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Domain structure of von Willebrand factor (VWF) showing ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) cleavage site within the A2 domain. Schematic representation of monomeric, dimeric, and multimeric VWF.
Source publication
Thrombotic microangiopathy (TMA) is a term used to describe a group of disorders characterized by hemolytic anemia (with prominent red blood cell fragmentation), thrombocytopenia, and thrombosis in the microvasculature. It may be used when describing patients with thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, atypical hemoly...
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Citations
... Neurological symptoms like headache and motoric dysphasia were present in 6 patients. Clinical manifestation at an acute TTP episode 24 The table below (Table 2) shows laboratory values at the onset of acute aTTP The median hemoglobin value was 89 (60-107) g/L. The median platelet count was 41 (12-101) x10 9 /L. ...
Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia with thrombocytopenia caused by low ADAMTS13. There is the acquired and the hereditary type. In the acquired type there is immune-mediated ADAMTS13 deficiency, caused by autoantibodies against ADAMTS13, and the hereditary TTP is caused by compound heterozygote or homozygote mutations in ADAMTS13 gene. The clinical picture of acute TTP presents with microangiopathic hemolytic anemia, thrombocytopenia, usually mild kidney impairment, neurological symptoms and sometimes fever. Since TTP is an emergency, which can end up in stroke, multiorgan failure and death, quick diagnosis and intervention is needed.
In this work retrospective analysis of 10 patients with TTP who were followed up in the Hematology outpatient clinic of the University Hospital Center Zagreb from 2016-2022 was performed. Two patients had hereditary and 8 patients had acquired TTP.
This work confirmed already existing facts about the disease and presents results about age and gender distribution, clinical symptoms, laboratory parameters, etiological factors, treatment outcome and long – term sequelae in these patients.
... ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is also called von Willebrand factor (VWF) cleaving protease (VWFCP). ADAMTS13 acts to cleave VWF multimers and thus reduce plasma VWF activity [1][2][3][4]. In turn, VWF represents a major adhesive protein and acts to bridge platelets to sites of vascular damage. ...
... An absence of VWF, or the presence of dysfunctional forms of VWF, can lead to bleeding, since platelet plug formation is compromised, and this condition occurs in von Willebrand disease (VWD, congenital) or acquired von Willebrand syndrome (AVWS) [6]. In contrast, an excess of VWF, in particular the so-called highmolecular-weight (HMW) forms of VWF, can lead to uncontrolled thrombus formation, or thrombosis [1][2][3][4]7]. In particular, an accumulation of VWF (especially "ultra-large" VWF multimers) can occur because of the absence or relative deficiency of ADAMTS13. In the most severe deficiency of ADAMTS13, thrombotic thrombocytopenia purpura (TTP), the level of plasma ADAMTS13 approaches zero [8]. ...
... As noted, the severest deficiency of ADAMTS13 arises in TTP, which can be congenital (where it may also be called Upshaw-Schulman syndrome), or acquired-largely due to the production of antibodies against ADAMTS13 that either clear ADAMTS13 from circulation or inhibit its activity [1][2][3][16][17][18][19]. There are a large number of other conditions in which a relative deficiency of ADAMTS13 may occur, potentially due to exhaustion of ADAMTS13 protein stocks because of sustained VWF release [3,[8][9][10][11][12][13][14]. ...
ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is also called von Willebrand factor (VWF) cleaving protease (VWFCP). ADAMTS13 acts to cleave VWF multimers and thus reduce plasma VWF activity. In the absence of ADAMTS13 (i.e., in thrombotic thrombocytopenia purpura, TTP), plasma VWF can accumulate, in particular as "ultra-large" VWF multimers, and this can lead to thrombosis. Relative deficiencies in ADAMTS13 can also occur in a variety of other conditions, including secondary thrombotic microangiopathies (TMA). Of contemporary interest, COVID-19 (coronavirus disease 2019) may also be associated with relative reduction of ADAMTS13 and also pathological accumulation of VWF, with this likely contributing to the thrombosis risk seen in affected patients. Laboratory testing for ADAMTS13 can assist in the diagnosis of these disorders (i.e., TTP, TMA), as well as in their management, and can be achieved using a variety of assays. This chapter therefore provides an overview of laboratory testing for ADAMTS13 and the value of such testing to assist the diagnosis and management of associated disorders.
