C1-Esterase Inhibitor: Biological Activities and Therapeutic Appl
Journal of Hematology & Thromboembolic Diseases

Journal of Hematology & Thromboembolic Diseases
Open Access

ISSN: 2329-8790

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Review Article - (2013) Volume 1, Issue 3

C1-Esterase Inhibitor: Biological Activities and Therapeutic Applications

Elena Karnaukhova*
Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, 20892, USA
*Corresponding Author: Elena Karnaukhova, PhD, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, National Institutes Of Health Building 29, Bethesda, Maryland 20892, USA, Tel: 301-402-4635, Fax: 301-402-2780 Email:


Human C1-esterase inhibitor (C1-INH) is a unique anti-inflammatory multifunctional plasma protein best known for its key role in regulation of the classical complement pathway, contact activation system and intrinsic pathway of coagulation. By sequence homology and mechanism of protease inhibition it belongs to the serine proteinase inhibitor (serpin) superfamily. However, in addition to its inhibitory capacities for several proteases, it also exhibits a broad spectrum of non-inhibitory biological activities. C1-INH plays a key role in the regulation of vascular permeability, best demonstrated in Hereditary Angioedema (HAE) which is triggered by the deficiency of functional C1-INH in plasma? Since 1963, when the link between HAE and C1-INH was first identified, considerable progress has been made in the investigation of C1-INH structure and biological activities, understanding its therapeutic potential, and in the research and development of C1-INH-based therapies for the treatment of HAE and several other clinical conditions. However, augmentation therapy with C1-INH concentrates for patients with HAE is currently the only approved therapeutic application of C1-INH. This manuscript provides an overview of the structure and functions of human C1-INH, its role in HAE, summarizes published data available for recently approved C1-INH therapeutic products, and considers possible use of C1-INH for other applications.

Keywords: C1-esterase inhibitor; C1-inhibitor deficiency; Hereditary angioedema


BK: Bradykinin; B2R: B2-receptor; C1-INH: C1- esterase inhibitor; FXIIa: activated factor XII; GAG: Glycosaminoglycan; HAE: Hereditary Angioedema; HMWK: High Molecular Weight Kininogen; IV: Intravenous; MASP-1 and MASP-2: Mannan-Binding Lectin-Associated Serine Proteases; pd: Plasma-Derived; RCL: Reactive Center Loop; Rhc1-INH: Recombinant Human C1-INH; SC: Subcutaneou


Human C1-INH is an important anti-inflammatory plasma protein with a wide range of inhibitory and non-inhibitory biological activities. By sequence homology, structure of its C-terminal domain, and mechanism of protease inhibition, it belongs to the serpin superfamily, the largest class of plasma protease inhibitors, which also includes antithrombin, α1-proteinase inhibitor, plasminogen activator inhibitor, and many other structurally similar proteins that regulate diverse physiological systems [1,2]. Best known for regulating the complement cascade system, C1-INH also plays a key role in the regulation of the contact (kallikrein-kinin) amplification cascade, and participates in the regulation of the coagulation and fibrinolytic systems [3-5]. Since 1963, when Donaldson and Evans linked the symptoms of hereditary angioedema (HAE, called hereditary angioneurotic edema at that time) to the absence of serum C1-INH, it has been the subject of multidisciplinary research [6,7]. Over the past fifty years, our knowledge about C1-INH structure and its biological functions, the cause(s) of its deficiency, and its role in HAE and other conditions has been significantly advanced. The majority of research still focuses on the mechanisms and efficient treatments of C1-INH-dependent types of HAE; however, the physiological and pharmacological activities of C1-INH are much broader. During the last five years, several C1-INH products have been licensed in the US and EU for the treatment C1-INH-deficient patients with HAE that dramatically improved the therapeutic options in the battle with this rare disease. Due to C1-INH involvement in a variety of physiological processes, its therapeutic potential for the treatment of other conditions has also been recognized, yet remains unexplored. This review considers the biochemistry of C1-INH, its biological activities, and recent advances in its therapeutic development.

C1-INH Structure and Functions

Abundance of C1-INH

Human C1-INH is a positive acute-phase plasma glycoprotein with normal concentration in healthy subjects ~ 240 μg/mL (~3 μM), but its level may increase by 2-2.5 times during inflammation [8,9]. Some characteristics of human C1-INH are summarized in table 1. Low plasma content of C1-INH or its dysfunction result in the activation of both complement and contact plasma cascades, and may affect other systems as well (vide infra) [10-12]. Decrease in C1-INH plasma content to levels lower than 55 μg/mL (~25% of normal) was shown to induce spontaneous activation of C1 [13].

Characteristics Description
Synonyms C1-esterase inhibitor, C1s-inhibitor, C1-inactivator, α2-neuramino-glycoprotein 
Common abbreviations C1-INH, C1INH, C1-Inh
Classification Serine proteinase inhibitor (serpin)
Substrates C1s, C1r, Plasmin, Kallikrein, aFXIIa, bFXIIa, FXIa, MASP-1 and MASP-2
Molecular weight ~74 kDa by mass spectrometric analysis; ~76 kDa by neutron scattering; ~105 kDa by SDS-PAGE
Polypeptide Single polypeptide chain of 478 amino acid residues
Domains Two-domain structure: C-terminal serpin domain (362 amino acid residues), and N-terminal domain (~113)
Glycosylation N- and O- attached carbohydrates (26% w/w)
Heterogeneity Highly heterogeneous protein
Half-life in circulation ~28 h (in healthy volunteers)a, 67.7± 4.9 h (in HAE patients)b
Concentration in blood ~240 mg/L (in healthy volunteers), may increase 2-2.5 times in response to inflammation
Major biological activities Inhibitory anti-serine proteinase activity Multiple non-inhibitory activities
Physiologically important mutants 237 different single mutations related to the deficiency or dysfunction of C1-INH in HAE patientsc
Known cofactors Glycosaminoglycans
a According to [9,10]
b As reported in [11]
c As identified by 2008 according to [12]

Table 1: Characteristics of Human C1-INH.

