A severe deficiency of ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) as detected by current assays, less than 5% of normal activity, may be specific for TTP.13 Furthermore, it has been proposed that severe AD-AMTS13 deficiency now defines TTP. Cerebrovascular manifestations in hematological diseases: an update. The treatment of other diseases presenting with TMA findings is directed toward treating the underlying illness.1. A thrombotic microangiopathy that can be life-threatening, TTP can be diagnosed only through measurement of ADAMTS13 activity, which is … serves as a consultant to Ablynx and Shire Pharmaceuticals. In thrombotic disorders, infusion of rADAMTS13 in animal models of ischemic stroke has been shown to reduce stroke volume,71  increase endothelial cell proliferation and perfusion, and decrease the permeability of the blood-brain barrier.73  A model using occlusive VWF-rich thrombi in the middle cerebral arteries of mice showed dissolution of the thrombi with rhADAMTS13 but not with tissue plasminogen activator.80  These results suggest a role for rADAMTS13 beyond cTTP and comprise the rationale for future studies. FOIA Inherited Thrombotic Thrombocytopenic Purpura Revealed by Recurrent Strokes in a Male Adult: Case Report and Literature Review. Comparing the group in the lowest quartile (ADAMTS13 activity <80%) with those with the highest activity (>102.27%), the former had higher risk of ischemic stroke (absolute risk, 7.3% vs 5.3%), transient ischemic attack (absolute risk, 6.8% vs 4%), and all cerebrovascular events (absolute risk, 17.8% vs 9.3%). Severe deficiency of ADAMTS13 activity (< 5% of normal plasma) is a strong risk factor for thrombotic thrombocytopenic purpura (TTP). ADAMTS13 is a plasma protein that cleaves ultra-large VWF multimers, thus regulating the interaction of platelets with von Willebrand. Units: % Department: Haemostasis and Thrombosis Department. Furlan et al. The likelihood of recurrence associated with severe ADAMTS13 deficiency when adjusted in the multivariate analysis was statistically significant (odds ratio, 2.9; 95% confidence interval [CI], 1.3-6.8). Thrombotic thrombocytopenic purpura (TTP), ADAMTS13 activity, adamts13, adam. Morici N, Cantoni S, Panzeri F, Sacco A, Rusconi C, Stucchi M, Oliva F, Cattaneo M. Thromb Res. … Bianchi et al. This results in a low platelet count, low red blood cells due to their breakdown, and often kidney, heart, and brain dysfunction. However, patients with acquired TTP present with Please enable it to take advantage of the complete set of features! Binding of TTP patients’ antibodies to full‐length rADAMTS13 and abolishing its proteolytic activity has been shown in vitro [21, 29], and the activity neutralizing property of anti‐ADAMTS13 antibodies could be addressed in this in vitro study. Conflict-of-interest disclosure: S.R.C. A better understanding of the role of ADAMTS13 TTP has led to insights regarding its role in CVD, as a regulator of thrombi formation and neovascularization through its action on VWF. ADAMTS13 deficiency. A deficiency in ADAMTS13 enzyme levels, along with an inhibitory antibody, is found in most patients with idiopathic TTP. J Neurol. Although the role of CICs in the pathophysiology of TTP is not entirely clear, Mancini et al45  noted a higher risk of recurrence in those patients who had CICs detected during acute episodes of TTP. 2021 Feb 13. doi: 10.1007/s00415-021-10441-9. Less than 10% ADAMTS13 activity is highly indicative of thrombotic thrombocytopenic purpura (TTP) in an appropriate clinical setting. 2020 Dec;10(12):200333. doi: 10.1098/rsob.200333. ADAMTS13 is a serine protease which controls the eventual size of the vW multimer that is in the circulation. Although initial treatment should not be delayed to await the results of ADAMTS13 testing, results are important to guide subsequent treatment. Symptoms may include large bruises, fever, weakness, shortness of breath, confusion, and headache. Postmortem PFH levels in the four non-TTP decedents ranged from 64 to 3,917 mg/dL. Search for other works by this author on: None of the above: thrombotic microangiopathy beyond TTP and HUS, International Working Group for Thrombotic Thrombocytopenic Purpura, Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies, Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombocytopenic