Laboratory testing for ADAMTS13: Utility for TTP diagnosis/exclusion and beyond

Abstract

The metalloproteinase ADAMTS13 (a disintegrin with a thrombospondin type 1 motif, member 13), also known as VWF (von Willebrand factor) protease, may be assessed in a vast array of clinical conditions. Notably, a severe deficiency of ADAMTS13 characterizes TTP (thrombotic thrombocytopenic purpura), a rare but potentially fatal disorder associated with thrombosis due to accumulation of prothrombotic ultra-large VWF multimers. Although prompt identification/exclusion of TTP can be facilitated by rapid ADAMTS13 testing, the most commonly utilized assays are based on ELISA (enzyme linked immunosorbent assay) and require long turnaround time and have relatively limited throughput. Nevertheless, several rapid ADAMTS13 assays are now available, at least in select geographies. The current mini-review discusses these issues, as well as the potential utility of ADAMTS13 testing in a range of other conditions, including coronavirus disease 2019 (COVID-19). | A SHORT EARLY HISTORY OF TTP AND ADAMTS13Thrombotic thrombocytopenic purpura was first characterized by Karl Singer and colleagues in 1947, 4 following pathological findings of thrombotic microangiopathy (TMA) by Eli Moschowitz in 1924. 5 Also key to understanding the pathophysiology of TTP and the involvement of ADAMTS13/VWF was the pioneering work of Moake et al. in 1982, 6 and Tsai et al. in 1996. 7,8 3 | BRIEF OVERVIEW OF TTP Note, TTP occurs either congenitally (ie, Upshaw Schulman Syndrome), or (more commonly) as an acquired event, typically due to development of anti-ADAMTS13 antibodies (commonly known as Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; BU, Bethesda Unit (inhibitor); CLIA, chemiluminescence immunoassay; COVID-19, coronavirus disease 2019; ELISA, enzyme linked immunosorbent assay; FRET, fluorescence resonance energy transfer; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura.

Thrombosis and thrombocytopenia in COVID-19 and after COVID-19 vaccination

“…Thus, the key to diagnosis is the detection of MAHA represented by elevated lactate dehydrogenase (LD) and total bilirubin, decreased hemoglobin, decreased or absent haptoglobin, and peripheral blood presence of red blood cell fragments. In addition, since acquired TTP is caused by autoantibody-induced depletion or inhibition of ADAMTS13, use of a rapid ADAMTS13 activity assay is crucial [59] , and the detection of ultra-large von Willebrand factor is also helpful for the diagnosis [60] .…”

The Intriguing Relationships of von Willebrand Factor, ADAMTS13 and Cardiac Disease

“…This may lead to an increased risk of thrombosis where the VWF-ADAMTS13 axis is increased, reflecting a relative increase of VWF and/or a relative decrease in ADAMTS13 activity, with acquired TTP being the most extreme example. In contrast, disturbances whereby the VWF-ADAMTS13 axis reflects a relative decrease of VWF also reflect a risk factor for bleeding, with AVWS being the most extreme example [13]. We recommend that workers in the field of cardiac disease take a greater interest in both VWF and ADAMTS13 [21], to both identify the opposing risks of bleeding and thrombosis, and to potentially consider supportive therapies or curative approaches, as the case may require.…”

“…There are over 20 different commercial options for the measurement of VWF: Ag, and publications do not always report the method used [10]. ADAMTS13 can also be measured as an antigen assay using enzyme-linked immunosorbent assays [13], or as an activity assay, with FRETS-based assays being common [13], or by using chemiluminescence [14] among other procedures [13]. However, in the main, studies reporting a single ADAMTS13 parameter report activity levels.…”

“…This can be identified as a disturbance of the VWF/ADAMTS13 axis or an increase in the relative VWF/ADAMTS13 ratio [21]. ADAMTS13 is most commonly known for its deficiency state as part of thrombotic thrombocytopenic purpura (TTP), a prothrombotic disorder [13]. Although rare, acquired TTP has been described following cardiac surgery [22,23].…”

Celebrating 50 Years of Seminars in Thrombosis and Hemostasis—Part II

“…Apart from its role in TTP, and as a regulator of microthrombosis, ADAMTS13 has begun to be identified as a prognostic and/or diagnostic marker of other diseases, such as those related to inflammatory processes, liver damage, metastasis of malignancies, sepsis, and different disorders related to angiogenesis. [18][19][20][21] Since its first description almost 100 years ago, the improvement of laboratory tests and the description of novel disease-causing variants along the ADAMTS13 gene have contributed to a better and faster diagnosis of patients under critical conditions. The ability of ADAMTS13 to dissolve platelet aggregates in vitro and its antithrombotic properties make recombinant human ADAMTS13 treatment a potential therapeutic approach targeting not only patients with cTTP but also other medical conditions.…”