Ticagrelor reversal:<i>in vitro</i>assessment of four haemostatic agents

Calmette, Leyla; Bonniec, Bernard Le; Zlotnik, Diane; Gouin‐Thibault, Isabelle; Bachelot‐Loza, Christilla; Gaussem, Pascale; Godier, Anne

doi:10.1136/jclinpath-2016-204117

Cited by 15 publications

(12 citation statements)

References 34 publications

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“…Other potential limitations of the study include manipulation of samples in vitro that may introduce additional variability not present in unaltered blood samples from patients taking antiplatelet therapy, and the addition of DMSO that may have had an impact on platelet function and may adversely affect repeatability. However, our overall results were in line with previously published work where > 1000 fold ticagrelor dosing was required due to the reduced solubility when not including DMSO [39]. For this study, we were able to use dosing equivalent to the prescribed dosing regimen for these drugs.…”

Section: Discussionsupporting

confidence: 87%

“…To our knowledge, this is the first time an ex vivo model has been described to test platelet function devices at clinically relevant concentrations of P2Y12 inhibitors in human whole blood. A previous study used TEG ® and Multiplate ® to assess the efficacy of hemostatic agents to improve hemostasis in vitro in ticagrelor-spiked blood samples; however, the ticagrelor concentrations used were not equivalent to prescribed dose regimens [39].…”

Section: Discussionmentioning

confidence: 99%

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Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition

Dias¹,

Pottgießer

Hartmann

et al. 2019

J Thromb Thrombolysis

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In the context of interventional cardiology, platelet function testing may identify patients treated with P2Y12-inhibitors at an increased risk of mortality, thrombosis and bleeding. Several whole blood point-of-care platelet function analyzers are available; however, inter-device differences have not been examined systematically. To compare three platelet function tests under standardized in vitro conditions. Healthy volunteer (n = 10) blood samples were spiked with increasing concentrations of ticagrelor (0-7500 ng/mL) and/or ASA (0-3280 ng/mL), measured on three platelet function analyzers (TEG ® 6s, Multiplate ® , and VerifyNow ®) and respective Effective Concentration (EC) levels EC10, EC50 and EC90 were calculated. Repeatability was assessed in a separate group of pooled blood samples (n = 10) spiked with ticagrelor at EC10, EC50 and EC90. ASA had no impact on ADP-activated channels for all three devices. TEG ® 6s was able to distinguish (p ≤ 0.05) between all ticagrelor EC zones; VerifyNow ® and Multiplate ® were able to distinguish between three and two zones, respectively. Multiplate ® showed the largest window between EC10 and EC90 (19-9153 ng/mL), followed by TEG ® 6s (144-2589 ng/mL), and VerifyNow ® (191-1100 ng/mL). Drug effect models distribution of disagreements were identified for TEG ® 6s (5.0%), VerifyNow ® (8.3%), and Multiplate ® (13.3%). TEG ® 6s showed the smallest average coefficient of variation between EC conditions (5.1%), followed by Multiplate ® (14.1%), and VerifyNow ® (17.7%). Linear models could be generated between TEG ® 6s and Multiplate ® , but not VerifyNow ®. Significant differences were found between whole blood point-of-care platelet function analyzers and the clinical impact of these differences needs to be further investigated.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition

Dias¹,

Pottgießer

Hartmann

et al. 2019

J Thromb Thrombolysis

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“…Indeed, this lack of effect resulted from a lower decrease in cAMP concentration elicited by these partial α 2 -adrenoreceptor agonists, clonidine, and dexmedetomidine, compared with full α 2 -agonists. Our results support the development of specific full and systemic α 2 -adrenoreceptor agonists for ticagrelor reversal.2 of 11 acid, and desmopressin are unlikely to reverse ticagrelor antiplatelet effects [2][3][4][5][6][7], and no specific antidote is currently available [8,9]. We recently showed that epinephrine, a vasopressor agent used to treat shock, is able in vitro to restore platelet functions inhibited by ticagrelor.…”

supporting

confidence: 66%

“…2 of 11 acid, and desmopressin are unlikely to reverse ticagrelor antiplatelet effects [2][3][4][5][6][7], and no specific antidote is currently available [8,9]. We recently showed that epinephrine, a vasopressor agent used to treat shock, is able in vitro to restore platelet functions inhibited by ticagrelor.…”

mentioning

confidence: 99%

Comparative In Vitro Study of Various α2-Adrenoreceptor Agonist Drugs for Ticagrelor Reversal

