Reversal Strategy For Antagonizing The P2Y12-Inhibitor Ticagrelor By Platelet Concentrates

Patients on anti-platelet therapy have a higher incidence of bleeding complications and reversal of anti-platelet drug effects is an important issue in emergency situations. For old and conventional anti-coagulants, reversal strategies are established. However, there is no experience or recommendation how to antagonize the reversible and highly effective P2Y12-inhibitor ticagrelor and how to restore platelet function following ticagrelor dosing. The aim of this study was to investigate an ex vivo model to reverse the effects of ticagrelor and to estimate the optimal quantity of platelet transfusions required to normalize platelet aggregation.

Healthy volunteers (n=20) ingested a loading dose of 180 mg ticagrelor. Blood samples were obtained at baseline to gain autologous platelet rich plasma and to perform aggregation studies after 3h, i.e. at the time of expected maximal ticagrelor concentrations and maximimal platelet inhibition. To normalize platelet aggregation, increasing amounts of autologous platelet rich plasma (PRP) were added ex vivo to hirudin anti-coagulated blood, by spiking PRP into blood at ratios of 1:10, 1:5 and 1:3. Platelet aggregation was assessed by whole blood multiple electrode aggregometry (MEA; Multiplate). For interpretation of aggregation, we defined a cutoff level of 40 U (Units) as the lower limit of the normal range. Volunteers above this level were considered to exhibit normal platelet reactivity. Nonparametric tests were used and statistical comparisons were performed with the Friedman ANOVA, and the Wilcoxon test for post-hoc comparisons. A two-tailed p-value of less than 0.05 was considered significant.

Ingestion of 180 mg ticagrelor reduced average aggregation responses from 71 to 16 A.U. (p<0.001) and the platelet reactivity index in the VASP-assay from 88 to 22 units (p<0.001) A clear dose-response was obtained after spiking whole blood with increasing amounts of PRP. After addition of PRP at a ratio of 1:10, platelet aggregation increased to 31±14 U. When assuming that one apheresis platelet concentrate (200 mL) typically contains a minimum of 2 x10¹¹ platelets, the ratio of 1:10 corresponds to 0.5 units of apheresis platelet concentrates. A ratio of 1:5 – equivalent to 1 unit of platelet concentrates – increased ADP induced platelet aggregation to 41±14 U. Platelet aggregation increased further to 48±18 U following the addition of PRP at a ratio of 1:3, which corresponds to 1.5 units of platelet concentrates (figure 1). All comparisons were significant at p<0.01.

Platelets dose-dependently improved ex vivo platelet aggregation of subjects after a loading dose of 180 mg of ticagrelor. It is estimated that > 2 units of apheresis platelet concentrates will be necessary to completely restore baseline platelet aggregation in the majority of patients. Point-of-care platelet function tests may be suitable tools to verify this concept in emergency patients and to estimate the extent of the reversal and de-risk on an individual patient’s level.

No relevant conflicts of interest to declare.