Biosynthesis and mutations

C1-INH is synthesized and secreted primarily by hepatocytes, but is also produced by monocytes, fibroblasts, macrophages, microglial cells, endothelial cells, and some other cells [14-18]. Biosynthesis of C1-INH can be stimulated by cytokines, particularly by interferon-γ [19,20].

Human C1-INH is encoded by the SERPING1 gene (17 kb) on chromosome 11 (11q12→q13.1) comprised of eight exons and seven introns [21-23]. A vast variety of large and small mutations identified in C1-INH for patients with HAE results from three types of alterations in the gene: (i) deletions or duplications due to high content of Alu repeat sequences in the introns that causes ~20% of genetic defects in HAE [23,24]; (ii) mutations in the codon for Arg444 of the reactive center loop (RCL) which results in dysfunctional C1-INH [25]; and (iii) a large number of single codon mutations over the length of the gene [12,26-28]. All this characterizes C1-INH deficiency as an extremely heterogeneous disease. It is of interest that some mutations in the SERPING1 gene are associated with the development of age-related macular degeneration [29,30].

Structural characterization

Human C1-INH is a single-chain polypeptide (478 amino acid residues) which forms two domains: (a) C-terminal domain (365 amino acids), which is a typical serpin; and (b) N-terminal domain (113 amino acids), the role of which is not clearly elucidated, but which seems to be important for protein integrity and stabilization of the serpin domain [31] and for interactions with lipopolysaccharides [32].

C1-INH is a heavily glycosylated protein with more than 26% (w/w) of carbohydrates. Whereas the calculated molecular weight of the polypeptide part is 52,869 Da [21], the molecular weight of the whole protein is ~76 kDa (by neutron scattering [33]). Using mass spectrometric analysis we detected it as an ~74 kDa protein (the author’s data); however, it is often referred to as an ~105 kDa glycoprotein as observed by electrophoretic mobility on SDS-PAGE [33,34]. Carbohydrates are very unevenly distributed over the C1-INH molecule: (1) three N-attached glycans belong to the serpin domain, attached to asparagine residues Asn216, Asn231, and Asn330, which is similar to the glycosylation of archetypal serpin α1-proteinase inhibitor; and (2) three N- and at least seven O-linked carbohydrates have been determined for N-terminal domain [35]. The protein integrity is maintained by connection of the domains with two disulfide bridges formed by Cys101 and Cys108 of the N-terminal domain and Cys406 and Cys183 of C-terminal domain [31]. Although the functional role of the exceptionally long and heavily glycosylated N-terminal domain is still unclear, it may be essential for the protein’s conformational stability, recognition, affinity to endotoxins and selectins, and clearance. The intrinsic heterogeneity of the carbohydrate moiety greatly contributes to the heterogeneity of the whole C1-INH. This may be one of the reasons why obtaining a crystal structure of native glycosylated C1-INH remains elusive.

To date, the only published crystal structure that is available for C1-INH has been performed by Beinrohr and co-workers for the non-glycosylated serpin domain of recombinant C1-INH, which crystallized in its latent form [36]. The crystal structure of the serpin domain features nine α-helices, three β-sheets, and a mobile RCL exposed for interaction with target serine proteases, features typical for serpins (Figure 1). The alignment of the C1-INH serpin domain structure with those of antithrombin III and α1-proteinase inhibitor illustrates the overall remarkable structural similarity between serpins [37]. The major difference revealed by Beinrohr et al. for this C1-INH serpin structure is that the C-terminal P’ part of the RCL shows as the new seventh strand of thus-extended β-sheet A, while in other known latent serpin structures it is just a flexible loop [36].


Figure 1: Crystal structure of the serpin domain of recombinant nonglycosylated C1-INH (PDB 2OAY) shown in two projections (the images were generated using PyMOL Molecular Graphics System). Arrow indicates the scissile bond Arg444-Thr445 of the RCL. Dotted blue circle marks the region of the N-terminal domain.

Similar to α1-proteinase inhibitor, C1-INH serpin domain is intrinsically folded into a metastable structure, which is not the most thermodynamically stable form, but is essential for inhibitory function. Like other inhibitory serpins, C1-INH neutralizes target proteases in a suicide fashion [7,38,39]. By attacking the RCL of the serpin, protease cleaves the scissile bond Arg444-Thr445, consistent with protease substrate specificity. Formation of the covalent complex between the protease and C1-INH is followed by a drastic conformational perturbation that results in the translocation of the protease over the C1-INH to the opposite side of the molecule, thus inserting the cleaved RCL into β-sheet A of the inhibitor.

Inhibition of proteases and other activities

C1-INH exhibits its inhibitory potential towards several proteases, and thus, plays a unique role in the down-regulation of four major plasmatic cascade systems. It is the only regulator of the early proteases of the classical complement pathway activation (C1s and C1r) [34,40,41]. By the inactivation of mannan-binding lectin-associated serine protease-2 (MASP-2), it also participates in the regulation of lectin pathway activation (in addition to α2-macroglobulin) [42,43]. Being the primary regulator of the contact system, C1-INH inactivates the activated plasma kallikrein and FXIIa; the inhibition of kallikrein by C1-INH proceeds with a much higher rate than that of α2-macroglobulin [44-46]. C1-INH also participates in the regulation of the fibrinolytic pathway by the inactivation of plasmin and tissue plasminogen activator [47], as well as it seems to be involved in the inhibition of thrombin and FXIa of the intrinsic coagulation pathway [48,49].

