FACTOR-XI DEFICIENCY IN ASHKENAZI JEWS IN ISRAEL

Background and Methods. Severe factor XI deficiency, which is relatively common among Ashkenazi Jews, is associated with injury-related bleeding of considerable severity. Three point mutations - a splice-junction abnormality (Type 1), Glu117 --> Stop (Type 11), and Phe 283 --> Leu (Type III) - have been described in six patients with factor XI deficiency. Clinical correlations with these mutations have not been carried out. We determined the relative frequency of the mutations and their association with plasma levels of factor XI clotting activity and bleeding, analyzing the mutations with the polymerase chain reaction and restriction-enzyme digestion. Results. The Type 11 and Type III mutations had similar frequencies among 43 Ashkenazi Jewish probands with severe factor XI deficiency; these two mutations accounted for 49 percent and 47 percent, respectively, of a total of 86 analyzed alleles. Among 40 of the probands and 12 of their relatives with severe factor XI deficiency, patients homozygous for Type III mutation had a significantly higher level of factor XI clotting activity (mean [+/- SD] percentage of normal values, 9.7 +/- 3.8 percent; n = 13) than those homozygous for Type 11 mutation (1.2 +/- 0.5 percent, n = 16) or compound heterozygotes with Type 11/111 mutation (3.3 +/- 1.6 percent, n = 23), as well as significantly fewer episodes of injury-related bleeding. Each of these three groups had a similarly increased proportion of episodes, of bleeding complications after surgery at sites with enhanced local fibrinolysis, such as the urinary tract, or during tooth extraction. Conclusions. Type II and Type III mutations are the predominant causes of factor XI deficiency among Ashkenazi Jews. Genotypic analysis, assay for factor XI, and consideration of the type and location of surgery can be helpful in planning operations in patients with this disorder.