Although the plasma assays in these studies were not physiologic, they were nonetheless innovative and informative. However, the results are not generally available quickly, so in most cases, the ADAMTS13 results either support or refute the TTP diagnosis after treatment has already begun. ADAMTS13 cleaves ULvWF multimers when there is sufficient shear to unfold the A2 domain and to expose the cleavage site. The mature ADAMTS13 transcript has a size of 4.7 kb, giving rise to a precursor protein of 1427 amino acid residues [11–13]. VWF self-association itself is regulated not only by shear stress but by plasma factors, which likely can change the course and severity of TTP episodes. For example, nonglycosylated recombinant VWF is cleaved more rapidly than its plasma-derived glycosylated counterparts. In people with aTTP, the body’s immune system makes proteins called autoantibodies that stop ADAMTS13 from cutting up vWF. FH normally deposits at the surface of human glomerular endothelial cells, protecting them against complement attack. In Pocket Companion to Brenner and Rector's The Kidney (Eighth Edition), 2011. Under physiologic shear stress, the platelet-decorated ULVWF strings are cleaved by ADAMTS13 and removed from the endothelial surface. To distinguish between autoimmune and genetic deficiency of ADAMTS13 in patients with negative plasma mixing tests, the presence of inhibitors may be inferred from less than expected increase in the plasma ADAMTS13 level following plasma therapy. Third, at this suboptimal pH, some inhibitory autoantibodies do not form stable complexes with ADAMTS13, and these antibodies remain undetected in inhibition studies. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. ADAMTS13: von Willebrand Factor-Cleaving Protease, Handbook of Proteolytic Enzymes (Third Edition), Thrombotic Thrombocytopenic Purpura and the Hemolytic-Uremic Syndrome, Structure, Biology, and Genetics of von Willebrand Factor, Thrombotic Thrombocytopenic Purpura and Related Thrombotic Microangiopathies, Consultative Hemostasis and Thrombosis (Fourth Edition), Oxidants not only have the ability to induce ULVWF secretion; they can also oxidize VWF so as to render it noncleavable by, Progress in Molecular Biology and Translational Science, Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndromes, Pocket Companion to Brenner and Rector's The Kidney (Eighth Edition). By processing von Willebrand factor in this way, the enzyme prevents it from triggering the formation of blood clots in normal circulation. 6-14 ADAMTS13 has also been referred to as von Willebrand factor-cleaving protease. ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 motifs 13), also known as "von Willebrand factor (VWF) cleaving protease" is responsible for modulating the range of multimeric species of VWF in the circulation. These include hemoglobin, IL-6, thrombospondin-1, and neutrophil α-defensins. Fourth, significant interference of the fluorescence signal by hemoglobin and bilirubin occurs due to spectral overlap. One study evaluated ADAMTS13 epitopes recognized by polyclonal autoantibodies in 25 patients with acquired TTP,113 finding that antibody targets invariably included the cysteine-rich/spacer domain (CS) sequence; in 3 patients this was the only region targeted by the antibodies. In general, the severity of ADAMTS13 deficiency in these conditions is not sufficient to cause thrombosis. Silvia Ferrari, ... Friedrich Scheiflinger, in Handbook of Proteolytic Enzymes (Third Edition), 2013. These dimers are then transported into the Golgi apparatus, where the propeptide catalyzes inter-dimer disulfide bonds between residues in the D3 domain, yielding long multimers composed of dimers linked head-to-head containing N-termini at both ends. Proteolysis of VWF multimers is responsible for the characteristic “triplet” pattern of satellite bands flanking each main multimer band that is observed on multimer analysis gels. Mutations in the ADAMTS13 gene25 may result in a reduced or an aberrant secretion of ADAMTS13 protein into the circulation. S.S. Apte, in Encyclopedia of Cell Biology, 2016. In 2008, a second international collaborative study was carried out to compare the performance of eight functional and three antigen assays for ADAMTS13.143 Comparison of these methods showed that cleavage assays based on modified VWF peptides as substrates offered high accuracy and reproducibility and low variance and between-method variability. In some patients, however, overt TTP episodes do not develop for years (e.g., during a first pregnancy),102 if ever. La púrpura trombocitopénica