In addition to its inhibitory potential, C1-INH also possesses a broad spectrum of non-inhibitory activities, including interactions with endogenous proteins, polyanions (glycosaminoglycans), various types of cells and infectious agents [7,50-52]. Figure 2 summarizes C1-INH major biological activities known so far.


Figure 2: Summary of currently known biological activities of C1-INH; the figure reflects C1-INH inhibitory (protease inhibition) activity and non-inhibitory interactions.

Potentiation by glycosaminoglycans

It is known that inhibitory activities of some serpins, including ATIII and C1-INH, are modulated by glycosaminoglycans (GAGs), particularly by heparin [53-55]. The potentiation of C1-INH by GAGs significantly enhances its inhibitory activity toward C1s and factor XIa (FXIa), but barely to C1r [56-59]. Over the last two decades, C1-INH interactions with various physiological GAGs (heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate) and non-physiological GAG derivatives (dextran sulfate, oversulfated chondroitin sulfate) have been under intensive investigation to define the influence of C1-INH potentiation on the complement, and other plasmatic, cascades [50,60-63].

Notably, no GAG-modulated influence on the inhibition of kallikrein and FXII by C1-INH was observed [62]. The available data suggest that C1-INH potentiation by GAGs is selective toward target proteases, and thus may selectively enhance the inactivation of the classical complement pathway and the intrinsic pathway of coagulation (via C1s and FXIa, respectively) without significant impact on fibrinolytic activity of activated factor XII or kallikrein.

In 2007 and 2008, multiple adverse events were reported in the US and elsewhere in the world caused by transfusions of heparin that was contaminated by oversulfated chondroitin sulfate [64,65]. Further investigation revealed that while heparin can inhibit the complement system via potentiation of C1-INH, the oversulfated chondroitin sulfate is much more potent inhibitor of complement than heparin [37,66].

Despite the structural similarity between serpins, the proposed mechanism of the C1-INH potentiation by GAGs (a “sandwich” mechanism), as well as a putative heparin binding site on C1-INH surface, differ from those of antithrombin III [36], whereas the archetypal serpin α1-proteinase inhibitor appears not to be a subject of GAG potentiation at all. According to the model proposed by Beinrohr et al. [36], by binding to C1-INH and neutralizing its positively charged surface patches the GAGs facilitate its interaction with C1s. To date, antithrombin remains the only serpin the enhancement of which by heparin (up to 4000-fold enhancement) has been further developed for use in current clinical practice. It is therefore feasible that currently available or emerging C1-INH-based therapies can also be enhanced by GAGs.

C1-INH Therapeutic Development

Due to the multiple biological activities of C1-INH and its essential role in many physiological processes, the pharmaceutical potential of C1-INH is attractive and promising, yet not easy to explore since C1-INH is involved in several interrelated plasmatic cascade systems. Recent years brought a dramatic breakthrough in the therapeutic development of C1-INH. Several C1-INH products became available for replacement (augmentation) therapy in C1-INH-deficient patients with HAE, leading to a marked reduction in morbidity and mortality.

C1-INH and HAE

The importance of functionally active C1-INH is clearly exemplified by its deficiency, considered to be the cause of HAE, a rare autosomal dominant disease (with an estimated frequency of 1:50 000) that is clinically manifested by recurrent acute attacks. The release of bradykinin (BK) caused by low content or dysfunction of C1-INH results in increased vascular permeability and edema in subcutaneous or submucosal tissues at various body sites (face, extremities, genitals, abdomen, oropharynx or larynx) [67-69]. These acute attacks cause pain and disability during subcutaneous and intestinal episodes, and are potentially life- threatening when edema strikes upper airways [70,71].

Although the descriptions of HAE appeared in the 19th century, with the first article published on the subject in 1888, the link between C1-INH and HAE was identified only in 1963 (reviews [72,73]). Abnormalities in C1-INH plasma content or in its functional activity (often referred to as a deficiency of functional C1-INH) result from various large and small mutations in the C1-INH gene (vide supra). There are generally two types of hereditary C1-INH deficiency. The more prevalent type I HAE (approximately 85% of HAE cases) is characterized by low content (below 35% of normal) and low inhibitory activity of C1-INH in the circulation. Type II HAE (approximately 15% of HAE cases) is associated with normal or elevated antigenic levels of C1-INH of low functional activity [68,74]. Recently, HAE with normal C1-INH (also known as type III HAE) has been described in two subcategories: (1) HAE due to mutation in the factor XII gene and, as a result, increased activity of factor XII leading to a high generation of BK, and (2) HAE of unknown genetic cause [75-77]. Contrary to hereditary angioedema, acquired angioedema (AAE) is associated with lymphoproliferative disease and/or C1-INH reactive autoantibodies that neutralize its inhibitory activity [78]. (For more details on HAE see comprehensive reviews [73,79-81]). Whereas activation of the contact system leads to the onset of BK-mediated acute attacks directly, the imbalance of C1-INH level greatly depends upon its consumption by other plasma cascades, also regulated by C1-INH, that may influence the activation of the contact pathway leading to edema, as well [69,82,83]. Figure 3 depicts major plasmatic cascades regulated by C1-INH to illustrate that C1-INH interactions with several target proteases of these plasmatic cascades suggest rapid depletion of functionally active C1-INH, leading to the development of angioedema, as well as resulting in possible overlap of highly diverse outcomes from the activation of the complement and other systems [82,83]. Whereas BK is the major mediator of vascular permeability and edema, a large body of evidence supports complex interrelationships between contact, complement, coagulation and fibrinolytic systems. During HAE attacks in C1-INH-deficient patients, low C2 and C4 levels indicate that the complement is activated, while increased levels of thrombin and generation of plasmin indicate that the coagulation and fibrinolytic systems are involved [84-87].