Bonete

Godiér

Gaussem

et al. 2020

JCM

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Ticagrelor, an antiplatelet adenosine diphosphate (ADP)-P2Y 12 receptor antagonist, increases the risk of bleeding. Its management is challenging because platelet transfusion is ineffective and no specific antidote is currently available. Epinephrine, a vasopressor catecholamine prescribed during shock, restores platelet functions inhibited by ticagrelor through stimulation of α 2A -adrenoreceptors. It subsequently inhibits cyclic adenosine monophosphate (cAMP) pathway and PI3K signaling. However, since epinephrine may expose a patient to deleterious hemodynamic effects, we hypothesized that other α 2 -adrenoreceptor agonist drugs used in clinical practice with fewer side effects could reverse the antiplatelet effects of ticagrelor. We compared in vitro the efficacy of clonidine, dexmedetomidine, brimonidine, and norepinephrine with epinephrine to restore ADP-and PAR-1-AP-induced washed platelet aggregation inhibited by ticagrelor, as well as resulting platelet cAMP levels. In ticagrelor-free samples, none of the α 2 -adrenoreceptor agonists induced aggregation by itself but all of them potentiated ADP-induced aggregation. Compared with epinephrine, norepinephrine, and brimonidine partially restored ADP-and fully restored PAR-1-AP-induced aggregation inhibited by ticagrelor while clonidine and dexmedetomidine were ineffective. Indeed, this lack of effect resulted from a lower decrease in cAMP concentration elicited by these partial α 2 -adrenoreceptor agonists, clonidine, and dexmedetomidine, compared with full α 2 -agonists. Our results support the development of specific full and systemic α 2 -adrenoreceptor agonists for ticagrelor reversal.2 of 11 acid, and desmopressin are unlikely to reverse ticagrelor antiplatelet effects [2][3][4][5][6][7], and no specific antidote is currently available [8,9]. We recently showed that epinephrine, a vasopressor agent used to treat shock, is able in vitro to restore platelet functions inhibited by ticagrelor. Epinephrine acts through stimulation of α 2A -adrenoreceptors coupled with G z -protein on the platelet membrane surface. The α subunit of G z -protein binds to adenylate cyclase and inhibits the synthesis of the second messenger cyclic adenosine monophosphate (cAMP), which plays a central role in platelet inhibition, while the dissociated βγ subunit activates phosphoinositide 3-kinase (PI3K) pathway [10,11]. Therefore, α 2A -adrenoreceptor stimulation participates in platelet activation. In combination with ADP stimulating the P2Y 1 receptor signaling and subsequent Ca 2+ mobilization, epinephrine induces aggregation of ticagrelor-treated platelets through inhibition of the cAMP pathway and activation of the PI3K pathway. However, epinephrine is a catecholamine and cumulates α 1 -, α 2 -, β 1 -, and β 2adrenoreceptor agonist effects that induce hemodynamic changes including tachycardia, heart rhythm disorders, peripheral arterial vasoconstriction, and lactic acidosis, which are potentially deleterious in the context of acute bleeding. We therefore hypothesized that ot...

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“…Interestingly, a trial in which recombinant activated factor VII, fibrinogen concentrate, and factor XIII concentrate were used to overcome antiplatelet effect by acting on fibrin formation or fibrinolysis may point to the cessation of ticagrelor-related unrestrained bleeding. 25 …”

Section: Superiority Of Ticagrelor Over Clopidogrel In Acsmentioning

confidence: 99%

Ticagrelor – toward more efficient platelet inhibition and beyond

Kubisa¹,

Jeżewski²,

Gąsecka³

et al. 2018

TCRM

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Novel antiplatelet drugs, including ticagrelor, are being successively introduced into the therapy of atherothrombotic conditions due to their superiority over a standard combination of clopidogrel with acetylsalicylic acid in patients with acute coronary syndromes (ACS). A P2Y12 receptor antagonist, ticagrelor, is unique among antiplatelet drugs, because ticagrelor inhibits the platelet P2Y12 receptor in a reversible manner, and because it demonstrates a wide palette of advantageous pleiotropic effects associated with the increased concentration of adenosine. The pleiotropic effects of ticagrelor comprise cardioprotection, restoration of the myocardium after an ischemic event, promotion of the release of anticoagulative factors and, eventually, anti-inflammatory effects. Beyond the advantageous effects, the increased concentration of adenosine is responsible for some of ticagrelor’s adverse effects, including dyspnea and bradycardia. Large-scale clinical trials demonstrated that both standard 12-month therapy and long-term use of ticagrelor reduce the risk of cardiovascular events in patients with ACS, but at the expense of a higher risk of major bleeding. Further trials focused on the use of ticagrelor in conditions other than ACS, including ischemic stroke, peripheral artery disease and status after coronary artery bypass grafting. The results of these trials suggest comparable efficacy and safety of ticagrelor and clopidogrel in extra-coronary indications, but firm conclusions are anticipated from currently ongoing studies. Here, we summarize current evidence on the superiority of ticagrelor over other P2Y12 antagonists in ACS, discuss the mechanism underlying the drug–drug interactions and pleiotropic effects of ticagrelor, and present future perspectives of non-coronary indications for ticagrelor.

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Ticagrelor reversal:in vitroassessment of four haemostatic agents

Cited by 15 publications

References 34 publications

Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition

Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition

Comparative In Vitro Study of Various α2-Adrenoreceptor Agonist Drugs for Ticagrelor Reversal

Ticagrelor – toward more efficient platelet inhibition and beyond

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Ticagrelor reversal:in vitroassessment of four haemostatic agents

Cited by 15 publications

References 34 publications

Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition

Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition

Comparative In Vitro Study of Various α2-Adrenoreceptor Agonist Drugs for Ticagrelor Reversal

Ticagrelor &ndash; toward more efficient platelet inhibition and beyond

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Product

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Ticagrelor – toward more efficient platelet inhibition and beyond