purpura, ADAMTS13 gene defects in two brothers with constitutional thrombotic thrombocytopenic purpura and normalization of von Willebrand factor-cleaving protease activity by recombinant human ADAMTS13, A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13, Potential for recombinant ADAMTS13 as an effective therapy for acquired thrombotic thrombocytopenic purpura, Gain-of-function ADAMTS13 variants that are resistant to autoantibodies against ADAMTS13 in patients with acquired thrombotic thrombocytopenic purpura, Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies, Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays, Structure-function and regulation of ADAMTS-13 protease, Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts, Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage, Recombinant CUB-1 domain polypeptide inhibits the cleavage of ULVWF strings by ADAMTS13 under flow conditions, An open conformation of ADAMTS13 is a hallmark of acute acquired thrombotic thrombocytopenic purpura, Localization of ADAMTS13 to the stellate cells of human liver, Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura, Human endothelial cells synthesize and release ADAMTS-13, Platelet-derived VWF-cleaving metalloprotease ADAMTS-13, Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets, Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura, Biologically active ADAMTS13 is expressed in renal tubular epithelial cells, ADAMTS-13 cleaves long von Willebrand factor multimeric strings anchored to endothelial cells in the absence of flow, platelets or conformation-altering chemicals, Recovery and half-life of von Willebrand factor-cleaving protease after plasma therapy in patients with thrombotic thrombocytopenic purpura, Multi-step binding of ADAMTS-13 to von Willebrand factor, Light chain of factor VIII is sufficient for accelerating cleavage of von Willebrand factor by ADAMTS13 metalloprotease, Shear-dependent interactions of von Willebrand factor with factor VIII and protease ADAMTS 13 demonstrated at a single molecule level by atomic force microscopy, Factor VIII and platelets synergistically accelerate cleavage of von Willebrand factor by ADAMTS13 under fluid shear stress, ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions, Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions, Shear stress enhances the proteolysis of von Willebrand factor in normal plasma, Force-induced cleavage of single VWFA1A2A3 tridomains by ADAMTS-13, Shear-dependent changes in the three-dimensional structure of human von Willebrand factor, Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor, FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay, Presenting ADAMTS13 antibody and antigen levels predict prognosis in immune-mediated thrombotic thrombocytopenic purpura, Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura, French Clinical and Biological Network on Adult Thrombotic Microangiopathies, Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity, IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura, Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura, Pathogenicity of Anti-ADAMTS13 Autoantibodies in Acquired Thrombotic Thrombocytopenic Purpura, Measurement and prevalence of circulating ADAMTS13-specific immune complexes in autoimmune thrombotic thrombocytopenic purpura, Persistence of circulating ADAMTS13-specific immune complexes in patients with acquired thrombotic thrombocytopenic purpura, Relation between ADAMTS13 activity and ADAMTS13 antigen levels in healthy donors and patients with thrombotic microangiopathies (TMA), ADAMTS13-specific circulating immune complexes as potential predictors of relapse in patients with acquired thrombotic thrombocytopenic purpura, Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015, ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients, A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura, von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome, Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura, Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura, Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases, Diagnostic and prognostic values of ADAMTS13 activity measured during daily plasma exchange therapy in patients with acquired thrombotic thrombocytopenic purpura, Demographic and ADAMTS13 biomarker data as predictors of early