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

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

doi: 10.1213/XAA.0000000000000156
Case Reports: Case Report
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We describe a case of a 67-year-old man who required emergency surgery for acute intracranial bleeding after having received a loading dose of aspirin and ticagrelor for an acute ST-elevation myocardial infarction. Before and during the craniocervical decompression, the assessment of platelet function was performed using the Multiplate® analyzer. Biological evaluation of platelet function was consistent with the clinical impression, suggesting that platelet transfusion and desmopressin administration in the presence of ticagrelor had very little, if any, hemostatic effect.

From the *Division of Anaesthesiology, University Hospitals of Geneva, Geneva, Switzerland; and Division of Angiology and Haemostasis, Geneva University Hospitals, Geneva Platelet Group, Faculty of Medicine, Geneva, Switzerland.

Accepted for publication December 10, 2014.

Funding: None.

Conflicts of Interest: Dr. Fontana received honoraria from Bayer, honoraria from Stago, research funding from Evolva, and research funding from Astra Zeneca. Dr. Bonhomme received honoraria from Astra Zeneca and research funding from Astra Zeneca. The remaining authors declare no conflicts of interest.

Address correspondence and reprint requests to Julien Maillard, MD, Division of Anaesthesiology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 41211 Geneva 14, Switzerland. Address e-mail to julien.maillard@hcuge.ch.

Intracranial hemorrhage in patients receiving antiplatelet drugs is associated with more frequent emergent surgical evacuation of hematomas,1 greater transfusion requirements,2 and a worse 30-day and 3-month mortality.3 In recent years, new antiplatelet drugs have emerged for the management of acute coronary syndromes. Ticagrelor, a reversible and direct-acting oral antagonist of the adenosine diphosphate (ADP) receptor P2Y12, provides a faster and more consistent P2Y12 inhibition than that provided by clopidogrel. In the PLATelet inhibition and patient Outcome (PLATO) study, ticagrelor reduced the relative risk of major adverse cardiac events compared with clopidogrel, without increasing total major bleeding events.4 In the noncardiac surgery setting, major bleeding was more common in ticagrelor-treated patients, although fatal bleeding and transfusion requirements did not differ between groups.5 The rate of fatal intracranial bleeding, however, was 10-fold greater with ticagrelor than with clopidogrel.5

Management of intracranial bleeding during emergent neurosurgery in patients receiving antiplatelet drugs is challenging, and standardized therapeutic strategies have not been defined. In vitro studies suggest that nonspecific treatments, such as tranexamic acid, desmopressin, or recombinant activated factor VII,6,7 might be effective in limiting antiplatelet drug-induced hemorrhage; however, platelet transfusions are deemed the most efficient therapy to reverse the inhibitory effect of antiplatelet drugs such as aspirin or clopidogrel.8

Point-of-care devices that are used to evaluate hemostatic variables have a class IIc recommendation in the management of bleeding events, frequently performed using the Multiplate® analyzer (Roche Diagnostics, Basel, Switzerland) in patients receiving antiplatelet drugs.

We present the perioperative management of a patient treated with aspirin and ticagrelor who required emergency surgery for acute intracranial bleeding. The patient died during this clinical case, and to avoid subjecting the family to unnecessary distress, we obtained a consent exemption from our local regional research ethics committee.

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CASE DESCRIPTION

A 67-year-old man was admitted to an emergency room with suspected acute coronary syndrome. He received 300-mg aspirin and 180-mg ticagrelor loading doses and subcutaneous enoxaparin 1 mg/kg according to institutional guidelines. A coronary angiogram confirmed a Thrombolysis in Myocardial Infarction risk score 0 thrombosis of the right coronary artery, and a bare metal stent was implanted. During the procedure, administration of tirofiban 600 μg/h over 24 hours was started. The patient was then transferred to the intensive care unit (ICU) with a prescription for aspirin and ticagrelor maintenance dosing (75 mg once a day and 90 mg twice a day, respectively).

At admission to the ICU, the patient was hemodynamically stable and free of chest pain but presented new and recurrent neck pain. The initial neurologic assessment was normal, with a Glasgow Coma Scale of 15 and no lateralization or cranial nerve deficit. Thirty hours after the coronary angiography, the patient’s neurologic status had deteriorated to Glasgow Coma Scale 3/15, and the patient’s trachea was intubated. Computed tomography confirmed a diffuse Fisher IV subarachnoid hemorrhage, extending to and compressing the cervical spinal cord. Cerebral arteriography excluded any primary etiology of bleeding with no evidence of aneurysm, arteriovenous malformation, or dissection. During this procedure, assessment of platelet function was performed with the Multiplate analyzer, which confirmed a strong platelet inhibition: ASPItest 8 U (norm 71–115), ADPtest 19 U (norm 57–113), and TRAPtest 46 U (norm 84–128). Platelet count, prothrombin time, activated partial thromboplastin time, and fibrinogen level were in the normal range. A thromboelastometry analysis was performed with the ROTEM® coagulation analyzer (Tem Innovations GmbH, Pentapharm GmbH, Munich, Germany) and revealed normal values for all tests. Given this life-threatening situation, 2 pooled platelet concentrates (PPCs) were administered and an emergency craniocervical decompression was performed.

