complement c1 inhibitor protein


Summary: An endogenous 105-kDa plasma glycoprotein produced primarily by the LIVER and MONOCYTES. It inhibits a broad spectrum of proteases, including the COMPLEMENT C1R and the COMPLEMENT C1S proteases of the CLASSICAL COMPLEMENT PATHWAY, and the MANNOSE-BINDING PROTEIN-ASSOCIATED SERINE PROTEASES. C1-INH-deficient individuals suffer from HEREDITARY ANGIOEDEMA TYPES I AND II.

Top Publications

  1. Farkas H, Varga L, Széplaki G, Visy B, Harmat G, Bowen T. Management of hereditary angioedema in pediatric patients. Pediatrics. 2007;120:e713-22 pubmed
    ..Thus, we review our experience and published data to provide an approach to hereditary angioneurotic edema in childhood. ..
  2. Zanichelli A, Vacchini R, Badini M, Penna V, Cicardi M. Standard care impact on angioedema because of hereditary C1 inhibitor deficiency: a 21-month prospective study in a cohort of 103 patients. Allergy. 2011;66:192-6 pubmed publisher
    ..Incomplete success does not appear to depend on limited efficacy of the drugs but on their limited use that can be overcome by implementing specific treatment strategies. ..
  3. Zeerleder S. C1-inhibitor: more than a serine protease inhibitor. Semin Thromb Hemost. 2011;37:362-74 pubmed publisher
    ..This review summarizes the biochemical characteristics of C1-inh and its role in the regulation of plasmatic cascade systems as well as the role of the nonserpin domain. ..
  4. Frank M, Jiang H. New therapies for hereditary angioedema: disease outlook changes dramatically. J Allergy Clin Immunol. 2008;121:272-80 pubmed publisher
    ..Although little has been published thus far, all of these products may prove effective. It is likely that HAE treatment will change dramatically within the next few years. ..
  5. Davis A. Hereditary angioedema: a current state-of-the-art review, III: mechanisms of hereditary angioedema. Ann Allergy Asthma Immunol. 2008;100:S7-12 pubmed
    ..Hereditary angioedema attacks are mediated by bradykinin generated via contact system activation. The specific factors that trigger attacks remain unclear. ..
  6. Ravindran S, Grys T, Welch R, Schapira M, Patston P. Inhibition of plasma kallikrein by C1-inhibitor: role of endothelial cells and the amino-terminal domain of C1-inhibitor. Thromb Haemost. 2004;92:1277-83 pubmed
    ..The requirement for high concentrations of C1-inhibitor to fully inhibit kallikrein is consistent with the fact that reduced levels of C1-inhibitor result in the kallikrein activation seen in angioedema. ..
  7. Davis A, Mejia P, Lu F. Biological activities of C1 inhibitor. Mol Immunol. 2008;45:4057-63 pubmed publisher
  8. Beinrohr L, Dobó J, Zavodszky P, Gal P. C1, MBL-MASPs and C1-inhibitor: novel approaches for targeting complement-mediated inflammation. Trends Mol Med. 2008;14:511-21 pubmed publisher
    ..Complement-mediated inflammation has been linked to ischemia-reperfusion injury, organ graft rejection and even neurodegeneration, so targeting this process has direct clinical implications. ..
  9. Cicardi M, Zanichelli A. The acquired deficiency of C1-inhibitor: lymphoproliferation and angioedema. Curr Mol Med. 2010;10:354-60 pubmed

More Information


  1. Bork K, Gul D, Dewald G. Hereditary angio-oedema with normal C1 inhibitor in a family with affected women and men. Br J Dermatol. 2006;154:542-5 pubmed
    ..Alternatively, our present observation of hereditary angio-oedema with normal C1 inhibitor affecting both sexes may represent a new disease entity, presumably with a different underlying defect. ..
  2. Dorresteijn M, Visser T, Cox L, Bouw M, Pillay J, Koenderman A, et al. C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia. Crit Care Med. 2010;38:2139-45 pubmed publisher
    ..Complement fragment C4 was not increased after lipopolysaccharide challenge. This study is the first to demonstrate that C1-esterase inhibitor exerts anti-inflammatory effects in the absence of classic complement activation in humans. ..
  3. Zuraw B, Busse P, White M, Jacobs J, Lumry W, Baker J, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363:513-22 pubmed publisher
    ..When used for prophylaxis, nanofiltered C1 inhibitor concentrate reduced the frequency of acute attacks. (Funded by Lev Pharmaceuticals; numbers, NCT00289211, NCT01005888, NCT00438815, and NCT00462709.) ..
