Blood-borne tissue factor (TF) plays a key role in thrombosis, challenging the traditional view that TF is primarily found in the vascular wall. This study shows that TF is present in circulating blood and can initiate thrombosis without requiring exposure of TF at the site of vascular injury. Using perfusion systems with pig arterial media and collagen-coated glass slides, the researchers found that thrombi formed in these systems were intensely stained for TF, much of which was not associated with cells. Antibodies against TF reduced thrombus formation, indicating that TF in blood is thrombogenic. TF was also found in leukocytes, suggesting they are the main source of blood-borne TF. Immunoelectron microscopy revealed TF-positive membrane vesicles near platelet surfaces, indicating that TF may be released from leukocytes into the bloodstream. TF activity was measured in blood and plasma, showing that it is present in circulating blood and can initiate coagulation. The study suggests that blood-borne TF can propagate thrombi by depositing on platelets in the nascent thrombus, forming "TF-platelet hybrids." This process may enhance thrombus propagation by generating coagulation factors on TF-containing microvesicles. The findings challenge the traditional view of thrombosis initiation and suggest that blood-borne TF is inherently thrombogenic and may play a significant role in thrombus propagation. The study also highlights the potential of anti-TF therapies as effective antithrombotic agents without causing bleeding. Overall, the research provides new insights into the role of blood-borne TF in thrombosis and its implications for understanding and treating thrombotic disorders.Blood-borne tissue factor (TF) plays a key role in thrombosis, challenging the traditional view that TF is primarily found in the vascular wall. This study shows that TF is present in circulating blood and can initiate thrombosis without requiring exposure of TF at the site of vascular injury. Using perfusion systems with pig arterial media and collagen-coated glass slides, the researchers found that thrombi formed in these systems were intensely stained for TF, much of which was not associated with cells. Antibodies against TF reduced thrombus formation, indicating that TF in blood is thrombogenic. TF was also found in leukocytes, suggesting they are the main source of blood-borne TF. Immunoelectron microscopy revealed TF-positive membrane vesicles near platelet surfaces, indicating that TF may be released from leukocytes into the bloodstream. TF activity was measured in blood and plasma, showing that it is present in circulating blood and can initiate coagulation. The study suggests that blood-borne TF can propagate thrombi by depositing on platelets in the nascent thrombus, forming "TF-platelet hybrids." This process may enhance thrombus propagation by generating coagulation factors on TF-containing microvesicles. The findings challenge the traditional view of thrombosis initiation and suggest that blood-borne TF is inherently thrombogenic and may play a significant role in thrombus propagation. The study also highlights the potential of anti-TF therapies as effective antithrombotic agents without causing bleeding. Overall, the research provides new insights into the role of blood-borne TF in thrombosis and its implications for understanding and treating thrombotic disorders.