| First Author | Banno F | Year | 2015 |
| Journal | Blood | Volume | 126 |
| Issue | 19 | Pages | 2247-53 |
| PubMed ID | 26251307 | Mgi Jnum | J:230086 |
| Mgi Id | MGI:5755360 | Doi | 10.1182/blood-2015-06-653162 |
| Citation | Banno F, et al. (2015) Exacerbated venous thromboembolism in mice carrying a protein S K196E mutation. Blood 126(19):2247-53 |
| abstractText | Protein S (PS) acts as an anticoagulant cofactor for activated protein C in regulation of blood coagulation. The K196E mutation in PS is a race-specific genetic risk factor for venous thromboembolism with a prevalence of approximately 2% within the Japanese population. To evaluate the thrombosis risk of the PS-K196E mutation, we generated PS-K196E knockin mice and heterozygous PS-deficient mice. We analyzed their thrombotic states, comparing with mice carrying the factor V Leiden mutation (FV-R504Q), a race-specific genetic risk for venous thrombosis in whites. PS-K196E mice grew normally but had decreased activated protein C cofactor activity in plasma. Purified recombinant murine PS-K196E showed the same decreased activated protein C cofactor activity. A deep vein thrombosis model of electrolytic inferior vena cava injury and pulmonary embolism models induced by infusion of tissue factor or polyphosphates revealed that PS-K196E mice, heterozygous PS-deficient mice, and FV-R504Q mice were much more susceptible to venous thrombosis compared with wild-type mice. Transient middle cerebral artery ischemia-reperfusion injury model studies demonstrated that both PS-K196E mice and heterozygous PS-deficient mice had cerebral infarction similar to wild-type mice, consistent with human observations. Our in vitro and in vivo results support a causal relationship between the PS-K196E mutation and venous thrombosis and indicate that PS-K196E mice can provide an in vivo evaluation system to help uncovering racial differences in thrombotic diseases. |
