Combined tissue factor pathway inhibitor and thrombomodulin deficiency produces an augmented hypercoagulable state with tissue‐specific fibrin deposition

• Published in: Journal of thrombosis and haemostasis Vol. 6; no. 1; pp. 111 - 117
• Main Authors: MARONEY, S. A., COOLEY, B. C., SOOD, R., WEILER, H., MAST, A. E.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-01-2008
• Subjects: Animals; Cerebrovascular Circulation; Female; fibrin; Fibrin - metabolism; Genotype; Lipoproteins - deficiency; Lipoproteins - genetics; Liver - blood supply; Mice; Microcirculation; Organ Specificity; Placenta - blood supply; Pregnancy; Pregnancy Outcome; thrombomodulin; Thrombomodulin - deficiency; Thrombomodulin - genetics; Thrombophilia - etiology; thrombosis; tissue factor pathway inhibitor
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2007.02817.x

Background and Objective: Tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) are endothelial‐associated anticoagulant proteins thought to control hemostasis in specific vascular beds. Here, we have examined the consequences of TFPI deficiency in the presence of a compounding procoagulant state caused by reduced TM function.
Methods and results: TFPI+/−/TMpro/pro mice are born at less than expected frequency in either TFPI+/−/TMpro/+ or TMpro/pro mothers but are born at near the expected frequency in TMpro/+ mothers. Adult TFPI+/−/TMpro/pro mice have elevated thrombin–antithrombin complex and increased thrombus volume in an electrical injury model of venous thrombosis. In striking contrast to mice with single deficiency of TFPI or TM, TFPI+/−/TMpro/pro mice exhibit augmented fibrin deposition not only in the liver, but also in the cerebral microvasculature.
Conclusions: TFPI+/−/TMpro/pro mice exhibit partial intrauterine lethality when carried by mothers with an underlying prothrombotic state, providing the first experimental evidence in an animal model that TFPI‐dependent control of hemostasis in the vascular bed of the placenta fulfills a critical role for successful pregnancy outcome. In addition to the placenta, partial TFPI deficiency interacts with decreased TM function in an organ selective manner to produce fibrin deposition in other specific vascular beds, the liver and brain.