When the surgical procedure started, a second evaluation of platelet function performed with the Multiplate assay showed persistent platelet inhibition with the ADPtest (10 U) and a decreased and reversible profile with TRAPtest (71 U). Two additional PPCs were administrated, along with desmopressin 0.3 μg/kg. At the end of the surgical procedure, the Multiplate assay showed a limited therapeutic response to platelet administration with the ADPtest (12 U) and TRAPtest (62 U).

The patient was transferred to the ICU. After all sedative drugs had been discontinued, in the presence of tetraplegia, severe autonomic dysfunction, and the lack of any spontaneous breathing, the decision was made to withdraw treatment. The patient died 48 hours later.

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DISCUSSION

Spontaneous intracranial or subarachnoid hemorrhage occurring in patients treated with antiplatelet drugs is associated with poor outcomes and increased mortality.3 Indeed, no pharmacologic treatment to reverse platelet inhibition and to improve outcome in such patients has been demonstrated in controlled studies, but platelet transfusion is suggested to have a favorable effect.8 Ex vivo studies have demonstrated that the effect of aspirin (100 mg) alone might be reversed by 5 platelet units (e.g., approximately 1 platelet concentrate) and clopidogrel by 10 platelet units (2 platelet concentrates) after a 300-mg loading dose or 12.5 units (2.5 platelet concentrates) after a 600-mg loading dose.8

Contrary to thienopyridines (clopidogrel and prasugrel), ticagrelor binds to platelet P2Y12 receptors in a reversible manner. In our patient treated with ticagrelor, it appears that platelet transfusions (4 PPCs) were ineffective in restoring platelet function based on the persistence of bleeding and platelet inhibition assessed by the ADPtest on the Multiplate analyzer. This inability to correct ticagrelor-induced platelet inhibition may have been attributable to the reversible binding of ticagrelor on platelet receptors and its putative ability to bind to the P2Y12 receptor of transfused platelets.

To our knowledge, no clinical data are available regarding the effect of platelet transfusion in ticagrelor-treated patients, and only a few in vitro or ex vivo studies have been published. One such ex vivo study showed that platelet aggregation in ticagrelor subjects is corrected by 2 or more platelet concentrates, but the cutoff level to assess the normalization of platelet function remains questionable.9 Another in vitro study demonstrated that platelet administration was significantly less effective in reversing ticagrelor-induced platelet inhibition compared with that induced by clopidogrel, even with multiple transfusions of platelets.10 Finally, a study performed in rats has shown that the prolongation of the bleeding time in ticagrelor-treated rats could not be corrected by high-dose platelet transfusion, whereas this correction did occur with prasugrel (an irreversible ADP inhibitor).11

The biological effect of P2Y12 receptor blockers (clopidogrel, prasugrel, and ticagrelor) can be measured by several different assays, including light transmission aggregometry, flow-cytometric analysis of intraplatelet vasodilator-stimulated phosphoprotein phosphorylation (VASP assay), platelet function analysis system (PFA-100; Siemens, Marburg, Germany), or several point-of-care assays.12 Because of the large heterogeneity among the methods, the correlation among these tests is often moderate.

The use of point-of-care assays to guide platelet transfusion is controversial because the literature is sparse. The thromboelastometry analysis alone provides global information on the dynamics of clot development, stabilization, and dissolution but cannot detect the effect of antiplatelet drugs. However, the Multiplate analyzer provides a bedside functional evaluation of platelets and the quantification of antiplatelet therapy inhibition. In the present case, the initial decision to transfuse 2 PPC before surgery was not based on the aggregation results alone but rather by the recent exposure to antiplatelet drugs. In addition, because we were facing persistent surgical bleeding after administration of 2 PPC, additional platelet function evaluations were performed and suggested an absence of significant reversal of the anti-P2Y12 effect of ticagrelor, despite the administration of 4 PPC.

Because the effects of aspirin are easily reversed by the addition of a relatively smaller quantity of uninhibited platelets,13,14 we assumed that aspirin was not causing the persistent bleeding. We cannot exclude the possibility that tirofiban was at least partly responsible for the persistent bleeding because the infusion had been stopped <12 hours before the surgery. However, the TRAPtest on the Multiplate analyzer is very sensitive to anti-GPIIb-IIIa and would have been more impaired in the case of a residual effect of tirofiban. There might be an impact of P2Y12 inhibition on TRAP-induced platelet aggregation that may thus explain the impact on the TRAPtest.15 Indeed, the TRAPtest was subnormal after platelet concentrate transfusions whereas the ADPtest was still very impaired, indicating that the ADP pathway was still inhibited by ticagrelor.

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CONCLUSIONS

This case illustrates that platelet transfusions at the usual doses may have little impact on correcting the platelet inhibition induced by ticagrelor.

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