The Role of Activated Thrombin Activatable Fibrinolysis Inhibitor on Thrombus Stability in Venous Thromboembolism

J. Chessum^1,2, S. Shaya^1,2, S. Cerroni^2,3, D. Rajab¹, J. Zhou², J.C.M. Meijers^4,5, J. Weitz^1,2,3,6, P. Gross^1,2,3, P. Kim^1,2,3

¹McMaster University, Hamilton, Canada, ²Thrombosis and Atherosclerosis Research Institute, Hamilton, Canada, ³Department of Medicine, McMaster University, Hamilton, Canada, ⁴Department of Experimental Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, ⁵Department of Molecular Hematology, Sanquin Research, Amsterdam, Netherlands, ⁶Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada

Abstract Number: LPB0064

Meeting: ISTH 2021 Congress

Theme: Fibrinogen, Fibrinolysis and Proteolysis » Fibrinolytic Factors and Inhibitors

Background: Thrombin-activatable fibrinolysis inhibitor (TAFI) levels have been correlated with the risk of thrombosis. However, the role of TAFI in venous thromboembolism (VTE) remains uncertain.

Aims: To determine the effect of TAFI on venous thrombus composition and stability in a murine model.

Methods: Male and female wild-type mice (WT) or TAFI-deficient mice (Cpb2^-/-) were used. Thrombosis in the isolated femoral vein was induced with FeCl₃. The thrombus, labeled with an antibody to platelets, was imaged using fluorescent intravital videomicroscopy at intervals to quantify embolization. Between intervals, thrombus montage images were used to quantify thrombus size. After 2-hours, organs were harvested and examined by histology. Composition of venous thrombi and pulmonary emboli were quantified using fluorescent antibodies against platelet GPIb and fibrin. Pulmonary embolism (PE) burden was assessed by counting the emboli in the lungs. Large emboli were defined as emboli having sizes greater than 4 standard deviations of average emboli size.

Results: Venous thrombus size increased over time only in male Cpb2^-/- and female WT mice. Male Cpb2^-/- mice had 3.7-fold and 5.8-fold more total and large embolic events compared with male WT mice, respectively. Compared with male WT mice, female WT and Cpb2^-/- mice had 10.4-fold and 9.4-fold more total embolic events, respectively, and 8.8-fold and 13.5-fold more large embolic events, respectively. Male Cpb2^-/- mice had 1.5-fold greater PE burden compared with male WT mice, while female Cpb2^-/- had a 2.1-fold greater PE burden than female WT mice. The compositions of clots also differed. Cpb2^-/- mice had more fibrin-rich emboli compared with WT. In venous thrombi, Cpb2^-/- mice exhibited greater platelet presence compared with WT.

Conclusions: Loss of TAFI contributes to thrombus instability, which translates to increased PE burden. Female mice appear to be at greater risk of PE than male mice.

To cite this abstract in AMA style:

Chessum J, Shaya S, Cerroni S, Rajab D, Zhou J, Meijers JCM, Weitz J, Gross P, Kim P. The Role of Activated Thrombin Activatable Fibrinolysis Inhibitor on Thrombus Stability in Venous Thromboembolism [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/the-role-of-activated-thrombin-activatable-fibrinolysis-inhibitor-on-thrombus-stability-in-venous-thromboembolism/. Accessed December 11, 2023.

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