Modulation of C4b-Binding Protein Isoforms during the Acute Phase Response Caused by Orthopedic Surgery

Abstract

Orthopedic surgery is described as an event with a high risk of thromboembolic diseases. This is probably a consequence of a synergistic combination of different risk factors in the patients subjected to this type of surgery, including age, immobilization, anesthesia and different hypercoagulable states. After surgery patients develop an acute-phase response that leads to changes in several plasma proteins. One of these proteins is the complement regulator C4b-binding protein (C4BP). We have recently shown that in some acute-phase patients C4BP is incorrectly controlled (with elevation of the C4BPΒ-containing isoforms), leading to a potential hypercoagulable state by decreasing the plasma levels of free (active) protein S. Here we have studied whether patients subjected to orthopedic surgery have an appropriate modulation of the C4BP isoforms during their postoperative acute-phase responses. We have analyzed the evolution of the C4BP isoforms in serial samples from 11 patients who have undergone knee (or hip) prosthesis surgery (mean age 70 years), or scoliosis surgery (mean age 18 years). Our data suggest a similar evolution of C4BP isoforms in all these patients, with an almost exclusive increase of C4BP isoforms lacking C4BPΒ polypeptides and steady levels of free protein S.

Cytokine-mediated up-regulation of CD55 and CD59 protects human hepatoma cells from complement attack

“…However, a similar requirement for prolonged stimulation with cytokines to increase CD55 expression has been reported for human lung carcinoma cell lines [12]. Our findings are also in agreement with the effects of the AP response in patients: for example, no increase in the serum levels of C4bp are seen in the first 24 h, but are instead observed over a 3±9-day period post-surgery [26].…”

“…Because we were unable to obtain primary hepatocytes, we chose a well‐characterized hepatoma cell line, Hep3B, and examined the effects of cytokines implicated in the AP response on expression of C regulators by the cells. A second hepatoma cell line, HepG2, was also examined and gave broadly similar results, but we chose to present results from Hep3B because we have previously found in studies of effects of AP response cytokines on expression of the fluid‐phase C regulatory protein, C4bp, that the response to AP cytokines in the latter cell more closely mirrors changes observed in vivo [16,26,27].…”

Influence of endotoxin challenge on protein S and C4b‐binding protein in healthy subjects

“…Possible explanations for this observation could be that the endotoxin dose was too low or the duration of the stimulus was too short to elicit an increase in C4BP, or that C4BP exhibits a delayed response. The latter is supported by the observation that increases in C4BP after orthopedic surgery do not become manifest until 48 h after surgery [14]. Another explanation for our observations could be that the APR activates the classical complement pathway modulated by C4BP leading to C4BP consumption and a subsequent transient decrease in C4BP levels [15].…”

“…This suggests that protein S and C4BP β + are not actively regulated during the APR. The transient decrease of total C4BP and C4BP β + and the subsequent lack of increase of their concentration above baseline was at first sight unexpected as it has been reported that the APR in patients increases the level of total C4BP, largely because of an increase in C4BP β ‐ [10,14]. Possible explanations for this observation could be that the endotoxin dose was too low or the duration of the stimulus was too short to elicit an increase in C4BP, or that C4BP exhibits a delayed response.…”

Interleukin-6 Induction of Protein S Is Regulated Through Signal Transducer and Activator of Transcription 3

“…Other studies, however, provide evidence for stable free PS levels during inflammation, showing only a rise in C4BP ␣-chain levels, but not in ␤-chain levels. 21,25 The observed discrepancy between the various studies may be explained by a differential regulation of C4BP ␣-and ␤-chains in different subpopulations of patients during the APR. 26 The IL-6 signaling pathway is well-defined.…”