Complement system and complement disorders

The complement system is a cascade of soluble plasma proteins, membrane receptors and membrane regulators that operates in plasma, in tissues, on cell surfaces and even inside cells. It is composed of more than 40 proteins, and the soluble components are produced mainly by the liver. Complement is best understood as an innate immune surveillance system rather than a simple lytic cascade. It contributes to host homeostasis, inflammation and defence against pathogens. It also links innate recognition to adaptive immunity by promoting opsonisation, antigen presentation and B-cell and T-cell responses. ^[2]

The central component is C3. Activation of each of the three pathways, the classical pathway, the lectin pathway and the alternative pathway, results in cleavage of inactive C3 into C3a and C3b. C3a is an inflammation mediator, while C3b is an opsonin that can bind covalently and tag any surface near the site where it was generated. This covalent tagging is the molecular basis of complement-mediated opsonisation. Because C3b can attach to almost any surface, the system needs powerful regulation to distinguish host from non-host. ^[1]

The guiding rule is that everything not specifically protected has to be attacked. Host cells carry an armamentarium of “don’t attack me” molecules, either expressed on the cell or recruited from plasma. Any cell, debris, microorganism or artificial material lacking these molecules and carrying hydroxyl or amino chemical groups can act as an activating surface and support covalent C3b deposition. The alternative pathway is permanently active and constantly probes the environment for such surfaces. This continuous low-level surveillance is why complement can respond within seconds, but it is also why loss of regulation can injure host tissue.

Pattern-recognition molecules provide a second layer of recognition. They identify material that should be eliminated, such as apoptotic cells, debris, pathogens and immune complexes, and activate the classical and lectin pathways. All pathways converge at C3 cleavage, generating C3a and C3b. The alternative pathway amplification loop then increases the level of C3 deposition. This amplification is quantitatively important: the alternative pathway assures more than 80% of the terminal complement activity during pathogen recognition. The amplification loop is therefore the heart of the cascade, turning a small initial signal into a large opsonisation and terminal pathway response. ^[1]

Complement can be a friend or a foe. It is a friend when it opsonises pathogens, directly kills them through the C5b–9 membrane attack complex and triggers inflammation through C3a and C5a. It becomes an enemy when pathogens hijack complement regulators, and when complement overactivation or dysregulation causes disease. Complement overactivation or dysregulation is a disease cause in atypical haemolytic uraemic syndrome and C3 glomerulopathies, whereas inadequate classical pathway activation contributes to systemic lupus erythematosus. Age-related macular degeneration and cancer are further examples showing that complement contributes to conditions far beyond classical complement deficiency.

Complement disorders can be grouped conceptually into deficiencies that remove protection or effector function, and overactivation states in which regulation fails. Individuals deficient in terminal complement components are at increased risk for recurrent meningitis, while C1 inhibitor deficiency produces hereditary angioedema through uncontrolled bradykinin generation. Paroxysmal nocturnal haemoglobinuria illustrates the opposite problem: loss of membrane complement regulators allows the terminal pathway to damage host erythrocytes. The rest of this page explains the pathways, the effector mechanisms and the clinical consequences of failure at each level.

The classical and lectin pathways are triggered by pattern-recognition molecules, while the alternative pathway is continuously active and amplifies whatever C3b has been deposited. The classical pathway is initiated when C1q binds to suitable targets, including immune complexes and apoptotic cells. The lectin pathway uses mannose-binding lectin and ficolins to recognise pathogen-associated or damaged-self surfaces. Both pathways generate C3 convertases that cleave C3 into C3a and C3b. They therefore provide a rapid, targeted start to complement activation.

The alternative pathway is different in style. It does not wait for a specific recognition event. It probes surfaces continuously and is permanently active at a low level. When C3b binds to an unprotected surface, factor B and factor D generate an alternative C3 convertase. Additional alternative pathway C3 convertases form on C3b molecules generated by classical pathway activation or by alternative pathway convertases. This chain reaction amplifies opsonisation of the target and increases generation of anaphylatoxins. The amplification loop augments the effect of all pathways and is the heart of the complement cascade.

The convertases are not equally efficient. When C3b binds covalently to a classical pathway C3 convertase, a trimolecular complex forms with about 1000-fold increased enzymatic activity toward C5 cleavage compared with the bimolecular complex. The classical pathway C5 convertase cleaves on average 1.5 C5 molecules per minute. The alternative pathway C5 convertase, formed from C3bBbC3b, is six to ninefold weaker compared with the classical, cleaving less than 0.3 C5 molecules per minute. To compensate, properdin stabilises the alternative pathway C5 convertase and increases its half-life from approximately 3–30 min. No natural stabiliser has been described for the classical C5 convertase. ^[1]

This quantitative difference matters clinically. The alternative pathway amplification loop generates many C3b molecules, making the alternative pathway C5 convertase the main source of the terminal pathway complex C5b-9. The ring model of amplification explains how activation spreads on a surface: deposited C3b forms alternative C3 convertases, new C3 convertases are formed, and C3b binds on top of the convertase to form C5 convertases. As activation spreads, older enzymes are inactivated by factor H and factor I, leaving an expanding inner core of inactivated C3b surrounded by an active band of C5 convertases. This spatial arrangement helps explain why complement activation can remain localised yet intense.

The classical pathway is tightly controlled by C1 inhibitor. C1 inhibitor binds and inactivates C1r and C1s, leading to dissociation of the C1 complex and liberation of free C1q, leaving inactive covalent complexes between C1 inhibitor and C1r or C1s. C1 inhibitor is also thought to bind and stabilise unactivated C1r and C1s in the C1 complex, retarding spontaneous activation. Beyond complement, C1 inhibitor regulates the contact, coagulation and fibrinolysis systems, and its deficiency increases bradykinin production. This broader role explains why C1 inhibitor deficiency produces angioedema rather than simply immunodeficiency.

The three pathways therefore cooperate rather than compete. Classical and lectin pathways provide recognition-driven initiation, while the alternative pathway provides amplification and continuous surveillance. All converge at C3, and the balance between amplification and downregulation determines whether complement remains a local tagging system or escalates into terminal lysis and inflammation. The next sections examine the two main effector outcomes: C3b-mediated opsonisation and the membrane attack complex.

C3b is the central opsonin of complement. When C3 is cleaved, the thioester in C3b becomes reactive and can form covalent bonds with hydroxyl or amino groups on nearby surfaces. This means C3b tags whatever is immediately adjacent to the activation site, whether that is a bacterium, an immune complex, an apoptotic cell or an artificial material. Because the tag is covalent, it persists on the target and provides a durable signal for phagocytes. C3b is described as the Swiss army knife of complement because it interacts with a large variety of ligands and receptors through multiple distinct binding sites.

The deposition of C3b is highly controlled on host cells. Host cells express membrane regulators such as membrane cofactor protein and complement receptor 1, and they recruit plasma regulators such as factor H, which bind to C3b. These proteins act as cofactors that allow factor I to cleave C3b into iC3b. This cleavage produces a conformational change that suppresses the ability of C3b to interact with factor B but exposes novel binding sites in iC3b, allowing it to interact with other complement molecules. Factor H also blocks the binding of factor B and factor D to C3b, preventing formation of C3 convertases. The overall effect is prevention of complement activation on host cells.

On an unprotected surface, the opposite happens. C3b recruits factor B, which is cleaved by factor D to form the alternative C3 convertase. This convertase generates more C3b, which deposits on the same surface and forms more convertases. The amplification loop therefore converts a small initial C3b deposit into a dense opsonin coat. C3b and iC3b are recognised by complement receptors on phagocytes, promoting adherence, ingestion and clearance. Opsonisation also plays a major role in mounting an adaptive immune response involving antigen-presenting cells, T lymphocytes and B lymphocytes.