... 6 Diagnosis of TTP can be challenging due to overlapping clinical features with many other thrombotic microangiopathies (TMA), including hemolytic uremic syndromes, catastrophic antiphospholipid syndrome, malignant hypertension, disseminated intravascular coagulation, and TMAs associated with pregnancy, transplant, malignancy or pharmacological agents. [7][8][9] Despite shared clinical features, pathophysiology and treatment modalities vary substantially. TTP is caused by severe deficiency of ADAMTS13 (A Disintegrin And Metalloproteinase with Thrombospondin-1-like motifs, member 13), 5,10,11 which reduces ultra large von Willebrand factor (ULVWF) multimers into smaller units. ...
... 17,31,32 These appear to be the most robust attributes of the Technoscreen assay, and is supportive of its proposed role as a screening assay. Notably, specificity and PPV from our study depended on study site, or more accurately on kit lot number used, which was substantially lower in Site A than published studies, but higher in Sites B to D. Close assessment of Study A results ( Figure 2D) 10 Two clinicopathological assessment scores are currently recommended: the French TMA score, with an optimal specificity of 94% if both criteria are met; 10 and the PLASMIC score, with a high score (6,7) suggesting an intermediate likelihood of TTP of 62%-82%. 10 We found Technoscreen has low specificity and PPV for severe ADAMTS13 deficiency when compared to quantitative testing ( ...
Introduction:
Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal microangiopathy, with an untreated mortality rate of around 90%. TTP is caused by severe deficiency in ADAMTS13, which results in accumulation of ultra large von Willebrand factor multimers, triggering a consumptive thrombocytopenia, microangiopathic hemolytic anemia and end-organ dysfunction and damage. Demonstration of severe ADAMTS13 deficiency is diagnostic for TTP, but long turnaround times for quantitative activity testing often necessitates empirical plasma exchange and/or caplacizumab treatment.
Methods:
Multisite (n = 4) assessment of the Technoscreen ADAMTS13 activity assay (semi-quantitative flow through screening assay) for diagnosis/exclusion of TTP compared to current standard practice of quantitative assays (ELISA or chemiluminescence AcuStar).
Results:
A total of 128 patient samples were analyzed, with quantitative ADAMTS13 values ranging from 0% to 150%. The Technoscreen assay demonstrated high sensitivity and negative predictive value (NPV) for ADAMTS13 deficiency, but low specificity and positive predictive value (PPV), especially with one lot of reagent. Good inter-observer reliability was demonstrated. Excluding one possibly compromised batch and other test failures, results of 80 samples yielded sensitivity of 100% (95% CI = 84-100), specificity of 90% (80-95), PPV 77% (58-89) and NPV 100% (93-100).
Conclusion:
The Technoscreen assay appears to be a reliable screening test for ADAMTS13 activity to exclude TTP in routine clinical practice. However, the assay falsely identified ADAMTS13 deficiency in many cases, partially batch related, which mandates confirmation with a quantitative assay, as well as initial assessment of kits as 'fit for purpose' prior to use for patient testing.
... ADAMTS13 is a metalloprotease enzyme that cleaves von Willebrand factor (VWF) -a protein involved in blood clotting at the site of injury. Deficiency of ADAMTS13 results in uncleaved ultra large VWF multimeres (UL-VWF MM), with additional triggers results in enhanced platelet aggregation, resulting in organ damage due to compromised circulation [3]. TTP mainly affects the central nervous system, but the heart and kidneys are the other commonly affected organs. ...
Thrombotic thrombocytopenic purpura (TTP) characterized by microangiopathic hemolytic anemia, thrombocytopenia and signs of organ dysfunction, is due to either congenital or acquired deficiency of ADAMTS13 gene. Guillian Barre Syndrome (GBS) is a post infectious disorder, most commonly associated with C. jejuni infection. Both conditions have high mortality if untreated and have been reported with other comorbid conditions. We found only one case report of sequential TTP and GBS. However, we report the first case of concurrent TTP and GBS infection in a 22 years old female after bloody diarrhea, successfully managed by symptomatic treatment, sessions of plasmapheresis, and hemodialysis. TTP and GBS have both been associated with bacterial and viral infections, and antibodies formed against them may result in cross reactivity due to molecular mimicry. It is suggested although unproven that in such cases, patients likely developed cross-reactivity against both platelet and neurogenic glycoproteins (the linking antigen) following predisposing infection.