  4. Craig T, Bewtra A, Bahna S, Hurewitz D, Schneider L, Levy R, et al. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks--final results of the I.M.P.A.C.T.2 study. Allergy. 2011;66:1604-11 pubmed publisher
    ..No inhibitory anti-C1-INH antibodies were detected in any patient. A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location. ..
  5. Cedzynski M, Madalinski K, Gregorek H, Swierzko A, Nowicka E, Obtułowicz K, et al. Possible disease-modifying factors: the mannan-binding lectin pathway and infections in hereditary angioedema of children and adults. Arch Immunol Ther Exp (Warsz). 2008;56:69-75 pubmed publisher
    ..These results suggest that the MBL complement activation pathway itself does not contribute to the frequency of angioedema attacks. Infections with H. pylori and HBV may slightly influence the disease score (not significant). ..
  6. Skattum L, van Deuren M, van der Poll T, Truedsson L. Complement deficiency states and associated infections. Mol Immunol. 2011;48:1643-55 pubmed publisher
    ..The roles of complement in host defense against common infections are also discussed. ..
  7. van Geffen M, Cugno M, Lap P, Loof A, Cicardi M, van Heerde W. Alterations of coagulation and fibrinolysis in patients with angioedema due to C1-inhibitor deficiency. Clin Exp Immunol. 2012;167:472-8 pubmed publisher
  8. Fu J, Lin G, Wu Z, Ceng B, Wu Y, Liang G, et al. Anti-apoptotic role for C1 inhibitor in ischemia/reperfusion-induced myocardial cell injury. Biochem Biophys Res Commun. 2006;349:504-12 pubmed
  9. Cicardi M, Bork K, Caballero T, Craig T, Li H, Longhurst H, et al. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012;67:147-57 pubmed publisher
    ..Here, we report the topics discussed during the meeting and evidence-based consensus about management approaches for HAE in adult/adolescent patients. ..
  10. Wasserman R, Levy R, Bewtra A, Hurewitz D, Craig T, Kiessling P, et al. Prospective study of C1 esterase inhibitor in the treatment of successive acute abdominal and facial hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2011;106:62-8 pubmed publisher
    ..the C1-INH concentrate dose of 20 U/kg provides rapid, effective, and safe treatment for successive HAE attacks at abdominal and facial locations. ..
  11. Serrano C, Guilarte M, Tella R, Dalmau G, Bartra J, Gaig P, et al. Oestrogen-dependent hereditary angio-oedema with normal C1 inhibitor: description of six new cases and review of pathogenic mechanisms and treatment. Allergy. 2008;63:735-41 pubmed
    ..Clinical and laboratory findings mirror the observations of previous reports of oestrogen-dependent angio-oedema with normal C1INH. This is the first published series of type III HAE in Spain. ..
  12. Farkas H, Csuka D, Gács J, Czaller I, Zotter Z, Fust G, et al. Lack of increased prevalence of immunoregulatory disorders in hereditary angioedema due to C1-inhibitor deficiency. Clin Immunol. 2011;141:58-66 pubmed publisher
    ..Appropriate management of the immunoregulatory disease thus identified improves the symptoms of HAE-C1-INH. ..
  13. Davis A, Cai S, Liu D. C1 inhibitor: biologic activities that are independent of protease inhibition. Immunobiology. 2007;212:313-23 pubmed
  14. Bork K, Wulff K, Meinke P, Wagner N, Hardt J, Witzke G. A novel mutation in the coagulation factor 12 gene in subjects with hereditary angioedema and normal C1-inhibitor. Clin Immunol. 2011;141:31-5 pubmed publisher
    ..Thr328Lys* and p.Thr328Arg* reported previously. Our findings confirm the association between F12 gene mutations modifying the proline-rich region of the FXII protein and hereditary angioedema with normal C1-inhibitor. ..
  15. Brown E, Ravindran S, Patston P. The reaction between plasmin and C1-inhibitor results in plasmin inhibition by the serpin mechanism. Blood Coagul Fibrinolysis. 2002;13:711-4 pubmed
    ..In addition, we show that hydrophobic interaction chromatography is an effective method to remove trace contaminants of inactive C1-inhibitor polymers. ..
  16. Heydenreich N, Nolte M, Göb E, Langhauser F, Hofmeister M, Kraft P, et al. C1-inhibitor protects from brain ischemia-reperfusion injury by combined antiinflammatory and antithrombotic mechanisms. Stroke. 2012;43:2457-67 pubmed publisher
    ..Moreover, C1-inhibitor showed strong antithrombotic effects. C1-inhibitor is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings. ..
