Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989). Some direct oral anticoagulant (DOAC) drugs are potent, competitive direct thrombin inhibitors (DTIs). They reversibly and specifically binds both clot-bound and free thrombin (unlike warfarin or heparin), as well as inhibiting thrombin-induced platelet aggregation. These drugs can be synthetic organic compounds (dabigatran, argatroban) or recombinant peptides (lepirudin, bivalirudin, desirudin). Dabigatran (brand name Pradexa) is formulated as a lipophilic prodrug, dabigatran etexilate, to promote gastrointestinal absorption before it is metabolised to the active drug. The kidneys excrete the majority (80%) of unchanged drug (Stangier et al. 2007). Argatroban is a synthetic inhibitor of thrombin derived from L-arginine, which has a relatively short period of binding only to thrombin’s active site (Hursting et al. 1997). It is given intravenously and is metabolised in the liver. Because of its hepatic metabolism, it may be used in patients with renal dysfunction. Lepirudin (brand name Refludan) is a recombinant hirudin derived from yeast cells (Weitz et al. 1990). Hirudin is a naturally occurring anticoagulant produced by the salivary glands of medicinal leeches. Bivalirudin (brand name Angiomax, Angiox) is a synthetic analog of hirudin, with a shorter period of binding to thrombin (Gladwell 2002). Desirudin (brand name Iprivask) is another recombinant hirudin derivative that directly inhibits free and fibrin-bound thrombin (Graetz et al. 2011). Melagatran is the active drug formed from the prodrug ximelagatran and is a competitive and rapid inhibitor of thrombin (Gustafsson et al. 1998). DuP 714 is a potent and specific thrombin inhibitor (Chiu et al. 1991).