recurrences of idiopathic thrombotic thrombocytopenic purpura, Caplacizumab for acquired thrombotic thrombocytopenic purpura, Results of the randomized, double-blind, placebo-controlled, phase 3 Hercules study of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura [abstract], Relationship between ADAMTS13 activity in clinical remission and the risk of TTP relapse, ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission, French Thrombotic Microangiopathies Reference Centre, Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura, Rituximab prophylaxis to prevent thrombotic thrombocytopenic purpura relapse: outcome and evaluation of dosing regimens, Clinical importance of ADAMTS13 activity during remission in patients with acquired thrombotic thrombocytopenic purpura, Evidence of persistent neurologic injury following thrombotic thrombocytopenic purpura, Headache prevalence following recovery from TTP and aHUS, Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura, Decreased ADAMTS-13 (A disintegrin-like and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failure, Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies, Differentiating malignant hypertension-induced thrombotic microangiopathy from thrombotic thrombocytopenic purpura, Association between thrombotic microangiopathy and reduced ADAMTS13 activity in malignant hypertension, von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke, ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion, ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery, Low ADAMTS13 activity is associated with an increased risk of ischemic stroke, Reduced ADAMTS13 levels in patients with acute and chronic cerebrovascular disease, Acquired intracoronary ADAMTS13 deficiency and VWF retention at sites of critical coronary stenosis in patients with STEMI, Von Willebrand factor, ADAMTS13, and the risk of mortality: the Rotterdam study, Low ADAMTS-13 activity and the risk of coronary heart disease - a prospective cohort study: the Rotterdam Study, Neutralization of inhibitory antibodies and restoration of therapeutic ADAMTS-13 activity levels in inhibitor-treated rats by the use of defined doses of recombinant ADAMTS-13, ADAMTS13-mediated thrombolysis of t-PA-resistant occlusions in ischemic stroke in mice, ADAMTS-13 activity and autoantibodies classes and subclasses as prognostic predictors in acquired thrombotic thrombocytopenic purpura, ADAMTS13 activity and antigen during therapy and follow-up of patients with idiopathic thrombotic thrombocytopenic purpura: correlation with clinical outcome, © 2018 by The American Society of Hematology, Copyright ©2020 by American Society of Hematology, https://doi.org/10.1182/blood-2018-02-791533, Higher levels associated with sustained remission, Associated with relapse vs no association. Conflict-of-interest disclosure: The authors declare no competing financial interests. 2015 Sep;94(9):1473-6. doi: 10.1007/s00277-015-2411-2. The measured ADAMTS13 activity may not reflect the true in vivo biological ADAMTS13 activity. 2016 Aug;42(2):155-60. doi: 10.1007/s11239-016-1342-7. 24.2). © 2019 by The American Society of Hematology. J Clin Med. Unable to load your collection due to an error, Unable to load your delegates due to an error. The distal part of the protease contains 7 additional TSP1 repeats and 2 CUB domains.9,10  Each domain has a different role in the function of ADAMTS13 activity, with the CUB and spacer domains being particularly important in TTP. A severe deficiency of ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) as detected by current assays, less than 5% of normal activity, may be specific for TTP.13 Furthermore, it has been proposed that severe AD-AMTS13 deficiency now defines TTP. Epub 2020 Dec 23. Better models for a more accurate prediction of relapse, incorporating additional biomarkers, are needed. Background: Atypical hemolytic uremic syndrome (aHUS) involves dysregulation of the complement system, but whether this also occurs in thrombotic thrombocytopenic purpura (TTP) remains unclear. In congenital TTP, mutations in the ADAMTS13 gene prevent normal production and/or secretion of the enzyme. When a patient presents with thrombocytopenia and MAHA without an alternative clinical explanation, ADAMTS13 activity of <10% confirms the diagnosis of TTP. These patients had a higher relapse rate (38.5%) when compared with those who recovered their activity at clinical response (5%). ADAMTS13 deficiency causes an acute haemolytic condition called Thrombotic Thrombocytopenic Purpura (TTP). Severe deficiency of ADAMTS-13 (activity <5-10%) may be acquired or congenital, and is a relatively specific finding in patients with a clinical diagnosis of thrombotic thrombocytopenic purpura (TTP). 