ACTIVATION OF THE COAGULATION CASCADE IN C1-INHIBITOR DEFICIENCIES

Activation of the contact and complement systems in C1-inhibitor defic iencies is thought to contribute to the pathogenesis of angioedema att acks by releasing kinins. Trigger stimuli of attacks may also activate coagulation. This is particularly important because experimental data suggest that thrombin, the main enzyme of the coagulation cascade, in creases vascular permeability and can thus influence edema formation. We have studied 19 patients with hereditary angioedema (HAE) during re mission, 5 HAE patients during acute attacks, and 6 patients with acqu ired angioedema (AAE) during remission and during seven attacks, Thirt y normal subjects, matched for sex and age, served as controls, Genera tion of thrombin was measured by enzyme-linked immunosorbent assay (EL ISA) as plasma levels of the prothrombin fragment 1 + 2 (F1 + 2); the initiators of the tissue factor and contact coagulation pathways were investigated by measuring plasma levels of activated factor VII (FVIIa ) coagulometrically and activated factor XII (FXIIa) by ELISA. Cleavag e of high molecular weight kininogen (HK) was evaluated by immunoblott ing analysis. F1 + 2 was slightly increased during remission and furth er significantly increased during attacks in both HAE (P =.0115) and A AE. FVIIa and FXIIa, normal during remission, increased strikingly dur ing attacks in both HAE (P =.0022 and P =.0044) and AAE, During remiss ion, cleaved HK was normal in HAE and high in AAE; during attacks it i ncreased in HAE (P =.0008) and remained elevated in AAE. Our data indi cate that in C1-inhibitor deficient patients there is increased genera tion of thrombin during attacks, with signs of activation of both the contact and tissue factor coagulation pathways. In conclusion, C1-inhi bitor deficiency, whether hereditary or acquired, has demonstrable act ivation of the coagulation and kinin-forming cascades during attacks a nd that thrombin should be considered a possible contributing factor i n the pathogenesis of edema in HAE and AAE. (C) 1997 by The American S ociety of Hematology.