Von Willebrand Factor, ADAMTS-13, and Thrombotic Thrombocytopenic Purpura

Abstract

For a disease with <80 years of history, clinical and basic research into thrombotic thrombocytopenic purpura (TTP) has been significantly accelerated since the identification of unusually large von Willebrand factor (VWF) multimers and deficiency of ADAMTS-13 ( A Disintegrin And Metalloproteinase with Thrombo Spondin-1-like domains) as the potential cause. The VWF-cleaving metalloprotease ADAMTS-13 has since been extensively characterized and its biological action tested in vitro and in vivo. There have also been considerable efforts to understand the interaction between ADAMTS-13 and its substrate VWF, as well as its biological regulation. This review focuses on recent advances in our understanding of the biology of VWF cleavage by ADAMTS-13 and how this newly gained knowledge will eventually help the clinical management of patients with TTP. This review also discusses the potential for ADAMTS-13 as a therapeutic drug for thrombotic conditions other than TTP.

Mechanisms of Bleeding and Approach to Patients With Axial-Flow Left Ventricular Assist Devices

“…A deficiency of this protease is responsible for large vWF multimers, which, in turn, are responsible for the development of the prothrombotic condition, thrombotic thrombocytopenic purpura. 23 Conversely, excessive cleavage of large multimers results in vWF multimer depletion and pathological bleeding, as seen in acquired von Willebrand disease. The relationship between the loss of high-molecularweight (HMW) vWF multimers (acquired von Willebrand disease) and GI tract bleeding was first described in a phenomenon called Heyde syndrome.…”

Preserved Expression of mRNA Coding von Willebrand Factor-Cleaving Protease ADAMTS13 by Selenite and Activated Protein C

“…ADAMTS13 is a plasma protease primarily synthesized and secreted from hepatic stellate cells (HSCs) and is the only enzyme reported to inactivate ulVWF, thereby reducing its thrombogenicity (14,15). Congenital or immunologically induced deficiency of ADAMTS13 has been identified to result in thrombotic thrombocytopenic purpura (TTP) (16). In sepsis, the term thrombotic microangiopathy (TMA) was introduced to characterize thrombotic occlusion of arterioles less than 100 μm diameter independent of the underlying pathophysiology (17,18).…”

Thrombotic thrombocytopenic purpura: reducing the risk?

“…ULVWF multimers expressed on activated endothelial cells are highly prothrombotic and also bind platelets with high avidity (12). What is also now clear is that the mechanisms by which vWF multimer composition is regulated are critical for normal or pathological vWF function (3,4,13) and that therapeutic control of aberrant vWF multimerization could have a major impact on clinical conditions such as TTP.…”

“…At increased shear stress, vWF becomes susceptible to proteolysis by ADAMTS13, which cleaves vWF within the A2 domain (between Y1605 and M1606), decreasing vWF multimer size and GPIb-dependent platelet adhesion (13). Shear stress applied to large multimers anchored to endothelial cells induces conformational changes to A2, facilitating proteolysis not only by ADAMTS13, but also by granzyme B from cytotoxic lymphocytes and other proteases that cleave in the same region (14-16).…”

“…Indeed, dysfunctional ADAMTS13, due to autoimmune or other causes, leads to thrombotic problems. TTP is the bestknown clinical example of ADAMTS13 dysfunction; it is a multifactorial disease where defective ADAMTS13 activity due to autoantibodies, mutations, or deficiency can result in ULVWF multimers, thrombocytopenia due to vWF-binding platelets, and multiple thrombotic microangiopathies (1,13). Acute thrombotic episodes can be triggered by other prothrombotic conditions, such as increased inflammation (17,18).…”