Proteolytic inactivation of plasma C1- inhibitor in sepsis.
Activation of both the complement system and the contact system of intrinsic coagulation is implicated in the pathophysiology of sepsis. Because C1 inhibitor (C1-Inh) regulates the activation of both cascade systems, we studied the characteristics of plasma C1-Inh in 48 patients with severe sepsis on admission to the Intensive Care Unit at the Free University of Amsterdam. The ratio between the level of functional and antigenic C1-Inh (functional index) was significantly reduced in the patients with sepsis compared with healthy volunteers (P = 0.004). The assessment of modified (cleaved), inactive C1-Inh (iC1-Inh), and complexed forms of C1-Inh (nonfunctional C1-Inh species) revealed that the reduced functional index was mainly due to the presence of iC1-Inh. On SDS-PAGE, iC1-Inh species migrated with a lower apparent molecular weight (Mr 98,000, 91,000, and 86,000) than native C1-Inh (Mr 110,000). Elevated iC1-Inh levels (greater than or equal to 0.13 microM) were found in 81% of all patients, sometimes up to 1.6 microM. Levels of iC1-Inh on admission appeared to be of prognostic value: iC1-Inh was higher in 27 patients who died than in 21 patients who survived (P = 0.003). The mortality in 15 patients with iC1-Inh levels up to 0.2 microM was 27%, but in 12 patients with plasma iC1-Inh exceeding 0.44 microM, the mortality was 83%. The overall mortality in the patients with sepsis was 56%. We propose that the cleavage of C1-Inh in patients with sepsis reflects processes that play a major role in the development of fatal complications during sepsis.
Nuijens
J H
JH
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam.
Eerenberg-Belmer
A J
AJ
Huijbregts
C C
CC
Schreuder
W O
WO
Felt-Bersma
R J
RJ
Abbink
J J
JJ
Thijs
L G
LG
Hack
C E
CE
D003174:Complement C1 Inactivator Proteins / Q000032:analysis / Q000378:metabolism*; D003171:Complement Pathway, Classical; D010450:Endopeptidases / Q000502:physiology*; D006801:Humans; D011379:Prognosis; D018805:Sepsis / Q000097:blood*; D012772:Shock, Septic / Q000097:blood
D003174:Complement C1 Inactivator Proteins; D010450:Endopeptidases