Reversal of the platelet inhibitory effect of the P2Y12 inhibitors clopidogrel, prasugrel, and ticagrelor in vitro: a new approach to an old issue

Schoener, Lisa; Jellinghaus, Stefanie; Richter, Bernhardt; Pfluecke, Christian; Ende, Georg; Christoph, Marian; Quick, Silvio; Loehn, Tobias; Speiser, Uwe; Poitz, David M.; Mierke, Johannes; Strasser, Ruth H.; Ibrahim, Karim

doi:10.1007/s00392-017-1128-8

Cited by 28 publications

(19 citation statements)

References 21 publications

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“…Schoener et al extended the reversal strategies for P2Y 12related platelet inhibition based upon platelet supplementation by an interesting approach considering the high plasma protein binding of ticagrelor and its AM. 31 Patients on DAPT (aspirin plus guideline-recommended dosing with clopidogrel, prasugrel, or ticagrelor) with an ACS were enrolled. Blood samples were drawn at trough of the respective chronic dosing regimen and not earlier than 24 hours after loading.…”

Section: Ticagrelormentioning

confidence: 99%

Antagonizing P2Y12 Receptor Inhibitors: Current and Future Options

et al. 2019

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There are clinical scenarios where the balance between the risk of ischemic and bleeding events leads to the clinical decision to reverse the antiplatelet effect of P2Y12 receptor inhibitors. These scenarios comprise emergency situations such as active severe bleeding, urgent procedures with presumed high bleeding risk, or major trauma with (anticipated) bleeding. Supplementation of platelets has been investigated in ex vivo as well as in in vivo studies. These studies indicate that the inhibition of adenosine diphosphate-induced aggregation by the irreversibly binding thienopyridine derivatives clopidogrel and prasugrel can be reversed by administration of platelet concentrates. Supplementation of platelets in patients on prasugrel is more effective if this can be transfused > 6 hours after last dosing. Studies on the reversal effect obtained by administration of platelet concentrates in patients on ticagrelor show conflicting results. Experimental data suggest that administration of serum albumin might increase the reversal effect. A monoclonal antibody fragment (PB2452) for neutralizing ticagrelor is currently in clinical development. A recently published first in man study shows that reversal of platelet inhibition occurs within 5 minutes after start of administration and the effect is maintained for 20 to 24 hours after a 16-hour infusion which is by far the most effective approach for reversal of ticagrelor.

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Section: Ticagrelormentioning

confidence: 99%

Antagonizing P2Y12 Receptor Inhibitors: Current and Future Options

et al. 2019

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“…Factors that are associated with the platelet storage lesions (including the collection and preparation methods, storage medium, plasma content, storage time, and temperature, etc. ), as well as the amount of protein in bank platelets, warrant further investigation in future reversal studies. Finally, although our data provide the best available evidence and mechanism to date for the reversal of the antiplatelet effect of ticagrelor using uninhibited platelets, there are only limited data on the association between in vitro platelet function and clinical events.…”

Section: Discussionmentioning

confidence: 99%

“…Hobl et al found that in vitro autologous platelets reversed the antiplatelet effect of ticagrelor as measured by whole blood multiple‐electrode aggregometry. However, most other studies found that autologous, donor, and pooled platelets had minimal effect on reversal of ticagrelor …”

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confidence: 96%

“…However, most other studies found that autologous, donor, and pooled platelets had minimal effect on reversal of ticagrelor. [13][14][15][16] Recent studies have indicated that timing of reversal after the last ticagrelor dose is important, 17,18 and it was suggested that residual drug would inhibit transfused platelets, thereby limiting their efficacy for ticagrelor reversal. 16,17 However, it is uncertain whether there is a platelet inhibition effect of the residual drug and whether this changes with timing.…”

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confidence: 99%

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Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion

Zhang

Mei

et al. 2019

Transfusion

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BACKGROUND Reversal of antiplatelet therapy is desirable in patients presenting with life‐threatening bleeding or requiring urgent surgery. This study aimed to examine ticagrelor reversal using donor platelets and to explore the effects of residual ticagrelor on donor platelets. STUDY DESIGN AND METHODS In Cohort 1, 16 healthy subjects were treated with ticagrelor 90 mg twice daily alone or in combination with aspirin 100 mg once daily for 7 days followed by single blood sampling for preparation of platelet‐rich plasma. An additional 16 healthy subjects served as controls. In Cohort 2, 16 healthy subjects were treated with ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 7 days followed by serial blood samplings for preparation of platelet‐poor plasma (PPP). An additional 16 healthy subjects served as controls. RESULTS In Cohort 1, inhibition of adenosine diphosphate–induced platelet aggregation (PLADP) by ticagrelor could not be fully reversed by mixing with up to 90% control platelets, whereas inhibition of arachidonic acid–induced platelet aggregation by aspirin was fully reversed with the addition of 60% control platelets. In Cohort 2, 10% PPP obtained from ticagrelor‐treated subjects reduced PLADP from 74% to 40% at 2 hours, 72% to 58% at 6 hours, and 73% to 59% at 10 hours, while 10% or 20% PPP obtained from clopidogrel‐treated subjects did not inhibit PLADP. CONCLUSION The antiplatelet effect of ticagrelor cannot be fully reversed by donor platelets, which could be explained by the presence of active drug. The effect of residual drug on donor platelets appears to be evident for at least 10 hours after ticagrelor ingestion.

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“…Although it effectively reduces the ischaemic events and mortality rates of cardiovascular patients, high nonlethal bleeding rates are observed and obvious undesirable side-effect appear [ 16 ]. The TRITON and PLATO clinical trials have both accounted for the long-standing hypothesis of more potent platelet inhibition translating into reduced atherothrombotic events at the expense of increased bleeding [ 15 , 16 , 17 , 18 ]. All these considerations reinforce the strong need of novel and safe P2Y 12 antagonists.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Novel Series of Amino Acid Prodrugs Based on Thienopyridine Scaffolds and Evaluation of Their Antiplatelet Activity

Zheng

Zhang

et al. 2018

Molecules

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The thienopyridines class of drugs used as P2Y12 receptor antagonists plays a vital role in antiplatelet therapy. To further optimized this compound class, we designed and synthesized a series of amino acid prodrugs of 2-hydroxytetrahydrothienopyridine. All compounds were then evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats and then ED50 and bleeding time of the most potent compounds were compared with commercial drugs. The results showed compound 5c could be a potent and safe candidate for further research.

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Reversal of the platelet inhibitory effect of the P2Y12 inhibitors clopidogrel, prasugrel, and ticagrelor in vitro: a new approach to an old issue

Cited by 28 publications

References 21 publications

Antagonizing P2Y12 Receptor Inhibitors: Current and Future Options

Antagonizing P2Y12 Receptor Inhibitors: Current and Future Options

Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion

Synthesis of a Novel Series of Amino Acid Prodrugs Based on Thienopyridine Scaffolds and Evaluation of Their Antiplatelet Activity

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