Download PDF
Thromb Haemost 2012; 108(02): 284-290
DOI: 10.1160/TH11-12-0889
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The anti-von Willebrand factor aptamer ARC1779 increases von Willebrand factor levels and platelet counts in patients with type 2B von Willebrand disease

Petra Jilma-Stohlawetz
2   Department of Blood Group Serology & Transfusion Medicine, Medical University of Vienna, Austria
,
Paul Knöbl
3   Department of Internal Medicine I, Division of Haematology, Medical University of Vienna, Austria
,
James C. Gilbert
4   Archemix Corporation, Cambridge, Massachusetts, USA
,
Bernd Jilma
1   Department of Clinical Pharmacology, Medical University of Vienna, Austria
› Author Affiliations
Further Information

Publication History

Received: 23 December 2012

Accepted after major revision: 03 May 2012

Publication Date:
25 November 2017 (online)

    Permissions and Reprints

Summary

Blockade of hyperactive von Willebrand factor (VWF) by ARC1779 blunted the platelet drop induced by desmopressin in patients with type 2B von Willebrand disease (VWD). Thus, we hypothesised that ARC1779 may increase VWF levels and correct thrombocytopenia. Three thrombocytopenic patients suffering from type 2B VWD received a loading dose of 0.23 mg/kg ARC1779 followed by 4 μg/kg/min intravenously for 72 hours in a prospective clinical trial. ARC1779 was well tolerated and safe. Plasma concentrations of ARC1779 increased to 76 μg/ml (59–130) leading to an immediate decrease of free VWF A1 domains. VWF/FVIII levels increased as early as 12 h after start of infusion, peaked near the end of infusion, and returned to baseline at follow-up. VWF ristocetin cofactor activity (VWF:RCo) showed a median 10-fold increase 8 hours after end of infusion, while the median VWF-antigen and FVIII increase was less (5-fold and 4-fold, respectively). Most importantly inhibition of hyperactive VWF rapidly increased platelet counts from 40x109/l (38–58 x109/l) to a maximum of 146 x109/l (107–248 x109/l). In conclusion, ARC1779 markedly increases VWF/FVIII levels and most importantly improves or even corrects thrombocytopenia in VWD type 2B patients. This underscores the in vivo potency of ARC1779.

