A simple experiment and a weakening paradigm: the contribution of blood to propensity for thrombus formation.

For many years, arterial thrombosis was considered a result of vascular injury combined with a “normal” response of circulating coagulation factors and formed elements. Indeed, the original articles describing tissue factor in atherosclerotic lesions1,2 implied that rupture or erosion of the plaque that results in contact of the circulating blood with plaque-bound tissue factor is sufficient to result in thrombus formation. These formulations ignore the fact that thrombi have been observed to occlude an artery within minutes of vascular perturbations.3 In retrospect, the role assigned to lesion-bound tissue factor is not physically realistic. The implied mechanism of thrombus growth is that surface-bound tissue factor rapidly binds circulating factor VII/VIIa, thereby forming the catalytic complex that proteolytically activates factors IX and X, thereby generating procoagulant intermediates that lead to thrombin production. This necessarily involves the diffusion of these intermediates from surfacebound tissue factor to platelets, where they form the catalytic complexes that directly generate thrombin from prothrombin. While on a microscopic level, these events are certainly accurate; occlusive thrombi are macroscopic structures that can rapidly grow to 3 mm. Consider that a protein of 50 kDa, typical of procoagulant intermediates, would, on average, take some 3 hours to diffuse 1 mm through water. In reality, the diffusion would be obstructed by adherent platelets and fibrin, which would reduce further the effective diffusion rate of these proteins.