trombótica es una enfermedad hemorrágica microangiopática poco frecuente. Most VWF in the blood is of endothelial origin. The large inter-laboratory variability was not primarily due to the use of different local standards, but to methodological differences between laboratories. In contrast to other ADAMTS proteases, ADAMTS13 is secreted into the circulation as an active enzyme [35] with a plasma half-life of approximately 2–3 days [62]. In this issue of Blood, Kremer Hovinga and colleagues demonstrate that a lower level of initial plasma ADAMTS13 activity (< 10%) is associated with higher risk of relapse in patients with TTP. [2] Púrpura significa que se presenta como moretones en la piel, característicos de la enfermedad. ADAMTS13 activity or an inhibitor suggests high risk of relapse in symptomatic TTP. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13)—also known as von Willebrand factor-cleaving protease (VWFCP)—is a zinc-containing metalloproteaseenzyme that cleaves von Willebrand factor (vWf), a large protein involved in … La enzima ADAMTS13 es una proteasa plasmática que divide el factor de von Willebrand en fragmentos más pequeños y, por lo tanto, elimina los multímeros de VWF inusualmente grandes que, de otro modo, se acumularían en las células endoteliales, donde pueden causar trombos plaquetarios. This study showed a consensus mean value of 0.91 units/mL of ADAMTS13 activity for this plasma with interlaboratory variability of 12.4%, and 0.92 units/mL of ADAMTS13 antigen with inter-laboratory variability of 16.3%. ADAMTS13 activity in serum and citrated or heparinized plasma can be measured with this improved substrate at physiological pH, ionic strength and calcium concentration, without interference from the endogenous VWF multimers, or bilirubin or hemoglobin in plasma.78 Another limitation of these peptide-based activity assays is that the ability of ADAMTS13 to cleave multimeric VWF under shear stress is not assessed. Drug-induced HUS/TTP is well recognized. Reduced plasma ADAMTS13 activity is a risk factor for myocardial infarction, cerebral stroke, preeclampsia, and cerebral malaria (Zheng, 2013). Silvia Ferrari, ... ... ADAMTS13 is predominantly synthesized in the... Microangiopathic Hemolytic Anemia. Production of ADAMTS13 autoantibodies is almost certainly genetically influenced. ADAMTS13 levels can be measured via laboratory testing, and such measurement is very important before starting plasma exchange in those suspected of having TTP or another thrombotic microangiopathy. Han-Mou Tsai, in Platelets (Third Edition), 2013. In all cases, the inhibitory agents apparently bind the substrate, VWF, preventing the VWF from being cleaved by ADAMTS13. 10.1016/j.hoc.2013.02.006. A variety of medical conditions may result in a mild to moderate deficiency of ADAMTS13 activity. results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery. syndrome: an update. vWF is synthesized by endothelial cells and megakaryocytes, and is released as ultra-large string-like structures which provide a markedly adhesive substrate for platelets (Zheng et al., 2002). ADAMTS13 assays determine proteolytic activity, antigen level, and level of anti-ADAMTS13 autoantibodies. The estimated normal plasma concentration of ADAMTS13 is approximately 1 µg ml−1 (5 nM) [9,63]. To use the sharing features on this page, please enable JavaScript. [1] El primer caso fue registrado en 1924 por Moschcowitz. First, preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) have many clinical features that overlap with TTP and may share certain pathophysiologic features such as systemic endothelial dysfunction and proteinuria (see Chapter 32).125 HELLP syndrome may be especially difficult to distinguish from TTP in that it also manifests microangiopathic hemolytic anemia, elevated LDH levels, and thrombocytopenia (although not usually as severe as in TTP).126 TTP in pregnancy may be associated with autoantibodies against ADAMTS13, and the disease usually manifests near term or postpartum.127 Estimates of the risk of recurrence during subsequent pregnancies vary widely, ranging from 26% to 73% per pregnancy.102. ADAMTS13, a protein, helps regulate clotting by cutting through von Willebrand factor, which catches platelets and helps them clot. For example, mutant VWF in a subtype of type 2A VWD exhibits enhanced susceptibility to ADAMTS13 cleavage, which results in loss of large VWF multimers. The ability of VWF or ULVWF multimers to self-associate into thicker fibers and cables becomes an important mechanism for regulating the adhesive properties of VWF. By mutagenesis, these