During the last five years treatment options for HAE patients in the US have been dramatically revolutionized. Until recently these patients were treated with transfusions of fresh-frozen plasma (which contains endogenous C1-INH), despite potential risk of blood-borne pathogens, and with antifiblinolytics and attenuated androgens, despite frequent adverse effects due to residual hormonal activity of androgens [88-90]. Currently, there are several therapies that are licensed specifically for treatment of HAE acute attacks or prophylaxis (Table 2) [91-93]. Owing to the genetic origin of HAE, these treatments do not cure the disease per se, but are rather intended to relieve symptoms and pain associated with acute attacks and to prevent the frequency and severity of HAE episodes. Considering HAE as a BK-mediated swelling disorder caused by C1-INH deficiency, current therapeutic strategies target three key steps in the contact (kallikrein-kinin) pathway leading from reduced levels of functional C1-INH to BK-induced edematous conditions, i.e.: (a) C1-INH replacement to restore plasma levels of functional C1-INH; (b) Inhibition of plasma kallikrein to prevent BK formation; and (c) Blockade of BK B2-receptor (Β2R) to prevent BK binding (Figure 3) [69,94,95].

Drug product Type Action Manufacturer Approval date Route Indication t1/2b
Cinryze® pd-C1-INH nanofiltered C1-INH replacement ViroPharma 10/2008 IV Prophylaxis 36-48 h
Berinert® pd-C1-INH pasteurized C1-INH replacement CSL Behring  9/2009
IV Acute attacks 36-48 h
Ruconest® rC1-INH from tg-rabbitsc C1-INH replacement Pharming Under FDA valuationd IV Acute attacks ~ 3 h
Kalbitor®(ecallantide) Recombinant polypeptide Kallikrein inhibitor Dyax Corp.  1/2009 SC Acute attacks ~ 2 h
Firazyr®(icatibant) Synthetic decapeptide BR B2R antagonist Shire Orphan Therapies  8/2011 SC Acute attacks 2-4 h
sup>a The data were collected from the recently published articles
b Half-life in the circulation
c Recombinant C1-INH (Human) produced in the milk of transgenic rabbits
d Approved by European Medicines Agency (EMA) in 2010

Table 2: Therapeutic products recently approved (or under consideration) for treatment of patients with hereditary angioedema in the USAa.

C1-INH replacement therapy

Plasma-derived C1-INH preparations: Since 1973, C1-INH concentrates have been widely used in Europe for treatment of acute attack episodes in patients with HAE [96], but have only recently been FDA-approved for marketing and distribution in the US.

To date, C1-INH replacement therapy for patients with HAE (Table 2) is the only FDA-approved therapeutic application of C1-INH. Two plasma-derived C1-INH (pd-C1-INH) products, Cinryze® and Berinert®, are available in the US for patients with HAE, for prophylaxis and for treatment of acute attacks, respectively (Table 2). The rationale for intravenous (IV) administration of the C1-INH concentrates to restore the levels of functional C1-INH in the circulation is addressing the primary cause of HAE. The human plasma origin of these C1-INH products ensures their tolerability. However, the potential risk of contamination with blood-borne viruses (including unknown and emerging pathogens) still exists in case of protein therapeutics derived from human plasma, despite effective viral clearance steps in the manufacturing procedures [97]. While, in general, the pd-C1-INH preparations are well tolerated, at higher than recommended doses, risk of thromboembolic events may exist [98-100]. The low abundance of C1-INH, limited plasma source per se, and high production cost of C1-INH concentrates from pooled human plasma led to the therapeutic development of recombinant C1-INH.

Recombinant Human C1-INH

Recombinant versions of C1-INH have been under research and development for decades. The gene for human C1-INH was successfully expressed in several hosts [36,101-105]. However, the relatively high yields, stability, and functional activity required for therapeutic-scale production have been achieved only when recombinant human C1-INH (rhC1-INH) has been produced in the milk of transgenic rabbits [106-108]. As an alternative and in addition to pd-C1-INH products, rhC1-INH (Ruconest®) was approved by the European Medicine Agency (EMA) for treatment of HAE in 2010 (Table 2). Currently, Ruconest® (International non-proprietary name: conestat alfa) is available in 30 European countries. The product is not yet approved in the US, as for the biological license application to be considered by the FDA, some additional clinical studies were necessary, recently completed [109,110].

Yet, given the theoretical advantage of being free from blood-borne pathogens (at least human ones) rhC1-INH bears a certain risk of inducing immune response to rabbit milk protein impurities. Whereas the potency of rhC1-INH is comparable to that of pd-C1-INH, due to differences in glycosylation patterns [111], its half-life in circulation is significantly lower than that of pd-product, thus making it more appropriate for treatment of acute attacks (Table 2). Production of therapeutic protein in transgenic rabbits opens up the possibility of a technically scalable and theoretically “unlimited” source of rhC1-INH.

Other drugs for treatment of HAE

Whereas the rationale for C1-INH-based treatment is to restore the plasma level of functional C1-INH, two recently approved compounds (Table 2; Figure 3) reflect treatment approaches other than replacement therapy, namely specific inhibition of plasma kallikrein (ecallantide) and its action by selective blockade of the BK B2-receptors (icatibant). Ecallantide (Kalbitor®) is a small recombinant protein (60 amino acid residues) produced in the yeasts Pichia pastoris; the drug specifically binds and inhibits plasma kallikrein [4,112]. Icatibant (Firazyr®) is a synthetic decapeptide that exhibits a sole specificity to BK B2-receptor (BK B2R); as a selective, competitive antagonist to BK B2R, it blocks the receptor for BK [69,113]. Notably, these two recently approved drugs provide a subcutaneous administration option for the first time (a subcutaneous infusion of C1-INH concentrates for long-term prophylaxis is under active consideration [88]).


Figure 3: Schematic presentation of the major steps of development of C1- INH-dependent HAE and current therapeutic strategies for the treatment of HAE. The circle on the top denotes the involvement of C1-INH in the regulation of major plasmatic cascade systems. BK –bradykinin; B2R – B2-receptor(s); HMWK-high molecular weight kininogen.

