Download PDF
Semin Thromb Hemost 2015; 41(02): 255-262
DOI: 10.1055/s-0035-1546466
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Next Generation Antithrombotic Therapy: Focus on Antisense Therapy against Coagulation Factor XI

Giuseppe Lippi
1   Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy
,
Job Harenberg
2   Clinical Pharmacology, Medical Faculty Mannheim, Ruprecht-Karls University Heidelberg, Mannheim, Germany
,
Camilla Mattiuzzi
3   Service of Clinical Governance, General Hospital of Trento, Trento, Italy
,
Emmanuel J. Favaloro
4   Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Pathology West, Westmead Hospital, Westmead, New South Wales, Australia
› Author Affiliations
Further Information

Publication History

Publication Date:
18 February 2015 (online)

    Permissions and Reprints

Abstract

Although the current therapeutic armamentarium of venous thrombosis encompasses the use of vitamin K antagonists, heparins, and direct oral anticoagulants, these drugs have several important drawbacks. Antisense oligonucleotides are relatively short single-stranded nucleic acid sequences, which hybridize with a target messenger RNA (mRNA) and suppress protein synthesis. Coagulation factor XI is a key player in blood coagulation, and thus represents a potential target for antisense therapy. The available evidence reviewed in this article suggests that factor XI antisense oligonucleotides may be more effective than conventional anticoagulants in preventing the onset and propagation of thrombosis, do not require factor measurement since the reduction of mRNA synthesis appears dose-dependently, robustly, and stably decreased for 3 to 5 weeks after the end of administration, with an incidence of major bleeding that is at least not greater than that associated with warfarin or low-molecular-weight heparin therapy. Despite conceptual simplicity, rational design, and relatively inexpensive cost, the preliminary findings in animal models and in patients undergoing knee surgery need to be validated in other prospective trials and cost-effective analyses before this attractive treatment option can be advocated as a new paradigm in prevention and treatment of venous thrombosis.

Keywords

anticoagulant therapy - antisense therapy - factor XI - venous thromboembolism - thrombosis
 

