https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871670/

https://www.ncbi.nlm.nih.gov/pubmed/32203452

One new paradigm

March 31, 2020

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00312/full

Mini Review ARTICLE

Front. Immunol., 26 February 2018 | https://doi.org/10.3389/fimmu.2018.00312

Interaction of the Human Contact System with Pathogens—An Update

imageSonja Oehmcke-Hecht* and imageJuliane Köhler

Classically, it is stated that FXII has to interact with negatively charged surfaces for activation, but the current paradigm is that any artificial surface has the potential for FXII autoactivation (2).HK, which is in a noncovalent complex with PPK (3), also binds to the surface, thereby exposing PPK for activation by FXII cleavage. In turn, activated plasma kallikrein (PK) cleaves and activates more FXII, forming a powerful activation feedback loop. When sufficient amounts of FXII are activated on the surface, FXII activates coagulation factor XI (FXI), leading to subsequent thrombin formation. This result—in vitro—in the formation of a fibrin clot and is used as a diagnostic coagulation test—the activated partial thromboplastin time (aPTT). However, individuals with congenital deficiencies in FXII, PPK, or HK, who show a prolonged aPTT, do not have bleeding diathesis or abnormal hemostasis, indicating that the intrinsic coagulation pathway does not contribute to physiological hemostasis (4). Moreover, contact activation in vivo always occurs under pathological conditions, such as thrombosis (5), sepsis, or ARDS (6, 7), which makes FXII a promising therapeutic target to limit thrombosis without increasing bleeding risk (8). Thus, it has been questioned whether activation of the intrinsic coagulation by FXII is really its main physiological function. Instead, it was suggested that the pro-inflammatory arm of the contact system—the kallikrein–kinin system—is more related to physiological in vivo functions (9).

 

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