Erythropoietin, Thrombopoietin and Leptin Receptors: Signal transduction pathways

International audienceErythropoietin (Epo), Thrombopoietin (Tpo) and leptin are hormones with distinct physiological properties. While the first two regulate survival, growth and differentiation of erythroid and megakaryocytic progenitors respectively, leptin is crucial for mammalian body weight regulation[1–3]. Receptors for these ligands have been isolated and well- characterized; they belong to the class I cytokine receptor family that includes most interleukin receptors involved in hematopoiesis as well as those for prolactin and growth hormone (see Chapter 7) which play an important role in metabolism and reproduction [4]. This family of receptors shares structural similarities both in their extracellular and intracellular domains and is characterized by the absence of an intrinsic tyrosine kinase. Nevertheless, ligand binding to this type of receptor induces the tyrosine phosphorylation of many cellular substrates including the receptor itself, leading to the activation of distinct signaling pathways. This review will focus first on the structure and biological properties of Epo, Tpo, leptin and their receptors. The second part will summarize the signal transduction pathways induced by these three ligands and their roles in cell proliferation, differentiation and survival

Vorapaxar in the secondary prevention of atherothrombotic events

Item does not contain fulltextBACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)