ADAMTS‐13 activity and autoantibodies classes and subclasses as prognostic predictors in acquired thrombotic thrombocytopenic purpura

Bettoni, Giuseppe; Palla, Roberta; Valsecchi, Carla; Consonni, Dario; Lotta, Luca A.; Trisolini, Silvia Maria; Mancini, Ilaria; Musallam, Khaled M.; Rosendaal, Frits R.; Peyvandi, Flora

doi:10.1111/j.1538-7836.2012.04808.x

Cited by 77 publications

(61 citation statements)

References 54 publications

(99 reference statements)

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“…Measurement of ADAMTS13 levels is helpful in the diagnosis. An ADAMTS13 level of no less than 5%, the absence of ADAMTS inhibitors, and expression of ADAMTS gene mutations will help confirm the diagnosis (48).…”

Section: Adamts In the Pathogenesis Of Obstetrics And Gynecology Disementioning

confidence: 99%

A new biological marker candidate in female reproductive system diseases: Matrix metalloproteinase with thrombospondin motifs (ADAMTS)

Demircan

Cömertoğlu

Akyol

et al. 2014

J Turkish German Gynecol Assoc

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Review 250Introduction A Disintegrin-like and Metalloproteinase with Thrombospondin type-1 motif (ADAMTS) proteinases, which are released outside the cell (soluble), have very critical roles in damage and repair of extracellular matrix (ECM) processes (remodeling) (1). The ADAMTS family, which degrades ECM structural substrates, such as collagen, aggrecan and versican, has 19 family members (2). These enzymes, which are associated with a great deal of vital physiological processes in the ECM, are inhibited by tissue inhibitors of metalloproteinases (TIMPs) (3, 4). Family members of this group are divided into various subgroups according to their tasks in the ECM (Figure 1). ADAMTS1 (METH-1), which was identified for the first time in colon adenocarcinoma, is associated with inflammation (5) and shows anti-angiogenic properties with ADAMTS8 (METH-2) (6, 7). Especially in the physiology of ovulation, there is interest in these proteases. ADAMTS1 also takes important roles in the process of normal growth, fertility, and organogenesis (8). ADAMTS 2, 3, and 14, also known pro-collagen N-proteinases, have important roles in collagen synthesis in the ECM. Various connective tissue diseases are seen in ADAMTS2 deficiency in this group (9). ADAMTS1, -4, -5, -8, -9, -15, -16, and -18 degrade aggrecan, which is the one of the main components of the ECM; so, they are called as aggrecanases (1). ADAMTS1, -4, and -5 degrade brevican and versican, other structural ECM components (10). Versican helps hyaluronan, which is the basic element of the ECM, to stabilize the matrix (11). ADAMTS5 and -6, expressed specifically in the placenta, are thought to be responsible for implantation (12). ADAMTS7 and -12 degrade Cartilage oligomeric matrix protein (COMP), which is an essential glycoprotein in cartilage matrix (13). ADAMTS10 has important roles in the development of tissues of skin and lens. In ADAMTS10 mutations, autosomal recessive Weill-Marchesani syndrome is seen (14). Known as von Willebrand cleaving protease, ADAMTS13 has effects on coagulation and homeostasis. This protease degrades ultralarge VWF multimers that are localized in endothelial surfaces; so, it prevents thrombus formation (9). Thrombotic thrombocytopenic purpura (TTP), a serious problem during pregnancy, occurs in ADAMTS13 deficiency (15). Increased by follicle-stimulating hormone (FSH) and luteinizing hormone (LH), ADAMTS16 degrades a-2 macroglobulin in the ECM (16). ADAMTS17 is involved in estrogen-induced apoptosis in cancer cells (16). ADAMTS9 and -20 are known Playing a key role in the pathophysiology of many diseases, A Disintegrin-like and Metalloproteinase with Thrombospondin type-1 motif (AD-AMTS) proteinases have been attracted more attention in obstetrics and gynecology. First discovered in 1997, this zinc-dependent proteinase family has 19 members today. These enzymes, which are located in the extracellular matrix (ECM), have a lot of very important functions, like matrix formation and resorption, angiogenesis, ovulation, and coagulation. In additio...