The balance between amplification and the C3b breakdown cycle determines the outcome. The amplification loop is the balance between two competing cycles acting on C3b–C3 convertase formation, enhancing both amplification and downregulation via the C3 breakdown cycle. Complement amplification depends on the balance between binding rates of each reaction. Several inhibitors of complement pathways, primarily against the alternative pathway, exist in the fluid phase and on host cells, and they have overlapping functionality. Factor H is a soluble inhibitor of the alternative C3 convertase, while membrane cofactor protein, decay acceleration factor and complement receptor 1 are membrane inhibitors. Factor H is a specific cofactor for C3b, C4 binding protein is primarily a cofactor for C4b, and membrane cofactor protein and complement receptor 1 act as cofactors for inactivation of both C3b and C4b via factor I.

Opsonisation is not merely a prelude to lysis. In many infections, phagocytic clearance of C3b-coated organisms is more important than direct membrane attack. Opsonisation also helps clear apoptotic cells silently. Complement activation occurs on apoptotic cells with low levels of C3b deposition to facilitate their elimination without releasing danger signals. This complement activation occurs by membrane alterations and decreased expression of complement regulators on apoptotic cells compared with resting cells. The silent clearance of apoptotic cells is assured by binding of classical pathway initiators such as C1q and lectin pathway initiators such as mannose-binding lectin and ficolins to phagocytic receptors, which elicit immune tolerance and prevent immune responses toward self-antigens. C3b is therefore both an antimicrobial tag and a homeostatic signal.

The terminal pathway begins with C5 cleavage and ends with assembly of the membrane attack complex, C5b-9. Activation of the terminal complement pathway results in membrane attack complexes that form large, 10 nm wide pores in the target membrane. These pores disrupt membrane integrity and can lyse susceptible cells. Each functional membrane attack complex is sufficient to lyse metabolically inert cells such as erythrocytes or liposomes by colloid osmosis. This is why terminal complement is so effective against cells that cannot repair membrane damage.

Gram-negative bacteria are susceptible to complement killing, particularly the meningitis-causing Neisseria species. Individuals deficient in terminal complement components are at increased risk for recurrent meningitis. Properdin deficiency is also associated with recurrent meningitis. Gram-positive bacteria have an extremely thick cell wall that the membrane attack complex cannot penetrate, leaving them resistant to complement elimination. Metabolically active nucleated cells are also resistant to lysis by complement. To induce killing in these cells, multiple membrane attack complexes must be inserted together with coordination of calcium flux and not well-understood signal transduction.

Host cells are protected from accidental terminal pathway attack by membrane regulators. CD59 is a glycosylphosphatidylinositol-anchored protein expressed on most cell types, and it blocks membrane perforation by C5b-8 and C5b-9. CD59 does not bind free C8 and C9, but interacts with the membrane attack complex/perforin domain of each protein upon conformational changes associated with C5b-9 complex formation. This specificity allows CD59 to recognise assembling terminal complexes rather than circulating components. The lytic terminal complex C5b-9 can also be removed within minutes of deposition on target cells, either by shedding via membrane vesicles or by internalisation and degradation. These repair mechanisms explain why nucleated cells can survive a limited terminal pathway hit.

The terminal pathway is therefore a powerful but narrowly effective weapon. It is most useful against metabolically inert targets and selected Gram-negative organisms. It is less effective against thick-walled bacteria and actively repairing nucleated cells. This selectivity has clinical consequences: terminal complement deficiency presents with recurrent neisserial infection rather than broad susceptibility to all pathogens. It also explains why membrane attack complex regulation is essential on host cells, and why loss of regulators such as CD59 can cause complement-mediated haemolysis.

Complement inhibitors exist in fluid phase and on membranes, and they have overlapping functions. C1 inhibitor is a serpin that controls the classical and lectin pathways by binding and inactivating C1r and C1s. Factor H is a soluble inhibitor of the alternative C3 convertase that competes with factor B for binding to C3b. It also serves as a cofactor for C3b inactivation by factor I and induces dissociation of the C3bBb complex. Factor H is composed of 20 complement control protein domains arranged as beads on a string, and CFHL1 is a shorter protein containing the seven N-terminal domains of factor H, generated by alternative splicing, that functions as a fluid-phase regulator. Factor H binds C3b and C3(H2O), but not uncleaved C3.

Membrane regulators provide a second layer of protection. Membrane cofactor protein, decay acceleration factor and complement receptor 1 work as membrane inhibitors. Factor H is a specific cofactor for C3b, C4 binding protein is primarily a cofactor for C4b, and membrane cofactor protein and complement receptor 1 act as cofactors for inactivation of both C3b and C4b via factor I. CD59 provides terminal pathway protection by blocking membrane perforation by C5b-8 and C5b-9. These inhibitors are not redundant; they act at different steps and in different compartments. Loss of one can produce a characteristic disease pattern.

Early complement deficiencies affect recognition and opsonisation. A deficiency of classical pathway components impairs clearance of immune complexes and apoptotic cells, and a deficiency of lectin pathway components impairs recognition of mannose-rich pathogens. These are textbook consequences of losing the functions described above. The passages do not provide specific prevalence figures for early component deficiencies, so the key principle is functional: early components initiate the cascade and generate C3b, and their loss reduces opsonisation and immune complex handling.

Terminal complement deficiencies produce a distinct pattern. Individuals deficient in terminal complement components are at increased risk for recurrent meningitis. Properdin deficiency is also associated with recurrent meningitis. This susceptibility reflects the importance of terminal pathway killing against Neisseria species. By contrast, deficiencies of early components are more often associated with immune complex disease and bacterial infections rather than isolated recurrent meningococcal disease. The clinical pattern therefore helps localise the defect within the cascade.

Inhibitor deficiencies cause overactivation rather than immunodeficiency. C1 inhibitor deficiency produces hereditary angioedema through uncontrolled bradykinin generation. Factor H dysfunction is associated with atypical haemolytic uraemic syndrome, particularly when mutations affect the C-terminal domains that mediate C3b and glycosaminoglycan interactions. These disorders illustrate the principle that complement disease can result from too little regulation as well as too little effector function.

Hereditary angioedema is an autosomal dominant disease characterised by oedema attacks with multiple organ involvement. It is caused by quantitative or functional deficiency of C1 inhibitor, a member of the serine protease inhibitor family. C1 inhibitor deficiency results in increased bradykinin production. Bradykinin increases vascular permeability, producing episodic swelling of the skin, subcutaneous tissues, gastrointestinal tract and upper airway. The disease is unknown to many health professionals and is therefore underdiagnosed.

The clinical consequences can be severe. The causes of death from hereditary angioedema include laryngeal oedema with asphyxia. In addition to oedema of the glottis, hereditary angioedema often results in oedema of the gastrointestinal tract, which can be incapacitating. Patients may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, mimicking an acute surgical abdomen. This is a classic diagnostic trap: unexplained recurrent abdominal pain in a young person should prompt consideration of hereditary angioedema.

Laboratory diagnosis relies on complement testing. Quantitative or qualitative C1 inhibitor deficiency leads to permanent activation of the complement system, accompanied by C4 consumption, even when patients are not experiencing an angioedema attack. In 2-5% of cases, C4 levels normalise during the intercrisis period. For paediatric patients suspected of hereditary angioedema, biochemical analysis of C4 level and C1 inhibitor antigenic and functional levels is recommended^[1]. Two congruent results are required for the confirmation or exclusion of the diagnosis of hereditary angioedema^[1]. This requirement reflects the need to avoid misdiagnosis when single tests are borderline or affected by age-related complement immaturity.

Acute treatment is age-dependent in paediatric guidance. In neonates and infants between birth and 2 years, intravenous plasma-derived C1 inhibitor concentrate is recommended as first-line therapy for acute angioedema attacks^[1]. In children aged between 2 and 12 years, first-line options are icatibant, intravenous plasma-derived C1 inhibitor concentrate, or intravenous recombinant human C1 inhibitor^[1]. In adolescents aged 12 years or older, first-line options include ecallantide, icatibant, intravenous plasma-derived C1 inhibitor concentrate, intravenous recombinant human C1 inhibitor, or sebetralstat^[1]. Treatment should be given as early as possible, and home treatment is recommended to ensure early treatment^[1].

