Intracellular Signaling as a Potential Target for Antiplatelet Therapy

Abstract

Three classes of inhibitors of platelet aggregation have demonstrated substantial clinical benfits. Aspirin acts by irreversibly inhibiting COX-1 and therefore blocking the synthesis of proaggregatory thromboxane A (2) (TxA(2)). The indirect acting (ticlopidine, clopidogrel, prasugrel) and the direct acting (ticagrelor) antagonists of P2Y(12) block the thrombus stabilizing activity of ADP. Parenteral GP IIb-IIIa inhibitors directly block platelet-platelet interactions. Despite well-established benefits, all antiplatelet agents have important limitations: increased bleeding and gastrointestinal toxicities (aspirin), high incidence of thrombotic thrombocytopenic purpura (ticlopidine), potentially nonresponders (clopidogrel), severe bleeding (prasugrel, GP IIb-IIIa antagonists) and "complicated" relationships with aspirin ticagrelor). In this chapter, we present the genetic and pharmacological evidence that supports the development and expectations associated with novel antiplatelet strategies directed at intrasignaling pathways.

Platelet procoagulant phenotype is modulated by a p38-MK2 axis that regulates RTN4/Nogo proximal to the endoplasmic reticulum: utility of pathway analysis

“…For over the past 20 years, biochemical and molecular studies of platelets have established critical roles for a number of intracellular signaling systems driving cell biological outputs underlying platelet function (reviewed in Refs. 4,5,32,45). Traditionally, mechanistic findings regarding the molecular bases of platelet physiology are built on hypothesis testing around insights afforded from the evolving literature and studies of other molecular regulatory systems generalized over a variety of other cell types.…”

Efficacy of Antiplatelet Treatment in Stroke Prevention: Past, Present, and Future

“…Thus, future studies require identification of novel pathways and a better understanding of platelet behavior in thrombosis and arteriosclerosis. The most advanced studies involve inhibitors of platelet receptor, e.g., GP VI [Nieswandt et al., ] and kinases like: spleen tyrosine kinase (Syk) that represent the main downstream effector of GP VI, which mediates platelet adhesion to vascular collagen [Andre et al., ; Hilgendorf et al., ], protein kinase C delta, phosphatidylinositide 3‐kinase, and p38 mitogen‐activated protein kinase as well as the kinases protein kinase B 2 (Akt2), Bruton's tyrosine kinase (Btk), and phospholipase D1 (PLD1) [Andre, ] that may have antithrombotic efficacy with a reduced effect on primary hemostasis. MicroRNAs (miRNA) particles, the 21–23 nucleotides controlling protein coding in the mammalian genome may be another approach as a marker of reactivity and a therapeutic tool.…”