  • References

  • 1 Dias N, Stein CA. Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther 2002; 1 (5) 347-355
    PubMedGoogle Scholar
  • 2 Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 2010; 50: 259-293
    CrossrefPubMedGoogle Scholar
  • 3 Lippi G, Favaloro EJ. Antisense therapy in the treatment of hypercholesterolemia. Eur J Intern Med 2011; 22 (6) 541-546
    CrossrefPubMedGoogle Scholar
  • 4 Castanotto D, Stein CA. Antisense oligonucleotides in cancer. Curr Opin Oncol 2014; 26 (6) 584-589
    CrossrefPubMedGoogle Scholar
  • 5 Mourich DV, Marshall NB. Antisense approaches to immune modulation for transplant and autoimmune diseases. Curr Opin Pharmacol 2005; 5 (5) 508-512
    CrossrefPubMedGoogle Scholar
  • 6 Falzarano MS, Passarelli C, Ferlini A. Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy. Nucleic Acid Ther 2014; 24 (1) 87-100
    CrossrefPubMedGoogle Scholar
  • 7 Gauvreau GM, Boulet LP, Cockcroft DW , et al. Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. Am J Respir Crit Care Med 2008; 177 (9) 952-958
    CrossrefPubMedGoogle Scholar
  • 8 Lu X, Yu Q, Binder GK , et al. Antisense-mediated inhibition of human immunodeficiency virus (HIV) replication by use of an HIV type 1-based vector results in severely attenuated mutants incapable of developing resistance. J Virol 2004; 78 (13) 7079-7088
    CrossrefPubMedGoogle Scholar
  • 9 de Jong YP, Jacobson IM. Antisense therapy for hepatitis C virus infection. J Hepatol 2014; 60 (1) 227-228
    CrossrefPubMedGoogle Scholar
  • 10 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over. Semin Thromb Hemost 2008; 34 (8) 747-761
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost 2013; 39 (6) 621-631
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Vercauteren E, Gils A, Declerck PJ. Thrombin activatable fibrinolysis inhibitor: a putative target to enhance fibrinolysis. Semin Thromb Hemost 2013; 39 (4) 365-372
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Salomon O, Steinberg DM, Zucker M, Varon D, Zivelin A, Seligsohn U. Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis. Thromb Haemost 2011; 105 (2) 269-273
    PubMedGoogle Scholar
  • 14 Löwenberg EC, Meijers JC, Monia BP, Levi M. Coagulation factor XI as a novel target for antithrombotic treatment. J Thromb Haemost 2010; 8 (11) 2349-2357
    CrossrefPubMedGoogle Scholar
  • 15 Zhang H, Löwenberg EC, Crosby JR , et al. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116 (22) 4684-4692
    CrossrefPubMedGoogle Scholar
  • 16 Que Liu ED, Claudette B, Shuting X , et al. ISIS-FXIRx, a novel and specific antisense inhibitor of factor XI, caused significant reduction in FXI antigen and activity and increased aPTT without causing bleeding in healthy volunteers. Blood 2011; 118: 209
    PubMedGoogle Scholar
  • 17 Younis HS, Crosby J, Huh JI , et al. Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys. Blood 2012; 119 (10) 2401-2408
    CrossrefPubMedGoogle Scholar
  • 18 Crosby JR, Marzec U, Revenko AS , et al. Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates. Arterioscler Thromb Vasc Biol 2013; 33 (7) 1670-1678
    CrossrefPubMedGoogle Scholar
  • 19 Yau JW, Liao P, Fredenburgh JC , et al. Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood 2014; 123 (13) 2102-2107
    CrossrefPubMedGoogle Scholar
  • 20 van Montfoort ML, Kuijpers MJ, Knaup VL , et al. Factor XI regulates pathological thrombus formation on acutely ruptured atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2014; 34 (8) 1668-1673
    CrossrefPubMedGoogle Scholar
  • 21 Büller HR, Bethune C, Bhanot S , et al; the FXI-ASO TKA Investigators. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372 (3) 232-240
    CrossrefPubMedGoogle Scholar
  • 22 Raskob GE, Angchaisuksiri P, Blanco AN , et al; ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Semin Thromb Hemost 2014; 40 (7) 724-735
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Dahl OE, Harenberg J, Wexels F, Preissner KT. Arterial and venous thrombosis following trauma and major orthopedic surgery: molecular mechanisms and strategies for intervention. Semin Thromb Hemost 2015; 41 (2) 141-145
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Zolfaghari S, Harenberg J, Froelich L, Wehling M, Weiss C. Development of a tool to identify patients' preference for vitamin K antagonist or direct oral anticoagulant therapy. Semin Thromb Hemost 2014; 40 (1) 121-128
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Lippi G, Favaloro EJ. Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): is there consensus?. Clin Chem Lab Med 2015; 53 (2) 185-197
    PubMedGoogle Scholar
  • 26 Favaloro EJ, Lippi G. The new oral anticoagulants and the future of haemostasis laboratory testing. Biochem Med (Zagreb) 2012; 22 (3) 329-341
    PubMedGoogle Scholar
  • 27 Riva N, Ageno W. Pros and cons of vitamin K antagonists and non-vitamin K antagonist oral anticoagulants. Semin Thromb Hemost 2015; 41 (2) 178-187
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Agnelli G, Prandoni P, Di Minno G , et al. Thromboprophylaxis with low molecular weight heparins. An assessment of the methodological quality of studies. Semin Thromb Hemost 2015; 41 (2) 113-132
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Favaloro EJ, Lippi G, Koutts J. Laboratory testing of anticoagulants: the present and the future. Pathology 2011; 43 (7) 682-692
    CrossrefPubMedGoogle Scholar
  • 30 Lippi G, Favaloro EJ, Mattiuzzi C. Combined administration of antibiotics and direct oral anticoagulants: a renewed indication for laboratory monitoring?. Semin Thromb Hemost 2014; 40 (7) 756-765
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Tripodi A, Di Iorio G, Lippi G, Testa S, Manotti C. Position paper on laboratory testing for patients taking new oral anticoagulants. Consensus document of FCSA, SIMeL, SIBioC and CISMEL1). Clin Chem Lab Med 2012; 50 (12) 2137-2140
    PubMedGoogle Scholar
  • 32 Harenberg J, Kraemer S, Du S , et al. Determination of direct oral anticoagulants from human serum samples. Semin Thromb Hemost 2014; 40 (1) 129-134
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Harenberg J, Du S, Krämer S, Weiss C, Krämer R, Wehling M. Patients' serum and urine as easily accessible samples for the measurement of non-vitamin K antagonist oral anticoagulants. Semin Thromb Hemost 2015; 41 (2) 228-236
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Bane Jr CE, Gailani D. Factor XI as a target for antithrombotic therapy. Drug Discov Today 2014; 19 (9) 1454-1458
    CrossrefPubMedGoogle Scholar
  • 35 Bird JE, Smith PL, Wang X , et al. Effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice: murine ortholog of the Fletcher trait. Thromb Haemost 2012; 107 (6) 1141-1150
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Flaumenhaft R. Making (anti)sense of factor XI in thrombosis. N Engl J Med 2015; 372 (3) 277-278
    CrossrefPubMedGoogle Scholar
  • 37 Morrissey JH. Targeting factor XI to prevent thrombosis. Arterioscler Thromb Vasc Biol 2013; 33 (7) 1454-1455
    CrossrefPubMedGoogle Scholar
  • 38 Buller HR, Cohen AT, Davidson B , et al; van Gogh Investigators. Extended prophylaxis of venous thromboembolism with idraparinux. N Engl J Med 2007; 357 (11) 1105-1112
    CrossrefPubMedGoogle Scholar
  • 39 Harenberg J, Vukojevic Y, Mikus G, Joerg I, Weiss C. Long elimination half-life of idraparinux may explain major bleeding and recurrent events of patients from the van Gogh trials. J Thromb Haemost 2008; 6 (5) 890-892
    CrossrefPubMedGoogle Scholar
  • 40 Crooke ST. Antisense Drug Technology: Principles, Strategies, and Applications. 2nd ed. New York, NY: CRC Press; 2007
    CrossrefGoogle Scholar