In summary, this work clarifies that (1) Mfsd2b is expressed in the plasma membrane in resting and activated platelets and that resting platelets store S1P the cytoplasm; (2) platelets are not the major provider of the plasma S1P pool and this pool is unlikely required for induction of venous thrombosis; (3) deletion of Mfsd2b causes S1P accumulation, which may trigger lipotoxic stress in platelets and severely impede their intrinsic thrombotic functions. Here, MFSD2B is linked to Venous thrombosis.