Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion

Zhang, Shuhua; Xu, Ke; Mei, Lianlian; Zhu, Hui; Li, Jimin; Wang, Fei; Yang, Lu; Zhang, Jing; Fan, Yanxin; Zou, Fengwei; Niles, Kelecia; Eikelboom, John W.; Li, Chunjian

doi:10.1111/trf.15219

Cited by 12 publications

(14 citation statements)

References 27 publications

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“…The mechanisms of T-PPP on the efficacy of PM-r-SAK need to be further elucidated. In our previous study, we found that ticagrelor-treated plasma could significantly inhibit the aggregation of donor platelets . As ticagrelor is not a prodrug and does not require metabolic activation for antiplatelet activity, the plasma parent ticagrelor can directly inhibit the aggregation of the donor platelets .…”

Section: Resultsmentioning

confidence: 93%

Platelet Membrane-Coated r-SAK Improves Thrombolytic Efficacy by Targeting Thrombus

Hua,

Li,

Lin

et al. 2024

ACS Appl. Mater. Interfaces

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Thrombolytic therapy is one of the most effective treatments for thrombus dissolution and recanalization of blocked vessels in thrombotic diseases. However, the application of the thrombolytic strategy has been limited due to unsatisfactory thrombolytic efficacy, relatively higher bleeding complications, and consequently restricted indications. Recombinant staphylokinase (r-SAK) is a third-generation thrombolytic agent produced by genetic engineering technology, which exhibits a better thrombolytic efficacy than urokinase and recombinant streptokinase. Inspired by the natural affinity of platelets in hemostasis and pathological thrombosis, we developed a platelet membrane (PM)-coated r-SAK (PM-r-SAK). Results from animal experiments and human in vitro studies showed that the PM-r-SAK had a thrombolytic efficacy equal to or better than its 4-fold dose of r-SAK. In a totally occluded rabbit femoral artery thrombosis model, the PM-r-SAK significantly shortened the initial recanalization time compared to the same dose and 4-fold dose of r-SAK. Regarding the recanalized vessels, the PM-r-SAK prolonged the time of reperfusion compared to the same dose and 4-fold dose of r-SAK, though the differences were not significant. An in vitro thrombolytic experiment demonstrated that the thrombolytic efficacy of PM-r-SAK could be inhibited by platelet-poor plasma from patients taking aspirin and ticagrelor. PM coating significantly improves the thrombolytic efficacy of r-SAK, which is related to the thrombus-targeting activity of the PM-r-SAK and can be inhibited by aspirin- and ticagrelor-treated plasma.

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Section: Resultsmentioning

confidence: 93%

Platelet Membrane-Coated r-SAK Improves Thrombolytic Efficacy by Targeting Thrombus

Hua,

Li,

Lin

et al. 2024

ACS Appl. Mater. Interfaces

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“…Given a number of recent clinical studies (Godier et al, 2015;Trenk et al, 2019;Willeman et al, 2018;Zhang et al, 2019) we sought to probe the reversibility of ticagrelor binding to the P2Y12R in comparison with other receptor antagonists.…”

Section: Discussionmentioning

confidence: 99%

“…More recent studies indicate that platelet supplementation via transfusion does not rescue platelet inhibition resulting from ticagrelor action (Godier et al, 2015;Trenk et al, 2019;Willeman et al, 2018;Zhang et al, 2019). Potentially this is because ticagrelor and its active metabolite (AR-C124910XX) have much longer half-lives ( 9and 12 hrs, respectively) than the thienopyridine derivatives prasugrel and ticagrelor with their ongoing presence able to inhibit fresh platelets at the time of the transfusion (Butler & Teng, 2010;Cave et al, 2019;Zhu et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Notably platelet transfusion efficiently reverses the inhibitory effect of clopidogrel and prasugrel on platelets in a dose-dependent manner (Bonhomme, Bonvini, Reny, Poncet, & Fontana, 2015;Li, Hirsh, Xie, Johnston, & Eikelboom, 2012;Schoener et al, 2017). However, the effectiveness of this approach with ticagrelor has been questioned in a number of recent studies (Godier, Taylor, & Gaussem, 2015;Trenk et al, 2019;Willeman et al, 2018;Zhang et al, 2019). Persistent inhibition of platelet aggregation is observed for several days after discontinuation of ticagrelor and can still be observed when plasma concentrations of ticagrelor are undetectable, with platelet reactivity only returning to near normal levels about 5 days following cessation of treatment (Storey et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Ticagrelor inverse agonist activity at the P2Y12 receptor is non-reversible versus its endogenous agonist ADP.

