Factor XII deficiency, APC-resistance, hyperhomocysteinemia and von Willebrand's disease type 1 in the same family

A young woman presenting with marked menstrual blood loss and prolonged ble eding after only minimal injuries was investigated. Because of an extremely prolonged PTT (more than 200 s) we measured the factor XII activity and fo und a severe deficiency. The bleeding symptoms however could be ascribed to the existence of von Willebrands disease type 1. In addition,the patient h ad an elevated resistance against activated protein C (APC-resistance) and a moderately elevated concentration of homocysteine in her blood plasma. At the genomic level we found heterozygosity for the factor V mutation G 1691 A and the mutation C 677 T in the methylenetetrahydrofolate reductase (MTH FR)-gene. The analysis of the factor XII gene revealed the existence of a p oint mutation in the promoter region (G-->C transversion, nt-8). The same m utation could be found in the paternal factor XII gene. The low factor XII activity in the woman seems to be the result of a second mutation originati ng from the maternal factor XII gene (compound heterozygosity). However,thi s second mutation could not be found up to now. In the sister of the women, a 15 year old girl, there is also a marked menstrual blood loss. The coagu lation analysis revealed reduced activities of the factor XII and also von Willebrands disease type 1. The reduced factor XII activity seems to be com patible with the heterozygous state of factor XII deficiency. In the girl t here was also an increased APC resistance, corresponding with heterozygosit y for the factor V mutation G 1691 A. Mother and father are heterozygous fo r the factor XII deficiency and the mutation C 677 T in the MTHFR gene. In the mother homozygosity for the mutation in the factor V gene (1691 AA) cou ld be found. All family members investigated exhibited elevated D-dimer con centrations in the plasma. Discussion: It is the aim of this report to give attention to menorrhagias as predominant features of von Willebrand's disease in females. Furthermore in women with von Willebrand's disease in combination with inherited risk factors for thrombophilia problems could arise from the use of oral contrac eptives and also during pregnancy. In our opinion, physicians, especially p aediatricians, who take care of adolescents, should be familiar with such p roblems.