C1-INH potential therapeutic applications other than HAE

As a potent anti-inflammatory agent, C1-INH has also been considered for treatment of several other serious pathological conditions, including sepsis, acute myocardial infarction, vascular leakage syndromes, ischemia-reperfusion injury, brain ischemic injury and some other conditions [7,50,51,114]. Although these applications are promising and seem to be safe, more clinical data are required to support their efficacy.


Current state and future perspectives of C1-INH research and development

Over the last fifty years, tremendous progress in the characterization of C1-INH structure and biological activities has been made. From the standpoint of the biochemistry of C1-INH, many aspects of its structure, potentiation, and interactions with various endogenous ligands still remain to be studied in more detail. In particular, it includes resolution of the crystal structure of the whole protein and elucidation of the role of the N-terminal domain and its excessive glycosylation. The investigation of C1-INH has been tightly linked to and accelerated by the importance of HAE. Not only do we now have a better understanding of C1-INH biochemistry and its therapeutic potential, but recent developments have also brought several licensed C1-INH therapeutic products for replacement therapy in patients with HAE to the US and to the EU. With respect to the recently approved C1-INH products, analyses of long-term safety and efficacy profiles over the coming years in clinical use will be essential. These C1-INH products, together with recently approved small protein drugs (ecallantide and icatibant), drastically changed the available treatment options. Given a high variability in acute attacks sites, frequency, and severity, these therapeutic options offer an opportunity for individualized treatment, selective or complex, specifically tailored for each HAE patient. As there are no head-to-head clinical trials yet, and no data that would allow any comparison between the therapies, future clinical experience is extremely important. From the standpoint of possible enhancement of already existing C1-INH therapies, the potentiation of C1-INH via fine tuning with GAGs is very attractive direction. From the standpoint of further research and development toward using C1-INH for treating conditions other than HAE (such as sepsis or ischemia-reperfusion injury), the next decade certainly will bring novel C1-INH therapeutic applications to light.


