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Deficiency of plasminogen activator inhibitor 2 in plasma of patients with hereditary angioedema with normal C1 inhibitor levels.
J Allergy Clin Immunol 2016; 137(6):1822-1829.e1JA

Abstract

BACKGROUND

Hereditary angioedema with normal C1 inhibitor levels (HAE-N) is associated with a Factor XII mutation in 30% of subjects; however, the role of this mutation in the pathogenesis of angioedema is unclear.

OBJECTIVE

We sought evidence of abnormalities in the pathways of bradykinin formation and bradykinin degradation in the plasma of patients with HAE-N both with and without the mutation.

METHODS

Bradykinin was added to plasma, and its rate of degradation was measured by using ELISA. Plasma autoactivation was assessed by using a chromogenic assay of kallikrein formation. Plasminogen activator inhibitors (PAIs) 1 and 2 were also measured by means of ELISA.

RESULTS

PAI-1 levels varied from 0.1 to 4.5 ng/mL (mean, 2.4 ng/mL) in 23 control subjects, from 0.0 to 2 ng/mL (mean, 0.54 ng/mL) in patients with HAE-N with a Factor XII mutation (12 samples), and from 0.0 to 3.7 ng/mL (mean, 1.03 ng/mL) in patients with HAE-N without a Factor XII mutation (11 samples). PAI-2 levels varied from 25 to 87 ng/mL (mean, 53.8 ng/mL) in control subjects and were 0 to 25 ng/mL (mean, 4.3 ng/mL) in patients with HAE-N with or without the Factor XII mutation. Autoactivation at a 1:2 dilution was abnormally high in 8 of 17 patients with HAE-N (4 in each subcategory) and could be corrected by supplemental C1 inhibitor in 4 of them. Bradykinin degradation was markedly abnormal in 1 of 23 patients with HAE-N and normal in the remaining 22 patients.

CONCLUSIONS

Bradykinin degradation was normal in all but 1 of 23 patients with HAE-N studied. By contrast, there was a marked abnormality in PAI-2 levels in patients with HAE-N that is not seen in patients with C1 inhibitor deficiency. PAI-1 levels varied considerably, but a statistically significant difference was not seen. A link between excessive fibrinolysis and bradykinin generation that is estrogen dependent is suggested.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC. Electronic address: josephk@musc.edu.Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC.Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.Department of Dermatology, Johannes Gutenberg University, Mainz, Germany.Department of Medicine, Medical University of South Carolina, Charleston, SC.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26395818

Citation

Joseph, Kusumam, et al. "Deficiency of Plasminogen Activator Inhibitor 2 in Plasma of Patients With Hereditary Angioedema With Normal C1 Inhibitor Levels." The Journal of Allergy and Clinical Immunology, vol. 137, no. 6, 2016, pp. 1822-1829.e1.
Joseph K, Tholanikunnel BG, Wolf B, et al. Deficiency of plasminogen activator inhibitor 2 in plasma of patients with hereditary angioedema with normal C1 inhibitor levels. J Allergy Clin Immunol. 2016;137(6):1822-1829.e1.
Joseph, K., Tholanikunnel, B. G., Wolf, B., Bork, K., & Kaplan, A. P. (2016). Deficiency of plasminogen activator inhibitor 2 in plasma of patients with hereditary angioedema with normal C1 inhibitor levels. The Journal of Allergy and Clinical Immunology, 137(6), pp. 1822-1829.e1. doi:10.1016/j.jaci.2015.07.041.
Joseph K, et al. Deficiency of Plasminogen Activator Inhibitor 2 in Plasma of Patients With Hereditary Angioedema With Normal C1 Inhibitor Levels. J Allergy Clin Immunol. 2016;137(6):1822-1829.e1. PubMed PMID: 26395818.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Deficiency of plasminogen activator inhibitor 2 in plasma of patients with hereditary angioedema with normal C1 inhibitor levels. AU - Joseph,Kusumam, AU - Tholanikunnel,Baby G, AU - Wolf,Bethany, AU - Bork,Konrad, AU - Kaplan,Allen P, Y1 - 2015/09/26/ PY - 2015/01/19/received PY - 2015/07/20/revised PY - 2015/07/29/accepted PY - 2015/9/24/entrez PY - 2015/9/24/pubmed PY - 2017/6/16/medline KW - C1 inhibitor KW - Hereditary angioedema KW - bradykinin KW - plasminogen activator inhibitor SP - 1822 EP - 1829.e1 JF - The Journal of allergy and clinical immunology JO - J. Allergy Clin. Immunol. VL - 137 IS - 6 N2 - BACKGROUND: Hereditary angioedema with normal C1 inhibitor levels (HAE-N) is associated with a Factor XII mutation in 30% of subjects; however, the role of this mutation in the pathogenesis of angioedema is unclear. OBJECTIVE: We sought evidence of abnormalities in the pathways of bradykinin formation and bradykinin degradation in the plasma of patients with HAE-N both with and without the mutation. METHODS: Bradykinin was added to plasma, and its rate of degradation was measured by using ELISA. Plasma autoactivation was assessed by using a chromogenic assay of kallikrein formation. Plasminogen activator inhibitors (PAIs) 1 and 2 were also measured by means of ELISA. RESULTS: PAI-1 levels varied from 0.1 to 4.5 ng/mL (mean, 2.4 ng/mL) in 23 control subjects, from 0.0 to 2 ng/mL (mean, 0.54 ng/mL) in patients with HAE-N with a Factor XII mutation (12 samples), and from 0.0 to 3.7 ng/mL (mean, 1.03 ng/mL) in patients with HAE-N without a Factor XII mutation (11 samples). PAI-2 levels varied from 25 to 87 ng/mL (mean, 53.8 ng/mL) in control subjects and were 0 to 25 ng/mL (mean, 4.3 ng/mL) in patients with HAE-N with or without the Factor XII mutation. Autoactivation at a 1:2 dilution was abnormally high in 8 of 17 patients with HAE-N (4 in each subcategory) and could be corrected by supplemental C1 inhibitor in 4 of them. Bradykinin degradation was markedly abnormal in 1 of 23 patients with HAE-N and normal in the remaining 22 patients. CONCLUSIONS: Bradykinin degradation was normal in all but 1 of 23 patients with HAE-N studied. By contrast, there was a marked abnormality in PAI-2 levels in patients with HAE-N that is not seen in patients with C1 inhibitor deficiency. PAI-1 levels varied considerably, but a statistically significant difference was not seen. A link between excessive fibrinolysis and bradykinin generation that is estrogen dependent is suggested. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/26395818/Deficiency_of_plasminogen_activator_inhibitor_2_in_plasma_of_patients_with_hereditary_angioedema_with_normal_C1_inhibitor_levels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(15)01104-5 DB - PRIME DP - Unbound Medicine ER -