Journal
BLOOD
Volume 126, Issue 19, Pages 2247-2253Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-06-653162
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Funding
- Ministry of Health, Labour and Welfare of Japan
- Japan Society for the Promotion of Science
- Mitsubishi Pharma Research Foundation
- Japan Cardiovascular Research Foundation
- Uehara Memorial Foundation
- National Institutes of Health, National Heart, Lung, and Blood Institute [HL31950, 21544]
- Takeda Scientific Foundation
- Grants-in-Aid for Scientific Research [25440060, 25461465] Funding Source: KAKEN
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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 similar to 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.
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