Complement Pathways
What are the three pathways of complement activation?
The classical pathway, the lectin pathway, and the alternative pathway.
Citation: "Complement is normally activated by one of three routes: the classical pathway, which is triggered by antigen: antibody complexes or antibody bound to the surface of a pathogen; the lectin pathway, which is activated by mannose-binding lectin (MBL) and the ficolins; and the alternative pathway, in which complement is activated spontaneously on the surface of some bacteria".
What genetic deficiency causes HAE?
Deficiency of C1 inhibitor (C1INH).
Citation: "In the absence of C1INH, active components of complement and bradykinin are produced. This is seen in hereditary angioedema (HAE), a disease caused by a genetic deficiency of C1INH".
How is HAE diagnosed using complement levels?
Low C1INH and low C4 levels, with normal C3 levels.
Citation: "C1INH levels were 16% of the normal mean and C4 levels were markedly decreased, while C3 levels were normal".
What is the inheritance pattern of HAE?
Autosomal dominant.
Citation: "Individuals like Richard with a hereditary deficiency of C1INH are subject to recurrent episodes... The inheritance of hereditary angioedema in Richard’s extended family" (illustrated as autosomal dominant in the family tree).
What is the emergency treatment for HAE with airway obstruction?
Intravenous C1INH.
Citation: "Purified C1INH can be used either routinely to prevent attack or before known triggers such as surgery or dental work. Purified or recombinant C1INH are effective therapy in terminating acute attacks".
What is the primary effector molecule in the complement system?
C3b.
Citation: "The principal effector molecule, and a focal point of activation for the system, is C3b, the large cleavage fragment of C3".
What is the primary mediator of HAE symptoms?
Bradykinin.
Citation: "Bradykinin is the main mediator responsible for HAE attacks by causing vasodilation and increasing the permeability of the postcapillary venules".
Why is the edema fluid in HAE free of cellular components?
Because it is caused by bradykinin-induced vascular leakage, not an inflammatory response.
Citation: "Bradykinin... causes vasodilation and increasing the permeability of the postcapillary venules by causing contraction of endothelial cells so as to create gaps in the blood vessel wall".
Can Richard’s children pass on HAE?
No, because they do not carry the mutation.
Citation: "Richard subsequently married and had two children. The C1INH level was found to be normal in both children".
Why wouldn’t epinephrine help during an HAE attack?
Because HAE is not mediated by histamine.
Citation: "HAE is not an allergic disease, and attacks are not mediated by histamine".
Which molecule cleaves complement component C3?
C3 convertase.
Citation: "The early part of each pathway is a series of proteolytic cleavage events leading to the generation of a convertase, a serine protease that cleaves complement component C3 and thereby initiates the effector actions of complement".
What symptoms are unique to HAE compared to allergic angioedema?
HAE does not involve itching or hives but may cause erythema marginatum.
Citation: "HAE attacks do not usually involve itching or hives, which is useful to differentiate this disease from allergic angioedema. However, a serpiginous, or linear and wavy, rash (called erythema marginatum) is sometimes seen before the onset of swelling symptoms"
What is the danger of laryngeal swelling in HAE?
Asphyxiation.
Citation: "Laryngeal swelling is most dangerous as it can lead to asphyxiation".
What is the probability of a child inheriting HAE from an affected parent?
50%.
Citation: This answer is inferred based on the autosomal dominant inheritance shown in Richard’s family tree, where affected individuals have a 50% chance of passing the mutation.
What prophylactic treatments are available for HAE?
Routine C1INH infusions and attenuated androgens like danazol.
Citation: "Purified C1INH can be used... routinely to prevent attack or before known triggers... Attenuated androgens, such as danazol, are also indicated for prophylaxis".