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Section: Adamts In the Pathogenesis Of Obstetrics And Gynecology Disementioning

confidence: 99%

A new biological marker candidate in female reproductive system diseases: Matrix metalloproteinase with thrombospondin motifs (ADAMTS)

Demircan

Cömertoğlu

Akyol

et al. 2014

J Turkish German Gynecol Assoc

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“…15 A number of studies have shown that anti-ADAMTS13 antibodies detected in the plasma of TTP patients are composed of subclasses IgG1 and IgG4. 8,10,16,17 Isotype switching from IgM to IgG is a characteristic feature of the humoral immune response, which depends on help from CD41 T cells. 10,16 Anti-ADAMTS13 antibodies have undergone affinity maturation through somatic hypermutation in germinal centers.…”

Section: Introductionmentioning

confidence: 99%

Preferential HLA-DRB1*11–dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells

Sorvillo

Haren

Kaijen

et al. 2013

Blood

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Key Points• ADAMTS13 derived peptides presented on HLA-DR; implications for acquired TTP.• CUB2 domain peptide binds to risk-allele HLA-DRB1*11.Autoantibodies directed against ADAMTS13 prohibit the processing of von Willebrand factor multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). Recently, HLA-DRB1*11 has been identified as a risk factor for the development of acquired TTP. Here, we identified ADAMTS13-derived peptides presented on MHC class II alleles from 17 healthy donors. Dendritic cells from a panel of both HLA-DRB1*11-positive and -negative donors were pulsed with ADAMTS13, and the HLA-DR-presented peptide repertoire was analyzed by mass spectrometry. Interestingly, at low antigen concentrations, HLA-DRB1*11-or DRB1*03-positive donors presented a limited number of CUB2-derived peptides. Pulsing of dendritic cells using higher concentrations of ADAMTS13 resulted in the presentation of larger numbers of ADAMTS13-derived peptides by both HLA-DRB1*11-positive and -negative donors. Although the presented peptides were derived from several ADAMTS13 domains, inspection of the peptide profiles revealed that CUB2 domainderived peptides were presented with a higher efficiency when compared with other peptides. Remarkably, dendritic cells from DRB1*11 donors pulsed with higher concentrations of ADAMTS13-present derivatives of a single CUB2-derived peptide. We hypothesize that functional presentation of CUB2-derived peptides on HLA-DRB1*11 contributes to the onset of acquired TTP by stimulating low-affinity, self-reactive CD41 T cells. (Blood. 2013;121(17):3502-3510) Introduction Acquired thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disorder characterized by the production of autoantibodies directed toward ADAMTS13, a plasma metalloprotease responsible for the cleavage of ultra-large von Willebrand factor (UL-VWF) multimers.1-3 Deficiency of ADAMTS13 causes the accumulation of UL-VWF strings on the surface of endothelial cells of the vessel wall and in the circulation. 4 Prolonged exposure of UL-VWF strings on the surface of endothelial cells promotes platelet adhesion, leading to low platelet counts and microvascular thrombosis. 5,6 The majority of the inhibitory anti-ADAMTS13 antibodies that develop in patients affected by acquired TTP targets a single epitope composed of Arg568, Phe592, Arg660, Tyr661, and Tyr665 on the outer surface of the spacer domain. This exposed region is crucial for binding of ADAMTS13 to unfolded VWF A2 domain.7-9 Antibodies targeting the CUB 1-2 and TSP2-8 regions of ADAMTS13 have also been detected in the plasma of several patients with acquired TTP. 10,11 The pathogenic role of anti-TSP2-8 and anti-CUB1-2 is still unclear. The carboxy-terminal ADAMTS13 TSP2-8 and CUB 1-2 regions not only modulate processing of VWF under flow 12-14 but are also necessary for the binding of ADAMTS13 to endothelial cells. 15A number of studies have shown that anti-ADAMTS13 antibodies detected in the plasma ...

