Denser matters

In this issue of Blood, Undas and colleagues show that the structure of the blood clot is altered in patients with venous thrombosis and their relatives compared with healthy controls.¹ 

It was known from previous studies that the structure of the blood clot is different in patients with coronary artery disease²  and their relatives.³  The findings presented in this issue by Undas et al contribute new and important lines of evidence, showing that blood clot structure may play a role in mechanisms of thrombosis. First, the clot characteristics found in the patients with venous thrombosis are similar to those found in patients with arterial thrombosis. They have a denser structure and smaller pores, suggesting that clot structure plays a role in thrombosis in both types of vasculature. Second, in agreement with previous findings in relatives of patients with coronary artery disease³  and peripheral arterial disease,⁴  the relatives of patients with venous thrombosis show clot structure characteristics that are intermediate between those of the patients and the controls, suggesting that genetic or common environmental factors play a role. Finally, the authors found that clot structure of patients with a complicating pulmonary embolism show different features compared with patients with deep vein thrombosis only, indicating a potential role of clot structure in the fragmentation of the thrombus.

It is tempting to speculate on how clot structure may contribute to thrombosis, but some caution is required until more is known about the mechanisms involved. The clot is composed mainly of polymerised fibrin, which is formed when thrombin cleaves fibrinopeptides A and B from fibrinogen. Other proteins and blood cells interact with the fibrin to generate a final blood clot. Clots generated in the arterial circulation are rich in platelets, while clots from the venous circulation are fibrin and erythrocyte rich. Flow has been shown to affect structure of the clot and to produce areas of different architecture in the blood clot.^5,6  It should be noted that in the current study, as was the case with most previous studies, clot structure was investigated ex vivo in the absence of flow and cells. Even so, the finding that similar features of fibrin clot structure associate with thrombosis in both the venous and arterial circulation indicate the existence of a common mechanism by which fibrin structure influences risk for thrombosis regardless of the effects of flow and cells.

Two possible mechanisms by which clot structure may influence the risk for thrombosis stand out from others. One of these involves the response of the clot to endogenous fibrinolytic mechanisms. The structure of the fibrin clot is a major determinant of the efficacy of fibrinolysis. Indeed, Undas et al show that the clots from patients with venous thrombosis are lysed more slowly than those of their relatives, which in turn lyse more slowly than those of the controls.¹  This is in complete agreement with the structural changes that were observed in these subjects. The second potential mechanism involves the response of the clot to mechanical deformation and stress induced by the flow of the blood. Fibrin is one of the most elastic natural polymers known to man.^7,8  The architecture of the fibrin network modulates visco-elastic properties of the clot. Differences in clot structure and elasticity could therefore influence the response of the clot to shear stress and flow, and possibly the risk of embolization. To investigate this, the authors used compaction as an estimate of clot stiffness and observed changes in the patients that correlate with the structural parameters of the fibrin clot.¹  Fibrin structure and compaction were different in the patients with pulmonary embolism, although counterintuitively perhaps they were intermediate to fibrin structure and compaction in the patients with deep vein thrombosis alone and their relatives. Nonetheless, these findings indicate that “brittleness” of the clots may play a role in thromboembolism and suggest that further research is required to fully characterize changes in visco-elastic properties of blood clots.

The implications of the findings presented by Undas et al are that the structure and function of the blood clot are important for thrombosis. Once the molecular mechanisms that underpin the relationship between clot structure and thrombosis have been fully delineated, consideration should be given to the diagnostic potential of characterizing clot structure and to the modulation of clot architecture as a possible treatment for thrombosis.