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Summaries of Findings

Paper I
Hereditary angioedema. New clinical observations and autoimmune screening, complement and kallikrein-kinin analyses.
Thirty-one affected members were identified. Through examples of inciting events and symptoms the study confirms the wide variation in symptomatology and the difficulty in taking general precautions. An extensive biochemical autoimmune screening did not show positive tests more frequently in affected members. HAE may be symptomatic in infancy. Symptoms of urinary tract infections during attacks and heartburn or ulcer is common. Sex-hormones seriously influence the character of the disease. Original observations indicate a role of HAE in provoking premature labour.

Paper II
Effect of time, temperature and additives on a functional assay of C1 inhibitor.
The functional C1-INH test with methylamine eliminates any disturbing effect of a variable alpha-2-macroglobulin concentration. After incubations of fresh plasma samples with different additives at different time and temperature conditions, it was found that the functional assay will discriminate well between normals and patients suffering from C1-INH deficiency. This was of interest as samples from family members living in remote areas were to be examined, and the findings suggest that serum samples sent by ordinary mail can be used.

Only a modest influence of temperature was demonstrated in these samples. The known experience of cold promoted activation of some normal plasma or sera which falsely yield low C1-INH functional values, also experienced in our laboratory, is discussed. We advise the keeping of samples at room temperature prior to analysis. Citrated plasma is significantly diluted proportional to the hematocrit, a fact that should be kept in mind when comparing reference intervals. Heparin or polybrene added to plasma gave falsely high or low C1-INH functional values, respectively.

Paper III
C1 Inhibitor and diagnosis of hereditary angioedema in newborns.
By establishing a functional assay for C1-INH and by utilising a reliable sampling procedure, reference intervals for C1-INH function in newborns were derived for the first time. The diagnosis of HAE was made in a newborn child. A new C4 activation assay and novel clinical observations of HAE in a baby were presented that validated the findings. The importance of providing adequate treatment to babies suffering from C1-INH deficiency was demonstrated.

Paper IV
C3 is activated in hereditary angioedema and C1/C1-inhibitor complexes rise during physical stress in untreated patients
The study was undertakened as physical exercise is known to incite bouts of angioedema, and several of the tests we wanted to apply necessitated that samples were analysed instantly. During analyses of the data it became clear that the intake of small doses of danazol as prophylaxis in two of the patients had profound effects on their biochemical parameters. The exercise provoked a significant increase of complexes between C1 and C1-INH only in untreated patients. It is shown that a substantial part of the low amount of C4 in HAE patients in fact consists of activation products. The study also demonstrated directly for the first time a modest activation of C3 in HAE patients, independent of exercise. The broad investigation by reliable and sensitive assays in the coagulation, white cells and the fibrinolytic systems did not disclose an influence of C1-INH deficiency on these systems during moderate physical stress.

Paper V
Factor VIIa in patients with C1-inhibitor deficiency.
Unopposed factor XIIa in HAE patients could theoretically activate factor VII. This was investigated by a completely new method, which for the first time reliably could measure the amount of FVIIa formed in vivo. Compared to 23 normal relatives, 21 remission HAE patients had nearly two-times higher FVIIa levels.

Paper VI
Activation of the complement, coagulation, fibrinolytic and kallikrein-kinin systems during attacks of hereditary angioedema.
The sensitivity of the new C4bc assay and particularly the ratio C4bc/C4 as shown in papers III and IV, was once again visualised by the ability to characterise attacks. Statistically significant rise of C1/C1-INH complexes during attacks is shown. The paper further examines how multiple cascade systems act in concert during attacks in HAE patients, and signs of activation of all 4 cascades could be demonstrated. By novel assays terminal complement activation was shown for the first time in hereditary angioedema, as was a modest activation of the coagulation system. By originally applying recently developed assays for FXI/serpin complexes, activation via FXI was not found in HAE patients.

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