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“…1 A severe deficiency of the plasma enzyme ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type-1 repeats), due to genetic mutations (congenital) 2 or anti-ADAMTS13 autoantibodies (acquired), 3,4 is the main mechanism in the pathogenesis of TTP. Autoantibodies against ADAMTS13 are predominantly of the IgG class, [5][6][7] particularly subclasses IgG4 and IgG1, [8][9][10] but autoantibodies belonging to classes IgM and IgA have also been described. 5,[9][10][11] Elevated levels of soluble circulating autoantibody-antigen immune complexes are the hallmark of many autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

“…Autoantibodies against ADAMTS13 are predominantly of the IgG class, [5][6][7] particularly subclasses IgG4 and IgG1, [8][9][10] but autoantibodies belonging to classes IgM and IgA have also been described. 5,[9][10][11] Elevated levels of soluble circulating autoantibody-antigen immune complexes are the hallmark of many autoimmune diseases. [12][13][14] Deposition of circulating immune complexes in tissues, mainly in capillary beds, promoting inflammation and tissue damage, is the most relevant pathological mechanism underlying immune complex-mediated diseases.…”

Section: Introductionmentioning

confidence: 99%

Persistence of circulating ADAMTS13-specific immune complexes in patients with acquired thrombotic thrombocytopenic purpura

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o nTTP. Sixty-eight patients were tested during the acute phase, with 48 patients experiencing their first acute episode and 20 a relapse. For 18 of these patients, corresponding samples in clinical remission were also available. Ten patients were analyzed only during remission, giving a total of 28 patients tested in remission. The patients' demographics and clinical features are summarized in Table 1. The inclusion criteria for patients with acute acquired TTP were: presence of severe ADAMTS13 deficiency (<10%), thrombocytopenia (platelet count <150x10 9 /L), microangiopathic hemolytic anemia (hemoglobin <12 g/dL) with presence of schistocytes on the peripheral blood smear, and elevated lactate dehydrogenase levels (>450 IU/L). Fever, neurological symptoms or renal failure were not mandatory. Remission was defined as a normal platelet count (>150x10 9 /L) and no plasma exchange treatment for ≥30 consecutive days. Relapse was defined as the reappearance of clinical manifestation and/or laboratory data compatible with TTP after remission.Frozen citrated plasma samples were obtained from four international centers. The study was approved by the ethic committees of the University Hospital of Berne, Switzerland; Medical University of Vienna, Austria; Lille University Hospital, France; and Icahn School of Medicine, New York, USA. ADAMTS13 assaysADAMTS13 activity (ADAMTS13:Ac) and ADAMTS13 functional inhibitor titers were measured using fluorometric FRETS-VWF73 assay as described elsewhere. 24,25 The limit of quantification of ADAMTS13:Ac was 0.05 U/mL (5%); values <0.10 U/mL (<10%) were considered severely reduced; levels of 0.10-0.50 U/mL as reduced and levels >0.5 U/mL as normal. An inhibitor titer <0.7 BU/mL was considered negative. Plasma ADAMTS13 antigen (ADAMTS13:Ag) levels were determined by ELISA as described previously. 20 The reference range of the assay was 403 -907 ng/mL; the limit of quantification was 10 ng/mL. Levels of 100 -403 ng/mL were considered reduced, levels <100 ng/mL as severely reduced, and values <10 ng/mL as undetectable. Detection of free anti-ADAMTS13 antibodies by enzyme-linked immunosorbent assayFree antibodies were detected as described elsewhere 25 with modifications (Online Supplementary Methods). Detection of ADAMTS13-specific immune complexesMicrotiter plates were coated with a polyclonal rabbit antihuman ADAMTS13 antibody. After blocking the non-specific sites, diluted patient's plasma samples and controls were added and incubated overnight at 4°C. The next day, the immunoglobulin fraction of the bound immune complexes was detected with horseradish peroxidase-conjugated class-specific secondary antibodies followed by detection with an appropriate chromogenic substrate. For details, see Online Supplementary Methods and Online Supplementary Figure S1.An ELISA to detect total IgG-immune complexes was not established, however, the total amount of IgG-immune complexes was investigated in selected patients by co-immunoprecipitation,...

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ADAMTS‐13 activity and autoantibodies classes and subclasses as prognostic predictors in acquired thrombotic thrombocytopenic purpura

Cited by 77 publications

References 54 publications

A new biological marker candidate in female reproductive system diseases: Matrix metalloproteinase with thrombospondin motifs (ADAMTS)

A new biological marker candidate in female reproductive system diseases: Matrix metalloproteinase with thrombospondin motifs (ADAMTS)

Preferential HLA-DRB1*11–dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells

Persistence of circulating ADAMTS13-specific immune complexes in patients with acquired thrombotic thrombocytopenic purpura

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