Evidence map›Paper›PMID 33540294›Full record

ArticleThrombosis research2021

Antisense oligonucleotides and nucleic acids generate hypersensitive platelets.

Alexander Zaslavsky, Mackenzie Adams, Xiu Cao, Adriana Yamaguchi, James Henderson, Peter Busch-Østergren, Aaron Udager, Sethuramasundaram Pitchiaya, Benjamin Tourdot, Tadas Kasputis and 10 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Thrombosis research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
2.0field-weighted citation impact, top 13% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed, 15 citations in OpenAlex.

  1. Review
  2. Review
  3. Review
  4. Article
  5. Review
  6. Review
  7. Article
  8. Article
  9. Review
  10. Platelet Innate Immune Receptors and TLRs: A Double-Edged Sword.International journal of molecular sciences · 2021
    Review
  11. Therapeutics Development for Alagille Syndrome.Frontiers in pharmacology · 2021
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors at 2 institutions in 2 countries.

Alexander ZaslavskyRogel 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.
Mackenzie AdamsRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
Xiu CaoRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
Adriana YamaguchiDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
James HendersonRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
Peter Busch-ØstergrenDepartment of Urology, Herlev and Gentofte Hospital, Herlev, Denmark.
Aaron UdagerRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Sethuramasundaram PitchiayaRogel 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.
Benjamin TourdotDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
Tadas KasputisRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
Samuel J ChurchRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
Samantha K LeeRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
Sydney OhlRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
Shivam PatelRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
Todd M MorganRogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
Ajjai AlvaRogel 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.
Thomas W WakefieldSection of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan Medical School, Ann Arbor, MI, USA.
Zachery ReichertDepartment of Internal Medicine-Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
Michael HolinstatDepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Ganesh S PalapattuRogel 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.
Gentofte Hospital · DKUniversity of Michigan–Ann Arbor · US

Funding

12-HETrE regulation of blood coagulation, hemostasis, and thrombosisR35GM131835 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI HOLINSTAT, MICHAEL ALLAN · 2019 to 2023
$2.3M
Role of 12-lipoxygenase in platelet reactivity and type 2 diabetes mellitusR01HL114405 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI HOLINSTAT, MICHAEL ALLAN · 2013 to 2017
$1.9M
12-HETrE regulation of plateletsR01GM105671 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI HOLINSTAT, MICHAEL ALLAN · 2013 to 2017
$1.6M
NHLBI NIH HHS R01 HL114405NIGMS NIH HHS R01 GM105671NIGMS NIH HHS R35 GM131835
6 · The paper itself

Abstract

introductionDespite 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.

methodsPlatelets 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.

resultsPlatelet 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.

conclusionOur 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.

Indexed as

Nucleic AcidsPharmaceutical PreparationsAnimalsBlood PlateletsHumansMiceOligonucleotides, AntisensePhosphorothioate OligonucleotidesNucleic AcidsOligonucleotides, AntisensePharmaceutical PreparationsPhosphorothioate OligonucleotidesAntisense oligonucleotidesPlateletsProstate CancerToll-like receptors

Identifiers

PMID33540294
PMCPMC8264460
OpenAlexW3123494922

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.