  17. Caliezi C, Zeerleder S, Redondo M, Regli B, Rothen H, Zürcher Zenklusen R, et al. C1-inhibitor in patients with severe sepsis and septic shock: beneficial effect on renal dysfunction. Crit Care Med. 2002;30:1722-8 pubmed
    ..Mortality rate was similar in both groups. There were no C1-inhibitor-related side effects. C1-inhibitor administration attenuated renal impairment in patients with severe sepsis or septic shock. ..
  18. Zwijnenburg P, van der Poll T, Florquin S, Polfliet M, van den Berg T, Dijkstra C, et al. C1 inhibitor treatment improves host defense in pneumococcal meningitis in rats and mice. J Infect Dis. 2007;196:115-23 pubmed
    ..C1-inh treatment increased bacterial clearance, possibly through an up-regulation of CR3. Hence, C1-inh may be a useful agent in the treatment of pneumococcal meningitis. ..
  19. Levi M, Choi G, Picavet C, Hack C. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol. 2006;117:904-8 pubmed
    ..Self-administration of C1-inhibitor concentrate could be a valuable and convenient treatment modality to prevent or treat angioedema attacks in patients with C1-inhibitor deficiency. ..
  20. Croner R, Lehmann T, Fallsehr C, Herfarth C, Klar E, Kirschfink M. C1-inhibitor reduces hepatic leukocyte-endothelial interaction and the expression of VCAM-1 in LPS-induced sepsis in the rat. Microvasc Res. 2004;67:182-91 pubmed
    ..The multifunctional regulator may reduce hepatic microcirculatory disturbances during sepsis under clinical conditions. ..
  21. Craig T, Wasserman R, Levy R, Bewtra A, Schneider L, Packer F, et al. Prospective study of rapid relief provided by C1 esterase inhibitor in emergency treatment of acute laryngeal attacks in hereditary angioedema. J Clin Immunol. 2010;30:823-9 pubmed publisher
    ..C1-INH concentrate is an effective and safe emergency treatment for providing reliable and rapid relief from the potentially life-threatening symptoms of laryngeal HAE attacks. ..
  22. Liu D, Lu F, Qin G, Fernandes S, Li J, Davis A. C1 inhibitor-mediated protection from sepsis. J Immunol. 2007;179:3966-72 pubmed
    ..Treatment with C1INH may provide a useful additional therapeutic approach in some patients with peritonitis and/or sepsis. ..
  23. Zuraw B. Hereditary angiodema: a current state-of-the-art review, IV: short- and long-term treatment of hereditary angioedema: out with the old and in with the new?. Ann Allergy Asthma Immunol. 2008;100:S13-8 pubmed
    ..The emergence of several promising drugs for the treatment of HAE attacks is, thus, an extraordinarily important development in the management of these patients. ..
  24. Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. 2006;343:1286-9 pubmed
    ..The predicted structural and functional impact of the mutations, their absence in 145 healthy controls, and their co-segregation with the phenotype in five families provide strong support that they cause disease. ..
  25. Heijnen B, Straatsburg I, Padilla N, van Mierlo G, Hack C, van Gulik T. Inhibition of classical complement activation attenuates liver ischaemia and reperfusion injury in a rat model. Clin Exp Immunol. 2006;143:15-23 pubmed
    ..Pre-ischaemic administration of C1-inh is an effective pharmacological intervention to protect against liver I/R injury. ..
  26. Bossi F, Fischetti F, Regoli D, Durigutto P, Frossi B, Gobeil F, et al. Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency. J Allergy Clin Immunol. 2009;124:1303-10.e4 pubmed publisher
    ..Our data suggest that both B1 receptor and gC1q receptor are involved in the vascular leakage induced by hereditary and acquired angioedema plasma. ..
  27. Bernstein J, Ritchie B, Levy R, Wasserman R, Bewtra A, Hurewitz D, et al. Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2010;105:149-54 pubmed publisher
    ..In contrast to other treatment options with shorter half-lives, the long half-life of pC1-INH concentrate may provide an extended period of protection, even after the symptoms of an attack have subsided. ..
  28. Zuraw B, Cicardi M, Levy R, Nuijens J, Relan A, Visscher S, et al. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol. 2010;126:821-827.e14 pubmed publisher
    ..Administration of rhC1INH at 100 or 50 U/kg was highly effective as a treatment of acute attacks in patients with HAE and appeared to be safe and well tolerated. ..