Keywords

von Willebrand disease - thrombocytopenia - aptamer
 

  • References

  • 1 Lillicrap D. Genotype/phenotype association in von Willebrand disease: is the glass half full or empty?. J Thromb Haemost 2009; 07 (Suppl. 01) 65-70.
    PubMedGoogle Scholar
  • 2 Sadler JE, Budde U, Eikenboom JC. et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Wille-brand Factor. J Thromb Haemost 2006; 04: 2103-2114.
    CrossrefPubMedGoogle Scholar
  • 3 Rayes J, Hommais A, Legendre P. et al. Effect of von Willebrand disease type 2B and type 2M mutations on the susceptibility of von Willebrand factor to ADAMTS-13. J Thromb Haemost 2007; 05: 321-328.
    CrossrefPubMedGoogle Scholar
  • 4 Zimmerman TS, Dent JA, Ruggeri ZM. et al. Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID, and IIE). J Clin Invest 1986; 77: 947-951.
    CrossrefPubMedGoogle Scholar
  • 5 Federici AB, Mannucci PM, Castaman G. et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Wille brand disease type 2B: a cohort study of 67 patients. Blood 2009; 113: 526-534.
    CrossrefPubMedGoogle Scholar
  • 6 Becker RC, Povsic T, Cohen MG. et al. Nucleic acid aptamers as antithrombotic agents: Opportunities in extracellular therapeutics. Thromb Haemost 2010; 103: 586-595.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Huang RH, Fremont DH, Diener JL. et al. A structural explanation for the anti-thrombotic activity of ARC1172, a DNA aptamer that binds von Willebrand factor domain A1. Structure 2009; 17: 1476-1484.
    CrossrefPubMedGoogle Scholar
  • 8 Gilbert JC, DeFeo-Fraulini T, Hutabarat RM. et al. First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers. Circulation 2007; 116: 2678-2686.
    CrossrefPubMedGoogle Scholar
  • 9 Diener JL, Daniel Lagasse HA, Duerschmied D. et al. Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779. J Thromb Haemost 2009; 07: 1155-1162.
    CrossrefPubMedGoogle Scholar
  • 10 Siller-Matula JM, Krumphuber J, Jilma B. Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases. Br J Pharmacol 2009; 159: 502-517.
    PubMedGoogle Scholar
  • 11 Jilma B, Paulinska P, Jilma-Stohlawetz P. et al. A randomised pilot trial of the antivon Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease. Thromb Haemost 2010; 104: 563-570.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Ruggeri ZM, Mannucci PM, Lombardi R. et al. Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand's disease subtypes. Blood 1982; 59: 1272-1278.
    PubMedGoogle Scholar
  • 13 Frontroth JP, Hepner M, Sciuccati G. et al. Prospective study of low-dose ristocetin-induced platelet aggregation to identify type 2B von Willebrand disease (VWD) and platelet-type VWD in children. Thromb Haemost 2010; 104: 1158-1165.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Spiel AO, Mayr FB, Ladani N. et al. The aptamer ARC1779 is a potent and specific inhibitor of von Willebrand Factor mediated ex vivo platelet function in acute myocardial infarction. Platelets 2009; 20: 334-340.
    CrossrefPubMedGoogle Scholar
  • 15 Jilma-Stohlawetz P, Gilbert JC, Gorczyca ME. et al. A dose ranging phase I/II trial of the von Willebrand factor inhibiting aptamer ARC1779 in patients with congenital thrombotic thrombocytopenic purpura. Thromb Haemost 2011; 106: 539-547.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Knobl P, Jilma B, Gilbert JC. et al. Anti-von Willebrand factor aptamer ARC1779 for refractory thrombotic thrombocytopenic purpura. Transfusion 2009; 49: 2181-2185.
    CrossrefPubMedGoogle Scholar
  • 17 Reiter RA, Mayr F, Blazicek H. et al. Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Blood 2003; 102: 4594-4599.
    CrossrefPubMedGoogle Scholar
  • 18 Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction. J Lab Clin Med 2001; 138: 152-163.
    CrossrefPubMedGoogle Scholar
  • 19 Jilma-Stohlawetz P, Hergovich N, Homoncik M. et al. Impaired platelet function among platelet donors. Thromb Haemost 2001; 86: 880-886.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Harrison P. The role of PFA-100 testing in the investigation and management of haemostatic defects in children and adults. Br J Haematol 2005; 130: 3-10.
    CrossrefPubMedGoogle Scholar
  • 21 Spiel AO, Bartko J, Schwameis M. et al. Increased platelet aggregation and in vivo platelet activation after granulocyte colony-stimulating factor administration. A randomised controlled trial. Thromb Haemost 2011; 105: 655-662.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Reiter RA, Varadi K, Turecek PL. et al. Changes in ADAMTS13 (von-Willebrand-factor-cleaving protease) activity after induced release of von Willebrand factor during acute systemic inflammation. Thromb Haemost 2005; 93: 554-558.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Spiel AO, Mayr FB, Firbas C. et al. Validation of rotation thrombelastography in a model of systemic activation of fibrinolysis and coagulation in humans. J Thromb Haemost 2006; 04: 411-416.
