Ex vivo bradykinin as a functional biomarker for angioedema with normal C1-inhibitor

Bradykinin-mediated angioedema (AE-BK) remains diagnostically challenging particularly in patients with normal C1-inhibitor, where diagnosis primarily relies on clinical criteria. Routine laboratory tests can identify complement deficiency in hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) but not directly assess kallikrein-kinin system dysregulation underlying these conditions.

We sought to investigate potential associations between BK generation following ex vivo cold activation and clinical phenotypes of AE-BK, with or without C1-inhibitor deficiency.

Functional total BK generation ex vivo was quantified using a validated LC-MS/MS assay in cold-activated EDTA blood samples from 181 individuals: 46 with HAE-C1INH, 68 with recurrent angioedema and normal C1-inhibitor clinically suspected to be AE-BK, and 67 controls. A subset of patients in both angioedema groups was receiving long-term prophylaxis with plasma kallikrein inhibitors.

Elevated total BK following ex vivo activation was observed in most patients not on long-term prophylaxis (90.3% of HAE-C1INH; 57.4% of suspected AE-BK). Serial measurements demonstrated marked BK increases during acute angioedema episodes and stable levels during remission. Total BK levels correlated with plasma kallikrein activity and were reduced toward the reference range in patients receiving long-term prophylaxis with plasma kallikrein inhibitor therapy in both AE-BK subtypes.

The measurement of ex vivo BK generation by LC-MS/MS is associated with clinical features of AE-BK and with pharmacologic inhibition of kallikrein-kinin system. These observations suggest that this assay may have a role in pathophysiology-based patient stratification and treatment monitoring for AE-BK, though further prospective multicenter studies are warranted to clarify its diagnostic performance and clinical utility.