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\begin{document}

\title{The Use of Point-of-care Testing in Detecting Platelet Function
Recovery in a Patient Treated with Prasugrel Undergoing Urgent Surgical
Revascularization}



\author[1]{Alessandra Verzelloni Sef}%
\author[1]{Francesca Caliandro}%
\author[1]{Davorin Sef}%
\author[1]{Shahzad G. Raja}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\textbf{INTRODUCTION}

Preoperative administration of dual antiplatelet therapy (DAPT) in
patients undergoing urgent coronary artery bypass grafting (CABG)
surgery remains controversial. DAPT including aspirin and a
P2Y\textsubscript{12}-inhibitor is most administered before urgent CABG
in the setting of acute coronary syndrome (ACS) in accordance with the
current guidelines {[}1{]}. Although preoperative
P2Y\textsubscript{12}-inhibitor treatment is associated with reduced
occurrence of ischemic events, there is a clear evidence that it can
increase the risk of surgery-related bleeding, especially in the case of
the third-generation thienopyridines such as prasugrel {[}2{]}. Current
guidelines recommend a discontinuation of prasugrel a minimum of 7 days
before non-emergent cardiac surgery to allow the recovery of platelet
function and attenuate the risk of perioperative bleeding {[}1{]}.

However, these recommendations do not account for highly variable
recovery of platelet reactivity following discontinuation of
P2Y\textsubscript{12}-inhibitor {[}3{]}. Prasugrel is an inactive
prodrug that is transformed into its active metabolite with a half-life
of 7 hours and results in a faster, more consistent platelet inhibition,
when compared to clopidogrel {[}1,2,4{]}. Preoperative point-of-care
(POC) platelet function testing (PFT) in patients receiving prasugrel
could be helpful to measure platelet reactivity and predict the risk of
perioperative bleeding and transfusion requirements {[}5-8{]}. We
presented a rare case of unexpected complete platelet function recovery
in a patient with ACS treated with prasugrel and revealed by
preoperative platelet function monitoring with thromboelastography (TEG)
platelet mapping before urgent surgical coronary revascularization.

\textbf{CASE PRESENTATION}

A 59-year-old male presented to the emergency department of a local
general hospital with inferior ST-elevated myocardial infarction
(STEMI). The patient had no previous medical history. His vital
parameters were stable. After the administration of 300 mg of aspirin
and 180 mg of ticagrelor loading dose, eptifibatide infusion was
commenced in combination with unfractionated heparin. Emergency
angiography revealed severe coronary artery disease (CAD) including long
segment disease in mid and distal right coronary artery (RCA), as well
as long segment stenosis in the proximal left anterior descending (LAD)
artery including ostium of the first diagonal artery. Consecutively, the
patient underwent an attempt of PCI to mid and distal RCA, but with
suboptimal result due to extensive calcification. Transthoracic
echocardiography (TTE) demonstrated a normal-sized left ventricle with a
mild systolic impairment. After a 60-mg loading dose of prasugrel, DAPT
with aspirin and a 10-mg daily maintenance dose of prasugrel was
commenced. The patient was transferred to our tertiary cardiothoracic
surgical center for urgent CABG due to the unsuccessful PCI.

At the admission, he remained stable. Troponin I was 625 ng/L and other
blood tests were unremarkable, including platelet count (367 10\^{}9/L).
Four days after discontinuation of prasugrel, a preoperative TEG
PlateletMapping (Haemonetics, Braintree, MA) was performed and
ADP-induced platelet aggregation test detected a complete platelet
function recovery with maximal platelet aggregation and normal maximum
amplitude on TEG (Fig. 1). Therefore, decision was made to proceed with
an urgent off-pump CABG which included LIMA-LAD, long saphenous vein to
the first diagonal artery and to the posterior descending artery
anastomoses. Perioperative blood loss was minimal and no cell salvage or
blood product transfusion was required. A loading dose of aspirin (300
mg) was administered within the first 6--24 hours after the surgery and
DAPT including 75 mg of both aspirin and clopidogrel was started on the
first postoperative day. Postoperative recovery was uneventful and the
patient was discharged on the 5\textsuperscript{th} postoperative day
and remained well during a 6-month follow-up. Informed consent and
patient's permission were obtained to report this case.