2012 Jul 12;120(2):440-8. Once a patient with iTTP has achieved clinical response (platelet count >150 × 109/L and normal lactate dehydrogenase, with stabilization or improvement of symptoms), 3 scenarios can occur2 : (1) clinical remission (continuous clinical response after cessation of PEX, maintained for >30 days); (2) exacerbation, defined as a recurrent thrombocytopenia and the need to restart PEX within 30 days of the last PEX procedure, which can occur in 40% to 50% of cases46 ; and (3) relapse, defined as a recurrence of TTP >30 days after the last PEX procedure (incidence of ∼30%-50%).46-48  Interestingly, neither the normalization of ADAMTS13 activity nor the variability during remission has been incorporated into the clinical definitions of TTP. In acquired TTP, the autoantibodies can inhibit function by binding to functional regions of ADAMTS13 (neutralizing), by causing accelerated ADAMTS13 clearance (non-neutralizing­), or through both neutralizing and non-neutralizing actions. Location: Viapath at St Thomas' Hospital. The French Clinical and Biological Network on Adult TMA published its experience regarding the prognostic value of ADAMTS13 activity and anti-ADAMTS13 antibody characteristics (Ig isotype, titer, and inhibitory effect) in a cohort of 35 patients.38  Samples were obtained within 7 days of achieving clinical response. Patients with hereditary TTP may appear to be healthy, but their increased risk of critical thrombosis is always present.” Hereditary Thrombotic Thrombocytopenic Purpura. Plasma ADAMTS13 activity is almost always absent or severely reduced in patients with familial TTP, 12,100,101 as a consequence of homozygous or compound heterozygous mutations of the ADAMTS13 gene. Low ADAMTS13 activity is found in patients with thrombotic thrombocytopenia purpura (TTP). Wu et al53  reported the prognostic value of ADAMTS13 activity when measured daily during PEX in 19 patients with iTTP who were severely deficient (<10%) at presentation. We will also discuss the latest evidence regarding the role of ADAMTS13 in other TMAs, stroke, and cardiovascular disease. In the TITAN study,55  75 patients with a clinical diagnosis of iTTP were randomly assigned to receive caplacizumab or placebo daily with PEX and to continue 30 days after the last PEX. ADAMTS13 has a structure similar to that of other members of the ADAMTS family, composed of 14 different domains: a metalloprotease, a disintegrin, a first thrombospondin type 1 repeat (TSP1), cys-rich, and spacer domains. This site needs JavaScript to work properly. These studies and others (Table 1) form the basis to consider prophylactic rituximab to prevent relapses in patients who are found to have severely deficient ADAMTS13 activity during remission.59-61  However, there are also data from patients with iTTP and persistently deficient ADAMTS13 activity in remission who do not uniformly experience relapse, with some patients having an isolated ADAMTS13 activity <10% that improves spontaneously.62  We recently calculated the sensitivity and specificity of ADAMTS13 activity measured during remission to predict relapses in the following 30 and 90 days.63  The assays were obtained every 3 months in 39 patients (total of 557 samples). Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that results in blood clots forming in small blood vessels throughout the body. Laboratory surveillance of immune-mediated thrombotic thrombocytopenic purpura. In summary, although severely deficient ADAMTS13 activity in remission may be a risk factor for relapse, it does not mean a relapse will absolutely occur. National Library of Medicine Studies have shown that low levels of ADAMTS-13 activity are associated with thrombotic thrombocytopenic purpura (TTP), a life-threatening hematological condition characterized by a low platelet count, microvascular thrombi, red cell fragmentation, and renal complications. In both cases, ultra-large vWF multimers build up in the