Prothrombin activation pathways and proposed model for prothrombin docking. (A) Schematic illustrates the 2 pathways for prothrombin processing by fXa and prothrombinase. fXa, with or without membranes, cleaves first at R271, releasing prethrombin-2 from fragment 1.2 (F1.2), followed by slow cleavage at R320 to form thrombin. Fully assembled prothrombinase first cleaves R320, leading to formation of the active intermediate, meizothrombin, followed by cleavage at R271, releasing thrombin from F1.2. (B) Representation of the proposed mode of prothrombin docking onto fully assembled prothrombinase. Prothrombin (gold semitransparent surface over cartoon) binds from the membrane (sticks) along the side of fVa (gray) to present the R320 cleavage site (indicated) to the active site of fXa (cyan; active site yellow). This initial docking mode keeps the otherwise favored R271 site remote from the active site of fXa.