Short-term prophylaxis is recommended before medical, dental and surgical procedures and any angioedema-inducing event, especially when procedures involve the upper airway^[1]. Intravenous plasma-derived C1 inhibitor is recommended as the first-line treatment for short-term prophylaxis in paediatric patients^[1]. Long-term prophylaxis is also age-specific. In children aged between 2 and 6 years, lanadelumab or plasma-derived C1 inhibitor is recommended as first-line long-term prophylaxis^[1]. In children aged between 6 and 12 years, the same first-line options apply^[1]. In adolescents aged 12 years or older, first-line long-term prophylaxis can be berotralstat, garadacimab, lanadelumab or plasma-derived C1 inhibitor^[1]. These recommendations reflect the principle that treatment should be matched to the developmental stage and the individual burden of attacks.

Paroxysmal nocturnal haemoglobinuria is a complement-mediated disorder of haematopoietic stem cells. It arises from acquired mutations that impair glycosylphosphatidylinositol anchor biosynthesis, so that affected blood cells lack glycosylphosphatidylinositol-anchored proteins on their surface. Among the missing proteins are complement regulators that normally protect host cells from alternative pathway activation and terminal pathway attack. The result is chronic intravascular haemolysis, because erythrocytes become vulnerable to complement-mediated lysis. The same loss of regulation can affect platelets and other cells, contributing to thrombosis and smooth muscle dystonia.

CD59 is central to this vulnerability. CD59 is a glycosylphosphatidylinositol-anchored protein expressed on most cell types, and it blocks membrane perforation by C5b-8 and C5b-9. When CD59 is absent from the red-cell membrane, the terminal pathway can assemble pores without efficient restraint. Complement regulators that act earlier in the cascade are also affected, allowing alternative pathway amplification to proceed on the cell surface. The disease therefore illustrates the general rule that host cells depend on membrane regulators to prevent complement attack.

The laboratory hallmarks follow from the pathophysiology. Intravascular haemolysis releases free haemoglobin, producing haemoglobinuria, and chronic loss of erythrocytes causes anaemia. Thrombosis is a major complication and can occur at unusual sites. Smooth muscle dystonia causes abdominal pain, dysphagia and erectile dysfunction. The diagnosis is confirmed by flow cytometry showing loss of glycosylphosphatidylinositol-anchored proteins on red cells and white cells. Complement testing helps exclude other causes of complement-mediated haemolysis, such as atypical haemolytic uraemic syndrome.

Paroxysmal nocturnal haemoglobinuria is a prime example of complement overactivation on host cells. The passages note that mini factor H molecules containing CCP1–4 and CCP19–20 bind C3b and C3d with high affinity and show better efficacy compared with native factor H in in vitro models of atypical haemolytic uraemic syndrome and paroxysmal nocturnal haemoglobinuria. A hybrid molecule, TT30, containing factor H CCP1–5 and complement receptor 2 CCP1–4, is designed to accumulate at sites already under complement-mediated attack. TT30 and its murine analogue showed significant improvement in models of age-related macular degeneration, ischaemia/reperfusion injury and paroxysmal nocturnal haemoglobinuria. These experimental strategies illustrate the therapeutic logic of restoring regulation at the cell surface.

Clinically, paroxysmal nocturnal haemoglobinuria is managed by terminal complement blockade, which prevents membrane attack complex formation and reduces intravascular haemolysis. The trade-off is an increased risk of meningococcal infection, because terminal complement is important for defence against Neisseria species. Vaccination and antimicrobial prophylaxis are therefore essential components of care. The disease reminds us that complement is not simply an antimicrobial system; it is a constant threat to any host cell that loses its protective regulators.

Complement disorders are individually uncommon but collectively important because they cause severe and life-threatening disease. Hereditary angioedema is underdiagnosed and unfamiliar to many health professionals. The estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40%. This figure is a powerful argument for early recognition and appropriate treatment. Patients with hereditary angioedema experience some degree of disability 20-100 days per year. The burden is therefore not limited to acute attacks; it includes lost schooling, work absence and reduced quality of life.

The epidemiology of complement overactivation extends beyond hereditary angioedema. Inadequate complement activation is a disease cause in atypical haemolytic uraemic syndrome, C3 glomerulopathies and systemic lupus erythematosus. Age-related macular degeneration and cancer are further examples of conditions in which complement contributes to pathology. These are not classic complement deficiency diseases, but they show that complement activation can be harmful when it occurs in the wrong place, at the wrong intensity or for too long. Complement is involved in chronic inflammation, immunosuppression, angiogenesis and cancer-related signalling.

Terminal complement deficiency has a distinctive epidemiological signature. Affected individuals are at increased risk for recurrent meningitis. Properdin deficiency is also associated with recurrent meningitis. This pattern reflects the importance of terminal pathway killing against Neisseria species. Because meningococcal disease can be fulminant, terminal complement deficiency should be considered in any patient with recurrent meningococcal infection or a family history of the same. The risk is not limited to classical complement deficiencies; properdin deficiency produces a similar susceptibility.

Age affects complement testing. Complement levels in umbilical cord blood of full-term neonates can be lower than maternal levels because of immaturity of the complement system^[1]. This is why paediatric diagnosis requires caution and why repeat testing may be needed. In hereditary angioedema, C4 levels normalise during the intercrisis period in 2-5% of cases. A normal C4 therefore does not exclude the diagnosis if the clinical picture is convincing and C1 inhibitor testing is abnormal. The epidemiology of complement disorders is therefore inseparable from the limitations of the tests used to detect them.

The aetiology of complement disorders can be genetic or acquired. Hereditary angioedema is an autosomal dominant disease caused by quantitative or functional deficiency of C1 inhibitor. Because it is dominant, a family history is often present, and first-degree relatives should be considered for screening. The passage notes that paediatric patients who are first-degree relatives of patients with hereditary angioedema with normal C1 inhibitor should be screened for the pathogenic variant known in the family^[1]. This is a clear example of genetic risk stratification.

Terminal complement deficiencies are also genetic risk factors for infection. Individuals deficient in terminal complement components are at increased risk for recurrent meningitis. Properdin deficiency is another inherited risk factor for recurrent meningitis. These deficiencies do not usually cause broad immunodeficiency; they produce a narrow susceptibility to Neisseria species. This specificity is clinically useful because it directs prophylaxis and vaccination strategies. It also illustrates the principle that the site of a complement defect determines the infection pattern.

Acquired factors can also disrupt complement regulation. Pathogens have evolved mechanisms to hijack host complement regulators. Bacteria, viruses, fungi and parasites can bind high levels of efficient complement regulators such as factor H, factor H-like 1 and C4 binding protein. Recruitment of these regulators accelerates decay of the C3 convertase and provides cofactors for factor I, which cleaves C4b and C3b, protecting the pathogen against complement attack. Staphylococcus aureus produces extracellular fibrinogen-binding protein, which inhibits conversion of C3 to C3b by binding the thioester domain. It also produces Ehp, which binds two molecules of C3b and inhibits the alternative C3 convertase. Surface immunoglobulin-binding protein forms a tripartite complex with C3b and functional factor H that potentiates inhibition of complement activation. Staphylococcal complement inhibitor family proteins bind C3b, compete with factor B and factor H, stabilise the C3 convertase and block C3 cleavage, thereby avoiding opsonisation and complement activation. These pathogen strategies are risk factors for infection because they allow microbes to escape complement.

Inflammation and tissue injury can also create complement-mediated risk. Prolonged complement activation supports chronic inflammation, promotes an immunosuppressive microenvironment, induces angiogenesis and activates cancer-related signalling pathways. In the tumour microenvironment, complement activation can promote tumour growth rather than control it. This is a reminder that complement is context-dependent: the same cascade that kills bacteria can damage host tissue or support malignant growth. Risk factors for complement-mediated disease therefore include genetic variants, acquired regulator deficiencies, pathogen evasion and chronic inflammatory states.

Finally, iatrogenic and procedural factors matter in hereditary angioedema. Medical, dental and surgical procedures, especially those involving the upper airway, can precipitate attacks, which is why short-term prophylaxis is recommended before such events^[1]. The risk is not evenly distributed across procedures; airway instrumentation is particularly dangerous because laryngeal oedema can obstruct the airway. Identifying these triggers allows anticipatory treatment and reduces mortality.

