Ticagrelor-Associated Bleeding in a Patient Undergoing Surgery for Acute Type A Aortic Dissection

Dalén, Magnus; Ivert, Torbjörn; Lindvall, Gabriella; Linden, Jan van der

doi:10.1053/j.jvca.2013.04.004

Cited by 16 publications

(13 citation statements)

References 6 publications

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“…Although platelet transfusions restore platelet function in patients on aspirin, 5 they have shown no or minimal ability to reverse adenosine 59-diphosphate (ADP)-induced aggregation in healthy volunteers treated with clopidogrel 6 or in ticagrelor-treated patients. 7,8 Because both antiplatelet and anticoagulant therapies are known to increase the risk of bleeding complications, specific antidotes are desired in the clinical situations of life-threatening bleeding or urgent surgery where patients cannot wait for the drugs' effects to stop naturally. 9 Recently, specific antidotes for anticoagulants have been described and are undergoing clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Structural and functional characterization of a specific antidote for ticagrelor

Buchanan

Newton

Pehrsson

et al. 2015

Blood

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• In the clinic, all oral antiplatelet medicines have a risk of bleeding complications.• We present an antidote for ticagrelor that reverses its antiplatelet effect in human platelet-rich plasma and its bleeding effect in mice.Ticagrelor is a direct-acting reversibly binding P2Y 12 antagonist and is widely used as an antiplatelet therapy for the prevention of cardiovascular events in acute coronary syndrome patients. However, antiplatelet therapy can be associated with an increased risk of bleeding. Here, we present data on the identification and the in vitro and in vivo pharmacology of an antigen-binding fragment (Fab) antidote for ticagrelor. The Fab has a 20 pM affinity for ticagrelor, which is 100 times stronger than ticagrelor's affinity for its target, P2Y 12 . Despite ticagrelor's structural similarities to adenosine, the Fab is highly specific and does not bind to adenosine, adenosine triphosphate, adenosine 59-diphosphate, or structurally related drugs. The antidote concentration-dependently neutralized the free fraction of ticagrelor and reversed its antiplatelet activity both in vitro in human platelet-rich plasma and in vivo in mice. Lastly, the antidote proved effective in normalizing ticagrelor-dependent bleeding in a mouse model of acute surgery. This specific antidote for ticagrelor may prove valuable as an agent for patients who require emergency procedures. (Blood. 2015;125(22):3484-3490)

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Section: Introductionmentioning

confidence: 99%

Structural and functional characterization of a specific antidote for ticagrelor

Buchanan

Newton

Pehrsson

et al. 2015

Blood

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“…Compared with ASA + ticagrelor, MEDI2452 treatment improved survival and reduced blood loss but the effects did not reach statistical significance: survival (7/10 vs. 4/9, P > 0.05), survival time (240 [97-240] vs. 169 min, P > 0.05) and bodyweight-adjusted total blood loss (33 vs. 37 mL kg À1 , P > 0.05). Corresponding data compared with ASA alone also indicate a positive effect, specifically in terms of survival as groups were not significantly different: survival (7/10 vs. 8/8, P > 0.05), survival time (240 [97-240] vs. 240 min [all survived for the full duration], P > 0.05), and bodyweightadjusted total blood loss (33 vs. 16 [13][14][15][16][17][18][19][20][21][22][23][24][25] mL kg À1 , P < 0.05). Considering the assay window for ticagrelor-enhanced bleeding, and the onset time for the effect of MEDI2452, the main opportunity for MEDI2452 to show a beneficial effect was in the 15-90min interval after the MEDI2452 administration.…”

Section: Survival Blood Loss and Mean Arterial Blood Pressurementioning

confidence: 80%

“…Ticagrelor reduced survival (4/9 vs. 8/8, P < 0.05), reduced survival time (169 vs. 240 [240-240] min, P < 0.05) and increased bodyweight-adjusted total blood loss (37 vs. 16 [13][14][15][16][17][18][19][20][21][22][23][24][25] mL kg À1 , P < 0.05) compared with ASA alone (Fig. 5).…”

Section: Survival Blood Loss and Mean Arterial Blood Pressurementioning

confidence: 99%

“…Thus if a major bleeding event occurs in a patient on DAPT, treatment options are limited. Although platelet transfusion restores platelet function in patients on ASA [13], it does not reverse the antiplatelet effect of ticagrelor in healthy volunteers [14] and is unlikely to be of clinical benefit in patients with bleeding [15][16][17]. Platelet transfusion in patients suffering an acute hemorrhagic stroke, mainly on aspirin monotherapy, has even been found to be harmful [18].…”

Section: Introductionmentioning

confidence: 99%

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Hemostatic effects of the ticagrelor antidote MEDI2452 in pigs treated with ticagrelor on a background of aspirin