\textbf{DISCUSSION}

Prasugrel has a potent, fast and consistent antiplatelet action and
little is known about its impact on platelet function recovery {[}2{]}.
Perioperative bleeding and blood transfusion requirement can be
significantly increased during and after prasugrel therapy {[}8{]}.
Hereby, we presented a patient with STEMI requiring an urgent CABG and
in whom a complete platelet function recovery after prasugrel was
detected by POC testing of platelet function. Despite the initial 60-mg
loading dose along with a 10-mg daily maintenance dose over the course
of 5 days, complete absence of biological response to prasugrel was
demonstrated already 4 days after its discontinuation by preoperative
TEG PlateletMapping.

Several factors can be associated with inadequate platelet inhibition by
prasugrel such as poor patient compliance, drug absorption disturbances,
underdosing and increased platelet turnover {[}9{]}, while none of these
was present in our case. Furthermore, patients with chronic renal
failure requiring hemodialysis might have a relatively high rate of
prasugrel hyporesponsiveness {[}10{]}; however, our patient had normal
renal function. On the other hand, \emph{Fiore et al.} have reported a
case of stent thrombosis presenting with recurrent acute onset of chest
pain despite being on DAPT including prasugrel and have found that this
was related to the drug resistance {[}9{]}. Our patient did not have any
signs nor predictors of prasugrel resistance. In addition, cytochrome
(CYP) variants have been identified in some of the studies as predictors
of prasugrel low response {[}11{]}. However, it was not possible to
perform the genotyping for various CYP single-nucleotide polymorphisms
to verify if our patient carried mutant alleles encoding enzymes
involved in prasugrel metabolic pathway. In view of the interindividual
variability in prasugrel response and platelet function recovery after
cessation, we performed a TEG PlateletMapping and we demonstrated a
complete recovery of platelet function already on the
4\textsuperscript{th} day after prasugrel discontinuation. By means of
POC testing of platelet function, we were able to reduce the waiting
time and proceed with surgery.

In a recent randomized double-blinded study, \emph{Price et al.} found
that in aspirin-treated patients with CAD, the greater antiplatelet
effect of prasugrel resulted in a more delayed recovery of platelet
function as compared with clopidogrel {[}12{]}. The authors observed
that antiplatelet effects of prasugrel had dissipated in [?]75\% of
patients 7 days after its cessation and these findings are consistent
with current guidelines regarding the recommended waiting time for
surgery after prasugrel discontinuation {[}12{]}. In a
meta-analysis,\emph{Li et al.} reported that prasugrel non-response was
observed neither at 4 hours following loading dose in 566 patients nor
at 9 days in 130 patients following maintenance dose {[}13{]}.
Furthermore, among patients who underwent CABG in the TRITON-TIMI 38
trial, the rate of CABG-related bleeding was significantly higher with
prasugrel compared with clopidogrel, and this increased risk persisted
up to 7 days from the most recent dose of study drug {[}2{]}.

Although current guidelines issue class IIb recommendations for
preoperative platelet function assays, the use of preoperative platelet
function monitoring to determine the timing of CABG in patients on
antiplatelet therapy has been suggested in previous studies {[}7,14{]}.
Recently, \emph{Mannaccio et al.} demonstrated the benefits of an
individualized preoperative waiting period in patients undergoing
off-pump CABG {[}14{]}. Importantly, this study challenges current
guidelines by showing that a strategy based on individualized POC
platelet function measurements resulted in an overall 38\% shortening of
the recommended preoperative waiting period for patients on clopidogrel
treatment and in a significant reduction of postoperative bleeding and
blood product consumption.

\textbf{CONCLUSIONS}

This case report highlights the interindividual variability in recovery
time after prasugrel withdrawal and the importance of preoperative PFT
in assessing the extent of platelet inhibition in patients who have
recently received antiplatelet therapy with prasugrel. We have
demonstrated a benefit in the use of preoperative TEG PlateletMapping in
a patient undergoing urgent CABG as it can assist in detecting a
complete recovery of platelet reactivity and guiding a decision on
timing of surgery and optimizing the therapeutic approach without
unnecessary blood product transfusion.

\textbf{Author contributions: AVS,DS:} Conceptualization; Investigation;
Methodology; Writing-original draft;
Writing--Review\&Editing.\textbf{FC,SGR} : Conceptualization;
Investigation; Writing--Review\&Editing.

\textbf{Data Availability Statement}

Data available on request due to privacy/ethical restrictions.

\textbf{Patient Consent Statement}

The patient agreed to the publication of this case report.



\emph{Figure Legends}\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1:} Preoperative TEG PlateletMapping.

Abbreviations: ActF, activator F; ADP, adenosine diphosphate; HKH,
kaolin with heparinase.



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