Objective:To explore new mechanisms of the traditional Chinese medicine (TCM)spleen-based treatment of immune thrombocytopenic purpura (ITP) from the perspective of blood neurotransmitters.Methods:In this randomized controlled multi-center clinical study,271 ITP patients who met the diagnostic criteria of syndrome of spleen failing to manage blood were randomized into three groups:group A administered Jianpi Yiqi Shexue (JYS) granules,1 bag per treatment,bid;group C administered prednisone as a draught at an initial dose of 1.0-1.5 mg/kg/day at 8:00 AM;and group B administered a combination of the interventions in groups A and C.Each treatment cycle lasted 21 days.Results:After treatment,scores of platelet distribution width (PDW) were significantly decreased in groups B and C,and there were significant differences among the three groups (P =.0131).Pairwise comparisons showed that PDW was significantly different between group A and group B (P =.005) and between group A and group C (P =.041) but not between group B and group C.Hemorrhage grading scores were significantly different between day 1 and day 7 in group A and group B (P ＜.001) but not in group C.The hemorrhage grading scores on day 14 and day 21 were significantly different from that on day 1 in all three groups (P ＜.001).Serum 5-hydroxytryptaminelevels did not change significantly before and after treatment in the three groups (P ＞.05).Serum β-endorphin and vasoactive intestinal peptide levels were significantly different between group A and group B (both P ＜.001).Conclusions:The JYS prescription may regulate the expression levels of blood neurotransmitters via the brain-gut axis in patients with spleen deficiency ITP and thus activate hemostatic mechanisms to promote hemostasis.β-EP and VIP are key neurotransmitters of the JYS-induced functional regulation.