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\begin{document}

\title{Can we think of a TAT, that is a ``tailored antiplatelet therapy''?}



\author[1]{luigi tritapepe}%
\author[1]{claudio ajmone cat}%
\affil[1]{San Camillo Forlanini Foundation}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\selectlanguage{english}
\begin{abstract}
What can be seen from the case report by Verzelloni et al. has a double
value, beyond the case itself. First of all, the use of platelet
aggregation assessment tests, such as TEG-PM, allows clinicians to
verify the exact timing between the suspension of thienopyridines and
the possibility of surgery without further temporal delays and is also
able to favor the evolution of ischemic problems or hemodynamic
instability not easily treatable. It therefore allows clinicians to
optimize the bleeding / thrombosis matching. Secondly, the use of point
of care methodologies for the evaluation of platelet aggregation allows
us to evaluate the adequacy of the anti-aggregation, facilitating, where
resistance or percentages of anti-aggregation are lower than expected,
modification of the therapeutic regimen.%
\end{abstract}%



\sloppy


\textbf{Can we think of a TAT, that is a ``tailored antiplatelet
therapy''?}

\textbf{Luigi Tritapepe\textsuperscript{1, 2}, Claudio Augusto Ajmone
Cat\textsuperscript{3}}

\textsuperscript{1} Associate Professor of Anesthesia and Intensive
Care, Sapienza University of Rome, Italy

\textsuperscript{2} Director of the Anesthesia and Intensive Care
Division, San Camillo-Forlanini Hospital, Rome, Italy

\textsuperscript{3} Division of Anesthesia and Intensive Care, San
Camillo-Forlanini Hospital, Rome, Italy

Corresponding Author: Luigi Tritapepe,\emph{luigitritapepe@gmail.com},
(0000-0003-0480-1705) - ORCID

Dual antiplatelet therapy (DAPT) is a key part of the medical management
of patients with coronary artery disease (CAD), particularly those with
recent acute coronary syndrome (ACS) events. DAPT includes aspirin plus
a P2Y12 receptor inhibitor (thienopyridines, such as clopidogrel,
prasugrel, and ticagrelor) and should be based on the patient's degree
of heart disease, type of stent, and proximity to stent placement. It
lasts from 1 month to 1 year {[}1{]}. Numerous studies have shown that
DAPT can reduce the risk of thrombosis in the stent. Depending on the
time since stent insertion, stopping treatment may increase this risk
{[}2{]}.

Thienopyridines inhibit the ADP-dependent pathway of platelet
activation. It is known that ADP plays an important role in both
hemostasis and thrombosis. Its transduction within the platelets
involves two receptors: P2Y1 and P2Y12. Of these, the second plays a
fundamental role in the platelet aggregation process. In particular, it
promotes an enhancement of platelet secretion independent of the
synthesis of thromboxane A2 (TXA2), causes the stabilization of platelet
aggregates induced by thrombin and promotes the regulation of platelet
function {[}3{]}.

Thienopyridines can indirectly or directly inhibit the platelet P2Y12
receptor. For a rapid action we can therefore use the direct inhibitors
of the P2Y12 receptor such as ticagrelor and cangrelor.

The International Guidelines recommend the suspension of clopidogrel and
ticagrelor 5 days before surgery, while prasugrel must be interrupted 7
days before surgery, in compliance with the elimination kinetics of the
mentioned antiplatelet drugs {[}4{]}.

In the case of thrombotic risk prevailing over hemorrhagic risk, bridge
therapy with cangrelor in continuous infusion is recommended, and must
be started 2-3 days after discontinuation of clopidogrel and ticagrelor
and 3-4 days after discontinuation of prasugrel, according to well-known
protocols in literature {[}5, 6{]}.

In this way, anti-aggregation is activated, with substantial benefits on
the patency of previously stented coronaries, avoiding the false safety
given by heparin which, being an anticoagulant, facilitates
perioperative bleeding without the benefits of anti-aggregation.

But the hope of solving the bleeding / thrombosis problem with
generalizable algorithms can produce controversial effects on the
surgical population.

The best indication, as can also be seen from the case report by
Verzelloni A et al. {[}7{]}, is to study residual platelet activity with
monitoring of platelet function.

Indeed, literature data have reported a large variability in platelet
reactivity after discontinuation of thienopyridine therapy, which means
that a considerable number of patients are not adequately protected when
discontinuing thienopyridine therapy for up to one week. {[}8{]}.

This is related to the finding in the literature of a lack or reduced
activity of antiplatelet agents, despite the correct dose and adherence
to therapy.

The mechanism, commonly called resistance to antiplatelet agents, is
actually due to the multifactoriality of the atherothrombosis process
which involves a reduced bioavailability of the antiplatelet drug,
pharmacodynamic alterations, different production sources of TXA2,
presence of alternative ways of platelet activation, increased platelet
turnover, genetic factors, tachyphylaxis {[}9{]}.

Specifically, for clopidogrel, extrinsic factors must be considered,
such as interaction with other drugs and reduced intestinal absorption,
and intrinsic factors, such as platelet P2Y12 receptor polymorphisms and
hepatic cytochrome P450 3A4 polymorphisms {[}8{]}.

