Editorial.
The requirement for platelets to maintain haemostasis has led to the
established long term use of aspirin and P2Y12antagonists for secondary prevention of cardiovascular events arising
from arterial thrombi, and the acute clinical use of glycoprotein
GPIIb/IIIa (integrin αIIbβ3) inhibitors
to prevent reactive restenosis after coronary angioplasty. There is now
an increasing appreciation and understanding that platelet activation
also occurs during host defence against infection. In this regard, the
functional characteristics of platelets are often causal to the ensuring
inflammatory response against various bacterial, viral, or fungal
pathogens, in a multitude of organs (Semple et al ., 2014; Yeaman
2011). Similar behaviours of platelets are also observed when the
inappropriate activation of inflammatory processes lead to the
pathogenesis of a plethora of diseases, including asthma, chronic
obstructive pulmonary disease (COPD), rheumatoid arthritis, inflammatory
bowel disease, eczema, atherosclerosis, cardiovascular
ischaemia-reperfusion injury; and neurological disorders for example
multiple sclerosis, Parkinsons disease, and Alzheimer’s disease. A
simple bibliographical search, using the terms ‘platelets’ and
‘inflammation’ on PubMed® returns 23,966 articles (conducted October
2023). Interest in these pro-inflammatory functions of platelets has
been expanding at an increasing rate each decade from the 1980s to the
present day (2022 alone returned 2,031 articles for ‘platelets’ and
‘inflammation’).
Some of these diseases have altered haemostasis with inflammation, and
the rationale for analysing the efficacy of existing anti-platelet drugs
in these contexts is self-evident. However, our understanding of
platelet activity is now evolving to question how we might control the
non-thrombotic functions of platelets specifically induced during
inflammatory diseases and infections where no alterations in haemostasis
exist, as promulgated by the concept of there being an existence of a
dichotomy (or polytomy) in platelet function (Page et al., 1988).
Will existing anti-platelet drugs confer sufficient anti-inflammatory
effects, or are novel approaches needed to control pro- inflammatory
platelet functions? The answer to this question might lead to a
different class of anti-platelet agents that suppress inflammation
whilst preserving haemostasis and avoiding the unwanted risk of
haemorrhage.
Nucleotides and nucleosides are essential in the control of both
haemostasis and inflammation (Burnstock 2014; Ferrari et al .,
2016; Gachet 2006; Idzko et al ., 2014). The study of the
extracellular ‘purinome’, and the receptors involved during inflammation
is therefore one starting point in understanding how platelets might get
activated in this context (Jacobson et al., 2011). It is therefore the
topic for this themed review series in the British Journal of
Pharmacology: ‘Platelet purinergic receptors and non-thrombotic
diseases’. The understanding of platelet activation via the
P2Y12 receptor in the context of inflammation is
discussed in cardiovascular and non-cardiovascular conditions,
recognising that direct and pleotropic effects of thienopyridines and
ticagrelor can make the pharmacological interpretation of clinical
studies complex (Parker & Storey 2023). This is complemented by a
review of evidence for P2Y12 activation in the
dysregulated immune response during sepsis and the challenges associated
with interpreting a dynamically changing inflammatory and then
conversely immunosuppressed state, combined with activation of
haemostatic pathways by Amoafo and colleagues (Amoafo et al .,
2023). In another review, the potential role for adenosine is discussed
(Boncler et al., 2023). Adenosine activation of platelet
A2A and A2B receptors suppresses
platelet activation during haemostasis. The potential control of
platelet activation in the context of adenosine suppression of
inflammation in thus introduced, including approaches to creating more
stable analogues of adenosine (Boncler et al ., 2023). Lastly, the
discovery that P2Y1 receptor activation by various
endogenous extracellular nucleotides can lead to selective platelet
inflammatory functions and not aggregation (Arkless et al .,
2023), leads to a discussion about the selective control of platelet
activation by P2Y1 during inflammation compared to
haemostasis, and the potential for safe anti-platelet drugs that
suppress inflammation whilst preserving haemostasis (Pan et al .,
2023).
Notwithstanding the possibility for other purinergic receptors expressed
by platelets to also have roles in inflammation (the ligand gated ion
channel P2X1 -activated by ATP; and the GPCR
P2Y14 -activated by UDP-glucose), it is hoped that this
themed issue in the British Journal of Pharmacology opens further debate
in the exploration of platelet function during inflammation, as
controlled by the ‘purinome’.