Complement is a surveillance cascade that converts recognition of an unprotected surface into opsonisation, inflammation and, when necessary, membrane lysis. On pathogens that lack specific complement regulators, C3b interacts with factor B and factor D to form a surface-bound alternative pathway C3 convertase, which cleaves C3 into C3a and C3b. This creates a positive feedback loop: each C3b molecule can seed further convertase formation, so a small initial signal becomes a dense opsonin coat. Maximum complement activation during pathogen recognition produces a pro-inflammatory milieu, supports adaptive immunity and promotes rapid elimination of the pathogen.

The classical pathway is not triggered by antibody alone. Efficient C1q binding requires specific non-covalent interactions between IgG Fc fragments and formation of ordered antibody hexamers on the antigen surface. Antigen size, density and fluidity affect clustering, so smaller antigen–antibody complexes allow only moderate complement activation. This explains why epitope distribution and antibody density influence the strength of classical pathway activation. The lectin pathway uses mannose-binding lectin and ficolins to recognise pathogen- or danger-associated patterns, and the alternative pathway provides continuous low-level probing through spontaneous C3 hydrolysis, often called tick-over. All three pathways converge at C3 cleavage, generating C3a and C3b.

C3b is the central effector fragment. It binds covalently to nearby surfaces and tags them for phagocytosis. The main role of complement in pathogen elimination is indirect: deposition of complement fragments on the pathogen surface allows recognition, ingestion and destruction by phagocytes, neutrophils, monocytes and macrophages. Complement opsonisation can act before adaptive antibodies appear, so it provides early protection. C3a and C5a are anaphylatoxins that activate immune and non-myeloid cells through G-protein-coupled receptors, inducing oxidative burst, histamine release and vasodilatation. These mediators recruit phagocytes and amplify inflammation.

The terminal pathway assembles the membrane attack complex on susceptible membranes. Complement activation also has direct lytic capacity to kill pathogens. The membrane attack complex is most effective against metabolically inert cells and some Gram-negative bacteria, whereas thick-walled Gram-positive bacteria and actively repairing nucleated cells are relatively resistant. Complement is therefore not only a lytic system; it is a powerful innate immune surveillance tool that modulates adaptive immunity and host homeostasis.

In hereditary angioedema, the primary defect is loss of C1 inhibitor, a serine protease inhibitor that normally inhibits C1r and C1s. Without this inhibition, the complement system becomes excessively activated. C1 inhibitor also regulates the contact, coagulation and fibrinolysis systems, and its deficiency results in increased bradykinin production. Bradykinin is now recognised as one of the principal mediators of hereditary angioedema. The contact system is an enzyme cascade initiated by activated factor XII and responsible for bradykinin production^[1]. This explains why hereditary angioedema is a bradykinin-mediated permeability disorder rather than a simple allergic reaction.

In atypical haemolytic uraemic syndrome, the hallmark is association with alternative pathway mutations. Endothelial damage is related to complement dysregulation, and unrestricted activation produces C5b–9 deposits on glomerular endothelial cells, leading to microthrombi and mechanical haemolysis. Loss of regulation results from mutations in factor H, factor I or CD46 genes in about 50% of cases. Factor H mutations are frequently in the C-terminal domains and reduce binding to C3b and cell-surface glycosaminoglycans. This is a clear example of a regulatory failure that turns a protective cascade against the endothelium.

Paroxysmal nocturnal haemoglobinuria reflects loss of membrane complement regulators on blood cells. The passages describe CD59 as a glycosylphosphatidylinositol-anchored protein that blocks membrane perforation by C5b-8 and C5b-9. When such regulators are absent, terminal pathway activity proceeds unchecked on the red-cell surface. The result is complement-mediated intravascular haemolysis, with downstream risks of thrombosis and smooth muscle dystonia. The pathophysiology is therefore a loss of the “don’t attack me” signal that normally protects host cells.

Complement also intersects with coagulation and adaptive immunity. Thrombin and activated coagulation factors can cleave C3 and C5, and C5a and C5b can be generated through thrombin independently of the plasma complement system. Complement fragments interact with B cells through CR2, which recognises C3d and iC3b on antigen surfaces and forms a co-receptor complex with CD19 and CD81. Complement can lower the threshold for B-cell activation, and C3d can break anergy in autoreactive B cells. This explains why complement dysregulation can contribute to autoimmunity as well as infection.

Complement disorders are best classified by the pathway or component affected, by whether the defect causes deficiency or overactivation, and by whether the disorder is inherited or acquired. There is no universal staging system comparable to cancer staging. Instead, clinical staging is practical: acute attack versus intercritical period, organ threatened versus not threatened, and regulated versus unregulated disease. This practical approach matters because the same complement defect can be silent between episodes and life-threatening during an attack.

Hereditary angioedema with C1 inhibitor deficiency can be divided biochemically. The diagnosis is established by quantitative and/or functional C1 inhibitor testing, and the quantitative and functional forms can be differentiated by these measurements^[1]. A further form, type III hereditary angioedema, is rarer than types I and II and principally affects females; it is characterised by normal C1 inhibitor levels and activity. This form is important because routine C1 inhibitor testing may be normal, so clinical suspicion and genetic or provocation testing become more important.

Atypical haemolytic uraemic syndrome is classified by its association with alternative pathway dysregulation. Screening for mutations in the components of the C3 convertase, including C3 and factor B, its regulators including factor H, factor I, membrane cofactor protein, CFHR1 and thrombomodulin, and anti-factor H antibodies has become an indispensable part of diagnosis. About 50% of cases have mutations in factor H, factor I or CD46. This classification is clinically useful because it identifies patients who may benefit from terminal complement blockade and because it informs family screening. ^[2]

Paroxysmal nocturnal haemoglobinuria is a clonal haematopoietic stem cell disorder classified by the loss of glycosylphosphatidylinositol-anchored proteins. It is not staged by pathway mutations in the same way as atypical haemolytic uraemic syndrome. Instead, the clinically important distinctions are the degree of haemolysis, the presence of thrombosis, and the need for terminal complement blockade. The disease illustrates a general principle: complement disorders can be classified by the level of the cascade that is unprotected, not only by the name of the clinical syndrome.

Complement disorders can also be classified by the type of tissue injury. Opsonisation defects predispose to infection and immune complex disease. Anaphylatoxin excess produces inflammation and vasodilatation. Terminal pathway excess produces membrane damage and haemolysis. Regulatory deficiency produces host-cell attack. This mechanistic classification helps explain why C1 inhibitor deficiency causes angioedema, terminal component deficiency causes meningococcal disease, and CD59 loss causes haemolysis.

In clinical practice, staging should include severity and site. An attack involving the upper airway is immediately threatening, whereas a subcutaneous attack may be distressing but not immediately dangerous. Gastrointestinal attacks can mimic an acute surgical abdomen. The time elapsed between symptom onset and diagnosis, and between diagnosis and treatment, contributes to morbidity and mortality. This is why early recognition and early treatment are treated as quality markers rather than optional extras.

Hereditary angioedema presents with attacks of non-pruritic oedema of the skin and submucosa affecting various organs. The most commonly affected sites are the face, extremities, genitalia, oropharynx, larynx and digestive system. Rarer manifestations include intense headaches from brain oedema, urinary retention and acute pancreatitis. The swelling is typically non-pruritic and non-urticarial, which helps distinguish it from mast-cell-mediated angioedema. Attacks can be spontaneous or triggered by procedures, infection, stress or hormonal change.

Laryngeal involvement is the most feared presentation. Oedema of the glottis can progress to airway obstruction and asphyxia. Because the swelling is bradykinin-mediated, it may not respond promptly to antihistamines, corticosteroids or adrenaline. Any patient with hereditary angioedema and throat symptoms, voice change, dysphagia or stridor requires urgent assessment and treatment. The clinical history is the principal component of diagnosis, and a family history of similar manifestations supports the diagnosis, although it can be absent in 20-25% of cases. ^[3]

Gastrointestinal attacks are a major source of diagnostic error. Patients may present with severe abdominal pain, vomiting, diarrhoea or distension, and the digestive tract can be the primary or only organ system involved. This can mimic an acute surgical abdomen. Repeated unnecessary laparotomies are a recognised hazard. A history of recurrent self-limiting abdominal attacks, especially with cutaneous or airway swelling, should prompt complement testing rather than repeated imaging alone.

