title: Complement C1 esterase inhibitor levels linked to infections and contaminated heparin-associated adverse events.
abstract: Activation of kinin-kallikrein and complement pathways by oversulfated-chondroitin-sulfate (OSCS) has been linked with recent heparin-associated adverse clinical events. Given the fact that the majority of patients who received contaminated heparin did not experience an adverse event, it is of particular importance to determine the circumstances that increase the risk of a clinical reaction. In this study, we demonstrated by both the addition and affinity depletion of C1inh from normal human plasma, that the level of C1inh in the plasma has a great impact on the OSCS-induced kallikrein activity and its kinetics. OSCS-induced kallikrein activity was dramatically increased after C1inh was depleted, while the addition of C1inh completely attenuated kallikrein activity. In addition, actual clinical infection can lead to increased C1inh levels. Plasma from patients with sepsis had higher average levels of functional C1inh and decreased OSCS-induced kallikrein activity. Lastly, descriptive data on adverse event reports suggest cases likely to be associated with contaminated heparin are inversely correlated with infection. Our data suggest that low C1inh levels can be a risk factor and high levels can be protective. The identification of risk factors for contact system-mediated adverse events may allow for patient screening and clinical development of prophylaxis and treatments.
authors.affiliation: Division of Monoclonal Antibodies, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Zhao-Hua
authors.initials: ZH
authors.lastname: Zhou
authors.forename: Trina
authors.initials: T
authors.lastname: Chen
authors.forename: Kamalpreet
authors.initials: K
authors.lastname: Arora
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hyams
authors.forename: Steven
authors.initials: S
authors.lastname: Kozlowski
mesh_terms: D002809:Chondroitin Sulfates / Q000494:pharmacology*; D003173:Complement C1s / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D007700:Kinetics; D010949:Plasma / Q000737:chemistry
chemical_list: D006493:Heparin; D002809:Chondroitin Sulfates; D007610:Kallikreins; D003173:Complement C1s