Abstract
Platelet recruitment to sites of vascular injury is mediated by von Willebrand factor (VWF). The shear-induced unraveling of ultra-large VWF multimers causes the formation of a “stringlike” conformation, which rapidly recruits platelets from the bloodstream. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) regulates this process by cleaving VWF to prevent aberrant platelet adhesion; it is unclear whether the activity of ADAMTS13 itself is regulated. The serine proteases α-thrombin and plasmin have been shown to cleave ADAMTS13. Based on sequence homology, we hypothesized that activated coagulation factor XI (FXIa) would likewise cleave ADAMTS13. Our results show that FXIa cleaves ADAMTS13 at the C-terminal domains, generating a truncated ADAMTS13 with a deletion of part of the thrombospondin type-1 domain and the CUB1-2 domains, while α-thrombin cleaves ADAMTS13 near the CUB1-2 domains and plasmin cleaves ADAMTS13 at the metalloprotease domain and at the C-terminal domain. Using a cell surface immunoassay, we observed that FXIa induced the deletion of the CUB1-2 domains from ADAMTS13 on the surface of endothelial cells. Removal of the C-terminal domain of ADAMTS13 by FXIa or α-thrombin caused an increase in ADAMTS13 activity as measured by a fluorogenic substrate (FRETS) and blocked the ability of ADAMTS13 to cleave VWF on the endothelial cell surface, resulting in persistence of VWF strands and causing an increase in platelet adhesion under flow conditions. We have demonstrated a novel mechanism for coagulation proteinases including FXIa in regulating ADAMTS13 activity and function. This may represent an additional hemostatic function by which FXIa promotes local platelet deposition at sites of vessel injury.
Highlights
After vascular injury, the large glycoprotein (GP) von Willebrand factor (VWF) binds to exposed collagen through its A3 domain
We have shown a novel mechanistic role by which the serine protease FXIa may regulate platelet deposition at sites of endothelial cell damage by inactivating ADAMTS13
This finding further expands the classical pathway by which activation of the contact pathway of coagulation promotes thrombus formation
Summary
The large glycoprotein (GP) von Willebrand factor (VWF) binds to exposed collagen through its A3 domain. VWF unravels into a “stringlike” conformation when it is exposed to increased shear forces [1]. This reveals the VWF-binding site located within the A1 domain for the platelet receptor GPIbα, resulting in the rapid recruitment and adhesion of platelets to VWF [2]. The presence of increased levels of UL-VWF multimers in plasma has been shown to initiate the formation of VWF-platelet microthrombi, resulting in debilitating thrombotic complications such as thrombotic thrombocytopenic purpura (TTP) [4]. The cause of increased UL-VWF levels in the majority of patients with TTP has been attributed to either congenital defects in a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) or due to the presence of autoantibody inhibitors that compromise the function of ADAMTS13 [4]
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