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Antisense oligonucleotides and nucleic acids generate hypersensitive platelets.
Zaslavsky, Alexander; Adams, Mackenzie; Cao, Xiu; Yamaguchi, Adriana; Henderson, James; Busch-Østergren, Peter; Udager, Aaron; Pitchiaya, Sethuramasundaram; Tourdot, Benjamin; Kasputis, Tadas; Church, Samuel J; Lee, Samantha K; Ohl, Sydney; Patel, Shivam; Morgan, Todd M; Alva, Ajjai; Wakefield, Thomas W; Reichert, Zachery; Holinstat, Michael; Palapattu, Ganesh S.
Afiliação
  • Zaslavsky A; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: azaslavs@med.umich.edu.
  • Adams M; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Cao X; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Yamaguchi A; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Henderson J; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Busch-Østergren P; Department of Urology, Herlev and Gentofte Hospital, Herlev, Denmark.
  • Udager A; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Pitchiaya S; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Tourdot B; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Kasputis T; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Church SJ; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Lee SK; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Ohl S; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Patel S; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Morgan TM; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Alva A; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine-Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Wakefield TW; Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Reichert Z; Department of Internal Medicine-Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Holinstat M; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Palapattu GS; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, Medical University of Vienna, Vienna, Austria. Electronic address: gpalapat@med.umich.edu.
Thromb Res ; 200: 64-71, 2021 04.
Article em En | MEDLINE | ID: mdl-33540294
ABSTRACT

INTRODUCTION:

Despite the great promise for therapies using antisense oligonucleotides (ASOs), their adverse effects, which include pro-inflammatory effects and thrombocytopenia, have limited their use. Previously, these effects have been linked to the phosphorothioate (PS) backbone necessary to prevent rapid ASO degradation in plasma. The main aim of this study was to assess the impact of the nucleic acid portion of an ASO-type drug on platelets and determine if it may contribute to thrombosis or thrombocytopenia.

METHODS:

Platelets were isolated from healthy donors and men with advanced prostate cancer. Effects of antisense oligonucleotides (ASO), oligonucleotides, gDNA, and microRNA on platelet activation and aggregation were evaluated. A mouse model of lung thrombosis was used to confirm the effects of PS-modified oligonucleotides in vivo.

RESULTS:

Platelet exposure to gDNA, miRNA, and oligonucleotides longer than 16-mer at a concentration above 8 mM resulted in the formation of hypersensitive platelets, characterized by an increased sensitivity to low-dose thrombin (0.1 nM) and increase in p-Selectin expression (6-8 fold greater than control; p < 0.001). The observed nucleic acid (NA) effects on platelets were toll-like receptor (TLR) -7 subfamily dependent. Injection of a p-Selectin inhibitor significantly (p = 0.02) reduced the formation of oligonucleotide-associated pulmonary microthrombosis in vivo.

CONCLUSION:

Our results suggest that platelet exposure to nucleic acids independent of the presence of a PS modification leads to a generation of hypersensitive platelets and requires TLR-7 subfamily receptors. ASO studies conducted in cancer patients may benefit from testing the ASO effects on platelets ex vivo before initiation of patient treatment.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas / Ácidos Nucleicos Limite: Animals / Humans Idioma: En Revista: Thromb Res Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas / Ácidos Nucleicos Limite: Animals / Humans Idioma: En Revista: Thromb Res Ano de publicação: 2021 Tipo de documento: Article