In vitro anti-platelet potency of ticagrelor in blood samples from infants and children

Söderlund, Fredrik; Asztély, Anna-Karin; Jeppsson, Anders; Nylander, Sven; Berggren, Anders; Nelander, Karin; Castellheim, Albert; Romlin, Birgitta

doi:10.1016/j.thromres.2015.07.013

Cited by 11 publications

(10 citation statements)

References 21 publications

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“…For all infant and child age groups, the potency of ticagrelor was comparable with that seen in adults. These findings suggest that at equivalent levels of drug exposure, children and adults would have a comparable antiplatelet response to ticagrelor, and that platelets in children do not react differently to ticagrelor, which are supported by our current findings in pediatric patients with SCD.…”

Section: Discussionsupporting

confidence: 84%

“…A similar platelet inhibition response in different age groups is consistent with the results of an in‐vitro investigation comparing the anti‐platelet potency of ticagrelor in children and adults . In this in vitro assessment, ticagrelor (0.01‐10 μmol/L) was added to platelet‐rich plasma from infants and children (0‐2, 2‐6 months, 6 months‐2 years, 2‐6, and 6‐12 years) and adults (≥18 years), and platelet inhibition was evaluated.…”

Section: Discussionsupporting

confidence: 75%

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A dose‐ranging study of ticagrelor in children aged 3‐17 years with sickle cell disease: A 2‐part phase 2 study

et al. 2018

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Antiplatelet treatment is a potential therapeutic approach for sickle cell disease (SCD). Ticagrelor inhibits platelet aggregation and is approved for adults with acute coronary syndrome and following myocardial infarction. HESTIA1 (NCT02214121) was a 2‐part, phase 2 dose‐finding study generating ticagrelor exposure, platelet inhibition, and safety data in children with SCD (3‐17 years). In part A (n = 45), patients received 2 ticagrelor single doses, 0.125‐2.25 mg/kg (washout ≥7 days), then 7 days of twice‐daily (bid) dosing with 0.125, 0.563, or 0.75 mg/kg. In the 4‐week blinded Part B extension (optional), patients received ticagrelor (0.125, 0.563, or 0.75 mg/kg bid; n = 16) or placebo (n = 7). Platelet reactivity decreased from baseline to 2 hours postdosing, and returned to near baseline after 6 hours postdosing. Dose‐dependent platelet inhibition was seen with ticagrelor; mean relative P2Y12 reaction unit inhibition 2 hours after a single dose ranged from 6% (0.125 mg/kg) to 73% (2.25 mg/kg). Ticagrelor plasma exposure increased approximately dose proportionally. No patients experienced a hemorrhagic event during treatment. No differences were seen between groups in pain ratings and analgesic use during Part B. Ticagrelor was well tolerated with no safety concerns, no discontinuations due to adverse events (AEs), and reported AEs were mainly due to SCD. In conclusion, a dose‐exposure‐response relationship for ticagrelor was demonstrated in children with SCD for the first time. These data are important for future pediatric studies of the efficacy and safety of ticagrelor in SCD.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 75%

A dose‐ranging study of ticagrelor in children aged 3‐17 years with sickle cell disease: A 2‐part phase 2 study

et al. 2018

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“…To examine whether Ticagrelor (provided by AstraZeneca for research purposes only) could inhibit polyP, DES, and/or IRA plasma effect on neutrophils, cells were pre-treated with 5 µM Ticagrelor for 30 min, prior to their exposure on each inducer. A bioactive isomer of Clopidogrel (Sigma-Aldrich, C0614, Munich, Germany) was used at a dose of 60 µM, as a control drug for 30 min, prior to exposure on each inducer [51][52][53][54]. Appropriate time and dose experiments were performed prior to Ticagrelor and Clopidogrel in vitro stimulations.…”

Section: Stimulation and Inhibition Studiesmentioning

confidence: 99%

Ticagrelor Exerts Immune-Modulatory Effect by Attenuating Neutrophil Extracellular Traps

