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Ultimately, P2Y 12 inhibition preserved cardiac function and reduced chronic adverse cardiac remodeling after MI. P2Y 12 knockout and P2Y 12 inhibitor treatment with prasugrel reduced emergency hematopoiesis and the excessive inflammatory response to MI, translating to lower numbers of downstream progeny and inflammatory cells in the blood and infarct. We were able to detect P2Y 12 in LSK, implicating a direct effect of ADP on LSK via P2Y 12 signaling. We found that ADP acts as a danger signal for the hematopoietic BM and fosters emergency hematopoiesis by promoting Akt phosphorylation and cell cycle progression. Complementary in vitro studies allowed for investigation of ADP-dependent effects on LSK cells. BM activation, inflammatory cell composition and cardiac function were assessed using global and platelet-specific gene knockout and pharmacological inhibition models for P2Y 12. Permanent coronary ligation was performed to induce MI in a murine model. In this study, we describe the influence of adenosine diphosphate (ADP)-dependent P2Y 12 -mediated signaling on emergency hematopoiesis and cardiac remodeling after MI. Decoding the regulation of the inflammatory cascade after MI may provide new avenues to improve post-MI remodeling. Increased proliferation of hematopoietic stem and progenitor cells (LSK) after MI enhances cell production in the bone marrow (BM) and replenishes leukocyte supply for local cell recruitment to the infarct. A higher rate of TIMI major bleeding related to instrumentation and a significantly higher rate of spontaneous TIMI major bleeding were seen in the prasugrel group than in the clopidogrel group ( Table 3).Įmergency hematopoiesis is the driving force of the inflammatory response to myocardial infarction (MI). Fatal TIMI major bleeding occurred in significantly more patients treated with prasugrel (0.4%) than those treated with clopidogrel (0.1%) (P = 0.002) ( Table 3), and more patients in the pra- sugrel group had nonfatal life-threatening bleed- ing (1.1%, vs. 0.9% in the clopidogrel group hazard ratio, 1.52 95% CI, 1.08 to 2.13 P = 0.01) at the end of the study, as well as from the time of randomization to day 3 (0.4% vs. excess of TIMI major bleeding included a higher rate of life-threatening bleeding in the pra- sugrel group (1.4%, vs.