  29. Lu F, Chauhan A, Fernandes S, Walsh M, Wagner D, Davis A. The effect of C1 inhibitor on intestinal ischemia and reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2008;295:G1042-9 pubmed publisher
    ..In addition to the protective activities mediated via inhibition of the complement system, these studies indicate that C1INH also plays a direct role in suppression of leukocyte transmigration into reperfused tissue. ..
  30. Pillai L, Sha J, Erova T, Fadl A, Khajanchi B, Chopra A. Molecular and functional characterization of a ToxR-regulated lipoprotein from a clinical isolate of Aeromonas hydrophila. Infect Immun. 2006;74:3742-55 pubmed
    ..Taken together, our data provided new information on the role of TagA as a virulence factor in bacterial pathogenesis. This is the first report of TagA characterization from any species of Aeromonas. ..
  31. Fischer M, Prodeus A, Nicholson Weller A, Ma M, Murrow J, Reid R, et al. Increased susceptibility to endotoxin shock in complement C3- and C4-deficient mice is corrected by C1 inhibitor replacement. J Immunol. 1997;159:976-82 pubmed
    ..Replacement of C1 INH rescued the endotoxin-challenged complement-deficient mice from shock and death. These findings suggest a novel therapy for treatment of endotoxemia with C1 INH protein. ..
  32. Oschatz C, Maas C, Lecher B, Jansen T, Björkqvist J, Tradler T, et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity. 2011;34:258-68 pubmed publisher
    ..Allergen exposure triggered edema attacks in hereditary angioedema patients, lacking C1 esterase inhibitor. The data indicate that heparin-initiated bradykinin formation plays a fundamental role in mast cell-mediated diseases. ..
  33. Kirschfink M, Nurnberger W. C1 inhibitor in anti-inflammatory therapy: from animal experiment to clinical application. Mol Immunol. 1999;36:225-32 pubmed
    ..These studies not only include pathophysiologically relevant animal models but also first attempts to prove the benefits of C1 inhibitor as a novel therapeutic approach in clinical trials. ..
  34. Frank M. Hereditary angiodema: a current state-of-the-art review, VI: novel therapies for hereditary angioedema. Ann Allergy Asthma Immunol. 2008;100:S23-9 pubmed
    ..The outlook for new, effective short-term therapy appears to be excellent. In the near future, a whole new therapeutic armamentarium to care for patients with HAE should be available in the United States. ..
  35. Joseph K, Tuscano T, Kaplan A. Studies of the mechanisms of bradykinin generation in hereditary angioedema plasma. Ann Allergy Asthma Immunol. 2008;101:279-86 pubmed publisher
    ..Production of factor XIIf, demonstrated for the first time in whole plasma, may be responsible for C1 activation based on C4a production. The factor XII-dependent fibrinolytic cascade is also activated. ..
  36. Bygum A, Andersen K, Mikkelsen C. Self-administration of intravenous C1-inhibitor therapy for hereditary angioedema and associated quality of life benefits. Eur J Dermatol. 2009;19:147-51 pubmed publisher
    ..Self-administration of C1-INH improved QOL on both physical and psychological parameters. Patients were able to resume a normal life without restrictions caused by the condition. ..
  37. Craig T, Levy R, Wasserman R, Bewtra A, Hurewitz D, Obtułowicz K, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. 2009;124:801-8 pubmed publisher
    ..C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief. ..
  38. Pappalardo E, Zingale L, Terlizzi A, Zanichelli A, Folcioni A, Cicardi M. Mechanisms of C1-inhibitor deficiency. Immunobiology. 2002;205:542-51 pubmed
    ..Such conditions, as extensively investigated in sepsis, are of great relevance because they open the possibility of using C1-Inh as therapeutic agent in several different diseases. ..
  39. Nielsen E, Mollnes T, Harlan J, Winn R. C1-inhibitor reduces the ischaemia-reperfusion injury of skeletal muscles in mice after aortic cross-clamping. Scand J Immunol. 2002;56:588-92 pubmed
    ..836). The data support a beneficial role for C1-INH in the treatment of ischaemia-reperfusion injuries of skeletal muscles. ..
  40. Joseph K, Tholanikunnel B, Kaplan A. Factor XII-independent cleavage of high-molecular-weight kininogen by prekallikrein and inhibition by C1 inhibitor. J Allergy Clin Immunol. 2009;124:143-9 pubmed publisher
    ..PK is an enzyme that can cleave HK to release bradykinin, and this reaction is inhibited by C1INH. This might account, in part, for circulating bradykinin levels and initiation of kinin formation in C1INH deficiency. ..
