Lack of Effect of Platelet Transfusions and Desmopressin on Intracranial Bleeding in a Patient Receiving Ticagrelor

Maillard, Julien; Faessler, Vanessa Cartier; Fontana, Pierre; Bonhomme, Fanny

doi:10.1213/xaa.0000000000000156

Cited by 15 publications

(16 citation statements)

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“…Moreover, the plasma concentrations of both ticagrelor and its active metabolite remain much higher (5.2-fold and 7.7-fold, respectively) than the concentration required to induce half the maximum platelet effect (EC50) for at least 24 h [4]. This observation is consistent with recent clinical observations that we and others described recently reporting biological and clinical inefficacy of platelet transfusions in ticagrelor-treated patients with life-threating bleeding [29,30]. Studies based on multiple electrode aggregometry testing on whole blood showed that even a high dose of non-inhibited platelets had a limited effect in restoring platelet reactivity to ADP in patients treated with ticagrelor compared with clopidogrel [31,32].…”

Section: Discussionsupporting

confidence: 89%

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

et al. 2015

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Managing bleeding in patients receiving P2Y12 inhibitors is challenging. Few data are available regarding the efficacy of platelet transfusion in patients treated with prasugrel or ticagrelor. The aim of this study was to evaluate the minimal amount of platelet supplementation (in terms of ratio of non-inhibited platelets to inhibited platelets) necessary to restore platelet reactivity in platelet-rich plasma (PRP) of patients treated with aspirin and a prasugrel or ticagrelor loading dose for an acute coronary syndrome. PRP samples from patients were mixed ex vivo with increasing proportions of pooled PRP from healthy volunteers. Platelet reactivity was challenged with adenosine diphosphate (ADP), arachidonic acid, collagen or thrombin receptor activating peptide using light transmission aggregometry. The primary endpoint was the proportion of patient samples recovering an ADP-induced maximal aggregation (ADP-Aggmax) value above 40%. In patients treated with prasugrel (n = 32), ADP-Aggmax increased progressively with supplements of pooled PRP, with an average increase of 7.9% (95% CI [7.1; 8.8], p < 0.001) per each 20% increase in the ratio of non-inhibited platelets to inhibited platelets. A ratio of 60% was associated with 90% of patients reaching the primary endpoint. In patients treated with ticagrelor (n = 15), ADP-Aggmax did not significantly increase with any level of supplements. In conclusions, ex vivo addition of non-inhibited platelets significantly improved ADP-Aggmax in patients treated with prasugrel with a dose-dependent effect. There was no evidence of such a reversal in patients treated with ticagrelor. These results suggest that platelet transfusion may be more effective in blunting bleeding in patients treated with prasugrel, than those treated with ticagrelor.

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Section: Discussionsupporting

confidence: 89%

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

et al. 2015

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“…Our findings provide a mechanistic explanation for the failure of transfusion to adequately restore platelet function in ticagrelor‐treated patients, as highlighted in two recent case reports , and confirm and extend similar observations by others . These preceding studies, however, examined healthy donor samples spiked with ticagrelor , or platelets from patients receiving loading doses of P2Y12 inhibitors , or a combined patient pool that received either loading or maintenance doses of ticagrelor or prasugrel 6–24 h prior to blood sampling .…”

Section: Discussionsupporting

confidence: 89%

Reversibility of platelet P2Y12 inhibition by platelet supplementation: ex vivo and in vitro comparisons of prasugrel, clopidogrel and ticagrelor

Bertling

Fender

Schüngel

et al. 2018

Journal of Thrombosis and Haemostasis

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Background Platelet transfusion is the conventional approach to restore platelet function during acute bleeds or surgery, but successful outcome depends on the specific antiplatelet therapy. Notably ticagrelor is associated with inadequate recovery of platelet function after platelet transfusion. We examined whether plasma and/or platelets from ticagrelor-treated patients influence donor platelet function, in comparison with clopidogrel and prasugrel. Methods Platelet transfusion was mimicked ex vivo by mixing naïve donor platelet-rich plasma (PRP) or gel-filtered platelets (GFP) in defined proportions with PRP, plasma or GFP from cardiovascular patients receiving standard care including medication with prasugrel, clopidogrel or ticagrelor (n = 20 each). Blood was taken 4 h after the previous dose. HLA2/HLA28 haplotyping let us distinguish net (all platelet) and individual patient/donor platelet reactivity in mixtures of patient/donor platelets, measured by flow cytometry analysis of ADP-induced fibrinogen binding and CD62P expression. Results ADP responsiveness of donor platelets was dramatically reduced by even low (10%) concentrations of PRP or plasma from ticagrelor-treated patients. Clopidogrel and prasugrel were associated with more modest donor platelet inhibition. GFP from ticagrelor-treated patients but not patients receiving clopidogrel or prasugrel also suppressed donor GFP function upon mixing, suggesting the transfer of ticagrelor from patient platelets to donor platelets. This transfer did not lead to recovery of ADP responsiveness of patient's platelets. Conclusion Collectively, these observations support the concept that ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets, which might compromise the effectiveness of platelet transfusion therapy.

