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C1 inhibitor (C1-INH) is known to form complexes with the lectin complement pathway serine proteases MASP-1 and MASP-2. Deficiency of C1-INH is associated with hereditary angioedema (HAE), an autosomal inherited disease characterized by swelling attacks caused by elevated levels of bradykinin. MASP-1 was shown to cleave high m.w. kininogen into bradykinin; therefore, we hypothesized that MASP-1 levels and the quantity of MASP-1/C1-INH complexes might be associated with different paraclinical and clinical outcomes of HAE. We measured MASP-1 serum concentrations and endogenous MASP-1/C1-INH complex levels in 128 HAE patients and 100 controls. Relatively high levels of pre-existing MASP-1/C1-INH complexes were observed in normal serum, and we found that both the serum levels of MASP-1 and the complex formation between MASP-1 and C1-INH were significantly reduced in HAE patients compared with matched controls (p < 0.0001). The level of MASP-1 and MASP-1/C1-INH complexes in HE patients correlated with the level of C1-INH (p = 0.0009 and p = 0.0047, respectively), the level of C4 (p = 0.0084 and p < 0.0001, respectively), and the number of attacks in the year of blood sampling (p = 0.0075 and p = 0.0058, respectively). In conclusion, we show that MASP-1/C1-INH complexes circulate in normal human blood. The levels of MASP-1 and MASP-1/C1-INH complexes are reduced in HAE patients compared with controls. Both MASP-1 and MASP-1/C1-INH complexes are related to the degree of complement C4 consumption, as well as the severity of disease. These results suggest that MASP-1 may exert a previously unrecognized role in the pathophysiology of HAE.

BACKGROUND: The activation of plasma enzyme systems is insufficiently controlled in hereditary angioedema due to the deficiency of C1-inhibitor (C1-INH) (HAE-C1-INH). Recently, it was suggested that the ficolin-lectin pathway (ficolin-LP) might play a more dominant role than the mannose-binding lectin-lectin pathway in the pathomechanism of HAE-C1-INH.OBJECTIVE: Because the role of the ficolin-LP during edematous attacks is still enigmatic, we analyzed its activity during such episodes.METHODS: Thirty-five patients with HAE-C1-INH, who have experienced severe attacks on 106 occasions, were enrolled. We analyzed blood samples drawn during attacks, and obtained 35 samples from the same patients during symptom-free periods. The serum levels of ficolin-2, ficolin-3, MASP-2, ficolin-3/MASP-2 complex, C1-INH, and C4, as well as the extent of ficolin-3-mediated terminal complement complex (FCN3-TCC) deposition, were measured using ELISA-based methods.RESULTS: Levels of MASP-2 and of the ficolin-3/MASP-2 complex were elevated (P < .0001 and .033, respectively), whereas that of FCN3-TCC was lower (P < .0001) during attacks than during the symptom-free period. During symptom-free periods, FCN3-TCC deposition was significantly related to concentrations of ficolin-3 (R = 0.2778; P = .0022), antigenic C1-INH (R = 0.3152; P = .0006), and C4 (R = 0.5307; P < .0001). Both ficolin-3 and MASP-2 levels correlated inversely with the time from the onset of the attack until blood sampling.CONCLUSIONS: There is a marked heterogeneity of the pathomechanism and development of hereditary angioedema attacks in different patients. Our results suggest that the activation of the ficolin-LP may deplete the innately low level of C1-INH and thus, it may contribute to the uncontrolled activation of plasma cascade systems, and thereby to edema formation.

BACKGROUND: The activation of plasma enzyme systems is insufficiently controlled in hereditary angioedema due to the deficiency of C1-inhibitor (C1-INH) (HAE-C1-INH). Recently, it was suggested that the ficolin-lectin pathway (ficolin-LP) might play a more dominant role than the mannose-binding lectin-lectin pathway in the pathomechanism of HAE-C1-INH.OBJECTIVE: Because the role of the ficolin-LP during edematous attacks is still enigmatic, we analyzed its activity during such episodes.METHODS: Thirty-five patients with HAE-C1-INH, who have experienced severe attacks on 106 occasions, were enrolled. We analyzed blood samples drawn during attacks, and obtained 35 samples from the same patients during symptom-free periods. The serum levels of ficolin-2, ficolin-3, MASP-2, ficolin-3/MASP-2 complex, C1-INH, and C4, as well as the extent of ficolin-3-mediated terminal complement complex (FCN3-TCC) deposition, were measured using ELISA-based methods.RESULTS: Levels of MASP-2 and of the ficolin-3/MASP-2 complex were elevated (P < .0001 and .033, respectively), whereas that of FCN3-TCC was lower (P < .0001) during attacks than during the symptom-free period. During symptom-free periods, FCN3-TCC deposition was significantly related to concentrations of ficolin-3 (R = 0.2778; P = .0022), antigenic C1-INH (R = 0.3152; P = .0006), and C4 (R = 0.5307; P < .0001). Both ficolin-3 and MASP-2 levels correlated inversely with the time from the onset of the attack until blood sampling.CONCLUSIONS: There is a marked heterogeneity of the pathomechanism and development of hereditary angioedema attacks in different patients. Our results suggest that the activation of the ficolin-LP may deplete the innately low level of C1-INH and thus, it may contribute to the uncontrolled activation of plasma cascade systems, and thereby to edema formation.