We are therefore faced with two situations that may have different but
coincident meanings: a low antiplatelet activity, which must be
carefully evaluated in order not to run the risk of undertreatment, and
a suspension of thienopyridines with unjustifiably prolonged periods, in
the hope of seeing a reactivation of the platelet activity.

Only the monitoring of platelet activity enables us to highlight the
real activity of the antiplatelet drug, both to improve its action and
to monitor the effects of anti-aggregation upon suspension.

While there are various laboratory investigations capable of measuring
the individual response to aspirin, such as the direct dosage of TXA2
produced by platelets, or the analysis of platelet function with
specific tests, the discourse with thienopyridines is different
{[}10{]}.

Since clopidogrel specifically inhibits one of the two ADP receptors
(P2Y12), the measurement of maximum platelet aggregation from ADP by
optical aggregometry is the most common laboratory method used to
evaluate the response to clopidogrel. The 'point of care' method most
recently proposed as an alternative to traditional tests is the
VerifyNow P2Y12 Assay {[}11{]}. The state of phosphorylation of VASP
(vasodilator-stimulated phosphoprotein) represents a specific
intracellular marker of the residual activity of the P2Y12 receptor and
can be measured with flow cytometry. This technique is probably the most
specific indicator of the residual activity of the P2Y12 receptor in
patients treated with a P2Y12 inhibitor. The test result is expressed in
Aspirin Reaction Unit (ARU) or P2Y12 Reaction Unit (PRU) which express a
percentage of inhibition of platelet aggregation associated respectively
with treatment with ASA and / or inhibitors of the P2Y12 platelet
receptor. However, it is a painstaking method, which requires expert
personnel and has a high cost, so it is not suitable for large-scale
application {[}12{]}.

Viscoelastic tests provide a dynamic assessment of coagulation,
exploring the time to clot formation and clot strength. Using specific
activators or inhibitors, additional factors may ALSO be explored, such
as the contribution of fibrinogen to clot strength. Since the early
days, various attempts have been made to measure platelet function with
viscoelastic testing. In general, the difference between the maximum
clot strength and the contribution of fibrinogen are considered an index
of the contribution of platelets. However, this parameter does not
clearly separate platelet count from function; furthermore, the large
thrombin generation of standard activated viscoelastic assays activates
platelets through the activated receptor protease, bypassing the other
pathways. For this reason, standard viscoelastic tests cannot be used to
assess platelet reactivity under the effects of aspirin or P2Y12
inhibitors. To overcome this limitation, a specific test (platelet
thromboelastography mapping) was developed. This test was evaluated
against the gold standard of light transmission aggregometry and other
point-of-care tests, with conflicting results. In general, the use of
viscoelastic tests to evaluate the effects of antiplatelet agents is
still limited. On the contrary, the contribution of platelets to the
strength of the clot in the context of coagulopathy causes bleeding,
which is considered an important parameter for triggering targeted
therapies {[}12{]}.

For clinical use and the promptness of the result, the point of care
systems of the TEG-Platelet Mapping (TEG-PM) type are easier, which use
a single cartridge capable of carrying out all the analysis.

The TEG-PM analyzer is used to detect platelet function. The analyzer
measures the percentage of platelet inhibition activated by adenosine
diphosphate (ADP) and arachidonic acid (AA). This parameter is
calculated by comparing the maximum amplitude (MA), which represents the
viscoelastic force of the thrombus, created through three TEG channels
as follows: 1) The MA reflects thrombin-activated platelets (MA Trombin)
measured from a citrated blood activated with kaolin / Ca2 + sample; 2)
a sample of heparinized blood activated by reptylase and activator F,
which represents the contribution of fibrin alone to the strength of the
clot (MA Fibrin); and 3) heparinized blood mixed with 2-mM ADP (MA ADP)
or 1-mM AA (MA AA) combined with activator F as platelet agonists
reflects the platelet response to ADP and AA. The equation 100 - ((MA
ADP or MA AA) -- MA Fibrin) / (MA Thrombin - MA Fibrin)) \selectlanguage{ngerman}× 100 is used
to calculate the percentage of platelet inhibition in response to ADP
and AA {[}12, 13{]}.

What can be seen from the case report by Verzelloni et al. {[}7{]} has a
double value, beyond the case itself.

First of all, the use of platelet aggregation assessment tests, such as
TEG-PM, allows clinicians to verify the exact timing between the
suspension of thienopyridines and the possibility of surgery without
further temporal delays and is also able to favor the evolution of
ischemic problems or hemodynamic instability not easily treatable. It
therefore allows clinicians to optimize the bleeding / thrombosis
matching.

Secondly, the use of point of care methodologies for the evaluation of
platelet aggregation allows us to evaluate the adequacy of the
anti-aggregation, facilitating, where resistance or percentages of
anti-aggregation are lower than expected, modification of the
therapeutic regimen.

We could therefore speak of TAT, that is ``tailored antiplatelet
therapy''.

In conclusion, we can finally arrive at a personalized anti-platelet
therapy by minimizing side effects or lack of effects.

References

\begin{enumerate}
\tightlist
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\item
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