  1. Gooptu B, Lomas DA (2009) Conformational pathology of the serpins: themes, variations, and therapeutic strategies. Annu Rev Biochem 78: 147-176.
  2. Silverman GA, Whisstock JC, Bottomley SP, Huntington JA, Kaiserman D, et al. (2010) Serpins flex their muscle: I. Putting the clamps on proteolysis in diverse biological systems. J Biol Chem 285: 24299-24305.
  3. Davis AE 3rd (2006) Mechanism of angioedema in first complement component inhibitor deficiency. Immunol Allergy Clin North Am 26: 633-651.
  4. Davis AE 3rd (2008) New treatments addressing the pathophysiology of hereditary angioedema. Clin Mol Allergy 6: 2.
  5. Bos IG, Hack CE, Abrahams JP (2002) Structural and functional aspects of C1-inhibitor. Immunobiology 205: 518-533.
  6. Davis AE 3rd, Lu F, Mejia P (2010) C1 inhibitor, a multi-functional serine protease inhibitor. Thromb Haemost 104: 886-893.
  7. Wouters D, Wagenaar-Bos I, van Ham M, Zeerleder S (2008) C1 inhibitor: just a serine protease inhibitor? New and old considerations on therapeutic applications of C1 inhibitor. Expert Opin Biol Ther 8: 1225-1240.
  8. Kalter ES, Daha MR, ten Cate JW, Verhoef J, Bouma BN (1985) Activation and inhibition of Hageman factor-dependent pathways and the complement system in uncomplicated bacteremia or bacterial shock. J Infect Dis 151: 1019-1027.
  9. Woo P, Lachmann PJ, Harrison RA, Amos N, Cooper C, et al. (1985) Simultaneous turnover of normal and dysfunctional C1 inhibitor as a probe of in vivo activation of C1 and contact activatable proteases. Clin Exp Immunol 61: 1-8.
  10. Quastel M, Harrison R, Cicardi M, Alper CA, Rosen FS (1983) Behavior in vivo of normal and dysfunctional C1 inhibitor in normal subjects and patients with hereditary angioneurotic edema. J Clin Invest 71: 1041-1046.
  11. Brackertz D, Isler E, Kueppers F (1975) Half-life of C1INH in hereditary angioneurotic oedema (HAE). Clin Allergy 5: 89-94.
  12. Gösswein T, Kocot A, Emmert G, Kreuz W, Martinez-Saguer I, et al. (2008) Mutational spectrum of the C1INH (SERPING1) gene in patients with hereditary angioedema. Cytogenet Genome Res 121: 181-188.
  13. Windfuhr JP, Alsenz J, Loos M (2005) The critical concentration of C1-esterase inhibitor (C1-INH) in human serum preventing auto-activation of the first component of complement (C1). Mol Immunol 42: 657-663.
  14. Katz Y, Strunk RC (1989) Synthesis and regulation of C1 inhibitor in human skin fibroblasts. J Immunol 142: 2041-2045.
  15. Prada AE, Zahedi K, Davis AE 3rd (1998) Regulation of C1 inhibitor synthesis. Immunobiology 199: 377-388.
  16. Schmaier AH, Smith PM, Colman RW (1985) Platelet C1- inhibitor. A secreted alpha-granule protein. J Clin Invest 75: 242-250.
  17. Yeung Laiwah AC, Jones L, Hamilton AO, Whaley K (1985) Complement-subcomponent-C1-inhibitor synthesis by human monocytes. Biochem J 226: 199-205.
  18. Walker DG, Yasuhara O, Patston PA, McGeer EG, McGeer PL (1995) Complement C1 inhibitor is produced by brain tissue and is cleaved in Alzheimer disease. Brain Res 675: 75-82.
  19. Lotz M, Zuraw BL (1987) Interferon-gamma is a major regulator of C1-inhibitor synthesis by human blood monocytes. J Immunol 139: 3382-3387.
  20. Zuraw BL, Lotz M (1990) Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon gamma. J Biol Chem 265: 12664-12670.
  21. Bock SC, Skriver K, Nielsen E, Thøgersen HC, Wiman B, et al. (1986) Human C1 inhibitor: primary structure, cDNA cloning, and chromosomal localization. Biochemistry 25: 4292-4301.
  22. Carter PE, Duponchel C, Tosi M, Fothergill JE (1991) Complete nucleotide sequence of the gene for human C1 inhibitor with an unusually high density of Alu elements. Eur J Biochem 197: 301-308.
  23. Tosi M (1998) Molecular genetics of C1 inhibitor. Immunobiology 199: 358-365.
  24. Stoppa-Lyonnet D, Carter PE, Meo T, Tosi M (1990) Clusters of intragenic Alu repeats predispose the human C1 inhibitor locus to deleterious rearrangements. Proc Natl Acad Sci U S A 87: 1551-1555.
  25. Skriver K, Radziejewska E, Silbermann JA, Donaldson VH, Bock SC (1989) CpG mutations in the reactive site of human C1 inhibitor. J Biol Chem 264: 3066-3071.
  26. Bissler JJ, Aulak KS, Donaldson VH, Rosen FS, Cicardi M, et al. (1997) Molecular defects in hereditary angioneurotic edema. Proc Assoc Am Physicians 109: 164-173.
  27. Zuraw BL, Herschbach J (2000) Detection of C1 inhibitor mutations in patients with hereditary angioedema. J Allergy Clin Immunol 105: 541-546.
  28. Roche O, Blanch A, Duponchel C, Fontán G, Tosi M, et al. (2005) Hereditary angioedema: the mutation spectrum of SERPING1/C1NH in a large Spanish cohort. Hum Mutat 26: 135-144.
  29. Ennis S, Jomary C, Mullins R, Cree A, Chen X, et al. (2008) Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Lancet 372: 1828-1834.
  30. Gibson J, Hakobyan S, Cree AJ, Collins A, Harris CL, et al. (2012) Variation in complement component C1 inhibitor in age-related macular degeneration. Immunobiology 217: 251-255.
  31. Bos IG, Lubbers YT, Roem D, Abrahams JP, Hack CE, et al. (2003) The functional integrity of the serpin domain of C1-inhibitor depends on the unique N-terminal domain, as revealed by a pathological mutant. J Biol Chem 278: 29463-29470.
  32. Liu D, Gu X, Scafidi J, Davis AE 3rd (2004) N-linked glycosylation is required for c1 inhibitor-mediated protection from endotoxin shock in mice. Infect Immun 72: 1946-1955.
  33. Perkins SJ, Smith KF, Amatayakul S, Ashford D, Rademacher TW, et al. (1990) Two-domain structure of the native and reactive centre cleaved forms of C1 inhibitor of human complement by neutron scattering. J Mol Biol 214: 751-763.
  34. Schapira M, de Agostini A, Schifferli JA, Colman RW (1985) Biochemistry and pathophysiology of human C1 inhibitor: current issues. Complement 2: 111-126.
  35. Wagenaar-Bos IG, Hack CE (2006) Structure and function of C1-inhibitor. Immunol Allergy Clin North Am 26: 615-632.
  36. Beinrohr L, Harmat V, Dobó J, Lörincz Z, Gál P, et al. (2007) C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease. J Biol Chem 282: 21100-21109.
