As adult programs of newer anthrombotic agents, such as those directed against FXIa, are underway, there is both a pressing need and a great opportunity to optimize the design, conduct, and analysis of future pediatric trials. Recommendations for the development of new anticoagulation drugs for pediatric use were last published in 2015 on behalf of the ISTH SSC. The objective of the present manuscript is to provide updated guidance recommendations for the development of new antithrombotic drugs in children. Key recommendations include: 1) initiating pediatric pharmaceutical development (including oral formulation development) well before the intended start of pediatric clinical studies; 2) engaging multidisciplinary experts in pediatric thrombosis clinical care, clinical trials, and translational science; 3) employing extrapolation where appropriate, to assure that patient sample sizes in pediatric trials are no larger than necessary; 4) using modeling approaches to minimize patient sample sizes and optimize timing and frequency of blood sampling in pediatric PK/PD studies; 5) augmenting preclinical data from animal models (or non-animal approaches) with in vitro spiking studies using biospecimens obtained from relevant human pediatric populations; 6) addressing residual uncertainty in dose-finding, PK or PD from early-phase trials in the design of late-phase trials; and 7) committing to make all pediatric formulations found to be safe and efficacious in late-phase trials commercially available in all countries in which the trials are conducted. Additional guidance recommendations will be provided in a subsequent manuscript.