**3. C1‐inhibitor deficiency**

C1‐INH is a serine protease inhibitor (serpin) that regulates the following closely interrelated proteolytic pathways: complement system, coagulation system, contact system, and fibrinolysis system [12, 13] (**Figure 2**). It is also known as SERPING1, belongs to the SERPIN superfamily, and is mainly synthesized in hepatocytes [9].

First, C1‐INH inhibits C1r, C1s, and mannose‐binding‐lectin‐associated serine proteases (MASP1, MASP2) in the complement system. The inhibition of C1r and C1s is the function that gives name to this protein, "C1 inhibitor." The C1 fraction of complement, also known as C1 esterase, is the first protein of the complement system, and circulates in an inactive form. C1 esterase is activated during immunological processes, initiating the complement cascade and splitting off proteins from the classical pathway (C4 and C2) [9]. In patients with C1‐INH deficiency, an increase in C1 esterase functioning produces decreased C2, C4 levels, the natural substrates of the complement C1s fraction, which diminish much more during AE attacks [9]. C3, the protein that follows C2 in the classical complement cascade, is usually normal in patients with C1‐INH‐HAE, since it is not controlled by C1‐INH [9].

**Figure 2.** C1‐INH regulates different pathways: (A) complement system, (B) contact system, and (C) fibrinolysis system.

Besides, C1‐INH inhibits factor XI and thrombin in the coagulation system and tissue plas‐ minogen activator and plasmin in the fibrinolytic system [9].

Finally, C1‐INH also inhibits factor XII and kallikrein in the contact system, being the main inhibitor of the contact system and of BK formation [9]. This is the crucial action involved in AE development when C1‐INH is lacking.

C1‐INH deficiency can produce an activation of the four described cascades, with a final increase in BK. BK produces vascular hyperpermeability and edema formation [9].

C1‐INH is the most potent inhibitor of the contact system and thus low C1‐INH function can activate this system, with uncontrolled activation of FXII and increased formation of kallikrein. Kallikrein releases BK from high‐molecular‐weight kininogen (HMWK). The lack of C1‐INH also produces an increase in plasmin through the activation of the fibrinolytic system. The split of BK from HMWK induced by kallikrein is facilitated by the presence of plasmin [9].

C1‐INH is a glycoprotein with 478 amino acids. It is heavily glycosylated (approximately 30% by weight). Its apparent molecular weight on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE) is 104 kilodalton (kDa), but its calculated molecular weight is 76 kDa. It is formed by an N‐terminal domain of 113 amino acids and a serpin domain of 365 amino acids [14].

The genetic study of *SERPING1* gene, which codes C1‐INH, has identified more than 300 different mutations causing C1‐INH‐HAE [7].

There are classically two main types of AE due to C1‐INH deficiency: hereditary (C1‐INH‐HAE) and acquired (C1‐INH‐AAE). In turn, two types of C1‐INH‐HAE [9] have been described; in patients with type I (85%) there is decreased antigenic C1‐INH (consequently resulting in decreased functional activity); type II (15%) is characterized by normal C1‐INH levels with decreased functional C1‐INH (the molecule being dysfunctional) [9]. The acquired subtype is characterized by low levels of either antigenic and/or functional C1‐INH, associated in most cases with B‐cell lymphoproliferative disorders.

Hereditary or acquired deficiency of C1‐INH is characterized by recurrent episodes of circum‐ scribed, non‐itchy AE in submucosal or subcutaneous locations. AE attacks can be triggered by estrogens, trauma, infection, or stress.
