scholarly journals The Role of ADAMTS13-Specific Circulating Immune Complexes in Prediction of Recurrence of Acquired Thrombotic Thrombocytopenic Purpura

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1467-1467
Author(s):  
Barbara Ferrari ◽  
Carla Valsecchi ◽  
Silvia Pontiggia ◽  
Ilaria Mancini ◽  
Luca Andrea Lotta ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Severity ◽  
Immune Complexes ◽  
Research Funding ◽  
Cox Regression ◽  
Fold Increase ◽  
Circulating Immune Complexes ◽  
First Episode ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

Abstract Introduction. Acquired thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy due to the development of autoantibodies against the VWF-cleaving protease ADAMTS13. We recently developed and validated a new ELISA method for the detection of ADAMTS13-specific circulating immune complexes (CICs) in acquired TTP patients. This study aims at investigating the clinical relevance of ADAMTS13-specific CICs at disease presentation in a large cohort of acquired TTP patients. Methods. We measured ADAMTS13-specific CICs by ELISA in 51 patients from the Milan TTP Registry, at the first episode of acquired TTP. All patients presented anti-ADAMTS13 autoantibodies by western blotting and severe ADAMTS13 deficiency (i.e., <10% of normal) by FRETS-VWF73 or CBA assays. We studied the associations between ADAMTS13-specific CICs levels and (i) ADAMTS13-related measurements (i.e., ADAMTS13 antigen, anti-ADAMTS13 IgG), (ii) clinical and laboratory markers of disease severity (i.e., muco-cutaneous bleeding, neurological, renal and cardiovascular symptoms, number of platelets, LDH, hemoglobin, creatinine), (iii) short- and long-term clinical outcomes (i.e., number of plasma exchange procedures required to attain remission, recurrence). Statistical analyses were performed using linear, logistic and Cox regression models. Results. The prevalence of ADAMTS13-specific CICs in patients experiencing a first episode of acquired TTP was 39% (95% confidence intervals [CI]: 26-52%). ADAMTS13-specific CICs were only associated with ADAMTS13 antigen levels at regression analyses (beta per 10% increase in ADAMTS13 antigen, 95% CI: 0.05, 0.02-0.08). The presence of ADAMTS13-specific CICs was associated with more than a four-fold increase in the risk of recurrence at 2 years after the first TTP episode (hazard ratio, 95%CI: 4.2, 1.1-16.4). Conclusions. ADAMTS13-specific CICs are neither a biomarker of disease severity, nor a predictor of clinical outcome during acute phase. Conversely, ADAMTS13-specific CICs seem to have relevance in predicting the recurrence of acute TTP episodes. Disclosures Peyvandi: NovoNordisk: Research Funding; Kedrion : Research Funding; NovoNordisk: Speakers Bureau; CSL Behring : Speakers Bureau; Baxter: Speakers Bureau; Bayer: Speakers Bureau.

Variable Results With Plasma Exchange In Thrombotic Thrombocytopenic Purpura

1981 ◽  
Author(s):  
Toby L Simon
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Immune Complexes ◽  
Raji Cell ◽  
Disease Onset ◽  
Circulating Immune Complexes ◽  
Cardiac Complications ◽  
Thrombocytopenic Purpura ◽  
The Third ◽  
Fresh Frozen