... In 1998, deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), a von Willebrand factor-cleaving protease, has been recognized as the cause of TTP (3)(4)(5). Since then, several studies in patients with TMA have demonstrated that an ADAMTS13 activity below 10% is a specific feature of TTP. The diagnosis of TTP requires prompt attention given that it is a fatal condition that requires urgent plasmapheresis. ...
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency (activity <10%). Urgent intervention based on the timely evaluation of ADAMTS13 level is crucial to guide optimal therapy. The recently developed PLASMIC score based on seven items allows the rapid identification of patients at high risk for TTP due to severe ADAMTS13 deficiency. This retrospective study included 31 hospitalized patients with suspicious thrombotic microangiopathy in National Cheng Kung University Hospital from December 2016 to July 2021. Data on ADAMTS13 activity and medical and laboratory information were retrieved from medical records. The PLASMIC score could be calculated in 24 of the 31 patients with available data, and the final cohort was stratified according to the 7-point PLASMIC score. All patients with high PLASMIC score (6–7) exhibited severe ADAMTS13 deficiency (activity ≤10%). One patient with a brain tumor and a PLASMIC score of 6 did not have severe ADAMTS13 activity of ≤10%. The patients in the intermediate- and low risk groups (PLASMIC scores of 5 and 0–4, respectively) exhibited ADAMTS13 activities of above 10%. Given the role of prompt diagnosis in the timely delivery of appropriate therapy, these findings confirm and strengthen the predictive value of the PLASMIC score in patients at high risk for TTP due to severe ADAMTS13 deficiency.
... Recent studies have demonstrated that deficiency in the von Willebrand factor (vWF) cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) causes TTP. The deficiency of ADAMTS13 can be genetic or more common, acquired, resulting from autoimmune production of inhibitory anti-ADAMTS13 antibodies [2]. PEX (plasma exchange) has now become the cornerstone of the management of TTP. ...
Background
Acute thrombotic thrombocytopenic purpura (TTP) is an aggressive thrombotic microangiopathy that if not treated, can have a 90% mortality rate. Timely, extensive plasma exchange (PEX) has been indicated to reduce the mortality rate to < 10%, but its side effects are not well-known. We present here a case of a patient presented with Comb (+) TTP and developed catheter-associated deep vein thrombosis (DVT).
Case presentation
A 27-year-young man presented with persistent thrombocytopenia and Coombs positive anemia was firstly diagnosed with Evans syndrome. However, he was refractory to a methylprednisolone pulse therapy with a combination of platelet transfusion and eventually developed microangiopathy of central nerve system. Several pathological manifestations of the disease were prevented by PEX. The immediate start of PEX (1500 mL/d) induced a complete remission of acquired TTP and disappearance of neurological signs and symptoms. However, external iliac and femoro-popliteal venous thrombosis was diagnosed subsequently, inferior vena cava filter (IVC) filter was immediately implanted accompanied with anticoagulation therapy. Meanwhile, PEX session was sustained as well as oral anticoagulant (rivaroxaban). 14 days later, the patient got full recovery.
Conclusions
Catheter-related DVT under the setting of TTP should be cautious. It is necessary to start anticoagulation and antiplatelet therapy for thrombosis early, especially in such cases when PLT count > 50 × 10⁹/L.
... Original ADAMTS13 assays utilized plasma-derived VWF multimers as substrate and required time-consuming steps of conformational unfolding involving various agents. 16 Currently, most of the commonly utilized assays for measuring ADAMTS13 activity are based on enzyme linked immunosorbent assay (ELISA) or fluorescence resonance energy transfer (FRET)-based technologies utilizing recombinant VWF substrates. 2,13 Although some institutions still employ in-house methods, there are several commercial assays that have now become available. ...
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).
... This can lead to the classical presentation of TMA, with varying degrees of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and ischemic damage to target organs such as the brain and kidney, but can also affect multiple other organ systems such as the heart, lungs, and the gastrointestinal tract. 1,2 The severity and symptoms of the initial presentation are determined by which microvascular beds are involved, and the extent of the damage to these vessels. The kidney may be additionally injured by the release of free hemoglobin. ...
