Kininogen Cleavage Assay: Diagnostic Assistance for Kinin-Mediated Angioedema Conditions
Open Access
- 29 September 2016
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 11 (9), e0163958
- https://doi.org/10.1371/journal.pone.0163958
Abstract
Angioedema without wheals (AE) is a symptom characterised by localised episodes of oedema presumably caused by kinin release from kininogen cleavage. It can result from a hereditary 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 suspected or demonstrated in some cases. We 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 disease biomarker. We retrospectively investigated high molecular weight kininogen (HK) cleavage pattern, using gel electrophoresis and immunorevelation. Plasma samples were drawn using the same standardised procedure from blood donors or AE patients with normal C1Inh conditions, normal kinin catabolism, and without prophylaxis. Circulating native HK plasma concentrations were similar in the healthy men (interquartile range: 98–175μg/mL, n = 51) and in healthy women (90–176μg/mL, n = 74), while HK cleavage was lower (pp−4; 21–117μg/mL, n = 31 for men; 0–84μg/mL, n = 41 for women) and higher HK cleavage (p−4; 10–30% and 14–89%, respectively) than healthy donors. Pathological thresholds were set at: 14.4% HK cleavage for men; 33.0% HK cleavage for women, with >98% specificity achieved for all parameters. In plasma from patients undergoing recovery two months after oestrogen/progestin combination withdrawal (n = 13) or two weeks after AE attack (n = 2), HK cleavage was not fully restored, suggesting its use as a post-attack assay. As a diagnostic tool, HK cleavage can offer physicians supportive arguments for kinin production in suspected AE cases and improve patient follow-up in clinical trials or prophylactic management.Keywords
Funding Information
- European Framework 7 (HAEIII)
- Etablissement Français du Sang (TRALI APR2011)
- Ministère des Affaires Sociales et de la Santé (Rare disease program - CREAK)
This publication has 46 references indexed in Scilit:
- Enzymatic Assays for the Diagnosis of Bradykinin-Dependent AngioedemaPLOS ONE, 2013
- The plasma bradykinin-forming pathways and its interrelationships with complementMolecular Immunology, 2010
- C1 inhibitor, a multi-functional serine protease inhibitorThrombosis and Haemostasis, 2010
- C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progressTrends in Molecular Medicine, 2009
- Hereditary AngioedemaThe New England Journal of Medicine, 2008
- Increased Activity of Coagulation Factor XII (Hageman Factor) Causes Hereditary Angioedema Type IIIAmerican Journal of Human Genetics, 2006
- The syndrome of amniotic fluid embolism: A potential contribution of bradykininAmerican Journal of Obstetrics and Gynecology, 2005
- AngioedemaJournal of the American Academy of Dermatology, 2005
- Statistical Approaches to the Analysis of Receiver Operating Characteristic (ROC) CurvesMedical Decision Making, 1984
- Kinetics of activation and autoactivation of human factor XIIBiochemistry, 1984