Hereditary angioedema (HAE) is a rare genetic disorder causing a deficiency in C1 esterase inhibitor (C1-INH) that is manifested through unpredictable oedema. We describe a case of a patient with HAE who had previously been refused surgery for tonsillitis due to the potential for oedema, in whom regular monitoring of C1-INH levels combined with intensified therapy with danazol, tranexamic acid and C1-INH concentrate enabled an uncomplicated procedure with no oedema crisis. However, clinicians should be alerted that higher overall dosages of C1-INH concentrate for perioperative prophylaxis may be required than those typically used to treat acute HAE attacks.

Angioedema is a pathologic condition first descrive by Quincke and Osler. It can be genetically determined or acquired, and it is caused by a vascular reaction induced by deficiency or functional alteration of the C1 inhibitor (C1-INH), an enzyme involved in the regulation of complement, contact, fibrinolytic, and coagulation systems. Two forms of angioedema have been described in the literature: hereditary angioedema (HAE) and acquired or idiopathic angioedema (AAE). HAE is characterized by dominant autosomal transmission, early onset, and a positive family history. It is caused by a mutation of the gene for C1-INH, localized on chromosome 11. Type 1 HAE is the most frequent form (85% of cases) and is associated with deficiency of functional C1-INH in plasma (10%-30% of normal values). Type 2 HAE is characterized by normal or elevated plasma levels of dysfunctional C1- INH.8 Type 3 HAE occurs mainly in women. Affected persons display the typical clinical features of C1-INH deficiency but have normal plasma levels and functionality of C1-INH. Mutations in the coagulation factor XII gene have been detected in some of these patients. AAE is characterized by late onset, usually after the fourth decade, and is not associated with a positive family history.6 Type 1 AAE is caused by increate catabolism of C1-INH and is generally associated with a positive history of benign or malignant lymphoproliferative disorders. Type 2 AAE is associated with autoantibodies against C1-INH. Deficiency or dysfunction of C1-INH can cause a deregulation of the fibrinolytic system, of the complement pathway, of the contact system, and of the coagulation cascade, resulting in release of vasoactive substances, an increase in vessel permeability, and development of diffuse edemas. Hereditary and acquired forms of angioedema are clinically indistinguishable. Edemas develop gradually over a period of 12 to 36 hours and require 2 to 5 days to subside completely. The frequency and severity of edem

Angioedema is a pathologic condition first descrive by Quincke and Osler. It can be genetically determined or acquired, and it is caused by a vascular reaction induced by deficiency or functional alteration of the C1 inhibitor (C1-INH), an enzyme involved in the regulation of complement, contact, fibrinolytic, and coagulation systems. Two forms of angioedema have been described in the literature: hereditary angioedema (HAE) and acquired or idiopathic angioedema (AAE). HAE is characterized by dominant autosomal transmission, early onset, and a positive family history. It is caused by a mutation of the gene for C1-INH, localized on chromosome 11. Type 1 HAE is the most frequent form (85% of cases) and is associated with deficiency of functional C1-INH in plasma (10%-30% of normal values). Type 2 HAE is characterized by normal or elevated plasma levels of dysfunctional C1- INH.8 Type 3 HAE occurs mainly in women. Affected persons display the typical clinical features of C1-INH deficiency but have normal plasma levels and functionality of C1-INH. Mutations in the coagulation factor XII gene have been detected in some of these patients. AAE is characterized by late onset, usually after the fourth decade, and is not associated with a positive family history.6 Type 1 AAE is caused by increate catabolism of C1-INH and is generally associated with a positive history of benign or malignant lymphoproliferative disorders. Type 2 AAE is associated with autoantibodies against C1-INH. Deficiency or dysfunction of C1-INH can cause a deregulation of the fibrinolytic system, of the complement pathway, of the contact system, and of the coagulation cascade, resulting in release of vasoactive substances, an increase in vessel permeability, and development of diffuse edemas. Hereditary and acquired forms of angioedema are clinically indistinguishable. Edemas develop gradually over a period of 12 to 36 hours and require 2 to 5 days to subside completely. The frequency and severity of edem