blood stream. Measurement of ADAMTS13 activity is the most commonly used laboratory test in the workup of suspected TTP. Thirteen patients (41%) had undetectable activity at the time of clinical response. Therefore, the regulation of ADAMTS13 is likely to be at the substrate level (VWF), with 3 factors known to regulate its activity: (1) fluid shear stress, found in the microcirculation, which allows VWF to unfold and expose its A2 domain for ADAMTS13 binding; (2) factor VIII, which enhances the ADAMTS13 proteolytic activity by affecting the A1A2A3 domain-domain interaction when ADAMTS13 binds VWF under shear forces26,27 ; and (3) platelet glycoprotein 1bα (GP1bα), which increases ADAMTS13 function under static or shear conditions by exposing the VWF A2 domain when it binds to the A1 domain.28  The main function of the ADAMTS13 protease is the binding and cleavage of cell-bound ULVWF strings at the Tyr1605-Met1606 bond.29,30  Under shear stress, as seen in the microcirculation or after thrombus formation, VWF undergoes conformational changes that unfold its A2 domain, making the ADAMTS13 cleavage site accessible.31-34. There was a significant variability in ADAMTS13 activity, with 145 (26%) of the samples showing severely deficient activity of <10%; however, only 11 of these were followed by a relapse in the subsequent 90 days. 2021 Feb;19(2):513-521. doi: 10.1111/jth.15191. Although low ADAMTS13 activity is not the cause of TMAs other than TTP, it seems to have an important prognostic role. Compared with those who recovered their activity before day 7, these patients took a longer time to achieve a clinical response (P = .001). ADAMTS13 activity … Kalish Y, Rottenstreich A, Rund D, Hochberg-Klein S. J Thromb Thrombolysis. Patients with iTTP will have an autoantibody that targets the spacer domain of the protease.37  The detection of an acquired inhibitor is essential to differentiate iTTP from congenital TTP (cTTP). Accessibility Interpretation. These data confirm that even in situations in which ADAMTS13 activity is not measured before initiating PEX, there is still a diagnostic role for the test, with a sensitivity of 89%, 83%, and 78% after days 1, 2, and 3 of PEX, respectively. ADAMTS13 Activity with Reflex to Inhibitor - ADAMTS-13 is a zinc metalloprotease that cleaves ultra large vWF multimers. Open Biol. In conclusion, stroke is common after recovery from TTP and is associated with reduced ADAMTS13 activity during remission. There are several ADAMTS13 biomarker assays that are either available for routine clinical use or under study for their potential clinical applications. This can lead to Thrombotic Thrombocytopenic Purpura (TTP) … Not all patients with a clinical diagnosis of idiopathic thrombotic thrombocytopenic purpura (TTP) have a severe ADAMTS13 deficiency. It is no surprise then that the protease may also have a role in the pathophysiology of cardiovascular disease (CVD). ADAMTS13−/− mice had significantly reduced endothelial proliferation 2 weeks after stroke, with decreasing neovascularization. Camila Masias, Spero R. Cataland; The role of ADAMTS13 testing in the diagnosis and management of thrombotic microangiopathies and thrombosis. The measured ADAMTS13 activity may not reflect the true in vivo biological ADAMTS13 activity. There was no association found between the risk of relapse and the ADAMTS13 IgG levels. Jin et al57  found an association between lower ADAMTS13 activity measured in remission and an increased risk of relapse in 24 patients with iTTP followed with serial ADAMTS13 monitoring during remission for an average of 23 months. If the activity of ADAMTS13 is lowered for some reason, unusually large vWF multimers may accumulate within blood causing thrombosis due to platelet aggregation, which in turn may lead to TTP (thrombotic thrombocytopenic purpura). Of the 85 patients with at least two follow-up visits to measure ADAMTS13 activity, 44 (52%) had continuously normal ADAMTS13 activity (≥50%). CBC, complete blood count; LDH, lactate dehydrogenase. 24.2). 