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“…Although the authors observed a partial restoration of platelet aggregation in patients on maintenance treatment with these drugs, other studies and case reports provided conflicting data. 6,7,[9][10][11] The complete inefficacy of platelet transfusions to reverse the antiplatelet action of ticagrelor was nicely highlighted in a case report of a patient with intracranial hemorrhage, where platelet reactivity levels remained virtually unchanged despite transfusion of 17 U of platelets. 7 Other reports provided similar results.…”

Section: Sibbing and Massberg Restoring Platelet Function On Antiplatmentioning

confidence: 99%

“…As long as this is not the case, we have to take the data coming from (in vitro) studies such as APTITUDE 5 and others [6][7][8][9][10] as the best available evidence for guidance of patient treatment. Second, the comparatively low sample size for prasugrel-treated patients (n=6) and ticagrelor-treated patients (n=3) in the APTITUDE-CABG cohort precludes from drawing definite conclusions on the feasibility of immediate and sustained platelet restoration after platelet transfusion with these 2 agents.…”

Section: Sibbing and Massberg Restoring Platelet Function On Antiplatmentioning

confidence: 99%

“…7 Other reports provided similar results. 6,9 Furthermore, for APTITUDE-CABG, the authors merged prasugrel-and ticagrelor-treated patients into 1 group within their study. Such an approach, however, is debatable because it was shown in previous studies that their properties in terms of platelet function recovery may differ because of their specific pharmacological properties.…”

Section: Sibbing and Massberg Restoring Platelet Function On Antiplatmentioning

confidence: 99%

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Restoring Platelet Function in Patients on P2Y ₁₂ Receptor Inhibitor Treatment

Sibbing

Maßberg

2015

Circ: Cardiovascular Interventions

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Dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 receptor inhibitor is the current mainstay of pharmacological treatment in both patients with stable coronary artery disease and acute coronary syndrome managed invasively by percutaneous coronary intervention (PCI). 1 The primary goal of DAPT is to reduce the risk of ischemic events including (re)-infarction and stent thrombosis. Contrary, this well-recognized ischemic benefit of DAPT is cut down by an increased on-treatment bleeding risk including major and fatal bleeding in both a nonoperative and operative setting like coronary artery bypass grafting (CABG).2,3 Bleeding risks differ for the currently available oral P2Y 12 receptor inhibitors. On the basis of the results of large-scale clinical trials and the clinical experience in recent years, we considered that the risk of bleeding to be modest for the second-generation thienopyridine clopidogrel, whereas more potent platelet inhibition, such as it is delivered by the third-generation thienopyridine prasugrel or the cyclo-pentyl-triazolo-pyrimidine ticagrelor, comes along with a substantially higher risk of bleeding. 2-4Immediate and sustained restoration of platelet function in patients on DAPT may become mandatory in a nonoperative setting with acute bleeding (eg, intracranial bleeding) or during cardiac and noncardiac surgery. From a pharmacological point of view, the ability to restore platelet function may differ for the irreversibly acting P2Y 12 receptor inhibitors clopidogrel and prasugrel when compared with the directacting reversibly binding antiplatelet agent ticagrelor. This is because of the circumstance that active metabolites of both clopidogrel and prasugrel exhibit a short plasma half-life and their binding to the P2Y 12 receptor is irreversible. Hence, transfused allogeneic platelet concentrates remain uninhibited in patients on thienopyridine maintenance treatment. In contrast and because of its pharmacological properties, ticagrelor and its active metabolite may inhibit fresh platelets after allogeneic platelet transfusion. ) and in an in vivo setting with allogeneic platelet transfusion in cardiac surgery patients on DAPT who had excessive bleeding during surgery (APTITUDE-CABG). As a key result of the APTITUDE-ACS study (n=59 patients), the authors were able to show that the level of restoration of platelet function by ex vivo administration of autologous platelet-rich plasma significantly decreased with increasing potency of the antiplatelet agent. In clopidogrel-treated patients, platelet function restoration was highest, whereas restoration was lower in prasugreltreated subjects and by comparison lowest in the subgroup of ticagrelor-treated patients. In APTITUDE-CABG (n=52 patients), platelet transfusion resulted in a significant 23% relative increase (42.2±23.6% platelet reactivity index [PRI] before transfusion versus 56.6±23.6% PRI after transfusion; P=0.008) of the VASP PRI and the primary study end point was met. Of note, for the merged subgroup of patients (n=9) treat...

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Lack of Effect of Platelet Transfusions and Desmopressin on Intracranial Bleeding in a Patient Receiving Ticagrelor

Cited by 15 publications

References 0 publications

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

Reversibility of platelet P2Y12 inhibition by platelet supplementation: ex vivo and in vitro comparisons of prasugrel, clopidogrel and ticagrelor

Restoring Platelet Function in Patients on P2Y ₁₂ Receptor Inhibitor Treatment

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Lack of Effect of Platelet Transfusions and Desmopressin on Intracranial Bleeding in a Patient Receiving Ticagrelor

Cited by 15 publications

References 0 publications

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

Reversibility of platelet P2Y12 inhibition by platelet supplementation: ex vivo and in vitro comparisons of prasugrel, clopidogrel and ticagrelor

Restoring Platelet Function in Patients on P2Y 12 Receptor Inhibitor Treatment

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Product

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Restoring Platelet Function in Patients on P2Y ₁₂ Receptor Inhibitor Treatment