Complement C1 Esterase Inhibitor Levels Linked to Infections and Contaminated Heparin-Associated Adverse Events

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

Characteristics of AE associated with Heparin & Dialysis 2000–2010.

<p>Characteristics of AE associated with Heparin & Dialysis 2000–2010.</p

OSCS-induced kallikrein activation in patient plasma samples.

<p>(A) OSCS-induced kallikrein activation and (B) functional C1inh levels in plasma samples from normal individuals (n = 40) and from patients with septic shock (n = 32). (C) The relationship of OSCS-induced kallikrein activity and functional C1inh levels using the same samples. The error bars correspond to mean ± SD for each patient group. The correlation coefficient r = −0.413 indicates a negative association between functional C1inh levels and OSCS-induced kallikrein activation. Data shown here were representative of three independent experiments.</p

Complement components C1r and C1s compete with FXIIa for C1inh.

<p>Kallikrein activity of (A) different doses of prekallikrein incubated with a fixed dose (1 ng) of FXIIa; (B) a fixed dose (0.5 µg) of prekallikrein incubated with different doses of FXIIa; (C) different doses of C1inh premixed with a fixed dose (1 ng) of FXIIa before combining with prekallikrein (1 µg). (D) Kallikrein activity of 0.5 µg of prekallikrein incubated with different combinations of FXIIa, C1inh and C1r/C1s. Experiments were repeated independently at least three times. Duplicate samples were used in panels C and D.</p

Factors that can influence bradykinin levels.

<p>The level of bradykinin (BK) is determined by the levels of kallikrein (KAL), high molecular weight kininogen (HMWK) and enzymes that degrade BK, such a angiotensin converting enzyme (ACE), aminopeptidase P (APP) and neutral carboxypeptidase (CPN). Activated factor XII (FXIIa) generates KAL from prekallikrein (PK). C1 inhibitor (C1inh) can inhibit both FXIIa and KAL. OSCS can facilitate FXIIa activity through enhancing its generation from FXII and/or stabilizing a complex of FXIIa, PK and HMWK. OSCS may also have a direct effect on C1inh. Other factors in the complement pathway and coagulation cascade can interact with C1inh and thus decrease C1inh availability for limiting BK production.</p

Post-combat syndromes from the Boer war to the Gulf war: a cluster analysis of their nature and attribution

OBJECTIVES: To discover whether post-combat syndromes have existed after modern wars and what relation they bear to each other. DESIGN: Review of medical and military records of servicemen and cluster analysis of symptoms. DATA SOURCES: Records for 1856 veterans randomly selected from war pension files awarded from 1872 and from the Medical Assessment Programme for Gulf war veterans. MAIN OUTCOME MEASURES: Characteristic patterns of symptom clusters and their relation to dependent variables including war, diagnosis, predisposing physical illness, and exposure to combat; and servicemen's changing attributions for post-combat disorders. RESULTS: Three varieties of post-combat disorder were identified—a debility syndrome (associated with the 19th and early 20th centuries), somatic syndrome (related primarily to the first world war), and a neuropsychiatric syndrome (associated with the second world war and the Gulf conflict). The era in which the war occurred was overwhelmingly the best predictor of cluster membership. CONCLUSIONS: All modern wars have been associated with a syndrome characterised by unexplained medical symptoms. The form that these assume, the terms used to describe them, and the explanations offered by servicemen and doctors seem to be influenced by advances in medical science, changes in the nature of warfare, and underlying cultural forces

OSCS kallikrein activation kinetics and dose response.

<p>(A) Kinetics of kallikrein activation in normal plasma and C1inh-depleted plasma with the addition of 25 µg/ml of OSCS. Kallikrein activity was also determined in (B) normal human plasma and (C) C1inh-depleted plasma with different doses of OSCS. The OSCS dose response was also evaluated with plasma samples treated with antibody-coated bacteria. Experiments were repeated independently twice. Duplicate samples were used in panel A.</p