  37. Rajabi M, Struble E, Zhou Z, Karnaukhova E (2012) Potentiation of C1-esterase inhibitor by heparin and interactions with C1s protease as assessed by surface plasmon resonance. Biochim Biophys Acta 1820: 56-63.
  38. Huntington JA, Read RJ, Carrell RW (2000) Structure of a serpin-protease complex shows inhibition by deformation. Nature 407: 923-926.
  39. Lomas DA, Belorgey D, Mallya M, Miranda E, Kinghorn KJ, et al. (2005) Molecular mousetraps and the serpinopathies. Biochem Soc Trans 33: 321-330.
  40. Sim RB, Reboul A, Arlaud GJ, Villiers CL, Colomb MG (1979) Interaction of 125I-labelled complement subcomponents C-1r and C-1s with protease inhibitors in plasma. FEBS Lett 97: 111-115.
  41. Ziccardi RJ (1981) Activation of the early components of the classical complement pathway under physiologic conditions. J Immunol 126: 1769-1773.
  42. Matsushita M, Thiel S, Jensenius JC, Terai I, Fujita T (2000) Proteolytic activities of two types of mannose-binding lectin-associated serine protease. J Immunol 165: 2637-2642.
  43. Petersen SV, Thiel S, Jensen L, Vorup-Jensen T, Koch C, et al. (2000) Control of the classical and the MBL pathway of complement activation. Mol Immunol 37: 803-811.
  44. de Agostini A, Lijnen HR, Pixley RA, Colman RW, Schapira M (1984) Inactivation of factor XII active fragment in normal plasma. Predominant role of C-1-inhibitor. J Clin Invest 73: 1542-1549.
  45. Pixley RA, Schapira M, Colman RW (1985) The regulation of human factor XIIa by plasma proteinase inhibitors. J Biol Chem 260: 1723-1729.
  46. Schapira M, Scott CF, Colman RW (1982) Contribution of plasma protease inhibitors to the inactivation of kallikrein in plasma. J Clin Invest 69: 462-468.
  47. Huisman LG, van Griensven JM, Kluft C (1995) On the role of C1-inhibitor as inhibitor of tissue-type plasminogen activator in human plasma. Thromb Haemost 73: 466-471.
  48. Wuillemin WA, Minnema M, Meijers JC, Roem D, Eerenberg AJ, et al. (1995) Inactivation of factor XIa in human plasma assessed by measuring factor XIa-protease inhibitor complexes: major role for C1-inhibitor. Blood 85: 1517-1526.
  49. Cugno M, Bos I, Lubbers Y, Hack CE, Agostoni A (2001) In vitro interaction of C1-inhibitor with thrombin. Blood Coagul Fibrinolysis 12: 253-260.
  50. Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, et al. (2000) C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema. Pharmacol Rev 52: 91-112.
  51. Davis AE 3rd, Mejia P, Lu F (2008) Biological activities of C1 inhibitor. Mol Immunol 45: 4057-4063.
  52. Zeerleder S (2011) C1-inhibitor: more than a serine protease inhibitor. Semin Thromb Hemost 37: 362-374.
  53. Caughman GB, Boackle RJ, Vesely J (1982) A postulated mechanism for heparin's potentiation of C1 inhibitor function. Mol Immunol 19: 287-295.
  54. Boackle RJ, Caughman GB, Vesely J, Medgyesi G, Fudenberg HH (1983) Potentiation of factor H by heparin: a rate-limiting mechanism for inhibition of the alternative complement pathway. Mol Immunol 20: 1157-1164.
  55. Wuillemin WA, te Velthuis H, Lubbers YT, de Ruig CP, Eldering E, et al. (1997) Potentiation of C1 inhibitor by glycosaminoglycans: dextran sulfate species are effective inhibitors of in vitro complement activation in plasma. J Immunol 159: 1953-1960.
  56. Lennick M, Brew SA, Ingham KC (1986) Kinetics of interaction of C1 inhibitor with complement C1s. Biochemistry 25: 3890-3898.
  57. Nilsson T, Wiman B (1983) Kinetics of the reaction between human C1-esterase inhibitor and C1r or C1s. Eur J Biochem 129: 663-667.
  58. Pixley RA, Schmaier A, Colman RW (1987) Effect of negatively charged activating compounds on inactivation of factor XIIa by Cl inhibitor. Arch Biochem Biophys 256: 490-498.
  59. Sim RB, Arlaud GJ, Colomb MG (1980) Kinetics of reaction of human C1-inhibitor with the human complement system proteases C1r and C1s. Biochim Biophys Acta 612: 433-449.
  60. Caldwell EE, Andreasen AM, Blietz MA, Serrahn JN, VanderNoot V, et al. (1999) Heparin binding and augmentation of C1 inhibitor activity. Arch Biochem Biophys 361: 215-222.
  61. Rossi V, Bally I, Ancelet S, Xu Y, Frémeaux-Bacchi V, et al. (2010) Functional characterization of the recombinant human C1 inhibitor serpin domain: insights into heparin binding. J Immunol 184: 4982-4989.
  62. Wuillemin WA, Eldering E, Citarella F, de Ruig CP, ten Cate H, et al. (1996) Modulation of contact system proteases by glycosaminoglycans. Selective enhancement of the inhibition of factor XIa. J Biol Chem 271: 12913-12918.
  63. Yu H, Muñoz EM, Edens RE, Linhardt RJ (2005) Kinetic studies on the interactions of heparin and complement proteins using surface plasmon resonance. Biochim Biophys Acta 1726: 168-176.
  64. Blossom DB, Kallen AJ, Patel PR, Elward A, Robinson L, et al. (2008) Outbreak of adverse reactions associated with contaminated heparin. N Engl J Med 359: 2674-2684.
  65. Kishimoto TK, Viswanathan K, Ganguly T, Elankumaran S, Smith S, et al. (2008) Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 358: 2457-2467.
  66. Zhou ZH, Rajabi M, Chen T, Karnaukhova E, Kozlowski S (2012) Oversulfated chondroitin sulfate inhibits the complement classical pathway by potentiating C1 inhibitor. PLoS One 7: e47296.
  67. Frank MM, Gelfand JA, Atkinson JP (1976) Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 84: 580-593.
  68. Zuraw BL (2008) Clinical practice. Hereditary angioedema. N Engl J Med 359: 1027-1036.
  69. Tourangeau LM, Zuraw BL (2011) The new era of C1-esterase inhibitor deficiency therapy. Curr Allergy Asthma Rep 11: 345-351.
  70. Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, et al. (2004) Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 114: S51-131.
  71. Banerji A (2011) Hereditary angioedema: classification, pathogenesis, and diagnosis. Allergy Asthma Proc 32: 403-407.
  72. deShazo RD, Frank MM (2010) Genius at work: Osler's 1888 article on hereditary angioedema. Am J Med Sci 339: 179-181.
  73. Cicardi M, Johnston DT (2012) Hereditary and acquired complement component 1 esterase inhibitor deficiency: a review for the hematologist. Acta Haematol 127: 208-220.
  74. Longhurst H, Cicardi M (2012) Hereditary angio-oedema. Lancet 379: 474-481.