11,13-18 Studies have shown that quantitative immunoassays for IgG-specific autoantibodies to ADAMTS13 are more sensitive than the functional (ie, inhibition) assays for detecting antibodies against ADAMTS13. In this study, 11 patients (28%) experienced an exacerbation in the placebo arm, compared with 3 (8%) in the caplacizumab group, supporting the hypothesis that caplacizumab prevents exacerbations of iTTP. Very low levels of activity can be seen in congenital TTP, whereas modestly decreased levels have been reported in a number of clinical settings. The ADAMTS13 activity assay is an in vitro assay using a synthetic substrate peptide in a static liquid environment. A narrative review. 2019 Jun;28(6):1537-1539. doi: 10.1016/j.jstrokecerebrovasdis.2019.03.011. The mechanism involved in this process may be related to downregulation of angiopoietin-1 and galectin-3, as well as a decrease in phosphorylation of VEGFR-2 in ADAMTS13-deficient mice.73  These studies noted abnormal findings in ADAMTS13−/− mice, but mice that were also deficient in VWF behaved similarly to WT mice, implying that the role of ADAMTS13 in stroke is dependent on its action on VWF. Anti-ADAMTS13 autoantibodies can circulate freely in plasma or bind to ADAMTS13, forming a complex42-44  that can be detected by an ELISA. During this time, 13 patients had a disease relapse. It is secreted in blood and degrades large vWf multimers, decreasing their activity. The investigators also observed a 5.68% decrease in ADAMTS13 activity per 10-year increase in age and an 8.6% higher activity in women compared with men. Contribution: C.M. 2017 Apr;39:79-83. doi: 10.1016/j.ejim.2016.11.003. The presence of ADAMTS13 inhibition (positive inhibitor screen) with a measurable antibody titer is most consistent with an acquired TTP. TTP can be distinguished from other causes of MAHA by the finding of severely deficient ADAMTS13, typically <10% of normal.2  ADAMTS13 is a plasma protease responsible for the cleavage of von Willebrand factor (VWF), preventing the accumulation of ultra-large VWF (ULVWF) multimers that can spontaneously interact with platelets, leading to microvascular thrombosis. The ADAMTS13 protease has also been the focus of recent research toward the development of novel agents,3-8  with exciting new potential therapeutic options for patients with TTP. Eur J Intern Med. Deficiencies of ADAMTS13 leads to Ultra Large vWM (UL-VWM) circulating in the bloodstream, the size of these molecules mean that they can cross-link non activated platelets and generate spontaneous thromboses. Epub 2015 Jun 11. Even after 3 PEX procedures, 14 of the 19 patients still had ADAMTS13 activity <10% (measured immediately before the next PEX procedure). Deficiency of ADAMTS‐13 activity, either because of an inherited or an … There are multiple diseases in which the ADAMTS13 level or activity is low predisposing to thrombosis; thrombotic thrombocytopenic purpura (TTP) is a classic example and more recently, Thrombocytopenia Associated Multiple Organ Failure (TAMOF) has been shown to also arise from diminished ADAMTS13 activity. ADAMTS proteases in cardiovascular physiology and disease. In addition to the risk of relapse, TTP survivors have higher all-cause mortality than the general population and increased rates of chronic morbidities, including hypertension, depression, and mild cognitive impairment. and S.R.C. In the follow-up phase 3 Hercules study, a similar decrease in exacerbations was seen in the caplacizumab arm compared with placebo (3% vs 28%), with the presumption that persistently severely deficient ADAMTS13 activity was a significant factor in the development of exacerbations.56  In this study, physicians were encouraged (but not required) to continue caplacizumab until there was clear improvement and correction of the severe ADAMTS13 deficiency to avoid recurrences of TTP after stopping caplacizumab. Although severely deficient ADAMTS13 activity in TTP may lead to microthrombi that can be clinically evident as seizures, focal neurologic deficits, and coma, a moderate reduction in ADAMTS13 activity has been found to be a risk factor for ischemic stroke and coronary occlusion. In addition, for the 2 patients with ADAMTS13 activity continuously between 25-50% and 1 patient with ADAMTS13 activity continuously between 10-25%, there were no iTTP relapses. Although the diagnosis of TTP may be confirmed with ADAMTS13 activity and inhibition studies, the decision to initiate plasma exchange should not be delayed pending results of this assay. Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management. Department of Medicine, Ohio State University, Columbus, OH.