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Complement activation and plasma levels of C4b-binding protein in critical limb ischemia patients.

Martin, Myriam LU ; Gottsäter, Anders LU ; Nilsson, Peter LU ; Mollnes, Tom E; Lindblad, Bengt LU and Blom, Anna LU (2009) In Journal of vascular surgery : official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 50(1). p.100-106
Abstract
OBJECTIVE: Critical limb ischemia (CLI) is a peripheral arterial disease manifested by drastically diminished blood flow to the legs, pain at rest, nonhealing wounds, and gangrene caused by atherosclerosis. Significant tissue necrosis is associated with late stage CLI and the patients have a poor prognosis. Necrotic and apoptotic cells activate complement and bind complement inhibitor C4b-binding protein (C4BP). The major isoform of C4BP is composed of seven identical alpha-chains and one beta-chain, here termed C4BP(beta), whereas upon inflammation a normally less abundant isoform is upregulated that is exclusively composed of alpha-chains. Measuring the alpha-chains of C4BP includes both isoforms and is termed total C4BP (C4BP(tot)). The... (More)
OBJECTIVE: Critical limb ischemia (CLI) is a peripheral arterial disease manifested by drastically diminished blood flow to the legs, pain at rest, nonhealing wounds, and gangrene caused by atherosclerosis. Significant tissue necrosis is associated with late stage CLI and the patients have a poor prognosis. Necrotic and apoptotic cells activate complement and bind complement inhibitor C4b-binding protein (C4BP). The major isoform of C4BP is composed of seven identical alpha-chains and one beta-chain, here termed C4BP(beta), whereas upon inflammation a normally less abundant isoform is upregulated that is exclusively composed of alpha-chains. Measuring the alpha-chains of C4BP includes both isoforms and is termed total C4BP (C4BP(tot)). The hypothesis of this study was that levels of complement activation and C4BP are predictive for the severity of the disease and that their measurement might be of clinical advantage. METHODS: This was a prospective, single-center study of 259 consecutive patients with CLI admitted to a secondary referral center for vascular diseases. Interventions included evaluation of soluble terminal complement complexes (C5b-9), C4BP(tot) and C4BP(beta), lipid levels, the inflammatory mediators tumor necrosis factor-alpha, interleukin-6, 8-iso-prostaglandin F(2alpha), high-sensitivity C-reactive protein, neopterin, plasma homocysteine, and plasma endothelin-1 in plasma as well as resistance to activated protein C and ankle blood pressure. All data were compared with an age-matched population based control group of 219 currently healthy individuals. RESULTS: The data are presented as mean +/- SEM/median. CLI patients showed systemic complement activation (1.17 +/- 0.06/1.13 AU/mL vs 0.69 +/- 0.07/0.59 AU/mL in healthy controls, P < .0001), which was even higher in patients with gangrene (1.33 +/- 0.11/1.28 AU/mL vs 1.1 +/- 0.08/1.0 AU/mL, P = .0264), who also showed increased C4BP levels (421 +/- 28.6/386 microg/mL vs 341 +/- 10.8/318 microg/mL for C4BP(tot), P = .0248; 374 +/- 25.4/332 microg/mL vs 305 +/- 9.5/285 microg/mL for C4BP(beta), P = .0581). C4BP plasma levels were significantly elevated in CLI patients in comparison to healthy controls (351 +/- 8.1/322 microg/mL vs 297 +/- 8.0/288 microg/mL for C4BP(tot), P = .0001; 314 +/- 7.0/287 microg/mL vs 265 +/- 7.0/263 microg/mL for C4BP(beta), P = .0004) and correlated to levels of interleukin-6 (P(tot/beta) = .0048/.0019), high-sensitivity C-reactive protein (P < .0001), leukocyte (P(tot/beta) = .0086/.0043) and platelet count (P = .0001), LDL/HDL ratio (P(tot) = .0151) and HDL (P(tot/beta) = .0047/.0177), but not to tumor necrosis factor-alpha. CONCLUSIONS: Increased complement activation and C4BP plasma levels are related to the degree of tissue necrosis and disease severity of critical limb ischemia. This knowledge in combination with the found correlations to other biomarkers is useful for understanding the pathophysiology of the disease. (Less)
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keywords
Ischemia: immunology, Ischemia: blood, Ischemia: physiopathology, Peripheral Vascular Diseases: blood, Peripheral Vascular Diseases: physiopathology, Peripheral Vascular Diseases: immunology, Biological Markers: blood, Complement C4b-Binding Protein: analysis
in
Journal of vascular surgery : official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
volume
50
issue
1
pages
100 - 106
publisher
Mosby
external identifiers
  • wos:000267498500015
  • pmid:19563958
  • scopus:67649236801
ISSN
1097-6809
DOI
10.1016/j.jvs.2008.12.033
language
English
LU publication?
