kaolinite and Angioedemas--Hereditary

Mutations in Factor XII, plasminogen gene, angiopoietin-1 gene and kininogen 1 gene have been found in some patients with hereditary angioedema with normal C1 inhibitor (HAE-nl-C1inh), but the underlying disease mechanisms remain unclear. Additionally, there are no accepted biomarkers for this disease. Because the contact system has been implicated in hereditary angioedema with C1 inhibitor deficiency (HAE-C1inh), we studied the fragmentation patterns of serum glycoprotein 120 (sgp120), a protein that is highly susceptible to cleavage by kallikrein, in 31 HAE-C1inh and 13 HAE-nl-C1inh patient plasma samples. Compared to normal controls, the majority of plasma samples from patients with HAE-C1inh contained fragmented sgp120. These samples also showed increased kallikrein amidolytic activity indicating spontaneous contact system activation. In contrast, most samples from HAE-nl-C1inh patients exhibited intact sgp120. However, if these samples were incubated at 4 °C in plastic, significant sgp120 fragmentation and spontaneous contact system activation were observed. Concurrently, there was C1 inhibitor fragmentation that generated the nonfunctional 94 kD fragment and a reduction in C1 inhibitor function. Normal samples did not show sgp120 or C1 inhibitor fragmentation after incubation. We sequenced sgp120 and found it to be identical to inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4). These results suggest that sgp120 or ITIH4 is cleaved when the contact system is activated and that this cleavage could be used as a biomarker in patients with HAE-nl-C1inh.

Topics: Angioedemas, Hereditary; Biomarkers; Blood Coagulation Factors; Chromatography; Complement Activation; Complement C1 Inhibitor Protein; Factor XII; Humans; Kallikreins; Kaolin; Peptide Fragments; Plasminogen; Plastics; Proteinase Inhibitory Proteins, Secretory; Proteolysis

Factor XII-dependent bradykinin formation is thought to be responsible for the swelling associated with the various forms of C1 inhibitor deficiency, and complement activation is augmented during attacks of swelling.. To further elucidate the interactions of the kinin-forming cascade that lead to complement activation during attacks of swelling and to determine whether fibrinolysis is augmented as well.. We compared spontaneous and kaolin-induced activation of normal plasma with the plasma of patients with hereditary angioedema.. Hereditary angioedema plasma demonstrated augmented factor XII activation, production of factor XIIf, prekallikrein activation, and high-molecular-weight kininogen cleavage, and, as a result, bradykinin formation was markedly increased. Baseline levels of C4a and plasmin-alpha 2 antiplasmin complexes increased, and, on activation with kaolin, levels increased further.. All parameters indicative of activation of the bradykinin-forming cascade are activated in hereditary angioedema plasma vs normal plasma. Production of factor XIIf, demonstrated for the first time in whole plasma, may be responsible for C1 activation based on C4a production. The factor XII-dependent fibrinolytic cascade is also activated.

Topics: alpha-2-Antiplasmin; Angioedemas, Hereditary; Blotting, Western; Bradykinin; Complement Activation; Complement C1 Inhibitor Protein; Complement C4a; Electrophoresis, Polyacrylamide Gel; Factor XII; Factor XIIa; Fibrinolysin; Fibrinolysis; Humans; Kallikreins; Kaolin; Kininogens; Models, Biological; Prekallikrein