Eicosanoids in platelets and the effect of their modulation by aspirin in the cardiovascular system (and beyond)

Abstract

Platelets are important players in thrombosis and haemostasis with their function being modulated by mediators in the blood and the vascular wall. Among these, eicosanoids can both stimulate and inhibit platelet reactivity. Platelet Cyclooxygenase (COX)-1-generated Thromboxane (TX)A₂ is the primary prostanoid that stimulates platelet aggregation; its action is counter-balanced by prostacyclin, a product of vascular COX. Prostaglandin (PG)D₂ , PGE₂ and 12-hydroxyeicosatraenoic acid (HETE), or 15-HETE, are other prostanoid modulators of platelet activity, but some also play a role in carcinogenesis. Aspirin permanently inhibits platelet COX-1, underlying its anti-thrombotic and anti-cancer action. While the use of aspirin as an anti-cancer drug is increasingly encouraged, its continued use in addition to P₂ Y₁₂ receptor antagonists for the treatment of cardiovascular diseases is currently debated. Aspirin not only suppresses TXA₂ but also prevents the synthesis of both known and unknown antiplatelet eicosanoid pathways, potentially lessening the efficacy of dual antiplatelet therapies. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.

Figure 1

Diagram of the biosynthesis of the main eicosanoids that affect platelet function and where it occurs. The yellow, green and red boxes represent the origin of the eicosanoids as platelets, ECs and leukocytes respectively. The receptors for each eicosanoid are shown as well as the associated effects on platelet activation.

Figure 2

Main pathways of eicosanoid‐mediated crosstalk between platelets and other cells. The eicosanoid exchanges between platelets and ECs and their effects on the vessel homeostasis are illustrated in (A) and (B). Some of the PGH₂ released by platelets may be used by COX‐1 in the ECs to produce PGI₂ which induces vasodilation and prevents further platelet activation (A). ECs, on the other hand, can synthesize EETs starting from AA, through the action of CYP450. EETs reduce platelet activation (B). (C) and (D) represent some routes of platelet‐leukocyte crosstalk. LTs are synthesized in leukocytes by 5‐LOX and act together with other agonists to potentiate platelet activation. However, platelets can also use LTs to make lipoxins which reduce the activation of platelets (C). 12‐LOX in platelets also produces epoxy‐resolvins that can be used by the leukocytes to make maresins, molecules important for the resolution of inflammation (D).

Figure 3

Schematic representation of platelet function tests used to monitor responses to aspirin in cardiovascular patients.

Figure 4

Effects of platelet COX‐1‐derived eicosanoids and of aspirin treatment in the progression of cancer. The preventive role of aspirin in the progression of cancer depends at least in part on its ability to block the formation of eicosanoids by platelet COX‐1. TXA₂ and PGE₂ are released in the tumour micro‐environment and favour the transformation of cells from a normal to a cancerous phenotype (A). 15‐HETE is another eicosanoid synthesised by COX‐1 in platelets that promotes angiogenesis, a process that further promotes cancer progression (B). TXA₂ and PGE₂ mediate the formation of platelet aggregates around the metastatic cancer cells, protecting them from the immune system and assisting their spread throughout the body (C).