ABSTRACTFactor Va serves as the nonenzymatic protein cofactor for the prothrombinase complex, which converts prothrombin to thrombin in the events leading to formation of a hemostatic plug. Several observations support the concept that platelet‐derived factor V/Va is physically and functionally distinct and plays a more important role in thrombin generation at sites of vascular injury as compared to its plasma counterpart. Platelet‐derived factor V/Va is generated following endocytosis of the plasma‐derived molecule by the platelet precursor cells, megakaryocytes, via a two receptor system consisting of low density lipoprotein (LDL) receptor‐related protein‐1 (LRP‐1) and an unidentified specific “binding site”. More recently, it was suggested that a cell surface‐expressed β‐galactoside binding protein, galectin‐8, was involved in factor V endocytosis. Endocytosed factor V is trafficked through the cell and retailored prior to its storage in α‐granules. Given the essential role of platelet‐derived factor Va in clot formation, understanding the cellular and molecular mechanisms that regulate how platelets acquire this molecule will be important for the treatment of excessive bleeding or clotting. J. Cell. Biochem. 116: 2121–2126, 2015. © 2015 Wiley Periodicals, Inc.