Thrombin Generation in Hemorrhage Control and Vascular Occlusion

Hippocrates and Aristotle recognized that blood clots outside the body, but it was not until 1720 that John Louis Petit recognized that control of hemorrhage after amputation was associated with the blood clotting process.1 One hundred thirty-eight years later, Rudolph Virchow formulated his postulates regarding clots in venous thrombosis.2 The association of blood clots with acute arterial occlusion was advanced by James B. Herrick3 in 1912, but the significance of blood clotting in acute arterial events was only resolved by studies in the 1980s.4–6 As a consequence, our knowledge base has largely been driven by studies of the hemostatic process that have been extrapolated to describe the pathological occlusive clotting events in venous and arterial thrombosis.Vascular integrity and blood fluidity are maintained by complex interplay between procoagulant and anticoagulant properties provided by the blood, the vasculature, and subvascular elements. Our knowledge of the inventory and connectivity between the blood-supplied components of the hemostatic and anticoagulant matrix was initially provided by genetic accidents that produced hemostatic and thrombotic defects, most of which have been ratified by experiments conducted with transgenic mice. Additional blood and vascular elements were discovered by use of in vitro assays that identified new entities and required additions to the coagulation/anticoagulation circuits. Pathways for the clotting process were described that were dependent on the plasma coming into contact with a foreign surface (the intrinsic pathway)7–9 or that were associated with the introduction of tissue components (now identified as membrane displayed tissue factor [TF]) into the plasma (the extrinsic pathway; Figure 1A).10,11 However, the absence of bleeding pathology with individuals or transgenic mice that display molecular abnormalities in the factor (F) XII12 and high-molecular-weight kininogen13 components of the contact enzyme (dotted box in …