Atypical haemolytic uraemic syndrome presents with the triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury. The passages describe it as a renal thrombotic microangiopathy characterised by glomerular microvascular endothelial cell activation and damage, leading to microthrombi and mechanical haemolysis. Patients may develop hypertension, oedema, oliguria and progressive renal failure. Extrarenal involvement can occur, but the kidney is the central target.

Paroxysmal nocturnal haemoglobinuria presents with chronic intravascular haemolysis. Patients may report dark urine, especially in the morning, fatigue, jaundice and anaemia. Thrombosis is a major complication and can involve unusual sites. Smooth muscle dystonia produces abdominal pain, dysphagia and erectile dysfunction. The clinical picture can be subtle, and a high index of suspicion is needed when haemolysis is Coombs-negative and complement-mediated.

Other complement disorders produce overlapping features. Systemic lupus erythematosus can arise from impaired clearance of apoptotic cells due to lack of C1q, C1r, C1s, C2 or C4, and it can also arise from complement overactivation due to anti-C1q antibodies or complement-activating immune complexes. Age-related macular degeneration is associated with chronic alternative pathway activation in the retina. Complement activation in the tumour microenvironment can promote chronic inflammation, immunosuppression, angiogenesis and cancer-related signalling.

The most important differential for hereditary angioedema is mast-cell-mediated angioedema. Mast-cell-mediated angioedema, as in anaphylaxis with or without urticaria, is associated with a rapid onset and progression within minutes to a few hours, a good response to antihistamines, glucocorticoids or epinephrine, and resolution within 12 to 24 h from onset^[1]. Wheezing, hypotension and nausea or vomiting may be associated, and exposure to a known trigger can support the diagnosis^[1]. Hereditary angioedema attacks are typically slower in onset, non-pruritic, and not accompanied by urticaria or wheeze.

Upper airway angioedema in children has a broad differential. The differential diagnosis of upper airway angioedema in paediatrics includes allergic food reactions, croup, pseudocroup, foreign body aspiration and acute epiglottitis^[1]. Progression of symptoms and treatment response can help narrow the differential^[1]. A child with stridor, drooling, fever or toxic appearance needs urgent exclusion of epiglottitis and foreign body, while a child with recurrent self-limiting swelling and a family history needs complement testing.

Abdominal attacks require a surgical differential. Hereditary angioedema can mimic acute surgical abdomen, and patients may undergo unnecessary surgical interventions. Other causes of recurrent abdominal pain, such as inflammatory bowel disease, biliary colic, pancreatitis and gynaecological disorders, should be considered. The clue is the association with cutaneous or airway swelling and the absence of peritoneal signs between attacks. Imaging may show bowel wall oedema or free fluid, but these findings are non-specific.

Hereditary angioedema with normal C1 inhibitor is an important differential because its clinical manifestation is almost the same as that of hereditary angioedema with C1 inhibitor deficiency^[1]. This disorder should be considered when the clinical picture is convincing but C1 inhibitor antigenic and functional levels are normal. If clinical suspicion remains despite normal C4 and normal C1 inhibitor levels, these tests should be performed again during an angioedema attack. If the results are again normal, a diagnosis of type III hereditary angioedema is suggested.

Atypical haemolytic uraemic syndrome must be distinguished from other thrombotic microangiopathies, including thrombotic thrombocytopenic purpura and disseminated intravascular coagulation. The passages do not provide a full differential, but the principle is that aHUS is complement-mediated and associated with alternative pathway mutations. Severe ADAMTS13 deficiency suggests thrombotic thrombocytopenic purpura, while prolonged prothrombin time and fibrinogen consumption suggest disseminated intravascular coagulation. Renal biopsy may show thrombotic microangiopathy but is not always necessary.

Paroxysmal nocturnal haemoglobinuria should be distinguished from other causes of intravascular haemolysis, including microangiopathic haemolysis, autoimmune haemolysis and mechanical haemolysis. The Coombs test is typically negative in PNH, and flow cytometry demonstrates loss of glycosylphosphatidylinositol-anchored proteins. Complement testing may show terminal pathway activation. The differential matters because treatments differ: terminal complement blockade is effective in PNH, whereas immunosuppression is used for autoimmune haemolysis.

The investigation of hereditary angioedema begins with complement testing. C4 levels are low in hereditary angioedema with C1 inhibitor deficiency because of activation of the classical pathway, and C4 is used as a screening test in resource-limited settings^[1]. Specific biochemical analysis of quantitative and functional C1 inhibitor and C4 is mandatory for a definitive diagnosis^[1]. This means that a low C4 alone is not enough, and a normal C1 inhibitor antigenic level does not exclude a functional defect.

The accurate performance of plasma complement tests requires careful sample collection, freezing and storage^[1]. Recently, dry blood spot sampling was introduced for complement testing, making sample handling easier^[1]. Pre-analytical error is a common cause of apparently discordant results, so a normal result in a patient with a strong clinical picture should be interpreted with caution. Functional C1 inhibitor assays are particularly vulnerable to handling problems.

In atypical haemolytic uraemic syndrome, screening for and characterisation of mutations in the components of the C3 convertase, its regulators and anti-factor H antibodies has become an indispensable part of diagnosis. This includes C3, factor B, factor H, factor I, membrane cofactor protein, CFHR1 and thrombomodulin. About 50% of cases have mutations in factor H, factor I or CD46. Genetic results can guide prognosis, family screening and treatment decisions, but they may not be available urgently.

Paroxysmal nocturnal haemoglobinuria is diagnosed by flow cytometry showing loss of glycosylphosphatidylinositol-anchored proteins on red cells and white cells. Complement testing may show evidence of terminal pathway activation. The passages describe CD59 as a glycosylphosphatidylinositol-anchored regulator that blocks membrane perforation by C5b-8 and C5b-9. Loss of CD59 is therefore a functional marker of the disease. Bone marrow examination may be needed if aplastic anaemia or myelodysplasia is suspected.

General complement testing can include CH50 and AP50, but these are not described in the passages. A low CH50 with a normal AH50 suggests classical pathway deficiency, a low AH50 with a normal CH50 suggests alternative pathway deficiency, and a reduction in both suggests terminal pathway deficiency. These tests are useful for screening but do not replace specific component assays. Interpretation requires attention to age, because complement levels in umbilical cord blood of full-term neonates can be lower than maternal levels due to immaturity of the complement system^[1].

In hereditary angioedema, C4 levels can normalise between attacks. The passages in this part do not provide the exact percentage, but the principle is that a normal C4 during the intercritical period does not exclude the diagnosis. If clinical suspicion remains despite normal C4 and normal C1 inhibitor levels, tests should be repeated during an attack. This is why the clinical history takes precedence, particularly where laboratory tests are unavailable or when type III hereditary angioedema is suspected.

The diagnosis of hereditary angioedema is primarily clinical, supported by biochemical testing. The patient’s clinical history is the principal component of diagnosis. A family history of similar manifestations supports the diagnosis, although it is absent in approximately 25% of cases. The presence of hereditary angioedema is confirmed when patients meet one major clinical criterion and one biochemical criterion. The major clinical criterion is recurrent non-pruritic angioedema without urticaria, and the biochemical criterion is abnormal C1 inhibitor antigenic or functional testing, usually with low C4.

Biochemical confirmation requires quantitative and functional C1 inhibitor testing. The diagnosis of hereditary angioedema with C1 inhibitor deficiency is easily established by biochemical evaluation of quantitative and/or functional C1 inhibitor^[1]. Quantitative and functional forms can be differentiated based on these measurements^[1]. C4 is low in hereditary angioedema with C1 inhibitor deficiency because of classical pathway activation, and it is used as a screening test in resource-limited settings^[1]. Specific biochemical analysis of quantitative and functional C1 inhibitor and C4 is mandatory for a definitive diagnosis^[1].

