ADAMTS-13 in the Diagnosis and Management of Thrombotic Microangiopathies

Abstract

Thrombotic microangiopathies (TMAs) comprise a group of distinct disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis. For many years distinction between these TMAs, especially between thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), remained purely clinical and hard to make. Recent discoveries shed light on different pathogenesis of TTP and HUS. Ultra-large von Willebrand factor (UL-VWF) platelet thrombi, resulting from the deficiency of cleavage protease which is now known as ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), were found to cause TTP pathology, while Shiga toxins or abnormalities in regulation of the complement system cause microangiopathy and thrombosis in HUS. TMAs may appear in various conditions such as pregnancy, inflammation, malignancy, or exposure to drugs. These conditions might cause acquired TTP, HUS, or other TMAs, or might be a trigger in individuals with genetic predisposition to ADAMTS-13 or complement factor H deficiency. Differentiation between these TMAs is highly important for urgent initiation of appropriate therapy. Measurement of ADAMTS-13 activity and anti-ADAMTS-13 antibody levels may advance this differentiation resulting in accurate diagnosis. Additionally, assessment of ADAMTS-13 levels can be a tool for monitoring treatment efficacy and relapse risk, allowing consideration of therapy addition or change. In the past few years, great improvements in ADAMTS-13 assays have been made, and tests with increased sensitivity, specificity, reproducibility, and shorter turnaround time are now available. These new assays enable ADAMTS-13 measurement in routine clinical diagnostic laboratories, which may ultimately result in improvement of TMA management.

Keywords: ADAMTS-13; HUS; TTP; UL-VWF; Von Willebrand factor; aHUS; thrombotic microangiopathies.

Figure 1.

Proposed Relation among the Absence of ADAMTS-13 Activity In Vivo, Excessive Adhesion and Aggregation of Platelets, and Thrombotic Thrombocytopenic Purpura. In Panel A, in normal subjects, ADAMTS-13 (von Willebrand factor–cleaving metalloprotease) molecules attach to binding sites on endothelial cell surfaces and cleave unusually large multimers of von Willebrand factor as they are secreted by stimulated endothelial cells. The smaller von Willebrand factor forms that circulate after cleavage do not induce the adhesion and aggregation of platelets during normal blood flow. The ADAMTS-13 may use one of its thrombospondin-1–like domains or its arginine–glycine–aspartate (RGD) sequence to attach to the surface of endothelial cells. In Panel B, absent or severely reduced activity of ADAMTS-13 in patients with thrombotic thrombocytopenic purpura prevents timely cleavage of unusually large multimers of von Willebrand factor as they are secreted by endothelial cells. The uncleaved multimers induce the adhesion and aggregation of platelets in flowing blood. A congenital deficiency of ADAMTS-13 activity or an acquired defect of ADAMTS-13 (such as that caused by autoantibodies or by a change in the production or survival of the protein) can lead to thrombotic thrombocytopenic purpura. Interference with the attachment of ADAMTS-13 to endothelial cells in vivo (for example, as a result of ADAMTS-13–receptor blockade by other types of autoantibodies) may also cause thrombotic thrombocytopenic purpura in patients with normal ADAMTS-13 activity in plasma. From: Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;347:587–600. Copyright © Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 2.

ADAMTS-13 Domain Structure. ADAMTS-13 N-terminal composed of a signal peptide and propeptide, which are cleaved during the protein processing. The catalytic domain consists of the metalloprotease and disintegrin domains. A first thrombospondin-1 (TSP 1) is followed by a cysteine-rich domain (Cys), a spacer, and sevenadditional TSP 1 repeats (TSP 2–8). The C terminus contains two complement components C1r/C1s, embryonic sea urchin protein, and bone morphogenic protein-1(CUB) domains.