Nonneutralizing IgM and IgG antibodies to von Willebrand factor–cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura

Scheiflinger, Friedrich; Knöbl, Paul; Trattner, Bettina; Plaimauer, Barbara; Mohr, Gabriele; Dockal, Michael; Dorner, Friedrich; Rieger, Manfred

doi:10.1182/blood-2003-05-1616

Cited by 210 publications

(202 citation statements)

References 23 publications

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“…8,12 Microtiter plates were coated with rADAMTS13 (Baxter Bioscience), patient plasma was added and incubated for 1 hour, and any anti-ADAMTS13 IgG present was detected using anti-human globulin. A standard curve was prepared by diluting an index reference plasma in PBS/BSA to achieve 100%, 80%, 40%, 20%, 10%, 5%, and 0% concentrations.…”

Section: Assaysmentioning

confidence: 99%

A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura

Scully

McDonald

Cavenagh

et al. 2011

Blood

366

377

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The safety and efficacy of weekly rituximab 375 mg/m 2 (؋4), given within 3 days of acute TTP admission, with standard therapy (PEX and steroids) was evaluated. Clinical outcomes were compared to historical controls (n ‫؍‬ 40) who had not received rituximab. Within the trial group, 15 of 40 required ICU admission and 15% of all cases with the highest troponin T levels on admission were ventilated. Before the second rituximab infusion, 68% of cases had a platelet count > 50 ؋ 10 9 /L and 38% > 150 ؋ 10 9 /L. Fewer PEX were required in whites compared to nonwhite in the rituximab group (mean 14 vs 21, P ‫؍‬ .0095). Inpatient stay was reduced by 7 days in the non-ICU trial cases compared to historical controls (P ‫؍‬ .04), especially in whites, with a mean reduction of 7 days (P ‫؍‬ .05). Ten percent of trial cases relapsed, median, 27 months (17-31 months), compared to 57% in historical controls, median 18 months (3-60 months; P ‫؍‬ .0011).There were no excess infections or serious adverse events with rituximab. In conclusion, rituximab appears a safe and effective therapy. Inpatient stay and relapse are significantly reduced in the rituximab cohort. Rituximab should be considered in conjunction with standard therapy on acute presentation of TTP. This study was registered at www.clinicaltrials.gov as NCT009-3713. (Blood. 2011;118(7): 1746-1753)

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Section: Assaysmentioning

confidence: 99%

A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura

Scully

McDonald

Cavenagh

et al. 2011

Blood

366

377

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“…Non-neutralizing antibodies can only be identified by enzyme-linked immunosorbent assay (ELISA) [7]. Such antibodies may contribute to increasing ADAMTS13 clearance from the circulation or may interfere with ADAMTS13 interaction with cells or other plasma proteins [6]. Principally, the ELISA assay detects neutralizing or non-neutralizing antibodies against ADAMTS13.…”

Section: Introductionmentioning

confidence: 99%

“…The antibody response to ADAMTS13 includes neutralizing or non-neutralizing antibodies [4][5][6]. Neutralizing antibodies block the proteolytic activity of ADAMTS13 towards VWF and are detected with in vitro functional assays.…”

Section: Introductionmentioning

confidence: 99%

IgG subclass distribution of anti‐ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura

Ferrari

Mudde²,

Rieger

et al. 2009

Journal of Thrombosis and Haemostasis

168

154

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Summary. Background: ADAMTS13‐neutralizing IgG autoantibodies are the major cause of acquired thrombotic thrombocytopenic purpura (TTP). Objective: To analyze the IgG subclass distribution of anti‐ADAMTS13 antibodies and a potential relationship between subclass distribution and disease prognosis. Methodology: An enzyme‐linked immunosorbent assay‐based method was used to quantify the relative amounts of IgG subclasses of anti‐ADAMTS13 antibodies in acquired TTP plasma. Results: IgG4 (52/58, 90%) was the most prevalent IgG subclass in patients with acquired TTP, followed by IgG1 (52%), IgG2 (50%), and IgG3 (33%). IgG4 was found either alone (17/52) or with other IgG subclasses (35/52). IgG4 was not detected in 10% of the patients. There was an inverse correlation between the frequency and abundance of IgG4 and IgG1 antibodies (P < 0.01). Patients with high IgG4 levels and undetectable IgG1 are more prone to relapse than patients with low IgG4 levels and detectable IgG1. Conclusions: All IgG subclasses of anti‐ADAMTS13 antibodies were detected in patients with acquired TTP, with IgG4, followed by IgG1, antibodies dominating the anti‐ADAMTS13 immune response. Levels of IgG4 could be useful for the identification of patients at risk of disease recurrence.

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“…Alternatively, some patients may have antibodies that bind ADAMTS13 and facilitate clearance without inhibiting ADAMTS13 activity, and such nonneutralizing antibodies have been reported. 48 Unexpectedly, patients with ADAMTS13 inhibitors often respond to plasma exchange with resolution of their thrombocytopenia and hemolysis, even though the inhibitor titer stays elevated and the ADAMTS13 activity remains undetectable (Figure 2). Such findings were also obtained by Kremer-Hovinga et al 49 These results suggest that ADAMTS13 deficiency is not always sufficient to cause thrombotic microangiopathy, which is consistent with the variable clinical course of patients with congenital ADAMTS13 deficiency.…”

mentioning

confidence: 99%

Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura

Zheng

Kaufman

Goodnough

et al. 2004

Blood

422

401

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Therapeutic plasma exchange is an effective empiric treatment for thrombotic thrombocytopenic purpura (TTP), but how therapy affects the level of a disintegrin and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) or inhibitor has not been reported in many patients. We prospectively analyzed ADAMTS13 activity and inhibitor levels in 37 adults with TTP. ADAMTS13 level at presentation was lower than 5% in 16 of 20 patients with idiopathic TTP and in none of 17 patients with TTP associated with hematopoietic stem cell transplantation, cancer, drugs, or pregnancy (P < .00001). Seven of the 16 patients with ADAMTS13 activity lower than 5% (Ϸ 44%) had inhibitors. For 8 patients followed serially with ADAMTS13 activity lower than 5% but no inhibitor at presentation, plasma exchange led to complete clinical remission and a rise in ADAMTS13 level. In contrast, 4 patients with low ADAMTS13 activity but high-titer inhibitor (> 5 units/mL) had neither a rise in ADAMTS13 activity nor a reduction in the inhibitor titer: 3 had recurrent disease and 1 died. Among 17 patients with AD-AMTS13 activity at presentation higher than 25%, 10 died. Mortality rate for idiopathic TTP was 15%, whereas mortality for nonidiopathic TTP was 59% (P < .02). We conclude that assays of ADAMTS13 activity and inhibitors in addition to the clinical categories (idiopathic TTP and nonidiopathic TTP) are predictive of outcome and may be useful to tailor patient treatment. (Blood. 2004;103:4043-4049)

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Nonneutralizing IgM and IgG antibodies to von Willebrand factor–cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura

Cited by 210 publications

References 23 publications

A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura

A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura

IgG subclass distribution of anti‐ADAMTS13 antibodies in patients with acquired 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

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