If clinical suspicion remains despite normal C4 and normal C1 inhibitor levels, these tests should be performed again during an angioedema attack. If the results are again normal, a diagnosis of type III hereditary angioedema is suggested. Type III hereditary angioedema is rarer than types I and II and principally affects females; it is characterised by normal C1 inhibitor levels and activity. This form requires a high index of suspicion and, in selected cases, genetic testing or a therapeutic trial.

Atypical haemolytic uraemic syndrome is diagnosed when there is a thrombotic microangiopathy with evidence of alternative pathway dysregulation. The hallmark is association with alternative pathway mutations. Screening for mutations in C3, factor B, factor H, factor I, membrane cofactor protein, CFHR1 and thrombomodulin, and for anti-factor H antibodies, is part of diagnosis. About 50% of cases have mutations in factor H, factor I or CD46. The diagnosis is supported by low C3, normal C4, and evidence of terminal pathway activation, although the passages do not specify these thresholds.

Paroxysmal nocturnal haemoglobinuria is diagnosed by flow cytometry demonstrating loss of glycosylphosphatidylinositol-anchored proteins. The passages describe CD59 as a glycosylphosphatidylinositol-anchored protein that blocks membrane perforation. The diagnosis should be considered in any patient with Coombs-negative intravascular haemolysis, especially with thrombosis or cytopenia. Bone marrow failure can coexist, and the distinction from aplastic anaemia requires careful morphological and flow cytometric assessment.

The diagnostic process for complement disorders should include family screening where relevant. Paediatric patients with hereditary angioedema deserve special attention, and early diagnosis, family screening, education and counselling of patients and caregivers are essential^[1]. The time elapsed between symptom onset and diagnosis, and between diagnosis and treatment, contributes to morbidity and mortality. This is why diagnostic delay is not a neutral outcome; it is a modifiable risk factor.

Management of hereditary angioedema is organised around the stage of disease and the clinical setting. The stages are acute attack, short-term prophylaxis before procedures, long-term prophylaxis, and the intercritical period. The settings are home, emergency department, operating theatre and resource-limited environments. The guideline covers diagnosis, treatment of attacks, short-term and long-term prophylaxis, self-administration, individualised therapy, quality of life and comprehensive care^[1]. Treatment should be started as early as possible, and patients should be educated about self-administration where appropriate.

For acute attacks, the priority is to secure the airway and treat early. Laryngeal attacks are emergencies because they can progress to asphyxia. Gastrointestinal attacks require analgesia, antiemetics and fluid resuscitation, and surgical consultation should be avoided unless there is genuine diagnostic uncertainty. Fresh plasma or solvent/detergent-treated plasma, which contains C1 inhibitor, can be used when specific therapies are unavailable, but only as a grade D recommendation. This type of treatment can worsen attacks because fresh plasma also contains the remaining complement, coagulation and contact system components. There are also concerns about transfusion-related acute lung injury, anaphylaxis and viral transmission, and the volume load may be problematic. ^[3]

For short-term prophylaxis, the goal is to prevent attacks before medical, dental or surgical procedures, especially those involving the upper airway. The guideline covers short-term prophylaxis as part of comprehensive care^[1]. The choice of agent depends on availability and patient factors. Where specific therapies are available, they are preferred over plasma transfusion because of the risks described above. Patients should be assessed individually, and a therapeutic strategic plan should be developed with shared decision-making^[1].

For long-term prophylaxis, the goal is to reduce the frequency and severity of attacks and improve quality of life. The guideline covers long-term prophylaxis and individualised therapy^[1]. The choice of agent should be based on attack frequency, site, burden of disease, patient preference and access. Monitoring should include efficacy, safety and quality of life. Patients and caregivers should be educated about the disease and its treatment, and regular follow-up is essential^[1].

Special populations require additional consideration. Paediatric patients with hereditary angioedema deserve special attention in diagnosis and management^[1]. Early diagnosis, family screening, education and counselling of patients and caregivers, selection of appropriate individualised therapy, development of a therapeutic strategic plan with shared decision-making, centralised care and regular follow-up are essential to ensure that young patients can lead normal lives similar to their peers^[1]. Complement levels in umbilical cord blood of full-term neonates can be lower than maternal levels because of immaturity of the complement system, so testing in the first year of life requires caution^[1].

In atypical haemolytic uraemic syndrome, management centres on terminal complement blockade. Eculizumab targets human C5 and blocks cleavage by C5 convertases. Eculizumab blocks the terminal complement pathway but leaves the C3 convertases unaffected. Eculizumab is approved for use in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. Because terminal complement is important for defence against Neisseria species, vaccination and antimicrobial prophylaxis are required. The passages do not provide doses, so the principle is to use terminal blockade as part of a specialist protocol. ^[2]

In paroxysmal nocturnal haemoglobinuria, terminal complement blockade reduces intravascular haemolysis and thrombosis risk. The same terminal pathway blockade is used in this condition. The same trade-off applies: blocking terminal complement increases susceptibility to meningococcal infection. Patients should receive meningococcal vaccination and, in many protocols, antimicrobial prophylaxis. Breakthrough haemolysis can occur if complement is not fully controlled, and monitoring of lactate dehydrogenase and haemoglobin is standard.

Earlier complement blockade is an active area of research. Compstatin is a 13-residue peptide that binds C3 and blocks its cleavage. It has shown efficacy in complement blocking in vitro and in animal models, including extracorporeal circulation, sepsis and paroxysmal nocturnal haemoglobinuria. Both compstatin and eculizumab are species-specific and act only in humans and monkeys, not in mice or rats. This illustrates the principle that complement therapeutics must be matched to the species and to the level of the cascade being targeted. ^[1]

In resource-limited settings, diagnosis and management must be adapted. C4 is used as a screening test where full complement testing is unavailable^[1]. Fresh plasma or solvent/detergent-treated plasma can be used when specific therapies are unavailable, but with the caveats described. The clinical history takes precedence when laboratory tests are unavailable. These adaptations are not ideal, but they reflect the reality that complement disorders are neglected diseases in many health systems.

The most immediate complication of hereditary angioedema is airway obstruction. Laryngeal oedema can progress to asphyxia and death. Because attacks can be unpredictable, patients with a history of airway involvement need an emergency plan, access to treatment and education about when to seek help. The time elapsed between symptom onset and diagnosis, and between diagnosis and treatment, contributes to morbidity and mortality. This makes early recognition a life-saving intervention.

Gastrointestinal attacks can cause severe pain, vomiting, diarrhoea and dehydration. They can mimic an acute surgical abdomen, leading to unnecessary laparotomy. Repeated attacks can cause significant disability and absence from school or work. The passage notes that patients with hereditary angioedema may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved. This is a preventable complication of delayed diagnosis.

Atypical haemolytic uraemic syndrome can cause acute kidney injury, hypertension, proteinuria and progressive renal failure. The renal thrombotic microangiopathy is characterised by glomerular microvascular endothelial cell activation and damage, leading to microthrombi and mechanical haemolysis. Patients may require dialysis, and some progress to end-stage renal disease. Extrarenal complications include neurological involvement, cardiac involvement and gastrointestinal ischaemia. Early terminal complement blockade improves outcomes.

Paroxysmal nocturnal haemoglobinuria causes chronic haemolysis, anaemia, fatigue and jaundice. Thrombosis is a major cause of morbidity and mortality and can occur at unusual sites, including hepatic, cerebral and mesenteric veins. Smooth muscle dystonia causes abdominal pain, dysphagia and erectile dysfunction. Chronic haemolysis can lead to pulmonary hypertension and renal impairment. Terminal complement blockade reduces these complications but requires lifelong monitoring and infection prophylaxis.

Complement overactivation contributes to many other diseases. In systemic lupus erythematosus, both impaired clearance of apoptotic cells and complement overactivation can drive disease. In age-related macular degeneration, chronic alternative pathway activation contributes to retinal damage. In cancer, complement activation in the tumour microenvironment can promote chronic inflammation, immunosuppression, angiogenesis and cancer-related signalling. Complement is therefore a double-edged sword: it is essential for host defence but can cause or perpetuate tissue injury when dysregulated.

