Novel Murine Venous Thromboembolism Model to Evaluate Role of Factor XIII in Pulmonary Embolism Risk
ISTH Academy. Kattula S. Jul 10, 2019; 273797; OC 74.1 Topic: Fibrinogen & Factor XIII
Sravya Kattula
Sravya Kattula
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OC 74.1

Novel Murine Venous Thromboembolism Model to Evaluate Role of Factor XIII in Pulmonary Embolism Risk

S. Kattula, A. Silver, A. Matrai Boulle, G. deRidder, B. Cooley, A. Wolberg
UNC Chapel Hill, Chapel Hill, United States

Main Topic: Fibrinolysis and Proteolysis
Category: Fibrinogen & Factor XIII

Background: Venous thrombosis and pulmonary embolism (PE), collectively venous thromboembolism, cause high morbidity and mortality. Factor XIII (FXIII) crosslinks fibrin and promotes red blood cell (RBC) retention in contracted thrombi, increasing thrombus size and stability. FXIII-mediated fibrin stabilization may also influence PE risk. Elucidating FXIII's role in PE is limited by the lack of models that recapitulate human PE characteristics.
Aims: Develop a model that permits embolization of fibrin- and RBC-rich thrombi formed in static blood. Determine the contribution of FXIII to PE risk.
Methods: We characterized the composition of human PEs and compared these to wild-type mouse venous thrombi (electrolytic, ferric chloride, inferior vena cava [IVC] stasis, and IVC stenosis), and mouse PEs generated by intravenous thrombin infusion (TI) or IVC stasis with subsequent ligature removal to permit embolization (LR model). We determined PE incidence in F13a+/+, F13a+/-, and F13a-/- mice subjected to the TI or LR models.
Results: Femoral vein electrolytic and ferric chloride injury rapidly produced small thrombi with few RBCs (5% and 4%, respectively), whereas IVC stasis and stenosis produced slower-forming, large thrombi with higher RBC content (68% and 76%, respectively), similar to human PEs (68%). Although F13a+/+, F13a+/-, and F13a-/- mice had similar PE incidence (60%, 67%, and 70%, respectively) in the TI model, PE were small, with low RBC content (≤ 7%), unlike human PEs. The LR model permitted embolization of existing RBC-rich thrombi, resulting in large PEs. In the LR model, compared to F13a+/+ (13%), F13a+/- and F13a-/- mice had similar or increased PE incidence (17% and 64%, respectively).
Conclusions: The TI model produces microthrombi histologically-dissimilar to human PEs. The LR model produces fibrin- and RBC-rich PEs similar to human PEs. Complete FXIII deficiency increases PE incidence, but partial deficiency does not. Partial FXIII reduction may beneficially decrease VT burden without increasing PE.

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