Hemostatic/fibrinolytic protein changes in C3H/HeN mice infected with Rickettsia conorii--a model for Rocky Mountain spotted fever
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Published on: June 29, 2015
A H Schmaier1, S Srikanth, M T Elghetany
1Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0640, USA. aschmaie@umich.edu
Abstract:
Changes in plasma hemostatic and fibrinolytic proteins were determined during courses of a murine model of fatal and non-fatal Rocky Mountain spotted fever. C3H/HeN mice were infected with Rickettsia conorii and coagulation and histopathologic studies were performed at prescribed periods of time. A significant decrease in plasma factor VIII activity and rise in plasma factor V procoagulant activity correlated with a fatal infection. Factor VII levels were unchanged; factor XI levels dropped early in the course in the lethally infected animals, but returned to normal. Factor XII, high molecular weight kininogen, and prekallikrein levels were unchanged by the sublethal infection. Prekallikrein levels fell during the lethal infection. Antithrombin concentrations were decreased significantly in all animals, but plasma plasminogen levels did not change in either group of animals. Nonocclusive thrombi were microscopically observed rarely and only in animals surviving a sublethal infection. A fall in tissue plasminogen activator activity and a rise in plasminogen activator inhibitor activity highly correlated with a lethal outcome. Lethal infection with R. conorii is associated with primary endothelial cell injury resulting in decreased tissue plasminogen activator and increased plasminogen activator inhibitor.
Insights
Fatal Rocky Mountain spotted fever in mice involves significant changes in blood clotting proteins, including decreased factor VIII and increased factor V. Lethal outcomes correlate with reduced tissue plasminogen activator and increased plasminogen activator inhibitor.
Area of Science:
- Hematology
- Infectious Diseases
- Vascular Biology
Background:
- Rocky Mountain spotted fever (RMSF) is a severe tick-borne illness caused by Rickettsia rickettsii.
- Understanding the hemostatic and fibrinolytic alterations in RMSF is crucial for predicting disease severity.
- Murine models provide valuable insights into the pathogenesis of infectious diseases.
Purpose of the Study:
- To investigate the dynamic changes in plasma hemostatic and fibrinolytic proteins during fatal and non-fatal Rocky Mountain spotted fever (RMSF) in a murine model.
- To correlate specific protein level alterations with disease outcome.
- To elucidate the role of endothelial cell injury in the pathogenesis of lethal RMSF.
Main Methods:
- C3H/HeN mice were infected with Rickettsia conorii to establish models of fatal and non-fatal RMSF.
- Coagulation and histopathologic studies were conducted at predetermined time points.
- Plasma levels of various coagulation factors (e.g., Factor V, Factor VIII, Factor VII, Factor XI, Factor XII), kininogen, prekallikrein, antithrombin, and fibrinolytic proteins (plasminogen, tissue plasminogen activator, plasminogen activator inhibitor) were measured.
Main Results:
- A significant decrease in plasma factor VIII activity and a rise in plasma factor V procoagulant activity were observed in mice with fatal infections.
- Prekallikrein levels fell during lethal infection, while Factor XII, high molecular weight kininogen, and prekallikrein levels were unchanged in sublethal infections.
- A fall in tissue plasminogen activator activity and a rise in plasminogen activator inhibitor activity strongly correlated with a lethal outcome, suggesting primary endothelial cell injury.
Conclusions:
- Lethal Rocky Mountain spotted fever in this murine model is associated with specific alterations in the coagulation and fibrinolytic systems.
- Decreased tissue plasminogen activator and increased plasminogen activator inhibitor point to endothelial dysfunction as a key mechanism in fatal infections.
- These findings highlight the potential for targeting hemostatic and fibrinolytic pathways in managing severe RMSF.