... On completion and full authorship approval of the initial draft of the article, 9 revision opportunities were arranged from 2018 to 2020. At each of these revision milestones, all authors were asked to review both their own sections and provide internal peer review of the entire article with the following aims: (1) remove information and references that had been superseded by newer information, (2) update existing references with newer and/or higher quality references, and (3) add new information and references arising since the last revision. Authors obtained this information through their own search of the literature predominantly by using PubMed, participation in research projects, and attendance of conferences and medical education events. ...
Purpose of review:
Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli-induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment.
Sources of information:
Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors.
Methods:
This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies.
Key findings:
Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli-induced hemolytic uremic syndrome, also known as "typical" HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA.
Limitations:
The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach.
... Recent studies have demonstrated that de ciency in the von Willebrand factor (vWF) cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) causes TTP. The de ciency of ADAMTS13 can be genetic or more common, acquired, resulting from autoimmune production of inhibitory anti-ADAMTS13 antibodies [2] . PEX (plasma exchange) has now become the cornerstone of the management of TTP. ...
Background: Acute thrombotic thrombocytopenic purpura (TTP) is an aggressive thrombotic microangiopathy that if not treated, can have a 90% mortality rate. Timely, extensive plasma exchange (PEX) has been indicated to reduce the mortality rate to<10%, but its side effects are not well-known. We present here a case of a patient presented with Comb (+) TTP and developed catheter-associated deep vein thrombosis (DVT).
Case presentation: A 27-year-young man presented with persistent thrombocytopenia and Coombs positive anemia was firstly diagnosed with Evans syndrome. However, he was refractory to a methylprednisolone pulse therapy with a combination of platelet transfusion and eventually developed microangiopathy of central nerve system. Sever pathogenesis was prevented by PEX. The immediate start of PEX (1500ml/d) induced a complete remission of acquired TTP and disappearance of neurological signs and symptoms. However, external iliac and femoro-popliteal venous thrombosis was diagnosed subsequently, inferior vena cava filter (IVC) filter was immediately planting accompanied with anticoagulation therapy. Meanwhile, PEX session was sustained as well as oral anticoagulant (rivaroxaban). 14 days later, the patient got full recovery.
Conclusions: Catheter-related DVT under the setting of TTP should be cautious. It is necessary to start anticoagulation and antiplatelet therapy for thrombosis early, especially in such cases when PLT count > 50×109/L.
... VWF stored in Weibel-Palade bodies (endothelial cells) or alpha granules (megakaryocytes), is rich in extremely large multimers, and gets cleaved into smaller multimers of different size by ADAMTS-13, after secretion. 5 Under normal conditions, VWF circulates in the plasma in its globular form. Under high shear stress or vascular injury, VWF unfurls and exposes platelet GPIb receptor binding sites located in its A1 domain. ...
Background
Phenotypic von Willebrand disease (VWD) classification requires multiple tests including analysis of multimeric distributions von Willebrand factor (VWF) and evaluation of its structure. VWF multimer analysis is labor intensive, nonstandardized, and limited to specialized laboratories. A commercial semiautomatic assay, HYDRAGEL VW multimer assay (H5/11VWM, Sebia), has become available.
Objectives
Establishment of reference ranges for H5/11VWM to improve VWD classification.
Methods
Implementation validation, establishment and validation of normal and pathological reference intervals (NRIs/PRIs), comparison with in‐house method using 40 healthy volunteers and 231 VWD patients.
Results
Qualitative and quantitative validation of NRI obtained sensitivity of 88% and 79%, respectively, for type 2. Comparison of the two methods showed an overall concordance of 86% with major conflicting results in all atypical 2B (n = 7) and 50% 2M‐GPIb (n = 41) showing quantitative and qualitative multimeric loss, that was not detected with in‐house method. We were able to use established PRIs, with 73% validity in type 2 cases, to distinguish individual type 2A subtypes (IIA, IIC, IID, IIE) from 2M and 2B.
Conclusion
H5/11VWM could be used for all clinical purposes because its reliability and its rapid and accurate diagnostic ability and reduced observer bias. Although H5/11VWM cannot evaluate triplet structures, we were able to define 2A subtypes by stripping back to the percentage of intermediate/high‐molecular‐weight multimers. H5/11HWM could be an efficient and widely available alternative for the “gold standard” technique.