Mitsios

Chrysanthopoulou

Αραμπατζιόγλου

et al. 2020

IJMS

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Neutrophils through the release of neutrophil extracellular traps (NETs) containing active tissue factor (TF) are key components of thrombo-inflammation. Platelets-neutrophils interplay in ST elevation myocardial infarction (STEMI) promotes NET formation via inorganic polyphosphates (polyP) released by thrombin-activated platelets. NETs, however, are also induced by biomaterials in a platelet-independent manner. Considering the possible pleiotropic effects of Ticagrelor beyond platelet inhibition and the clinical need for novel antithrombotic strategies targeting inflammation, we investigated the effects of Ticagrelor on polyP and stent-induced NETs in STEMI. Neutrophils from healthy individuals and patients receiving Ticagrelor were stimulated with polyP or drug-eluting stents (DES) to produce NETs. To induce TF expression, neutrophils were further incubated with plasma obtained from the infarct-related artery (IRA) of STEMI patients. The effects of Ticagrelor on NETs and TF loading were assessed using fluorescence microscopy, flow cytometry, myeloperoxidase(MPO)/DNA complex ELISA, and a Western blot. Ticagrelor interrupts platelet–neutrophil interaction by attenuating NETs induced by polyP. However, Ticagrelor does not affect polyP secretion from thrombin-activated platelets. Similarly, the intracellular production of TF in neutrophils triggered by IRA plasma is not hindered by Ticagrelor. Furthermore, DES induce NETs and synchronous stimulation with IRA plasma leads to the formation of thrombogenic TF-bearing NETs. Ticagrelor inhibits stent-induced NET release. These findings suggest a novel immune-modulatory effect of Ticagrelor when it attenuates the formation of thrombogenic NETs.

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“…Platelet count was adjusted using platelet poor plasma (PPP) to get 2.5 × 10 8 platelet/ ml. Then, PRP was treated by aspirin (Sanofi, Toulouse, France) at a final concentration of 2 mM (Laudy et al, 2016;Dotto et al, 2017), a concentration relatively high compared to circulating peak reached in vivo, in order to totally acetylate platelet cyclooxygenase, or by ticagrelor (AstraZeneca AB S-151 85 Södertälje, Sweden) at a final concentration of 10 mM (Söderlund et al, 2015) or by the combination of the two drugs, or by tirofiban (Agrastat, United Kingdom) at a final concentration of 0.5 mM (Ciborowski et al, 2008). A part of PRP remained untreated.…”

Section: Platelet Preparationmentioning

confidence: 99%

Antiplatelet Agents Have a Distinct Efficacy on Platelet Aggregation Induced by Infectious Bacteria

Hannachi¹,

Ogé-Ganaye

Baudoin³

et al. 2020

Front. Pharmacol.

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Platelets are the cornerstone of hemostasis. However, their exaggerated aggregation induces deleterious consequences. In several diseases, such as infectious endocarditis and sepsis, the interaction between platelets and bacteria leads to platelet aggregation. Despite platelet involvement, no antiplatelet therapy is currently recommended in these infectious diseases. We aimed here, to evaluate, in vitro, the effect of antiplatelet drugs on platelet aggregation induced by two of the bacterial pathogens most involved in infectious endocarditis, Staphylococcus aureus and Streptococcus sanguinis. Blood samples were collected from healthy donors (n = 43). Treated platelet rich plasmas were incubated with three bacterial strains of each species tested. Platelet aggregation was evaluated by Light Transmission Aggregometry. CD62P surface exposure was evaluated by flow cytometry. Aggregate organizations were analyzed by scanning electron microscopy. All the strains tested induced a strong platelet aggregation. Antiplatelet drugs showed distinct effects depending on the bacterial species involved with different magnitude between strains of the same species. Ticagrelor exhibited the highest inhibitory effect on platelet activation (p <0.001) and aggregation (p <0.01) induced by S. aureus. In the case of S. sanguinis, platelet activation and aggregation were better inhibited using the combination of both aspirin and ticagrelor (p <0.05 and p <0.001 respectively). Aggregates ultrastructure and effect of antiplatelet drugs observed by scanning electron microscopy depended on the species involved. Our results highlighted that the effect of antiplatelet drugs depended on the bacterial species involved. We might recommend therefore to consider the germ involved before introduction of an optimal antiplatelet therapy.

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In vitro anti-platelet potency of ticagrelor in blood samples from infants and children

Cited by 11 publications

References 21 publications

A dose‐ranging study of ticagrelor in children aged 3‐17 years with sickle cell disease: A 2‐part phase 2 study

A dose‐ranging study of ticagrelor in children aged 3‐17 years with sickle cell disease: A 2‐part phase 2 study

Ticagrelor Exerts Immune-Modulatory Effect by Attenuating Neutrophil Extracellular Traps

Antiplatelet Agents Have a Distinct Efficacy on Platelet Aggregation Induced by Infectious Bacteria

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