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.

Pharmacology of Heparin and Related Drugs

“…It has been noted that adverse reactions to OSCScontaminated heparin are inversely correlated with C1inh plasma levels (Zhou et al, 2012a). On one hand, OSCS appears to activate the contact system through prekallikrein activation; on the other hand, OCSC seems to inhibit the contact system through potentiation of C1inh.…”

Oversulfated Chondroitin Sulfate Binds to Chemokines and Inhibits Stromal Cell-Derived Factor-1 Mediated Signaling in Activated T Cells

“…Oversulfated chondroitin sulfate (OSCS), a contaminant in heparin linked to the 2008 heparin adverse events in the United States, has become the subject of multidisciplinary investigations [1] , [2] . Initially, OSCS was found to cause the activation of contact system (also known as the intrinsic pathway of coagulation or kallikrein/kinin system [3] ) through binding with factor XII and generation of plasma kallikrein and bradykinin, as well as the anaphylatoxins C3a and C5a [4] , [5] . OSCS also interacts with other parts of the innate immune system including most of the elements in the classical complement pathway [6] .…”

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

“…However, the majority of patients who received contaminated heparin did not experience an adverse event. To clarify this fact, a study was performed including the analysis of patient data and plasma samples [65]. It revealed that low C1-INH levels turned out as a risk factor for adverse events, whereas high levels were suggested to be protective, which once again emphasizes the importance of an appropriate C1-INH function.…”