Download PDF
Thromb Haemost 2011; 105(03): 545-552
DOI: 10.1160/TH10-08-0520
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura

Petra Jilma-Stohlawetz   *
1   Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
,
Monika E. Gorczyca   *
2   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
Bernd Jilma
2   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
Jolanta Siller-Matula
2   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
James C. Gilbert
4   Archemix Corp, Cambridge, Massachusetts, USA
,
Paul Knöbl
3   Department of Internal Medicine I, Div. of Haematology and Haemostasis, Medical University of Vienna, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Received: 11 August 2010

Accepted after minor revision: 25 November 2010

Publication Date:
27 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Thrombotic thrombocytopenic purpura (TTP) can cause severe organ damage due to enhanced platelet aggregation by ultra-large von Wille-brand factor (VWF) multimers. Thus inhibition of VWF by the anti-VWF ARC1779 might potentially be beneficial for TTP patients. This prospective trial tested the safety, pharmacokinetics and pharmacodynamics of the anti-VWF aptamer ARC1779 added to plasma exchange therapy (PEX) in patients with acute TTP. Seven patients received bolus primed continuous i.v. infusions of ARC1779 (1–2 μg/kg/min) in addition to PEX until remission of TTP was induced or for 14 days. Mean steady state ARC1779 plasma concentrations of 9.9 μg/ml reduced VWF activity to 5% (mean baseline activity was 125% in TTP patients compared to a reference plasma). PEX reduced ARC1779 levels by 50%, but steady state concentrations were restored rapidly with a mini-bolus. After discontinuation of PEX, ARC1779 alone further increased platelet counts in one patient. Stopping ARC1779 was associated with an immediate drop of platelet counts in this patient. This suggests that ARC1779 can block the progression of TTP in patients with severe ADAMTS13 is deficiency. ARC1779 was generally well tolerated without any signs of bleeding. Pharmacokinetics and pharmacodynamics of ARC1779 were well predictable and in agreement with those observed in a previous trial with healthy volunteers. Based on its mechanism of action and the observed effect on platelet counts, ARC1779 used as an adjunctive to PEX may help accelerate recovery from organ dysfunction.

Keywords

Aptamer - ARC1779 - thrombotic thrombocytopenic purpura (TTP) - platelets - von Willebrand factor (VWF)

* These authors contributed equally.


 

