Hereditary FXI deficiency is a common coagulation disorder in Ashkenazi and Iraqi Jews with a heterozygote frequency of 8% and 3.3%, respectively; however, it is very rarely seen in other ethnic groups, with a frequency of 1:1,000,000 [16
]. Patients with FXI deficiency show mutations in the F11
gene encoding FXI. Type II (Glu117X) and type III (Phe283Leu) mutations are particularly prevalent in the Jewish population, and these 2 mutations account for approximately 95% of F11
mutations among the Jews [17
]. However, a variety of mutations have been reported in other ethnic groups, with those prevalent among Ashkenazi and Iraqi Jews accounting for only a small percentage of the total population of disease alleles [20
]. Currently, the FXI deficiency mutation database contains information on 192 disease-causing mutations of the F11
gene, which was obtained from 487 patients with FXI deficiency reported in the literature [12
Patients with FXI deficiency show wide variation in the manifestation of bleeding symptoms, and these manifestations are largely affected by the genotype and the site of injury. Patients with homozygous mutations usually have severe FXI deficiency (FXI activity <15%), whereas those with heterozygous mutations have mild/partial FXI deficiency (FXI activity, 20-50%) [22
]. However, unlike the findings in hemophilia A and B, spontaneous bleeding is rarely seen even in patients with severe FXI deficiency. The common presentation of severe FXI deficiency is injury- or surgery-related bleeding, especially when the trauma involves anatomical sites with high fibrinolytic activity, such as the oral or nasal cavities, the prostate, and the uterus. In patients with heterozygous mutations, the bleeding risk has not been conclusively determined and is not well predicted by plasma FXI level [23
In Korea, hereditary FXI deficiency is rare, and only 8 cases have been reported [7
]. A history of spontaneous bleeding has not been reported even in patients with severe deficiency, except in 1 case with intermittent nasal bleeding, which was easily controlled. In most of the cases, the diagnosis of FXI deficiency was made on the basis of coagulation test results without molecular genetic study. Only 1 case, in which severe deficiency was observed due to compound heterozygous mutations (Val498Met and Tyr503ValfsX32) of the F11
gene, has been genetically confirmed to date [11
]. The patient showed no spontaneous or postoperative bleeding despite the severely decreased FXI activity (1%). Our patient is the second genetically confirmed case of FXI deficiency and the first genetically confirmed case of mild FXI deficiency in Korea. In this patient, a slightly prolonged aPTT of 45.2 sec was accidentally detected during preoperative screening, and the patient had no personal history of bleeding symptoms. Further coagulation tests and molecular studies revealed that she had mild FXI deficiency with an FXI coagulant activity (FXI:C) of 35% because of a heterozygous novel missense mutation Asp506Gly in exon 13 of the F11
gene, which encodes the catalytic domain of FXI. The results of bioinformatics analysis predicted that Asp506Gly is tolerated or may show damaging effects on FXI function [14
]. Structural analysis shows that this mutation disrupts the hydrogen-bonding interaction with Arg202 on the A3 domain, which is involved in binding interactions with the substrate FIX and is therefore required for the activation of this substrate [24
]. Thus, the mutation may cause a conformational change in the A3 domain, consequently reducing the activity of the FXI protein.
Management of mild/partial FXI deficiency is difficult because of the variability and unpredictability of the bleeding tendency [23
]. Prophylactic treatment is generally not required for patients who do not show hemostatic abnormalities. However, prophylactic treatment with desmopressin could be an option for patients with a history of bleeding [21
]. Coagulation factor concentrates may be required for major surgery [23
]. Our patient has not undergone an operation for the resection of the lipoma on her back; therefore, we need to follow up her clinical course.
In conclusion, we report a novel missense mutation in a catalytic domain of the FXI protein. The Asp506Gly mutation is associated with mild FXI deficiency and did not cause spontaneous bleeding in this case. This is the first report on a genetically confirmed case of mild FXI deficiency in Korea. Few genetically confirmed cases have been reported to date. Additional reports on the relation between coagulation and the FXI deficiency and molecular studies on FXI deficiency are needed to facilitate clinical decision-making.