    CrossrefPubMedGoogle Scholar
  • 24 Jilma-Stohlawetz P, Kursten FW, Walasek C. et al. Safety of a universal, virus-inactivated and prion-depleted, pharmaceutical-quality plasma: a randomized, double-blind, clinical trial in healthy volunteers. Transfusion 2011; 51: 1228-1240.
    CrossrefPubMedGoogle Scholar
  • 25 Leitner JM, Jilma B, Spiel AO. et al. Massive pulmonary embolism leading to cardiac arrest is associated with consumptive coagulopathy presenting as disseminated intravascular coagulation. J Thromb Haemost 2010; 08: 1477-1482.
    CrossrefPubMedGoogle Scholar
  • 26 de Romeuf C, Mazurier C. Comparison between von Willebrand factor (VWF) and VWF antigen II in normal individuals and patients with von Willebrand disease. Thromb Haemost 1998; 80: 37-41.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Favaloro EJ. The utility of the PFA-100 in the identification of von Willebrand disease: a concise review. Semin Thromb Hemost 2006; 32: 537-545.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Mayr FB, Knobl P, Jilma B. et al. The aptamer ARC1779 blocks von Willebrand factor-dependent platelet function in patients with thrombotic thrombocytopenic purpura ex vivo. Transfusion 2010; 50: 1079-1087.
    CrossrefPubMedGoogle Scholar
  • 29 Jilma-Stohlawetz P, Gorczyca ME, Jilma B. et al. Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura. Thromb Haemost 2011; 105: 545-552.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Sadler JE, Mannucci PM, Berntorp E. et al. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost 2000; 84: 160-174.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Casonato A, Gallinaro L, Cattini MG. et al. Reduced survival of type 2B von Wille-brand factor, irrespective of large multimer representation or thrombocytopenia. Haematologica 2010; 95: 1366-1372.
    CrossrefPubMedGoogle Scholar
  • 32 Sporn LA, Marder VJ, Wagner DD. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell 1986; 46: 185-190.
    CrossrefPubMedGoogle Scholar
  • 33 Tsai HM, Nagel RL, Hatcher VB. et al. The high molecular weight form of endothelial cell von Willebrand factor is released by the regulated pathway. Br J Haematol 1991; 79: 239-245.
    CrossrefPubMedGoogle Scholar
  • 34 Giblin JP, Hewlett LJ, Hannah MJ. Basal secretion of von Willebrand factor from human endothelial cells. Blood 2008; 112: 957-964.
    CrossrefPubMedGoogle Scholar
  • 35 Arvan P, Castle D. Protein sorting and secretion granule formation in regulated secretory cells. Trends Cell Biol 1992; 02: 327-331.
    CrossrefPubMedGoogle Scholar
  • 36 Erent M, Meli A, Moisoi N. et al. Rate, extent and concentration dependence of histamine-evoked Weibel-Palade body exocytosis determined from individual fusion events in human endothelial cells. J Physiol 2007; 583: 195-212.
    CrossrefPubMedGoogle Scholar
  • 37 Henry SP, Novotny W, Leeds J. et al. Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense Nucleic Acid Drug Dev 1997; 07: 503-510.
    CrossrefPubMedGoogle Scholar
  • 38 Sieghart W, Homoncik M, Jilma B. et al. Antiviral therapy decreases GpIIb/IIIa activation of platelets in patients with chronic hepatitis C. Thromb Haemost 2006; 95: 260-266.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Homoncik M, Sieghart W, Formann E. et al. Erythropoietin treatment is associated with more severe thrombocytopenia in patients with chronic hepatitis C undergoing antiviral therapy. Am J Gastroenterol 2006; 101: 2275-2282.
    CrossrefPubMedGoogle Scholar
  • 40 Derhaschnig U, Schweeger-Exeli I, Marsik C. et al. Effects of aspirin and NO-aspirin (NCX 4016) on platelet function and coagulation in human endotoxemia. Platelets 2010; 215: 320-328.
    PubMedGoogle Scholar
  • 41 Homoncik M, Blann AD, Hollenstein U. et al. Systemic inflammation increases shear stress-induced platelet plug formation measured by the PFA-100. Br J Haematol 2000; 111: 1250-1252.
    CrossrefPubMedGoogle Scholar
  • 42 Firbas C, Siller-Matula JM, Jilma B. Targeting von Willebrand factor and platelet glycoprotein Ib receptor. Expert Rev Cardiovasc Ther 2010; 08: 1689-1701.
    CrossrefPubMedGoogle Scholar
  • 43 Siller-Matula JM, Merhi Y, Tanguay JF. et al. ARC15105 Is a Potent Antagonist of Von Willebrand Factor Mediated Platelet Activation and Adhesion. Arterioscler Thromb Vasc Biol 2012; 32: 902-909.
    CrossrefPubMedGoogle Scholar
  • 44 Hamilton A, Ozelo M, Leggo J. et al. Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study. Thromb Haemost 2011; 105: 501-508.
    Article in Thieme ConnectPubMedGoogle Scholar