Infections are a particular complication of terminal complement blockade and terminal component deficiency. Individuals deficient in terminal complement components are at increased risk for recurrent meningitis. Properdin deficiency is also associated with recurrent meningitis. Patients receiving terminal complement inhibitors require vaccination against Neisseria species and, in many protocols, antimicrobial prophylaxis. Fever or meningococcal symptoms in such patients require urgent assessment.

Thrombosis is a complication of both paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. In paroxysmal nocturnal haemoglobinuria, thrombosis can be the presenting feature and can occur despite anticoagulation. In atypical haemolytic uraemic syndrome, microthrombi in the glomeruli cause renal injury, and systemic thrombotic microangiopathy can affect other organs. Complement activation on endothelial cells is central to both conditions. Anticoagulation may be used in selected patients, but the primary treatment is control of complement activation.

Long-term complications include chronic kidney disease, pulmonary hypertension, osteoporosis from repeated glucocorticoid exposure, and psychological burden. Patients with hereditary angioedema may experience anxiety and depression because of unpredictable attacks. A comprehensive care model with education, counselling, individualised therapy and regular follow-up improves quality of life^[1]. The goal is not only to prevent death but to enable patients to lead normal lives similar to their peers^[1].

The prognosis of complement disorders depends on the pathway affected, the speed of recognition and whether effective treatment is available. Hereditary angioedema is often underdiagnosed, and the prevalence is approximately 1∶50,000, with estimates ranging from 1∶10,000 to 1∶150,000; the disease affects various ethnic groups and accounts for 2% of all cases of angioedema. Because attacks can involve the airway, delayed diagnosis is not a neutral outcome. The condition is inherited in an autosomal dominant pattern, and children of a patient with hereditary angioedema have a 50% chance of carrying the anomalous gene. A family history is characteristic, but in 20-25% of cases a family history of disease is absent, and new spontaneous mutations can be observed. Approximately 200 hereditary angioedema-associated mutations have been identified to date. Although genetic defects are found in patients of both genders with equal frequency, the phenotype is more common in female patients, for whom the disease is more severe. ^[3]

For hereditary angioedema, long-term prognosis has improved with recognition and prophylaxis. First-line long-term prophylaxis should be with plasma-derived C1-INH, lanadelumab, or berotralstat; androgens are no longer recommended as first-line therapy due to their side-effect profile. However, androgens are ineffective in controlling attacks of hereditary angioedema because it takes approximately 48 h for the drugs to begin to take effect. Acute treatment therefore cannot rely on androgens. Icatibant has changed acute management: a single dose of icatibant was effective in 90% of the attacks of hereditary angioedema. This high response rate supports early treatment and home treatment strategies. ^[3]

Atypical haemolytic uraemic syndrome has a different prognosis. It is a rare thrombotic microangiopathy that predominates in the kidney. Without appropriate treatment, it leads to end stage renal disease in approximately 60% of patients. Atypical haemolytic uraemic syndrome occurs at any age and has a poor prognosis prior to the development of eculizumab. By contrast, typical haemolytic uraemic syndrome is predominantly a paediatric disease and has a favourable renal outcome. The distinction matters because the two conditions look similar in some respects but behave very differently. Atypical haemolytic uraemic syndrome is not associated with infection by Shiga toxin-producing bacteria or ADAMTS13 deficiency. Recognising this distinction prevents inappropriate reassurance and supports early complement-directed therapy. ^[1]

Other complement disorders also carry long-term consequences. C1q deficiency can cause defective clearance of apoptotic cells and autoimmunity, and because C1q is produced by myeloid cells, a bone marrow transplantation can overcome this deficiency. Plasma therapy was the first line treatment for atypical haemolytic uraemic syndrome before the development of the anti-C5 blocking antibody eculizumab. This historical detail is clinically useful because it explains why plasma exchange remains a rescue option in settings where eculizumab is unavailable. The prognosis of complement disorders is therefore not fixed; it is modifiable by early diagnosis, appropriate prophylaxis and access to targeted therapies.

Prevention in complement disorders has two aims: avoid triggers that precipitate attacks and identify affected individuals before they come to harm. In hereditary angioedema, the aim of primary prevention is to avoid trigger factors, while keeping activities and lifestyle as normal as possible^[1]. Physical activity should be encouraged individually, and unjustified restrictions on activity should be avoided^[1]. Dental, surgical procedures and endoscopy may provoke attacks^[1]. Upper airway infections are common triggers of hereditary angioedema attacks, so their prevention can reduce the impact of the disease^[1]. Mandatory and non-mandatory vaccinations are recommended as they have proven to be both safe and effective^[1].

Family screening is high-yield because inheritance of hereditary angioedema is autosomal dominant, meaning that screening first-degree relatives carries a high yield^[1]. Family history of hereditary angioedema with C1 inhibitor deficiency can be absent in 25% of cases due to de novo pathogenic variants^[1]. This is why a negative family history must not be used to exclude the diagnosis. Genetic testing is not required to confirm the diagnosis of hereditary angioedema with C1 inhibitor deficiency unless preimplantation diagnosis or prenatal testing is considered, or when biochemical tests are uncertain^[1]. When the family genetic variant is known, genetic testing can be a convenient and accurate method of neonatal testing^[1]. However, the gene variant responsible for C1 inhibitor deficiency, SERPING1, is only identified in 90% to 92% of patients with hereditary angioedema with C1 inhibitor deficiency^[1]. A negative genetic test therefore does not totally exclude the diagnosis when the family variant is unknown^[1].

Short-term prophylaxis is used before procedures that may provoke attacks. Fresh frozen plasma can be administered intravenously at a dose of 2 U the night before surgery or on the day of surgery (grade D recommendation). C1 inhibitor concentrates are safe and effective at doses of 500-1,000 U when administered intravenously (grade C recommendation). These options are used when targeted therapies are unavailable or when the clinical setting requires cover. The choice should be individualised according to the procedure, the site involved and the patient’s history. Procedures involving the upper airway deserve particular caution because swelling in that area can obstruct breathing.

Screening also applies to atypical haemolytic uraemic syndrome. The hallmark is association with alternative pathway mutations, and screening for and characterisation of mutations in the components of the C3 convertase, its regulators and anti-factor H antibodies has become an indispensable part of diagnosis. This allows family counselling and informs treatment. In paroxysmal nocturnal haemoglobinuria, screening is by flow cytometry for loss of glycosylphosphatidylinositol-anchored proteins. Prevention of complications includes vaccination against meningococcal disease before terminal complement blockade. These measures reduce the risk of infection while preserving the benefit of complement control.

Follow-up in hereditary angioedema should be clinical rather than purely biochemical. Although androgens increase the levels of C1 inhibitor and C4, symptomatic benefit is generally achieved at doses lower than those required to significantly alter the levels of complement components. Therefore, drug dosage is based on the patient's clinical symptoms rather than his or her biochemical parameters. This principle prevents unnecessary escalation of treatment based on laboratory numbers alone. It also means that follow-up must include attack frequency, severity, site, impact on school or work, and quality of life.

The pharmacokinetics of C1 inhibitor are relevant to follow-up. The fractional catabolic rate of C1 inhibitor is 2.5% of the plasma pool per hour. However, in patients with hereditary angioedema, the half-life of C1 inhibitor is longer than predicted by the fractional catabolic rate, more than 48 h versus 28 h. This difference is probably attributable to the observation that exogenous C1 inhibitor reduces consumption of endogenous C1 inhibitor, preventing C1 autoactivation. This helps explain why replacement therapy can have a longer effect than simple pharmacokinetics would predict. It also supports individualised dosing rather than a fixed schedule.

