BackgroundAngioedema without wheals (AE) is a symptom characterised by localised episodes ofoedema presumably caused by kinin release from kininogen cleavage. It can result from ahereditary deficiency in C1 Inhibitor (C1Inh), but it can present with normal level of C1Inh.These forms are typically difficult to diagnose although enhanced kinin production is suspectedor demonstrated in some cases.ObjectivesWe wanted to investigate bradykinin overproduction in all AE condition with normal C1Inh,excluding cases with enhanced kinin catabolism, and to propose this parameter as a diseasebiomarker.MethodsWe retrospectively investigated high molecular weight kininogen (HK) cleavage pattern,using gel electrophoresis and immunorevelation. Plasma samples were drawn using thesame standardised procedure from blood donors or AE patients with normal C1Inh conditions,normal kinin catabolism, and without prophylaxis.ResultsCirculating native HK plasma concentrations were similar in the healthy men (interquartilerange: 98±175μg/mL, n = 51) and in healthy women (90±176μg/mL, n = 74), while HKcleavage was lower (p<0.001) in men (0±5%) than women (3±9%). Patients exhibitedlower native HK concentration (p<10−4; 21±117μg/mL, n = 31 for men; 0±84μg/mL, n = 41for women) and higher HK cleavage (p<10−4; 10±30% and 14±89%, respectively) thanhealthy donors. Pathological thresholds were set at: <72μg/mL native HK, >14.4% HKcleavage for men; <38μg/mL; native HK, >33.0% HK cleavage for women, with >98%specificity achieved for all parameters. In plasma from patients undergoing recovery twomonths after oestrogen/progestin combination withdrawal (n = 13) or two weeks after AEattack (n = 2), HK cleavage was not fully restored, suggesting its use as a post-attackassay.ConclusionAs a diagnostic tool, HK cleavage can offer physicians supportive arguments for kinin productionin suspected AE cases and improve patient follow-up in clinical trials or prophylacticmanagement.