Regulation of Hemostasis and Thrombosis
Insights from Murine Models
This issue of Arteriosclerosis, Thrombosis, and Vascular Biology contains the first of a series of articles describing the use of murine models to explore the regulation of hemostasis and thrombosis.
See page 454
Thrombotic complications of atherosclerosis, such as myocardial infarction and stroke, remain the leading cause of mortality in the Western world. Despite advances in therapies such as statins, which retard the progression of atherosclerosis and reduce vascular complications, myocardial infarction and stroke continue to dominate the healthcare system. Thus there is an urgent need to develop effective chronic therapeutic interventions for prevention of these thrombotic vascular complications. Current treatment is limited in part because of insufficient knowledge regarding the important regulatory factors in atherothrombosis and also because therapies targeting this process may also impair hemostasis leading to bleeding complications. Therapeutic interventions are similarly limited for prophylaxis of deep venous thrombosis and thrombi occurring in the atrial appendages. It is also likely that different factors affect the predisposition to thrombosis in different disease states and vascular beds, and that disease-specific antithrombotic treatments will be necessary.
Because thrombosis appears to be affected by many factors, including circulating blood cells, the vessel wall, blood flow patterns, and many other unknown elements, an in vivo model may be required to accurately assess the impact of potential important regulatory factors. Because mice are particularly amenable to genetic manipulation, the mouse has become a valuable tool to study thrombosis. There are now several models of induced and spontaneous thrombosis available in the mouse. The use of mice to study thrombosis has steadily increased over the last 2 decades as depicted in the Figure.
Thi s series of brief reviews will highlight the potential of the mouse to advance our understanding of vascular thrombosis. The first review in this issue by Tollefsen will demonstrate the utility of mouse models toward characterizing the physiological relevance of a serpin with thrombin inhibitory activity, heparin cofactor II, and how these studies have enhanced our knowledge of the underlying antithrombotic mechanisms of this protein. Other reviews will demonstrate how mouse models have elucidated the physiological impact of other putative regulators of coagulation as well as platelet adhesion molecules. The availability of various thrombosis models and the capacity of different models to address disease-specific questions will also be addressed. In addition, molecular imaging of dynamic thrombus formation in mice will be covered as this technology may provide direct evidence of the sequence of events and spatial orientation of the various molecules and cell types involved in a forming thrombus. Another review will describe how mice are being used to explore the pathogenesis of a common complication of heparin therapy, heparin-induced thrombocytopenia. Although most investigations using mice have involved assessing the impact of a specific genetic alteration in mice, there may also be utility in determining the potential of cardiovascular risk factors on a thrombotic endpoint in mice. Because the mechanisms by which many factors increase MI and stroke are not clear, it is possible that some of these factors directly affect thrombosis. For example, animal models will be reviewed that demonstrate effects of obesity, diabetes, dietary interventions, inflammation, and elevated homocysteine on thrombosis. In addition to directly showing the impact of these complex perturbations on a thrombotic end point, these phenotypes will be amenable to molecular and genetic dissection using mice, and new therapeutic targets may be identified.
Mouse models of thrombosis have already had a large impact toward our understanding of thrombosis regulation. The rate at which this area of research is progressing will likely translate into new therapeutic interventions for the prevention of arterial and venous thrombotic disease in the near future.