investigators determined that the regions Thr572-Asn579 and Val657-Gly666 in the spacer domain of ADAMTS13 were the common epitopes for autoantibody binding.116 When Arg660, Tyr661, or Tyr665 was substituted with alanine, the binding of the autoantibodies from the six TTP patients was eliminated.117. The propeptide region was also identified by 20% of autoantibodies,113 indicating that removal of the propeptide is not required for secretion of active enzyme.114 Autoantibodies inhibit the activity of ADAMTS13 or decrease its survival. ULvWF multimers that appear in plasma after WPB secretion are cleaved within 2 hours by ADAMTS13 to form shorter, less hemostatically active multimers. thrombocytopenic purpura? Hematol Oncol Clin North Am. ADAMTS13 ADAMTS13: von Willebrand Factor-Cleaving Protease. The ADAMTS13 enzyme cuts von Willebrand factor into smaller pieces to regulate its interaction with platelets. In the presence of stimuli that activate the complement system, reduced levels of MCP may lead to microvascular damage. In the remaining few patients with negative plasma mixing tests for inhibitors, IgG isolated from their heated plasma or serum samples often demonstrate inhibitory activity toward the ADAMTS13. In 2015, the first international standard for ADAMTS13 was established and tested in 32 laboratories from 14 countries for ADAMTS13 activity and antigen levels against local standards.147 This plasma standard, designated WHO IS (12/252), was derived from pooled plasma from 38 normal healthy donors. Other mutations lead to the production of an abnormally small version of the enzyme that cannot function properly. Inhibitors of ADAMTS13, measured by mixing patient and normal plasma samples, are detectable in 80–90% of the patients. In synthetic microvessels induced to secrete VWF by agonist stimulation, VWF secreted from the vessel wall could assemble into strands capable of spanning the lumen of the vessel, particularly at bifurcations and curves.68 The ability of VWF to form strands and cables of such enormous dimensions and string those cables across the path of flow not only increases the chances of the strands capturing platelets but also enhances their ability to shred erythrocytes into schistocytes. This protein is involved in the first step of blood clotting at the site of injury, which is to help cells called platelets stick together and attach to the walls of blood vessels, forming temporary clots. 24.2). Siemieniak DR, Stark KR, Gruppo R, Sarode R, Shurin SB, Chandrasekaran V, Stabler Ticlopidine, an antiplatelet agent, was associated with the development of TTP with an estimated incidence of 1 case per 1600 to 9000 patients treated. Inhibitors of ADAMTS13, measured by mixing patient and normal plasma samples, are... Molecular Cell Biology. Stefano Lancellotti, Raimondo De Cristofaro, in Progress in Molecular Biology and Translational Science, 2011, The human ADAMTS13 gene is located on chromosome 9 at position 9q34. We evaluated the performance of the HemosIL AcuStar ADAMTS13 activity assay (Instrumentation Laboratory, Bedford, Massachusetts, United States), a fully automated chemiluminescent immunoassay with an analytical time of 33 minutes. Is severe deficiency of ADAMTS-13 specific for thrombotic ADAMTS13-vWF axis is partially involved in the pathophysiology of kidney ischemic reperfusion injury. Copyright © 2021 Elsevier B.V. or its licensors or contributors. Plasma ADAMTS13 activity in healthy adults ranges from approximately 50% to 178% of normal pooled plasma using currently available static assays. Serum appropriately treated with protease inhibitors is also suitable for testing.78. José A. López MD, ... Dominic W. Chung PhD, in Consultative Hemostasis and Thrombosis (Fourth Edition), 2019. Non-neutralizing antibodies are detected by immunoblotting.148. The plasma ADAMTS13 level is variably decreased in a variety of pathological conditions, including metastatic neoplastic disease, sepsis, DIC, liver disease, pregnancy, and P. falciparum infection.85–91 Some of the ADAMTS13 deficiency reports remain controversial.92,93 ADAMTS13 is quite stable in normal plasma but may quickly deteriorate to very low levels in the plasma samples of patients with pathological conditions. ADAMTS13 (una desintegrina y metaloproteasa)—también conocida como proteasa de clivaje del factor de von Willebrand— es una enzima metaloproteasa (con zinc) que cliva el factor de von Willebrand, una gran proteína involucrada en el proceso de coagulación.Es secretada a la sangre y se encarga de degradar los multímeros del factor vWF, disminuyendo su actividad.