  75. Bork K, Barnstedt SE, Koch P, Traupe H (2000) Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 356: 213-217.
  76. Bork K (2012) Current management options for hereditary angioedema. Curr Allergy Asthma Rep 12: 273-280.
  77. Zuraw BL, Bork K, Binkley KE, Banerji A, Christiansen SC, et al. (2012) Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel. Allergy Asthma Proc.
  78. Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M (2009) C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med 15: 69-78.
  79. Bork K, Meng G, Staubach P, Hardt J (2006) Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 119: 267-274.
  80. Cicardi M, Bork K, Caballero T, Craig T, Li HH, et al. (2012) Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 67: 147-57.
  81. Weis M (2009) Clinical review of hereditary angioedema: diagnosis and management. Postgrad Med 121: 113-120.
  82. Csuka D, Munthe-Fog L, Skjoedt MO, Kocsis A, Zotter Z, et al. (2013) The role of ficolins and MASPs in hereditary angioedema due to C1-inhibitor deficiency. Mol Immunol 54: 271-277.
  83. Björkqvist J, Sala-Cunill A, Renné T (2013) Hereditary angioedema: a bradykinin-mediated swelling disorder. Thromb Haemost 109: 368-374.
  84. Cugno M, Hack CE, de Boer JP, Eerenberg AJ, Agostoni A, et al. (1993) Generation of plasmin during acute attacks of hereditary angioedema. J Lab Clin Med 121: 38-43.
  85. Cugno M, Cicardi M, Bottasso B, Coppola R, Paonessa R, et al. (1997) Activation of the coagulation cascade in C1-inhibitor deficiencies. Blood 89: 3213-3218.
  86. Davis AE 3rd (2005) The pathophysiology of hereditary angioedema. Clin Immunol 114: 3-9.
  87. Nielsen EW, Johansen HT, Høgåsen K, Wuillemin W, Hack CE, et al (1996) Activation of the complement, coagulation, fibrinolytic and kallikrein-kinin systems during attacks of hereditary angioedema. Scand J Immunol. 44: 185-192.
  88. Zuraw BL (2010) HAE therapies: past present and future. Allergy Asthma Clin Immunol 6: 23.
  89. Buyantseva LV, Sardana N, Craig TJ (2012) Update on treatment of hereditary angioedema. Asian Pac J Allergy Immunol 30: 89-98.
  90. Hsu D, Shaker M (2012) An update on hereditary angioedema. Curr Opin Pediatr 24: 638-646.
  91. Christiansen SC, Zuraw BL (2011) Hereditary angioedema: management of laryngeal attacks. Am J Rhinol Allergy 25: 379-382.
  92. Kalfus IN, Gower RG, Riedl M, Bernstein JA, Lumry WR, et al. (2012) Hereditary angioedema: implications of treating a rare disease. Ann Allergy Asthma Immunol 109: 150-151.
  93. Riedl M, Gower RG, Chrvala CA (2011) Current medical management of hereditary angioedema: results from a large survey of US physicians. Ann Allergy Asthma Immunol 106: 316-322.
  94. Zuraw B, Cicardi M, Levy RJ, Nuijens JH, Relan A, et al. (2010) Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol 126: 821-827.
  95. Aberer W (2012) Hereditary angioedema treatment options: the availability of new therapies. Ann Med 44: 523-529.
  96. Brackertz D, Kueppers F (1973) Hereditary angioneurotic oedema. Lancet 2: 680.
  97. Cicardi M, Mannucci PM, Castelli R, Rumi MG, Agostoni A (1995) Reduction in transmission of hepatitis C after the introduction of a heat-treatment step in the production of C1-inhibitor concentrate. Transfusion 35: 209-212.
  98. Food and Drug Administration. Potential signals of serious risks/new safety information identified by the Adverse Event Reporting System (AERS) (2010).
  99. Eldering E, Nuijens JH, Hack CE (1988) Expression of functional human C1 inhibitor in COS cells. J Biol Chem 263: 11776-11779.
  100. Eldering E, Huijbregts CC, Lubbers YT, Longstaff C, Hack CE (1992) Characterization of recombinant C1 inhibitor P1 variants. J Biol Chem 267: 7013-7020.
  101. Lamark T, Ingebrigtsen M, Bjørnstad C, Melkko T, Mollnes TE, et al. (2001) Expression of active human C1 inhibitor serpin domain in Escherichia coli. Protein Expr Purif 22: 349-358.
  102. Wolff MW, Zhang F, Roberg JJ, Caldwell EE, Kaul PR, et al. (2001) Expression of C1 esterase inhibitor by the baculovirus expression vector system: preparation, purification, and characterization. Protein Expr Purif 22: 414-421.
  103. Bos IG, de Bruin EC, Karuntu YA, Modderman PW, Eldering E, et al. (2003) Recombinant human C1-inhibitor produced in Pichia pastoris has the same inhibitory capacity as plasma C1-inhibitor. Biochim Biophys Acta 1648: 75-83.
  104. van Doorn MB, Burggraaf J, van Dam T, Eerenberg A, Levi M, et al. (2005) A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol 116: 876-883.
  105. Choi G, Soeters MR, Farkas H, Varga L, Obtulowicz K, et al. (2007) Recombinant human C1-inhibitor in the treatment of acute angioedema attacks. Transfusion 47: 1028-1032.
  106. van Veen HA, Koiter J, Vogelezang CJ, van Wessel N, van Dam T, et al. (2012) Characterization of recombinant human C1 inhibitor secreted in milk of transgenic rabbits. J Biotechnol 162: 319-326.
  107. Davis B, Bernstein JA (2011) Conestat alfa for the treatment of angioedema attacks. Ther Clin Risk Manag 7: 265-273.
  108. Plosker GL (2012) Recombinant human c1 inhibitor (conestat alfa): in the treatment of angioedema attacks in hereditary angioedema. BioDrugs 26: 315-323.
  109. Koles K, van Berkel PH, Pieper FR, Nuijens JH, Mannesse ML, et al. (2004) N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits. Glycobiology 14: 51-64.
  110. Schneider L, Lumry W, Vegh A, Williams AH, Schmalbach T (2007) Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. J Allergy Clin Immunol 120: 416-422.
  111. Charignon D, Späth P, Martin L, Drouet C (2012) Icatibant, the bradykinin B2 receptor antagonist with target to the interconnected kinin systems. Expert Opin Pharmacother 13: 2233-2247.
  112. Singer M, Jones AM (2011) Bench-to-bedside review: the role of C1-esterase inhibitor in sepsis and other critical illnesses. Crit Care 15: 203.
Citation: Karnaukhova E (2013) C1-Esterase Inhibitor: Biological Activities and Therapeutic Applications. J Hematol Thromb Dis 1:113.

Copyright: © 2013 Karnaukhova E. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.