  • References

  • 1 Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008; 112: 11-18.
    CrossrefPubMedSearch in Google Scholar
  • 2 Zheng XL, Sadler JE. Pathogenesis of thrombotic microangiopathies. Annu Rev Pathol 2008; 3: 249-277.
    CrossrefPubMedSearch in Google Scholar
  • 3 Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002; 347: 589-600.
    CrossrefPubMedSearch in Google Scholar
  • 4 Benz K, Amann K. Pathological aspects of membranoproliferative glomerulonephritis (MPGN) and haemolytic uraemic syndrome (HUS) / thrombocytic thrombopenic purpura (TTP). Thromb Haemost 2009; 101: 265-270.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Terrell DR, Williams LA, Vesely SK. et al. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J Thromb Haemost 2005; 3: 1432-1436.
    CrossrefPubMedSearch in Google Scholar
  • 6 Wahl PM, Terrell DR, George JN. et al. Validation of claims-based diagnostic codes for idiopathic thrombotic thrombocytopenic purpura in a commercially-insured population. Thromb Haemost 2010; 103: 1203-1209.
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Franchini M, Lippi G. The role of von Willebrand factor in hemorrhagic and thrombotic disorders. Crit Rev Clin Lab Sci 2007; 44: 115-149.
    CrossrefPubMedSearch in Google Scholar
  • 8 Lammle B, Kremer Hovinga JA, Alberio L. Thrombotic thrombocytopenic purpura. J Thromb Haemost 2005; 3: 1663-1675.
    CrossrefPubMedSearch in Google Scholar
  • 9 Raife TJ, Montgomery RR. von Willebrand factor and thrombotic thrombocytopenic purpura. Curr Opin Hematol 2000; 7: 278-283.
    CrossrefPubMedSearch in Google Scholar
  • 10 Furlan M, Lammle B. von Willebrand factor in thrombotic thrombocytopenic purpura. Thromb Haemost 1999; 82: 592-600.
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Lenting PJ, Pegon JN, Groot E. et al. Regulation of von Willebrand factor-platelet interactions. Thromb Haemost 2010; 104: 449-455.
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Levy GG, Nichols WC, Lian EC. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488-494.
    CrossrefPubMedSearch in Google Scholar
  • 13 Cataland SR, Wu HM. Targeting the inhibitor of ADAMTS13 in thrombotic thrombocytopenic purpura. Expert Opin Pharmacother 2007; 8: 437-444.
    CrossrefPubMedSearch in Google Scholar
  • 14 Asada Y, Sumiyoshi A, Hayashi T. et al. Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic purpura, with special reference to factor VIII related antigen. Thromb Res 1985; 38: 469-479.
    CrossrefPubMedSearch in Google Scholar
  • 15 Kremer Hovinga JA, Meyer SC. Current management of thrombotic thrombocytopenic purpura. Curr Opin Hematol 2008; 15: 445-450.
    CrossrefPubMedSearch in Google Scholar
  • 16 McLeod BC. Therapeutic apheresis: history, clinical application, and lingering uncertainties. Transfusion 2010; 50: 1413-1426.
    CrossrefPubMedSearch in Google Scholar
  • 17 Nguyen L, Terrell DR, Duvall D. et al. Complications of plasma exchange in patients treated for thrombotic thrombocytopenic purpura. IV. An additional study of 43 consecutive patients, 2005 to 2008. Transfusion 2009; 49: 392-394.
    CrossrefPubMedSearch in Google Scholar
  • 18 Norda R, Stegmayr BG. Therapeutic apheresis in Sweden: update of epidemiology and adverse events. Transfus Apher Sci 2003; 29: 159-166.
    CrossrefPubMedSearch in Google Scholar
  • 19 Bramlage CP, Schroder K, Bramlage P. et al. Predictors of complications in therapeutic plasma exchange. J Clin Apher 2009; 24: 225-231.
    CrossrefPubMedSearch in Google Scholar
  • 20 Hovinga JA, Vesely SK, Terrell DR. et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010; 115: 1500-11 quiz 1662.
    CrossrefPubMedSearch in Google Scholar
  • 21 Zhan H, Streiff MB, King KE. et al. Thrombotic thrombocytopenic purpura at the Johns Hopkins Hospital from 1992 to 2008: clinical outcomes and risk factors for relapse. Transfusion 2010; 50: 868-874.
    CrossrefPubMedSearch in Google Scholar
  • 22 Heidel F, Lipka DB, von Auer C. et al. Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia. Thromb Haemost 2007; 97: 228-233.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Cataland SR, Wu HM. Immunotherapy for thrombotic thrombocytopenic purpura. Curr Opin Hematol 2005; 12: 359-363.
    CrossrefPubMedSearch in Google Scholar
  • 24 Bresin E, Gastoldi S, Daina E. et al. Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13 autoantibodies. Thromb Haemost 2009; 101: 233-238.
    Thieme ConnectPubMedSearch in Google Scholar
  • 25 Ojeda-Uribe M, Federici L, Wolf M. et al. Successful long-term rituximab maintenance for a relapsing patient with idiopathic thrombotic thrombocytopenic purpura. Transfusion 2010; 50: 733-735.
    CrossrefPubMedSearch in Google Scholar
  • 26 Caramazza D, Quintini G, Abbene I. et al. Relapsing or refractory idiopathic thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: the role of rituximab. Transfusion 2010; 50: 2753-2760.
    CrossrefPubMedSearch in Google Scholar
  • 27 Becker RC, Povsic T, Cohen MG. et al. Nucleic acid aptamers as antithrombotic agents: Opportunities in extracellular therapeutics. Thromb Haemost 2010; 103: 586-595.
