Activation of the coagulation cascade in C1-inhibitor deficiencies
M Cugno, M Cicardi, B Bottasso, R Coppola, R Paonessa, PM Mannucci and A Agostoni
Institute of Internal Medicine, University of Milan, Italy.
Activation of the contact and complement systems in C1-inhibitor
deficiencies is thought to contribute to the pathogenesis of angioedema
attacks 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,
increases vascular permeability and can thus influence edema formation. We
have studied 19 patients with hereditary angioedema (HAE) during remission,
5 HAE patients during acute attacks, and 6 patients with acquired
angioedema (AAE) during remission and during seven attacks. Thirty normal
subjects, matched for sex and age, served as controls. Generation of
thrombin was measured by enzyme- linked immunosorbent assay (ELISA) 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. Cleavage of high molecular
weight kininogen (HK) was evaluated by immunoblotting analysis. F1 + 2 was
slightly increased during remission and further significantly increased
during attacks in both HAE (P = .0115) and AAE. FVIIa and FXIIa, normal
during remission, increased strikingly during attacks in both HAE (P =
.0022 and P = .0044) and AAE. During remission, cleaved HK was normal in
HAE and high in AAE; during attacks it increased in HAE (P = .0008) and
remained elevated in AAE. Our data indicate that in C1-inhibitor deficient
patients there is increased generation of thrombin during attacks, with
signs of activation of both the contact and tissue factor coagulation
pathways. In conclusion, C1-inhibitor deficiency, whether hereditary or
acquired, has demonstrable activation of the coagulation and kinin-forming
cascades during attacks and that thrombin should be considered a possible
contributing factor in the pathogenesis of edema in HAE and AAE.
Volume 89,
Issue 9,
pp. 3213-3218,
05/01/1997
Copyright © 1997 by The American Society of Hematology