Khalil

Dimofte

Keith

et al. 2022

Preprint

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Background: Ticagrelor is labelled as a reversible, direct-acting platelet P2Y12 receptor (P2Y12R) antagonist that is indicated clinically for the prevention of thrombotic events in patients with acute coronary syndrome (ACS). As with many antiplatelet drugs, ticagrelor therapy increases bleeding risk in patients which in emergency situations requires platelet transfusion although there is ongoing debate on its effectiveness following ticagrelor therapy. The aim of this study was to further examine the reversibility of ticagrelor at the P2Y12R. Methods: Studies were performed in human platelets with both P2Y12R-stimulated GTPase activity and platelet aggregation assessed. Cell-based bioluminescence resonance energy transfer (BRET) assays were also undertaken to assess G protein subunit activation downstream of P2Y12R activation. Results: Initial studies revealed a range of P2Y12R ligands including ticagrelor displayed inverse agonist activity at the P2Y12R. Of these only ticagrelor was resistant to wash-out. In both human platelets and cell-based assays, washing failed to reverse ticagrelor-dependent inhibition of ADP-stimulated P2Y12R function in contrast to other P2Y12R antagonists. The P2Y12R agonist 2MeSADP, which was also resistant to wash-out, was able to effectively compete with ticagrelor. In silico docking revealed that ticagrelor and 2MeSADP penetrated more deeply into the orthosteric binding pocket of the P2Y12R than other P2Y12R ligands. Conclusion: Ticagrelor binding to the P2Y12R is prolonged and more akin to that of an irreversible antagonist especially versus the endogenous P2Y12R agonist ADP. This study highlights the potential clinical need for novel ticagrelor reversal strategies in patients with spontaneous major bleeding and bleeding associated with urgent invasive procedures.

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“…As a model, aspirin‐treated platelets can be mixed with untreated platelets. The addition of 10% to 60% v/v untreated platelets to aspirin‐inhibited platelets in vitro ameliorates aspirin‐mediated inhibition of ADP and AA‐induced aggregation, as only a fraction of the total platelet population must be replaced to restore full COX‐1 activity. This is of importance for transfused platelets, as they could affect the recipient’s COX‐1 activity if the donor had taken aspirin prior to donation.…”

Section: Nsaids and Implications For Transfusion Of Platelet Productsmentioning

confidence: 98%

Not all (N)SAID and done: Effects of nonsteroidal anti‐inflammatory drugs and paracetamol intake on platelets

Driver

Marks

Wal

2020

Research and Practice in Thrombosis and Haemostasis

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractPlatelets are key mediators of hemostasis and thrombosis and can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). As a result, platelet donors are temporarily deferred from donating if they have recently taken NSAIDs such as aspirin or ibuprofen. Despite these measures, a proportion of platelet donations show exposure to these drugs; however, little is known about the effect of NSAIDs and their metabolites on platelet quality in vivo and during storage. In this review, the effect of NSAIDs on platelet function is summarized, with a focus on the widely consumed over-the-counter (OTC) medications aspirin, ibuprofen, and the non-NSAID paracetamol. Aspirin and ibuprofen have well-defined antiplatelet effects. In comparison, studies regarding the effect of paracetamol on platelets report variable findings. The timing and order of NSAID intake is important, as concurrent NSAID use can inhibit or potentiate platelet activation depending on the drug taken. NSAID deferral periods and maximum platelet shelf-life is set by each country and are revised regularly. Reduced donor deferral periods and longer platelet storage times may affect the quality of platelet products, and it is therefore important to identify the possible impact of NSAID intake on platelet quality before and after storage. K E Y W O R D Sacetaminophen, anti-inflammatory agents, aspirin, blood platelets, ibuprofen, nonsteroidal Essentials• Nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit platelet aggregation and secretion by inhibiting cyclo-oxygenase 1.• The effect of paracetamol (acetaminophen) on platelets is poorly studied.• Little is known about the effect of NSAIDs and their metabolites on stored platelets.• Postponing platelet donation after NSAID intake may affect platelet quality following storage.

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Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion

Cited by 12 publications

References 27 publications

Platelet Membrane-Coated r-SAK Improves Thrombolytic Efficacy by Targeting Thrombus

Platelet Membrane-Coated r-SAK Improves Thrombolytic Efficacy by Targeting Thrombus

Ticagrelor inverse agonist activity at the P2Y12 receptor is non-reversible versus its endogenous agonist ADP.

Not all (N)SAID and done: Effects of nonsteroidal anti‐inflammatory drugs and paracetamol intake on platelets

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