ADAMTS13 conformations and mechanism of inhibition in immune thrombotic thrombocytopenic purpura

Abstract

Immune thrombotic thrombocytopenic purpura (iTTP) is an autoimmune disease, caused by autoantibody-mediated inhibition of a plasma metalloprotease ADAMTS13. [1][2][3][4][5] The only known function of ADAMTS13 to date is to cleave the glycoprotein von Willebrand factor (VWF), which recruits platelets to sites of vascular injury for hemostasis. 6,7 In the absence of functional ADAMTS13, ultra-large VWF multimers accumulate and cause a thrombotic microangiopathy that is potentially fatal unless being recognized early in the disease course and treated accordingly. 8-10 Though significant progresses have been made over the past decades regarding the understanding of pathogenesis of iTTP, treatment options remain crude and nonspecific. Therapeutic plasma exchange has been part of the standard of care for iTTP, and it must be initiated early in the disease course to prevent high mortality associated with disseminated microvascular thrombosis. [11][12][13] The monoclonal antibodies against CD20 on B-cells, rituximab and anti-VWF nanoboy, caplacizumab

A multicenter evaluation of the Technoscreen ADAMTS13 activity semi‐quantitative screening test for thrombotic thrombocytopenic purpura diagnosis and exclusion

“…The study samples reflected a broad range of ADAMTS13 activity levels, <1 to 150 IU/dL, with a high number of overall samples ( n = 23) consistent with TTP (i.e., <10 IU/dL ADAMTS13). Several samples were also derived from patients with moderate reductions in ADAMTS13 levels (Figure 2), reflective of the population from which specimens were drawn, being hospitalized sick patients, with inflammation known to modestly reduce plasma ADAMTS13 levels 4,5,33 …”

“…Several samples were also derived from patients with moderate reductions in ADAMTS13 levels (Figure 2), reflective of the population from which specimens were drawn, being hospitalized sick patients, with inflammation known to modestly reduce plasma ADAMTS13 levels. 4,5,33 Table 3 summarizes performance characteristics of the Technoscreen assay from this and previous studies. Our study found a high sensitivity (100%) and NPV (100%), which is consistent with previous findings.…”

Immune thrombotic thrombocytopenic purpura: pathogenesis and novel therapies: a narrative review

“…Hydrogen-deuterium exchange plus mass spectrometric (HX-MS) analysis demonstrates that the anti-spacer domain antibodies, isolated from iTTP patients, bind 5 small flexible loops where vWF binds, suggesting that these antibodies may physically block the interaction between ADAMTS13 enzyme and its substrate vWF ( 69 ). An alternative hypothesis is also possible in which the binding of these antibodies to the spacer domain may result in a conformational change in the catalytic domain, thus affecting the cleavage efficiency of ADAMTS13 protease ( 72 , 73 ). More studies are needed to delineate the mechanism of antibody-mediated inhibition of ADAMTS13 activity.…”