Pehrsson

Johansson

Janefeldt

et al. 2017

Journal of Thrombosis and Haemostasis

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Background Ticagrelor, a P2Y antagonist, is approved for the prevention of thromboembolic events. However, antiplatelet therapies carry a risk of bleeding. Objective To explore the hemostatic effects of MEDI2452, an antidote for ticagrelor. Methods Pigs, pre-treated with aspirin, were given an intravenous infusion of ticagrelor or vehicle. At the end of the infusion, a piece of a liver lobe was cut off and a bolus of MEDI2452 or vehicle was administered intravenously. Blood was collected to monitor blood loss, mean arterial blood pressure (MAP) was recorded and survival time was observed over 4 h. Blood samples for drug plasma exposures and platelet aggregation were collected. Results MEDI2452 eliminated the free concentrations of ticagrelor and its active metabolite AR-C124910XX within 5 min. ADP-induced platelet aggregation was close to normal at 60 min, which was not significantly different from aspirin alone. MEDI2452 numerically reduced ticagrelor-mediated effects: body-weight-adjusted blood loss in the 15- to 90-min interval, 12 (confidence interval [CI] 95% 7-28] vs. 17 (CI 95% 5-31) (ticagrelor and aspirin) vs. 5 (CI 95% 3-9) mL kg (aspirin alone), survival 70% (CI 95% 47-100) vs. 45% (CI 95% 21-92) (ticagrelor and aspirin) vs. 100% (CI 95% 100-100) (aspirin alone), and median survival time, 240 (CI 95% 180-240) vs. 169 (CI 95% 64-240) (ticagrelor and aspirin) vs. 240 (CI 95% 240-240) min (aspirin alone). Finally, MEDI2452 significantly attenuated the decline in MAP, 0.08 (CI 95% 0.07-0.09) vs. 0.141 (CI 95% 0.135-0.148) (ticagrelor and aspirin) vs. 0.04 (CI 95% 0.03-0.05) mmHg per min (aspirin alone) and maintained MAP at a significantly higher level, 73 (CI 95% 51-95) vs. 48 (CI 95% 25-70) (ticagrelor and aspirin) vs. 115 (CI 95% 94-136) mmHg (aspirin alone). Conclusion MEDI2452 eliminated free ticagrelor and AR-C124910XX within 5 min. This translated into a gradual normalization of ADP-induced platelet aggregation and significant improvement in blood pressure and numerical but non-significant improvements in blood-loss and survival.

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“…Severe bleeding diathesis refractory to multiple platelet transfusions had been reported after urgent/emergent cardiovascular surgery involving patients who were receiving a potent P2Y 12 inhibitor [68]. When faced with emergency surgery in patients on P2Y 12 inhibitors, adjunct hemostatic therapies may be necessary to mitigate postoperative hemorrhage refractory to platelet transfusion.…”

Section: Platelet Transfusion and Adjunct Therapiesmentioning

confidence: 99%

Perioperative management and monitoring of antiplatelet agents: a focused review on aspirin and P2Y₁₂inhibitors

Mazzeffi

Lee

Taylor

et al. 2017

Korean J Anesthesiol

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Platelets play pivotal roles in hemostasis as well as pathological arterial thrombosis. The combination of aspirin and a P2Y12 inhibitor has become the mainstay therapy in the ageing population with cardiovascular conditions, particularly during and after percutaneous coronary intervention. A number of novel P2Y12 inhibitors has become available in the recent years, and they markedly vary in pharmacokinetic and pharmacodynamic properties. Perioperative physicians today face a challenge of preventing hemorrhage due to platelet inhibitors, while minimizing thrombotic risks. There are several point-of-care platelet function tests available in the peri-procedural assessment of residual platelet aggregation. However, these platelet function tests are not standardized in terms of sample processing, agonist type and potency as well as methods of detecting platelet activity. Understanding the differences in pharmacological properties of antiplatelet agents, principles of platelet function tests, and pertinent hemostatic strategies may be useful to anesthesiologists and intensivists who manage perioperative issues associated with antiplatelet agents. The objectives of this review are: 1) to discuss clinical data on aspirin and P2Y12 inhibitors relating to perioperative bleeding, 2) to outline different features of point-of-care platelet function tests, and 3) to discuss therapeutic options for the prevention and treatment of bleeding associated with antiplatelet agents.

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Ticagrelor-Associated Bleeding in a Patient Undergoing Surgery for Acute Type A Aortic Dissection

Cited by 16 publications

References 6 publications

Structural and functional characterization of a specific antidote for ticagrelor

Structural and functional characterization of a specific antidote for ticagrelor

Hemostatic effects of the ticagrelor antidote MEDI2452 in pigs treated with ticagrelor on a background of aspirin

Perioperative management and monitoring of antiplatelet agents: a focused review on aspirin and P2Y₁₂inhibitors

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Ticagrelor-Associated Bleeding in a Patient Undergoing Surgery for Acute Type A Aortic Dissection

Cited by 16 publications

References 6 publications

Structural and functional characterization of a specific antidote for ticagrelor

Structural and functional characterization of a specific antidote for ticagrelor

Hemostatic effects of the ticagrelor antidote MEDI2452 in pigs treated with ticagrelor on a background of aspirin

Perioperative management and monitoring of antiplatelet agents: a focused review on aspirin and P2Y12inhibitors

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Product

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Perioperative management and monitoring of antiplatelet agents: a focused review on aspirin and P2Y₁₂inhibitors