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Firbas C, Siller-Matula JM, Jilma B. Targeting von Willebrand Factor and platelet glycoprotein Ib (GpIb) receptor. Expert Rev Cardiovasc Ther 2010; 8: 1689-1701.
    CrossrefPubMedSearch in Google Scholar
  • 29 Bouchard PR, Hutabarat RM, Thompson KM. Discovery and development of therapeutic aptamers. Annu Rev Pharmacol Toxicol 2010; 50: 237-257.
    CrossrefPubMedSearch in Google Scholar
  • 30 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.
    CrossrefPubMedSearch in Google Scholar
  • 31 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; 7: 1155-1162.
    CrossrefPubMedSearch in Google Scholar
  • 32 Jilma B, Paulinska P, Jilma-Stohlawetz P. et al. A randomised pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease. Thromb Haemost 2010; 104: 563-570.
    Thieme ConnectPubMedSearch in Google Scholar
  • 33 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.
    CrossrefPubMedSearch in Google Scholar
  • 34 Knobl P, Jilma B, Gilbert JC. et al. Anti-von Willebrand factor aptamer ARC1779 for refractory thrombotic thrombocytopenic purpura. Transfusion 2009; 49: 2181-2185.
    CrossrefPubMedSearch in Google Scholar
  • 35 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 2009; 11: 322-328.
    PubMedSearch in Google Scholar
  • 36 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.
    CrossrefPubMedSearch in Google Scholar
  • 37 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.
    CrossrefPubMedSearch in Google Scholar
  • 38 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; 21: 320-328.
    CrossrefPubMedSearch in Google Scholar
  • 39 Kato S, Matsumoto M, Matsuyama T. et al. Novel monoclonal antibody-based enzyme immunoassay for determining plasma levels of ADAMTS13 activity. Transfusion 2006; 46: 1444-1452.
    CrossrefPubMedSearch in Google Scholar
  • 40 Gerritsen HE, Turecek PL, Schwarz HP. et al. Assay of von Willebrand factor (vWF)-cleaving protease based on decreased collagen binding affinity of degraded vWF: a tool for the diagnosis of thrombotic thrombocytopenic purpura (TTP). Thromb Haemost 1999; 82: 1386-1389.
    Thieme ConnectPubMedSearch in Google Scholar
  • 41 Leitner JM, Firbas C, Mayr FB. et al. Recombinant human antithrombin inhibits thrombin formation and interleukin 6 release in human endotoxemia. Clin Pharmacol Ther 2006; 79: 23-34.
    CrossrefPubMedSearch in Google Scholar
  • 42 Patschan D, Witzke O, Duhrsen U. et al. Acute myocardial infarction in thrombotic microangiopathies--clinical characteristics, risk factors and outcome. Nephrol Dial Transplant 2006; 21: 1549-1554.
    CrossrefPubMedSearch in Google Scholar
  • 43 Hughes C, McEwan JR, Longair I. et al. Cardiac involvement in acute thrombotic thrombocytopenic purpura: association with troponin T and IgG antibodies to ADAMTS 13. J Thromb Haemost 2009; 7: 529-536.
    CrossrefPubMedSearch in Google Scholar
  • 44 Pene F, Vigneau C, Auburtin M. et al. Outcome of severe adult thrombotic microangiopathies in the intensive care unit. Intensive Care Med 2005; 31: 71-78.
    CrossrefPubMedSearch in Google Scholar
  • 45 Hawkins BM, Abu-Fadel M, Vesely SK. et al. Clinical cardiac involvement in thrombotic thrombocytopenic purpura: a systematic review. Transfusion 2008; 48: 382-392.
    PubMedSearch in Google Scholar
  • 46 Wahla AS, Ruiz J, Noureddine N. et al. Myocardial infarction in thrombotic thrombocytopenic purpura: a single-center experience and literature review. Eur J Haematol 2008; 81: 311-316.
    CrossrefPubMedSearch in Google Scholar
  • 47 Perez L, Ramappa P, Guzman JA. Myocardial injury in thrombotic thrombocytopenic purpura: a frequent, perplexing complication. Int J Cardiol 2008; 128: 257-260.
    CrossrefPubMedSearch in Google Scholar
  • 48 McCarthy LJ, Danielson CF, Skipworth EM. et al. Myocardial infarction/injury is relatively common at presentation of acute thrombotic thrombocytopenic purpura: the Indiana University experience. Ther Apher 2002; 6: 2-4.
    CrossrefPubMedSearch in Google Scholar
  • 49 Viswanathan S, Rovin BH, Shidham GB. et al. Long-term, sub-clinical cardiac and renal complications in patients with multiple relapses of thrombotic thrombocytopenic purpura. Br J Haematol 2010; 149: 623-625.
    CrossrefPubMedSearch in Google Scholar
  • 50 Kennedy AS, Lewis QF, Scott JG. et al. Cognitive deficits after recovery from thrombotic thrombocytopenic purpura. Transfusion 2009; 49: 1092-1101.
    CrossrefPubMedSearch in Google Scholar
  • 51 Lewis QF, Lanneau MS, Mathias SD. et al. Long-term deficits in health-related quality of life after recovery from thrombotic thrombocytopenic purpura. Trans-fusion 2009; 49: 118-124.
    CrossrefPubMedSearch in Google Scholar
  • 52 Bobbio-Pallavicini E, Gugliotta L, Centurioni R. et al. Antiplatelet agents in thrombotic thrombocytopenic purpura (TTP). Results of a randomized multicenter trial by the Italian Cooperative Group for TTP. Haematologica 1997; 82: 429-435.
    PubMedSearch in Google Scholar