Icatibant has a short plasma half-life. It is administered subcutaneously, and its plasma half-life is 2-4 h. Despite this short half-life, a single dose of icatibant was effective in 90% of attacks of hereditary angioedema (grade B recommendation). Follow-up after acute treatment should confirm resolution and detect rebound or recurrence. Patients should be educated about when to use acute therapy and when to seek emergency care. Home treatment is an important part of follow-up because early treatment improves outcomes. ^[3]

Long-term prophylaxis requires age-specific follow-up. Long-term prophylaxis is rarely needed in children under 6 years of age^[1]. If long-term prophylaxis is required in this age group, subcutaneously administered prefilled lanadelumab injection is the only approved treatment option for this indication between 2 and 6 years of age^[1]. In older children and adolescents, attenuated androgens could be considered only in adolescents with Tanner stage V and higher, with careful surveillance^[1]. Tranexamic acid is safe, but it is less efficacious than attenuated androgens^[1]. Follow-up should therefore include growth, pubertal development, liver function and adverse effects when androgens are used.

Follow-up in atypical haemolytic uraemic syndrome focuses on renal recovery, haematological response and prevention of relapse. Patients treated with terminal complement blockade require monitoring for breakthrough haemolysis, infection and meningococcal risk. Complement testing may be repeated to assess the degree of control. In paroxysmal nocturnal haemoglobinuria, follow-up includes haemoglobin, lactate dehydrogenase, reticulocyte count, thrombosis surveillance and assessment of transfusion need. The underlying principle is that complement disorders are chronic conditions requiring planned review, not single episodes of care.

Hereditary angioedema is an autosomal dominant disease caused by quantitative or functional deficiency of C1 inhibitor, a member of the serine protease inhibitor family. The prevalence is approximately 1∶50,000, with estimates ranging from 1∶10,000 to 1∶150,000, and it accounts for 2% of all cases of angioedema. Children of an affected patient have a 50% chance of carrying the anomalous gene. A family history is absent in 20-25% of cases. Approximately 200 hereditary angioedema-associated mutations have been identified. The phenotype is more common and more severe in female patients.

Atypical haemolytic uraemic syndrome is a renal thrombotic microangiopathy. Without appropriate treatment, it leads to end stage renal disease in approximately 60% of patients. It occurs at any age and has a poor prognosis prior to eculizumab. Typical haemolytic uraemic syndrome is predominantly a paediatric disease with a favourable renal outcome. Atypical haemolytic uraemic syndrome is not associated with Shiga toxin-producing bacteria or ADAMTS13 deficiency. The hallmark is association with alternative pathway mutations, and screening for mutations in C3, factor B, factor H, factor I, membrane cofactor protein, CFHR1 and thrombomodulin, and for anti-factor H antibodies, is part of diagnosis.

In hereditary angioedema, C3 levels are generally normal. The determination of C3 levels is unnecessary except in patients who are suspected of having acquired angioedema. In acquired angioedema, 75% of patients present with reduced serum levels of C1q. This is a useful discriminator between hereditary and acquired forms. The gene variant responsible for C1 inhibitor deficiency, SERPING1, is only identified in 90% to 92% of patients with hereditary angioedema with C1 inhibitor deficiency^[1]. A negative genetic test therefore does not totally exclude the diagnosis.

For acute attacks, androgens are ineffective because it takes approximately 48 h for the drugs to begin to take effect. Icatibant is effective: a single dose was effective in 90% of attacks of hereditary angioedema. Its plasma half-life is 2-4 h. For long-term prophylaxis, first-line therapy should be with plasma-derived C1-INH, lanadelumab or berotralstat; androgens are no longer recommended as first-line because of their side-effect profile. In children under 6 years, long-term prophylaxis is rarely needed^[1]. When required between 2 and 6 years, lanadelumab is the only approved treatment option^[1].

A common pitfall is to exclude hereditary angioedema because the family history is negative. A family history is absent in 20-25% of cases due to new mutations. Another pitfall is to exclude the diagnosis because genetic testing is negative. The gene variant responsible for C1 inhibitor deficiency is only identified in 90% to 92% of patients with hereditary angioedema with C1 inhibitor deficiency^[1]. A negative genetic test does not totally exclude the diagnosis when the family variant is unknown^[1]. The clinical history remains central, and complement testing should be repeated during an attack if suspicion remains.

A third pitfall is to measure C3 as a routine diagnostic test for hereditary angioedema. C3 levels are generally normal in hereditary angioedema. The determination of C3 levels is unnecessary except in patients who are suspected of having acquired angioedema. In acquired angioedema, 75% of patients present with reduced serum levels of C1q. C1q testing is therefore more useful than C3 when acquired angioedema is suspected. This distinction prevents unnecessary testing and helps identify the correct diagnosis.

A fourth pitfall is to confuse atypical haemolytic uraemic syndrome with typical haemolytic uraemic syndrome or thrombotic thrombocytopenic purpura. Atypical haemolytic uraemic syndrome is not associated with infection by Shiga toxin-producing bacteria or ADAMTS13 deficiency. It is a renal thrombotic microangiopathy that predominates in the kidney. Without appropriate treatment, it leads to end stage renal disease in approximately 60% of patients. Typical haemolytic uraemic syndrome is predominantly a paediatric disease with a favourable renal outcome. These differences influence both prognosis and treatment.

A fifth pitfall is to overuse long-term prophylaxis in young children. Long-term prophylaxis is rarely needed in children under 6 years of age^[1]. If long-term prophylaxis is required between 2 and 6 years, lanadelumab is the only approved treatment option for this indication^[1]. Attenuated androgens could be considered only in adolescents with Tanner stage V and higher, with careful surveillance^[1]. Tranexamic acid is safe, but it is less efficacious than attenuated androgens^[1]. Age and developmental stage must guide therapy.

Complement biology is used whenever a clinician assesses recurrent angioedema, thrombotic microangiopathy or unexplained haemolysis. In hereditary angioedema, the clinical history is the principal component of diagnosis. Patients present with attacks of non-pruritic oedema of the skin and submucosa affecting various organs. The most commonly affected sites are the face, extremities, genitalia, oropharynx, larynx and digestive system. Subcutaneous angioedema without wheals or itching is the most common and often the earliest symptom in paediatric patients^[1]. It may last 1 to 5 days before resolving spontaneously^[1]. Erythema marginatum, a map-like rash, is reported as a prodromal symptom in 42%–58% of paediatric patients^[1]. Recognising these features allows early testing and treatment.

In acute care, the practical question is whether the airway is threatened. Laryngeal attacks require urgent treatment, and icatibant is effective: a single dose was effective in 90% of attacks of hereditary angioedema. Its plasma half-life is 2-4 h. For procedures, short-term prophylaxis can use fresh frozen plasma at a dose of 2 U the night before or on the day of surgery (grade D recommendation). C1 inhibitor concentrates are safe and effective at doses of 500-1,000 U when administered intravenously (grade C recommendation). These options are chosen according to availability, procedure site and patient factors.

In nephrology, complement biology is used to diagnose and treat atypical haemolytic uraemic syndrome. The hallmark is association with alternative pathway mutations. Plasma therapy was the first line treatment for atypical haemolytic uraemic syndrome before the development of eculizumab. Eculizumab targets human C5 and blocks cleavage by C5 convertases. It blocks the terminal complement pathway but leaves the C3 convertases unaffected. Eculizumab has been accepted for treatment of complement-mediated diseases including paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. This is a clear example of mechanism-based therapy.

In immunology and haematology, complement testing is used to investigate C1q deficiency and terminal pathway disorders. Since C1q is produced by the myeloid cells, a bone marrow transplantation can overcome this deficiency. This was applied to a patient with systemic lupus erythematosus, resulting in normalisation of C1q levels and improvement of clinical status. In paroxysmal nocturnal haemoglobinuria, flow cytometry demonstrates loss of glycosylphosphatidylinositol-anchored proteins, and terminal complement blockade reduces haemolysis. The same principle applies across disciplines: identify the level of complement dysregulation, then choose a treatment that acts at that level.

In primary care and emergency medicine, the key is pattern recognition. Recurrent non-pruritic swelling without urticaria, unexplained abdominal attacks, a family history of similar symptoms or a known diagnosis should prompt consideration of hereditary angioedema. A family history is absent in 20-25% of cases. The gene variant responsible for C1 inhibitor deficiency is only identified in 90% to 92% of patients^[1]. Therefore, a negative family history or negative genetic test does not exclude the disease. Early referral to a specialist centre allows confirmatory testing, family screening and an individualised treatment plan.