Activation of the coagulation cascade in C1-inhibitor deficiencies.

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.

Non neutralizing antibodies to tissue type plasminogen activator in the serum of acute myocardial infarction patients treated with the recombinant protein.

Recombinant tissue-type plasminogen activator (rt PA) is currently used as a thrombolytic agent in the management of acute myocardial infarction (AMI). Since it is known that other recombinant proteins induce antibody formation when administered to humans, we determined the presence of anti-rt-PA antibodies in serial blood samples from 60 AMI patients (43 treated with and 17 without rt-PA). Blood samples were taken upon hospital admission, 15 days and 1, 3, 6 months thereafter. A blood sample was also collected from 200 healthy subjects. Using an ELISA, anti-rt-PA antibodies were detected as serum immunoglobulins specifically binding immobilized rt-PA, AMI patients before treatment and normal subjects exhibited negligible levels of anti-rt-PA antibodies; both groups had only one outlier value. Fifteen days after rt-PA treatment, 2 AMI patients showed an increase in antibody titer beyond the highest normal value. This titer progressively decreased during the following 6 months. The antibodies from these two patients bound rt-PA both in a solid and fluid phase. They bound melanoma t-PA to a lower degree and did not bind urokinase type plasminogen activator at all, indicating specificity for t-PA. The marked temporal relationship between rt-PA infusion and antibody appearance indicated that antibody formation had been elicited by the infusion of rt-PA. Nevertheless, the lack of anti-rt-PA antibody interference with rt-PA function in vitro, along with the favourable clinical outcome of those patients having such antibodies would indicate that the appearance of anti-rt-PA antibodies does not interfere with the physiological fibrinolytic activity.

Cleavage of high molecular weight kininogen in ascites and plasma of patients with cirrhosis.

The vasoactive peptide bradykinin may be involved in the pathogenesis of vasodilation, which has been considered the initiating event of ascites formation in cirrhotic patents. Since bradykinin is generated through the cleavage of high molecular weight kininogen (HK) by kallikrein, we looked for the cleavage of HK by an immunoblotting technique in plasma and ascitic fluid of 28 patients with cirrhosis of different etiology. The majority of patients showed massive cleavage of HK in ascitic fluid (median 50% of total HK; range 23-100%). Patients with severe ascites had more cleaved HK in plasma (29%; range 8-38%) than normal subjects (22%; range 11-32) (P = 0.02). Patients with high levels of plasma renin activity (5-60 ng/ml/hour), which is considered a consequence of peripheral vasodilation, had more plasma cleaved HK (31%; range 18-38)(p = 0.0097) than normals. Thus, our data support the view that cleavage of HK could play a role in the pathogenesis of vasodilation and ascites formation in patients with decompensated cirrhosis.