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Ongoing contact activation in patients with hereditary angioedema.
PLoS One. 2013; 8(8):e74043.Plos

Abstract

Hereditary angioedema (HAE) is predominantly caused by a deficiency in C1 esterase inhibitor (C1INH) (HAE-C1INH). C1INH inhibits activated factor XII (FXIIa), activated factor XI (FXIa), and kallikrein. In HAE-C1INH patients the thrombotic risk is not increased even though activation of the contact system is poorly regulated. Therefore, we hypothesized that contact activation preferentially leads to kallikrein formation and less to activation of the coagulation cascade in HAE-C1INH patients. We measured the levels of C1INH in complex with activated contact factors in plasma samples of HAE-C1INH patients (N=30, 17 during remission and 13 during acute attack) and healthy controls (N=10). We did not detect differences in enzyme-inhibitor complexes between samples of controls, patients during remission and patients during an acute attack. Reconstitution with C1INH did not change this result. Next, we determined the potential to form enzyme-inhibitory complexes after complete in vitro activation of the plasma samples with a FXII trigger. In all samples, enzyme-C1INH levels increased after activation even in patients during an acute attack. However, the levels of FXIIa-C1INH, FXIa-C1INH and kallikrein-C1INH were at least 52% lower in samples taken during remission and 70% lower in samples taken during attack compared to samples from controls (p<0.05). Addition of C1INH after activation led to an increase in levels of FXIIa-C1INH and FXIa-C1INH (p<0.05), which were still lower than in controls (p<0.05), while the levels of kallikrein-C1INH did not change. These results are consistent with constitutive activation and attenuated depletion of the contact system and show that the ongoing activation of the contact system, which is present in HAE-C1INH patients both during remission and during acute attacks, is not associated with preferential generation of kallikrein over FXIa.

Authors+Show Affiliations

Laboratory for Clinical Thrombosis and Haemostasis, Department of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24013493

Citation

Konings, Joke, et al. "Ongoing Contact Activation in Patients With Hereditary Angioedema." PloS One, vol. 8, no. 8, 2013, pp. e74043.
Konings J, Cugno M, Suffritti C, et al. Ongoing contact activation in patients with hereditary angioedema. PLoS One. 2013;8(8):e74043.
Konings, J., Cugno, M., Suffritti, C., Ten Cate, H., Cicardi, M., & Govers-Riemslag, J. W. (2013). Ongoing contact activation in patients with hereditary angioedema. PloS One, 8(8), e74043. https://doi.org/10.1371/journal.pone.0074043
Konings J, et al. Ongoing Contact Activation in Patients With Hereditary Angioedema. PLoS One. 2013;8(8):e74043. PubMed PMID: 24013493.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ongoing contact activation in patients with hereditary angioedema. AU - Konings,Joke, AU - Cugno,Massimo, AU - Suffritti,Chiara, AU - Ten Cate,Hugo, AU - Cicardi,Marco, AU - Govers-Riemslag,José W P, Y1 - 2013/08/27/ PY - 2013/05/29/received PY - 2013/07/26/accepted PY - 2013/9/10/entrez PY - 2013/9/10/pubmed PY - 2014/4/1/medline SP - e74043 EP - e74043 JF - PloS one JO - PLoS One VL - 8 IS - 8 N2 - Hereditary angioedema (HAE) is predominantly caused by a deficiency in C1 esterase inhibitor (C1INH) (HAE-C1INH). C1INH inhibits activated factor XII (FXIIa), activated factor XI (FXIa), and kallikrein. In HAE-C1INH patients the thrombotic risk is not increased even though activation of the contact system is poorly regulated. Therefore, we hypothesized that contact activation preferentially leads to kallikrein formation and less to activation of the coagulation cascade in HAE-C1INH patients. We measured the levels of C1INH in complex with activated contact factors in plasma samples of HAE-C1INH patients (N=30, 17 during remission and 13 during acute attack) and healthy controls (N=10). We did not detect differences in enzyme-inhibitor complexes between samples of controls, patients during remission and patients during an acute attack. Reconstitution with C1INH did not change this result. Next, we determined the potential to form enzyme-inhibitory complexes after complete in vitro activation of the plasma samples with a FXII trigger. In all samples, enzyme-C1INH levels increased after activation even in patients during an acute attack. However, the levels of FXIIa-C1INH, FXIa-C1INH and kallikrein-C1INH were at least 52% lower in samples taken during remission and 70% lower in samples taken during attack compared to samples from controls (p<0.05). Addition of C1INH after activation led to an increase in levels of FXIIa-C1INH and FXIa-C1INH (p<0.05), which were still lower than in controls (p<0.05), while the levels of kallikrein-C1INH did not change. These results are consistent with constitutive activation and attenuated depletion of the contact system and show that the ongoing activation of the contact system, which is present in HAE-C1INH patients both during remission and during acute attacks, is not associated with preferential generation of kallikrein over FXIa. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24013493/Ongoing_contact_activation_in_patients_with_hereditary_angioedema_ L2 - https://dx.plos.org/10.1371/journal.pone.0074043 DB - PRIME DP - Unbound Medicine ER -