Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis

Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 37232, USA.
Blood (Impact Factor: 10.45). 02/2006; 107(1):132-4. DOI: 10.1182/blood-2005-07-2681
Source: PubMed


Hepatic veno-occlusive disease (VOD) is a common complication of high-dose chemotherapy associated with bone marrow transplantation. While the pathogenesis of VOD is uncertain, plasminogen activator inhibitor-1 (PAI-1) has emerged as a diagnostic marker and predictor of VOD in humans. In this study, we investigated the role of PAI-1 in a murine model of VOD produced by long-term nitric oxide synthase inhibition using L-NAME. After 6 weeks, wild-type (WT) mice developed extensive fibrinoid hepatic venous thrombi and biochemical evidence of hepatic injury and dysfunction. In contrast, PAI-1-deficient mice were largely protected from the development of hepatic vein thrombosis. Furthermore, WT mice that received tiplaxtinin, an antagonist of PAI-1, were effectively protected from L-NAME-induced thrombosis. Taken together, these data indicate that NO and PAI-1 play pivotal and antagonistic roles in hepatic vein thrombosis and that PAI-1 is a potential target in the prevention and treatment of VOD in humans.

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    • "It has been proposed to be an early marker of VOD diagnosis both in pediatric and adult HSCT patients [11, 12]. PAI-1 inhibitor could prevent hepatic venous injury in murine models, and PAI-1-deficient mice were protected largely from VOD [27]. Some investigators also reported an elevated level of PAI-1 or t-PA/PAI in TA-TMA [14, 15]. "
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