yes
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1829e700-82b8-41b8-8e69-9bb624206545 (old id 1453526)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19563958?dopt=Abstract
date added to LUP
2009-08-04 09:26:03
date last changed
2017-07-23 03:58:24
@article{1829e700-82b8-41b8-8e69-9bb624206545,
  abstract     = {OBJECTIVE: Critical limb ischemia (CLI) is a peripheral arterial disease manifested by drastically diminished blood flow to the legs, pain at rest, nonhealing wounds, and gangrene caused by atherosclerosis. Significant tissue necrosis is associated with late stage CLI and the patients have a poor prognosis. Necrotic and apoptotic cells activate complement and bind complement inhibitor C4b-binding protein (C4BP). The major isoform of C4BP is composed of seven identical alpha-chains and one beta-chain, here termed C4BP(beta), whereas upon inflammation a normally less abundant isoform is upregulated that is exclusively composed of alpha-chains. Measuring the alpha-chains of C4BP includes both isoforms and is termed total C4BP (C4BP(tot)). The hypothesis of this study was that levels of complement activation and C4BP are predictive for the severity of the disease and that their measurement might be of clinical advantage. METHODS: This was a prospective, single-center study of 259 consecutive patients with CLI admitted to a secondary referral center for vascular diseases. Interventions included evaluation of soluble terminal complement complexes (C5b-9), C4BP(tot) and C4BP(beta), lipid levels, the inflammatory mediators tumor necrosis factor-alpha, interleukin-6, 8-iso-prostaglandin F(2alpha), high-sensitivity C-reactive protein, neopterin, plasma homocysteine, and plasma endothelin-1 in plasma as well as resistance to activated protein C and ankle blood pressure. All data were compared with an age-matched population based control group of 219 currently healthy individuals. RESULTS: The data are presented as mean +/- SEM/median. CLI patients showed systemic complement activation (1.17 +/- 0.06/1.13 AU/mL vs 0.69 +/- 0.07/0.59 AU/mL in healthy controls, P &lt; .0001), which was even higher in patients with gangrene (1.33 +/- 0.11/1.28 AU/mL vs 1.1 +/- 0.08/1.0 AU/mL, P = .0264), who also showed increased C4BP levels (421 +/- 28.6/386 microg/mL vs 341 +/- 10.8/318 microg/mL for C4BP(tot), P = .0248; 374 +/- 25.4/332 microg/mL vs 305 +/- 9.5/285 microg/mL for C4BP(beta), P = .0581). C4BP plasma levels were significantly elevated in CLI patients in comparison to healthy controls (351 +/- 8.1/322 microg/mL vs 297 +/- 8.0/288 microg/mL for C4BP(tot), P = .0001; 314 +/- 7.0/287 microg/mL vs 265 +/- 7.0/263 microg/mL for C4BP(beta), P = .0004) and correlated to levels of interleukin-6 (P(tot/beta) = .0048/.0019), high-sensitivity C-reactive protein (P &lt; .0001), leukocyte (P(tot/beta) = .0086/.0043) and platelet count (P = .0001), LDL/HDL ratio (P(tot) = .0151) and HDL (P(tot/beta) = .0047/.0177), but not to tumor necrosis factor-alpha. CONCLUSIONS: Increased complement activation and C4BP plasma levels are related to the degree of tissue necrosis and disease severity of critical limb ischemia. This knowledge in combination with the found correlations to other biomarkers is useful for understanding the pathophysiology of the disease.},
  author       = {Martin, Myriam and Gottsäter, Anders and Nilsson, Peter and Mollnes, Tom E and Lindblad, Bengt and Blom, Anna},
  issn         = {1097-6809},
  keyword      = {Ischemia: immunology,Ischemia: blood,Ischemia: physiopathology,Peripheral Vascular Diseases: blood,Peripheral Vascular Diseases: physiopathology,Peripheral Vascular Diseases: immunology,Biological Markers: blood,Complement C4b-Binding Protein: analysis},
  language     = {eng},
  number       = {1},
  pages        = {100--106},
  publisher    = {Mosby},
  series       = {Journal of vascular surgery : official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter},
  title        = {Complement activation and plasma levels of C4b-binding protein in critical limb ischemia patients.},
  url          = {http://dx.doi.org/10.1016/j.jvs.2008.12.033},
  volume       = {50},
  year         = {2009},
}