Researchers discovered that bradykinin production bypasses the kallikrein-kinin system (KKS) in hereditary angioedema (HAE) with a mutation in the plasminogen gene (HAE-PLG). They reported their finding in Frontiers in Physiology. 

HAE-PLG is one of 6 recognized types of HAE with normal C1 inhibitor levels. Patients with this condition have the same clinical symptoms as patients with classical HAE, which is driven by a deficiency in functional C1 inhibitors—recurrent, self-limiting edema episodes in various organs. 

Previous studies have elucidated the important role that the KKS plays in the release of bradykinin. In a nutshell, activated factor XII (FXII) converts prekallikrein to kallikrein, which cleaves high molecular weight kininogen (HMWK) to release bradykinin. 

Continue Reading

Scientists remain unclear whether bradykinin overproduction is still mediated by the KKS in HAE-PLG. The authors of this study hence studied the DNA of 7 individuals from a single 4-generation family who all carry the PLG mutation c.988A>G; p.K330E. The clinical data from these individuals were collected from the Angioedema Outpatient Service in Mainz, Germany. 

Read more about HAE etiology 

In addition to the PLG mutation described above, the research team was able to identify an additional F12 mutation in 5 of the 7 family members. They subsequently found no difference in the clinical presentation between the HAE-PLG family members with and without this additional F12 mutation. 

“Based on these results, we concluded that it is possible that mutant plasminogen is not acting via the KKS to produce increased amounts of bradykinin,” the authors of the study wrote. 

This raises the question of how the PLG mutation drives bradykinin production if it indeed bypasses the KKS. The research team discovered via in vitro studies that mutant plasminogen can potentially cleave to HMWK more efficiently than wild-type plasminogen, resulting in an increased release of bradykinin. The authors of the study hence proposed that treatment for HAE-PLG should be directly targeted at plasminogen. 


Hintze S, Möhl BS, Beyerl J, et al. Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykininFront Physiol. 2023;13:1090732. doi:10.3389/fphys.2022.1090732