Functional characterization of an abnormal factor XII molecule (F XII Bern)

Abstract

An 18-year-old healthy woman was found to have cross-reacting material (CRM)-positive factor XII (F XII) deficiency, F XII clotting activity was less than 0.01 U/mL, whereas F XII antigen was 0.11 U/mL. An F XII inhibitor was excluded. To partially characterize the molecular defect of the abnormal F XII, immunologic and functional studies were performed on the proposita's plasma. The abnormal F XII was a single chain molecule with the same molecular weight (80 Kd) and the same isoelectric points (pl, 5.9 to 6.8) as normal F XII. Dextran sulfate activation of the proposita's plasma showed no proteolytic cleavage of F XII even after 120 minutes, whereas F XII in pooled normal plasma, diluted 1:10 with CRM-negative F XII-deficient plasma, was completely cleaved after 40 minutes. Adsorption to kaolin was identical for both abnormal and normal F XII. In the presence of dextran sulfate and exogenous plasma kallikrein, the abnormal F XII was cleaved with the same rate as normal F XII. However, kallikrein-cleaved abnormal F XII was not able to cleave factor XI and plasma prekallikrein, in contrast to activated normal F XII. Thus, these studies show that the functional defect of this abnormal F XII, denoted as F XII Bern, is due to the lack of protease activity of the kallikrein-cleaved molecule. Therefore, the structural defect is likely to be located in the light chain region of F XII, containing the enzymatic active site.

Comparable Levels of Activity and Antigen in Factor XII Deficiency: A Study of 21 Homozygotes and 58 Heterozygotes

“…By far the most frequent form of FXII deficiency is the true deficiency; that is, patients have no detecteable FXII antigen or CRM in plasma. Only three of the 141 studied showed CRM in their plasmas (8,18). Only one of these patients had normal factor X antigen (factor XII Washington) (8,19,21).…”

“…FXII antigen in all heterozygotes was comparable to the FXII activity level in every instance (average 54% of normal). The careful evaluation of all published articles on this subject showed that altogether 120 patients with homozygous trait with homozygous FXII deficiency met the criteria (12)(13)(14)(15)(17)(18)(19)(20). The total number of normal pa- tients so far investigated from both a clotting and an immunologic point of view apperars to be equal to 141 (Table 1).…”