The clinical efficacy of plasma exchange with fresh frozen single donor plasma in thrombotic thrombocytopenic purpura (TTP) was evaluated. Six patients with the classical findings of TTP, had plasmapheresis using the Haemonetics Model 30. Treatments were initiated daily. Two to three liters total exchanges were done; 1-1½ liters fresh frozen plasma were infused with each exchange. In five of the six cases, therapy was begun immediately after diagnosis. Steroids and antiplatelet agents were also used. Five of the patients were comatose when treatment was begun; the sixth had neurological symptoms of memory loss and aphasia with severe hemolytic anemia and thrombocytopenia. Circulating immune complex measurements were performed in all patients prior to treatment using the Clq and Raji cell assays.Three patients (2 in coma) responded to therapy. The two comatose patients required more than four daily treatments before beginning to respond (followed by four and six alternate day treatments, respectively). The third patient went into remission after four daily treatments. Three patients in coma died, two deteriorating after the first plasma exchange. The third, treated after a delay due to severe cardiac complications, subsequently died.The three responding patients were younger than the three who died. The two in coma who responded to therapy had a longer course of symptoms (suggesting disease onset prior to onset of coma) than the three who died. Circulating immune complexes by the Clq assay were negative in all six patients. The Raji cell assay was positive in one patient.Even severely ill comatose patients with TTP respond to plasma exchange, but aggressive, persistent therapy may be required before response is seen. More fulminant disease with rapid onset may fail to respond. Circulating immune complexes do not appear to mediate the disease process.

scholarly journals Daratumumab for immune thrombotic thrombocytopenic purpura

2021 ◽  
Author(s):  
Jana Van den Berg ◽  
Johanna A Kremer Hovinga ◽  
Claudia Pfleger ◽  
Inga Hegemann ◽  
Gregor Thomas stehle ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Treatment Options ◽  
Current Treatment ◽  
First Episode ◽  
Thrombocytopenic Purpura ◽  
Life Threatening ◽  
Adamts13 Deficiency ◽  
Treatment Refractory ◽  
Circulating Autoantibodies

Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy. It is caused by a severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, 13) deficiency due to circulating autoantibodies, and is associated with significant morbidity and mortality. Current treatment options include plasma exchange, immunosuppression, and caplacizumab. When remission is achieved, the risk of relapse is high, especially in patients with persistent ADAMTS13 deficiency. We report the eradication of persistent ADAMTS13 inhibitory autoantibodies and restoration of normal ADAMTS13 activity using the anti-CD38 antibody daratumumab in two patients with iTTP. One patient had a frequently relapsing course, and the other a treatment-refractory first episode. There were no relevant adverse drug reactions.

Deficient ADAMTS13 Activity in Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura (TTP) in Populations From Japan in 2012: Validation of Findings Initially Reported in the United States in 1998 and 2000.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2203-2203
Author(s):  
Charles Bennett ◽  
Masanori Matsumoto ◽  
Peter Georgantopoulos ◽  
Sony Jacob ◽  
Brianne L Dunn ◽  
...  
Keyword(s):  
United States ◽  
Board Of Directors ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Research Funding ◽  
The United States ◽  
Advisory Committees ◽  
Laboratory Findings ◽  
Thrombocytopenic Purpura ◽  
Causal Pathway ◽  
Adamts13 Deficiency

Abstract Abstract 2203 Background: Thrombotic thrombocytopenic purpura (TTP) is frequently characterized by severe ADAMTS13 deficiency, the cause of which is unknown. An important exception is ticlopidine-associated TTP (tc-TTP), the most common drug-induced TTP syndrome. In 1998, a possible association of TTP with ticlopidine was reported. In 1999, two additional series reported this association. In 2000, a fourth study reported severe A DAMTS13 deficiency among six of seven tc-TTP persons- suggesting a causal pathway. All of these reports were from the United States. Recently, we reported characteristics of 186 acquired idiopathic (ai)- TTP patients in Japan with severe ADAMTS13 deficiency, noting that clinical and laboratory findings for ai-TTP patients in Japan differed from those for cohorts of ai-TTP patients in Europe and North America- raising concern that TTP findings vary by region of the world. (PLOS One 2011) We now on report clinical and laboratory characteristics of a cohort of TTP patients from Japan with tc-TTP, and compare these findings to three cohorts of tc-TTP in the United States and one cohort of ai-TTP patients from Japan. Methods: We queried a database of thrombotic microangiopathy patients identified from a national TTP referral laboratory in Japan of cases identified between 1998 and 2008. Severe ADAMTS13 deficiency was characterized by activity levels < 5%. All tc-TTP patients and 186 of 911 ai-TTP patients in the database had severe ADAMTS13 deficiency and first onset of TTP. Comparisons were made to tc-TTP patients reported previously from the United States. Results: Characteristics of ai- TTP with severe ADAMTS13 deficiency in Japan and tc-TTP in Japan and US Conclusions: These data from Japan validate insights about tc-TTP initially proposed in 1998, 1999, and 2000 in the United States. Ticlopidine is a likely cause of TTP, the mechanism is via a cross-reactive antibody to ADAMTS13:AC resulting in formation of an ADAMTS13:INH, and therapeutic plasma exchange is necessary for treatment. Disclosures: Ortel: Eisai: Research Funding; Glaxo SmithKline: Research Funding; Pfizer: Research Funding; Instrumentation Laboratory, Inc: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.

Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13 autoantibodies

2009 ◽  
Vol 101 (02) ◽  
pp. 233-238 ◽  
Author(s):  
Sara Gastoldi ◽  
Erica Daina ◽  
Daniela Belotti ◽  
Enrico Pogliani ◽  
Paolo Perseghin ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Therapeutic Option ◽  
Severe Disease ◽  
Renal Involvement ◽  
First Episode ◽  
High Morbidity ◽  
Sustained Remission ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Haemolytic Anemia

SummaryThrombotic thrombocytopenic purpura (TTP) is a rare and severe disease characterized by thrombocytopenia, microangiopathic haemolytic anemia, neurological and renal involvement associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. Persistence of high titers of anti-ADAMTS13 autoantibodies predisposes to relapsing TTP. Since relapses are associated with high morbidity and mortality rates, the optimal therapeutic option should be a pre-emptive treatment able to deplete anti-ADAMTS13 autoantibodies and avoid relapses. Five patients who presented with persistence of undetectable ADAMTS13 activity and high titers of autoantibodies, were treated with rituximab as pre-emptive therapy during remission. Four of them were affected by relapsing TTP and one was treated after the first episode. ADAMTS13 activity ranging from 15% to 75% with disappearance of inhibitors was achieved after three months in all patients, and persisted >20% without inhibitors at six months. In three patients disease-free status is still ongoing after 29, 24 and six months, respectively. Relapses were documented in two patients during follow-up: in one patient remission lasted 51 months; while in the other patient relapse occurred after 13 months. Results demonstrated that rituximab used as pre-emptive treatment may be effective in maintaining a sustained remission in patients with anti-ADAMTS13 antibodies in whom other treatments failed to limit the production of inhibitors, and suggests that re-treatment with rituximab should be considered when ADAMTS13 activity decreases and inhibitors reappear into the circulation, to avoid a new relapse.

scholarly journals Annual Incidence and Severity of Acute Episodes in Hereditary Thrombotic Thrombocytopenic Purpura

Blood ◽  
2021 ◽  
Author(s):  
Erika Tarasco ◽  
Lukas Bütikofer ◽  
Kenneth D. Friedman ◽  
James N George ◽  
Ingrid V Hrachovinova ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Premature Death ◽  
Annual Incidence ◽  
Prospective Data ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Survival Frequency ◽  
Overt Disease ◽  
Plasma Infusions

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in hTTP patients is largely lacking. This study reports prospective data of 87 patients from the Hereditary TTP Registry (ClinicalTrials.gov NCT01257269) for survival, frequency and severity of acute episodes from enrollment until December 2019. The 87 patients, followed for median 4.2 years (range 0.01-15), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and of 18 years (range 0.0-70 for both), respectively. Forty-three patients received regular plasma prophylaxis, while 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes of which 91 (69%) occurred in patients on regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95%CI 0.29-0.44) with and of 0.41 (95%CI 0.30-0.56) without regular plasma treatment. More than one third of acute episodes (n=51) were documented in children &lt;10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients &gt;40 years of age (1.18 [95% CI 0.88-1.55] vs. 0.14 [95% CI 0.08-0.23]). Prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, caregivers, patients and their guardians are reluctant to start regular plasma infusions, from which particularly children would benefit.

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