During human placentation extravillous trophoblasts (EVTs), arising from cell column trophoblasts (CCT) invade the highly differentiated uterine mucosa, called decidua, where they erode blood vessels and replace vascular endothelial cells. Maternal platelets have been detected in intercellular gaps of CCTs but their physiological role remained unclear so far.This study aimed to elucidate the impact of platelet-derived factors on trophoblasts that are exposed to maternal platelets through erosion of decidual blood vessels.Trophoblast cell line ACH-3P spheroids were incubated either with platelet-derived factors or isolated platelets obtained from pregnant women, and afterwards subjected to RNA sequencing, and validation by qPCR, ELISA and in situ padlock hybridization. Amongst deregulated genes, LAIR2 expression was confirmed in first trimester placenta and primary trophoblast organoids. The functional role of LAIR2 in trophoblast invasion and platelet activation was studied.Platelet-derived factors altered the transcription profile of ACH-3P spheroids, including deregulation of genes linked to embryonic development. Amongst them, LAIR2 was exclusively detected in CCTs and invaded EVTs of first trimester decidua. Histology showed extravasated maternal erythrocytes within interstitial gaps of highly invaded decidua samples, coinciding with LAIR2 positive EVTs. LAIR2 inhibited type 1 collagen -induced platelet activation and enhanced invasiveness of trophoblasts.This study suggests that maternal platelet-derived factors affect the transcription profile of trophoblasts, including upregulation of LAIR2, which may be involved in fine-tuning the coagulation of maternal blood leaking from eroded decidual blood vessels and could increase the invasiveness of EVTs into the decidua through an autocrine mechanism.