A MURINE MODEL OF FACTOR-XI DEFICIENCY

To facilitate investigations into the physiologic and pathologic roles of factor XI, we have developed a murine model of severe factor XI de ficiency using the technique of homologous recombination in embryonic stem cells. The factor XI gene was disrupted by introducing a neomycin phosphotransferase gene into the fifth exon. The activated partial th romboplastin times of homozygous null mice were prolonged (158- > 200 s) compared with wild type (25-34 s) and heterozygous null (40-61 s) l itter mates. Factor XI activity was absent from the plasma of mice hom ozygous for the null mutation and factor XI mRNA was undetectable by N orthern blot and reverse transcription/PCR in the livers of homozygous null animals. The genotypes of progeny from matings of mice heterozyg ous for the factor XI null allele followed the expected Mendelian rati o (1:2:1, wild type 26%, heterozygote null 54%, homozygous null 20%), indicating that severe factor XI deficiency did not result in increase d intrauterine death. Results of a tail transection bleeding time assa y were similar for wild type and homozygous null animals with, at most , a tendency for slightly prolonged bleeding in the homozygous null an imals. The factor XI deficient mice are a unique tool for evaluating t he role of factor XI in normal hemostasis and pathologic coagulation.