FXII and Inflammation

Explain how FXII and FXI are activated by vascular assist devices and show their connection with inflammation.

Here is an answer provided by one of the course participants:

The contact pathway may be initiated by FXII binding to a negatively charged surface such as found on vascular assist devices. The FXII heavy chain is noncatalytic, thus its activation is only possible when surface bound. Two important structural components that aid in its binding to vascular devices are its epidermal growth factor-1 (EGF1) and possibly its fibronectin type 1 (FN1) domains. A conformational change occurs when FXII binds to a surface, exposing its activation sites. After FXII is activated, it activates FXI entering the intrinsic pathway in a series of calcium-dependent cleavage events, leading to thrombin formation, and ultimately the formation of the fibrin clot.

Further, the activation of FXII to FXIIa contributes to bradykinin generation by cleaving prekallikrein (PK) to form protease plasma kallikrein (PKa). FXIa is a homolog of PK, a component of the pro-inflammatory plasma kallikrein-kinin system. In summary, after FXIIa cleaves PK to PKa, it further activates FXIIa through a positive feedback loop. PK then digests high molecular weight kininogen (HK), to release bradykinin (BK). BK is a pro-inflammatory peptide and the end product of the kallikrein-kinin system. Moreover, BK activates several signaling pathways that increase vascular permeability, vasodilation, and chemotaxis of neutrophils seen in inflammation.

References:

1. Goel A, Tathireddy H, Wang SH, et al. Targeting the contact pathway of coagulation for the prevention and management of medical device-associated thrombosis. Semin Thromb Hemost. 2023. doi: 10.1055/s-0043-57011.
2. Shamanaev A, Ivanov I, Sun MF, et al. Model for surface-dependent factor XII activation: the roles of factor XII heavy chain domains. Blood Adv. 2022;6:3142–54. doi: 10.1182/bloodadvances.2021005976.
3. Long AT, Kenne E, Jung R, et al. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost. 2016;14:42–-37. doi: 10.1111/jth.13235.
4. Mohammed BM, Matafonov A, Ivanov I, et al. An update on factor XI structure and function. Thromb Res. 2018;161:94-105. doi: 10.1016/j.thromres.2017.10.008.