Med., 15, 665-673 (2009). Nichols, W. L., Hultin, M. B., James, A. H., Manco-Johnson, M. J., Montgomery, R. R., Ortel, T. L., Rick, M. E., Sadler, J. E., Weinstein, M., and Yawn, B. P., von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia, 14, 171-232 (2008). Noris, P. and Balduini, C. L., Investigational drugs in throm-
1699
botic thrombocytopenic purpura. Expert Opin. Investig. Drugs, 20, 1087-1098 (2011). Raju, N. C., Eikelboom, J. W. and Hirsh, J., Platelet ADPreceptor antagonists for cardiovascular disease: past, present and future. Nat. Clin. Pract. Cardiovasc. Med., 5, 766-780 (2008). Rayes, J., Hommais, A., Legendre, P., Tout, H., Veyradier, A., Obert, B., Ribba, A. S., and Girma, J. P., Effect of von Willebrand disease type 2B and type 2M mutations on the susceptibility of von Willebrand factor to ADAMTS-13. J. Thromb. Haemost., 5, 321-328 (2007). Reininger, A. J., VWF attributes - impact on thrombus formation. Thromb. Res., 122 Suppl 4, S9-S13 (2008). Ruggeri, Z. M., The role of von Willebrand factor in thrombus formation. Thromb. Res., 120 Suppl 1, S5- S9 (2007). Sadler, J. E., Biomedicine. Contact--how platelets touch von Willebrand factor. Science, 297, 1128-1129 (2002). Sadler, J. E., Budde, U., Eikenboom, J. C., Favaloro, E. J., Hill, F. G., Holmberg, L., Ingerslev, J., Lee, C. A., Lillicrap, D., Mannucci, P. M., Mazurier, C., Meyer, D., Nichols, W. L., Nishino, M., Peake, I. R., Rodeghiero, F., Schneppenheim, R., Ruggeri, Z. M., Srivastava, A., Montgomery, R. R., and Federici, A. B., Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J. Thromb. Haemost., 4, 2103-2114 (2006). Scarborough, R. M., Kleiman, N. S., and Phillips, D. R., Platelet glycoprotein IIb/IIIa antagonists. What are the relevant issues concerning their pharmacology and clinical use? Circulation, 100, 437-444 (1999). Siller-Matula, J. M., Krumphuber, J., and Jilma, B., Pharma-
cokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases. Br. J. Pharmacol., 159, 502-517 (2010). Sostres, C. and Lanas, A., Gastrointestinal effects of aspirin. Nat. Rev. Gastroenterol. Hepatol., 8, 385-394 (2011). Spiel, A. O., Mayr, F. B., Ladani, N., Wagner, P. G., Schaub, R. G., Gilbert, J. C. and 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, 20, 334-340 (2009). Varga-Szabo, D., Pleines, I., and Nieswandt, B., Cell adhesion mechanisms in platelets. Arterioscler. Thromb. Vasc. Biol., 28, 403-412 (2008). Vischer, U. M., von Willebrand factor, endothelial dysfunction, and cardiovascular disease. J. Thromb. Haemost., 4, 1186-1193 (2006). von Willebrand, E. A., Hereditärpseudohemofili. Fin. Laekaresaellsk Hand. 68, 87-112. (1926). Wagner, D. D. and Burger, P. C., Platelets in inflammation and thrombosis. Arterioscler. Thromb. Vasc. Biol., 23, 21312137 (2003). Weitz, J. I., Hirsh, J., and Samama, M. M., New antithrombotic drugs: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th Edition). Chest, 133, 234S-256S (2008). Yago, T., Lou, J., Wu, T., Yang, J., Miner, J. J., Coburn, L., López, J. A., Cruz, M. A., Dong, J. F., McIntire, L. V., McEver, R. P., and Zhu, C., Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF. J. Clin. Invest., 118, 3195-3207 (2008).
Ok-Nam Bae Laboratory of Toxicology and Environmental Pathology, College of Pharmacy, Hanyang University Main Research Areas Role of endogenous/exogenous risk factors to development of chronic human diseases Target diseases; Stroke (neurovascular unit), diabetes (cardiovascular complications) and acute kidney injury (ischemia/reperfusion)