This Reactome event describes thrombin-catalyzed cleavage of factor XI (FXI) bound to the glycoprotein Ib (GPIb, GPIb:V:IX) complex on the platelet surface based on studies detailing the mechanism of thrombin-FXI interaction (Wu W et al., 2008; Shearin S & Venkateswarlu D 2022; Lakshmanan HHS et al., 2022; Barroeta AW et al., 2024). The reaction is further supported by studies using angiotensin II–infused mice, demonstrating that GPIbα-dependent, platelet-localized FXI is essential for thrombin-FXIa feedback activation in vivo (Kossmann S et al., 2017). These findings link FXI-dependent thrombin propagation on platelets with vascular inflammation and arterial hypertension (Kossmann S et al., 2017).

FXI, when bound to the cell surface, is converted to activated factor XI (FXIa) through a proteolytic cleavage at Arg387-Ile388 within its protease domain. In the body, this reaction occurs on the surfaces of activated platelets via interactions of FXI with platelet receptors such as GPIb (GPIb:V:IX), glycoprotein IV (CD36), and apolipoprotein E receptor 2 (ApoER2) (Baglia FA et al., 2004a, b; White-Adams TC et al., 2009; Emsley J et al., 2010; Kossmann S et al., 2017; Mohammed BM et al., 2018; Reitsma SE et al., 2021). Binding to the platelet surface appears to protect FXIa from platelet-derived inhibitors (Reitsma SE et al., 2021). Alternatively, FXI can be activated upon binding to negatively charged surfaces, such as polyphosphate secreted from the dense granules of activated platelets (Choi SH et al., 2011; Geng Y et al., 2013). Activation of FXI can be catalyzed by factor XIIa, initiating fibrin clot formation. However, the efficient activation of larger quantities of FXI, needed to propagate the blood clotting process, appears to be mediated by thrombin (FIIa) (Gailani D and Broze GJ 1993; Naito K and Fujikawa K 1991; von dem Borne PA et al., 1995; Oliver JA et al. 1999; Monroe DM et al. 2002; Kravtsov DV et al., 2009; Matafonov A et al., 2011). Additionally, FXIa can be generated via autoactivation (Wu W et al., 2008).

Cleavage of FXI induces a conformational change that exposes the factor IX interaction site in the A3 domain of FXIa, enabling it to activate FIX (Gailani D et al., 2014; reviewed by Lira AL et al., 2024). Once activated, FXIa converts factor IX to FIXa, which subsequently activates FX, amplifying thrombin generation in a positive feedback loop. Some direct oral anticoagulant (DOAC) drugs are potent, competitive direct thrombin inhibitors (DTIs). They reversibly and specifically bind 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 J 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 MJ 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 JI 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 TD 2002). Desirudin (brand name Iprivask) is another recombinant hirudin derivative that directly inhibits free and fibrin-bound thrombin (Graetz TJ et al. 2011). Melagatran is the active drug formed from the prodrug ximelagatran and is a competitive and rapid inhibitor of thrombin (Gustafsson D et al. 1998). DuP 714 is a potent and specific thrombin inhibitor (Chiu AT et al. 1991).