  41. Tallroth G. Long-term prophylaxis of hereditary angioedema with a pasteurized C1 inhibitor concentrate. Int Arch Allergy Immunol. 2011;154:356-9 pubmed publisher
    ..This treatment approach was well tolerated and effective, leading to a dramatic improvement in symptoms and improved quality of life. ..
  42. Maurer M, Magerl M. Long-term prophylaxis of hereditary angioedema with androgen derivates: a critical appraisal and potential alternatives. J Dtsch Dermatol Ges. 2011;9:99-107 pubmed publisher
    ..Patients might benefit from a dose reduction or the withdrawal of androgen prophylaxis and attacks can be controlled with demand-oriented acute treatment using C1-INH or icatibant. ..
  43. Bork K, Hardt J. Hereditary angioedema: increased number of attacks after frequent treatments with C1 inhibitor concentrate. Am J Med. 2009;122:780-3 pubmed publisher
    ..The control group did not show a similar increase in attacks during a comparable period of time. A possible explanation for the increase in the frequency of attacks may lie in the large number of injections of C1 inhibitor concentrate. ..
  44. Maurer M, Magerl M. Hereditary angioedema: an update on available therapeutic options. J Dtsch Dermatol Ges. 2010;8:663-72 pubmed publisher
    ..If androgen therapy has too negative an effect on quality of life, it may be worth reducing the dose or discontinuing therapy entirely and treating attacks with acute therapy. ..
  45. Frank M. Hereditary angioedema: the clinical syndrome and its management in the United States. Immunol Allergy Clin North Am. 2006;26:653-68 pubmed
    ..Thus HAE is in many ways a success story of modern medicine. ..
  46. Rajabi M, Struble E, Zhou Z, Karnaukhova E. Potentiation of C1-esterase inhibitor by heparin and interactions with C1s protease as assessed by surface plasmon resonance. Biochim Biophys Acta. 2012;1820:56-63 pubmed publisher
    ..The results of this study may be useful for further C-INH therapeutic development, ultimately for the enhancement of current C1-INH replacement therapies. ..
  47. Hecker J, Loss M, Klempnauer J, Winkler M. C1-inhibitor for therapy and prophylaxis of acute vascular rejection of porcine kidneys in cynomolgus monkeys. Transplant Proc. 2002;34:2382 pubmed
  48. Kaplan A, Joseph K. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway. Adv Immunol. 2014;121:41-89 pubmed publisher
    ..In allergy (anaphylaxis; perhaps other mast cell-dependent reactions), the oversulfated proteoglycan of mast cells, liberated along with histamine, also catalyze factor XII autoactivation. ..
  49. Lumry W, Manning M, Hurewitz D, Davis Lorton M, Fitts D, Kalfus I, et al. Nanofiltered C1-esterase inhibitor for the acute management and prevention of hereditary angioedema attacks due to C1-inhibitor deficiency in children. J Pediatr. 2013;162:1017-22.e1-2 pubmed publisher
    ..0 before treatment to 0.39 with C1 INH-nf use. In children, C1 INH-nf was well tolerated, provided relief from symptoms of hereditary angioedema attacks, and reduced the rate of attacks. ..
  50. de Beer F, Lagrand W, Glas G, Beurskens C, van Mierlo G, Wouters D, et al. Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia. Cell Biochem Biophys. 2016;74:545-552 pubmed
    ..Repeated treatment with nebulized C1-esterase inhibitor, although successfully delivered to the lungs, does not affect pulmonary complement activation, lung inflammation or lung injury. ..
  51. Bork K. Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations. Immunol Allergy Clin North Am. 2006;26:709-24 pubmed
    ..Recently, in some families mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected women. ..
  52. Tarzi M, Hickey A, Forster T, Mohammadi M, Longhurst H. An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema. Clin Exp Immunol. 2007;149:513-6 pubmed
    ..The diagnosis of HAE is not excluded by normal levels of complement C4. We conclude that C1 inhibitor studies should be performed regardless of serum C4 where a high index of clinical suspicion exists. ..
  53. Libert N, Scherier S, Dubost C, Franck L, Rouquette I, Tortosa J, et al. [Anaesthesic management of vaginal delivery in a parturient with C1 esterase deficiency]. Ann Fr Anesth Reanim. 2009;28:375-80 pubmed publisher
    ..The management included administration of C1 INH during labor and early epidural analgesia for pain relief. A short review of the pathophysiology and therapeutic options follows. ..