SELECTED ARTICLES FROM THE RECENT LITERATURE 2003

12/5/03

Protease inhibitor therapy in hereditary angioedema

Summary
Although hereditary angioedema (HAE) is a very uncommon disorder, it can cause considerable morbidity and even morta;lity. HAR has also taught us much about the interaction of the complement, coagulation, and bradykin generating systems. The basic defect in congenital HAE is in either deficient production of the C1 inhibitor (85% of cases) or production of a dysfunctional C1 inhibitor (C1 INH) molecule (15% of cases). There are also unusual acquired variants of HAE The major therapeutic approach in HAE has been to either stimulate production of C1 INH or replace it with a C1 INH concentrate (not yet FDA approved for use in the USA); see Arch Intern Med 2001;161:714-18).

However, it has been found that the pathogenic effect of C1 INH deficiency/dysfunction is due mainly to a loss of inhibition of proteases of the contact activation system leading to activation of the kallikrein-kinin, and coagulation/fibrinolytic systems. Ritchie of the Univ. of Alberta in Canada recently reviewed the therapeutic use of inhibitors of such proteases. Aprotonin, a potent inhibitor of kinin activation, contact activation, and plasmin activation is useful in treating acute angioedema episodes in HAE. Two drugs with anti-fibrinolytic activity (tranexamic acid and aminocaproic acid) are also effective in the treatment of acute HAE exacerbations. Indeed, these agents are more effective than treatment with exogenous C1 INH concentrate in the "acquired (autoimmune)" variant of HAE because the donated C1 INH is consumed very rapidly in such variant HAE. Tranexamic acid and aminocaproic acid are potent inhibitors of plasmin, a major trigger of kinin formation/release in HAE acute episodes. However, aprotonin is immunogenic and can cause allergic reactions including anaphylaxis with repeat treatment, limiting its use.

New compounds for inhibiting kallikrein and plasmin activation under current investigation with the hope that a small size molecule inhibitor can be found. Such small molecules are more likely to be feasible for oral administration and are usually not immunogenic.

Reference
Transfusion and Pharesis Science 2003; 29:259-67

Editor's Comments
This article is one of several very good, concise reviews of the pathogenesis, clinical expression and treatment of HAE and related disorders. One can learn much about the biochemical pathways involved in the contact activation, kallikrein-kinin and fibrinolytic systems by reading this article and several others in the special issue of this journal devoted to HAE (listed above).

It is worthy of mention that one has to be quite careful about the doses of either tranexamic acid or aminocaproic acid used to treat HAE acute episodes. Because of their inhibitory effects on plasmin-induced fibrinolysis, there is a risk of thrombotic complications during therapy with these agents.

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