A 'Double Hit' of Tissue
Factor is Necessary For
Arterial Thrombosis

By Thomas L. Ortel, M.D., Ph.D.

Secondary hemostasis is initiated when factor VII/factor VIIa binds to tissue factor. Historically, tissue factor was considered to be ‘extrinsic’ to the blood, located only in the blood vessel wall. Tissue factor is also expressed on the surface of non-vascular cells, however, and circulates in association with microparticles in the blood. Investigating the unique roles of these

two 'pools' of tissue factor, Dr. Bruce Furie presented the abstract entitled Initiation and Propagation of the Arterial Thrombus In Vivo: Contributions of Vessel Wall and Blood-Borne Microparticle Tissue Factor at the Plenary Session on Sunday. To study the two pools of tissue factor in vivo, the investigators used high-speed intravital digital microscopy with three fluorescence channels to monitor the contributions of platelets, tissue factor, and fibrin to a developing arterial thrombus in a living mouse. They used this technology to study the following mice:

• “Low TF” mice. These mice express no murine tissue factor, but do express very low levels of human tissue factor (~1% normal) in the vessel wall and in the microparticles.
• “Low TF” mice receiving a bone marrow transplant from normal mice. These animals have low levels of tissue factor in the vessel wall, but higher levels in the microparticles from the transplanted marrow cells.
• Normal mice receiving a bone marrow transplant from “low TF” mice. These animals have normal levels of tissue factor in the vessel wall, but low levels in the microparticles from the transplanted marrow cells.

Using these mice and the above approach, the investigators demonstrated the following:

• The “low TF” mice had very few platelets in the clot, with minimal tissue factor and fibrin.
• The “low TF” mouse with a bone marrow transplant from a normal mouse had fewer platelets in the clot, but more normal amounts of tissue factor and fibrin.
• The normal mouse with a bone marrow transplant from the “low TF” mouse had a smaller clot,minimal tissue factor accumulation, and an initial decrease, or delay, in fibrin levels.

These experiments demonstrated that the vessel wall tissue factor and the circulating microparticle tissue factor have distinct roles in the formation of an arterial clot. The tissue factor in the vessel wall promotes initial adherence of the platelets to a surface, whereas the tissue factor in microparticles promotes propagation of the thrombus with fibrin formation. Both functions are essential for normal clot formation.

Of note, Janet Chou, the first author on this abstract, received the 2003 Medical Student Merit Award from ASH for this work. Unfortunately, she was unable to present her work this year due to the snowstorm in Boston, but we are sure that she will continue to make outstanding contributions to hematology!