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Abstract: FVIItTA/− mice are heterozygous for the FVII− null allele and a gene-targeted allele expressing very low levels of FVII. Approximately half the FVIItTA/− in a mixed C57Bl/6:129x1/SVJ background survive much longer than mice in a C57Bl/6 background, suggesting that genetic background affects the survival of mice expressing very low levels of FVII. A lineage of long-term surviving FVIItTA/− mice in a predominantly C57Bl/6 background was generated by selecting 16 weeks or older FVIItTA/− males and breeding them with C57Bl/6 FVII+/− females. It is postulated that these mice maintain 129x1/SVJ alleles at putative hemostatic modifier loci necessary for the survival of mice expressing very low levels of FVII. A SNP genomic scan was performed on DNA from long-term surviving FVIItTA/− mice. The scan identified 8 regions enriched for 129x1/SVJ sequences that might contain putative hemostatic modifier genes. [Copyright &y& Elsevier]

Anticoagulant protein C (PC) is important not only for maintenance of normal hemostasis, but also for regulating the host immune response during inflammation. Because mice with a designed total genetic deficiency in PC (PC-/- mice) die soon after birth, attempts to dissect PC function in various coagulation/inflammation-based pathologies through use of mice with less than 50% of normal PC levels have not been successful to date. In the current investigation, we have used a novel transgenic strategy to generate different mouse models expressing 1-18% of normal PC levels. In contrast to PC-/- mice, mice with only partial PC deficiency survived beyond birth and also developed thrombosis and inflammation. The onset and severity of these phenotypes vary significantly and are strongly dependent on plasma PC levels. Our findings additionally provide the first evidence that maternal PC is vital for sustaining pregnancy beyond 7.5 days postcoitum, likely by regulating the balance of coagulation and inflammation during trophoblast invasion. These low PC-expressing transgenic mouse lines provide novel animal models that can be used to elucidate the importance of PC in maintenance of the organism and in disease. [ABSTRACT FROM AUTHOR]