A new study by Shida et al provides an elegant explanation for how vessel wall injuries are repaired without occluding the vessel.
The hemostatic repair of damaged endovasculature resembles an intricate symphony orchestrated by platelets and a variety of plasma proteins, all tightly regulated to prevent lumen occlusion and thromboembolism. One key player in this symphony, von Willebrand factor (VWF), functions to bridge exposed collagen on damaged subendothelial surfaces to receptors on circulating platelets and to bridge platelets to each other as the thrombus grows.1 Its ability to perform both tasks relates to the size of its multimers and exposure to shear stress.
VWF is synthesized in only 2 cell types, endothelial cells and megakaryocytes, and is released constitutively by endothelial cells or from storage granules of endothelial cells or platelets in response to secretagogues. The VWF newly released from granules is enormous (hence the designation ultra-large VWF or ULVWF) and hyperadhesive.2 ADAMTS13 rapidly converts ULVWF to smaller and less adhesive species through proteolytic cleavage at the peptide bond Y1605-M1606 within the A2 domain. Proteolysis is enhanced by shear stress3 and by platelet binding.4 Shear stress is also one of the variables that enhances the binding of plasma VWF to platelets.5 In this issue of Blood, Shida and colleagues provide a fascinating explanation for how shear stress can facilitate platelet thrombus formation while simultaneously limiting thrombus growth. In a simple and elegant experiment, the investigators examined the contribution of ADAMTS13 activity to the growth of platelet thrombi at different shear stresses. They perfused blood over a collagen-coated surface in a perfusion chamber and used 2 very valuable monoclonal antibodies to probe ADAMTS13 functions: one that blocked ADAMTS13 activity and one that bound only after ADAMTS13 cleaved VWF (N10). As expected, ADAMTS13 blockade increased thrombus growth rate and volume concurrent with decreased N10 antibody binding. When ADAMTS13 was unopposed, N10 binding increased, indicating increased VWF cleavage in the smaller thrombi that resulted, a phenomenon that became more pronounced with increased shear stress. N10 staining also increased with increased distance from the base of the thrombus, being greatest at the surface. Extrapolated to a high-shear mural thrombus in vivo, these results suggest that as shear stress increases by progressive luminal narrowing, so does cleavage of VWF by ADAMTS13. Thus, not only does ADAMTS13 control VWF reactivity by reducing the size and reactivity of its ultra-large forms, it also acts on the form of VWF normally found in plasma as it participates in the buildup of thrombi.
These findings suggest a mechanism that allows repair of vessel wall defects without the repair process completely occluding the vessel. They also provide further insight into the pathophysiology of the most extreme manifestation of ADAMTS13 deficiency: thrombotic thrombocytopenic purpura (TTP). In TTP, ADAMTS13 deficiency may have 2 important but distinct roles: first, it allows ULVWF to linger on the vessel wall and bind the first layer of platelets; and second, it is unable to prevent platelets that attach to the thrombus subsequently from completely occluding the vessel.
This elegant study also demonstrates that experiments need not be particularly complicated in nature or technologically difficult to provide mechanistic insights; they just have to be carefully considered.
Conflict-of-interest disclosure: The authors declare no competing financial interests. ■
