Paradigm shift of childhood thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency

2012 ◽  
Vol 41 (3) ◽  
pp. e137-e155 ◽  
Author(s):  
Hideo Yagi ◽  
Masanori Matsumoto ◽  
Yoshihiro Fujimura
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Paradigm Shift ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

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 <10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients >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.

Thrombotic Thrombocytopenic Purpura Associated with von Willebrand Factor-Cleaving Protease (ADAMTS13) Deficiency in Children

2006 ◽  
Vol 32 (2) ◽  
pp. 090-097 ◽  
Author(s):  
Chantal Loirat ◽  
Agnès Veyradier ◽  
Jean-Pierre Girma ◽  
Anne-Sophie Ribba ◽  
Dominique Meyer
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children

2009 ◽  
Vol 24 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Chantal Loirat ◽  
Jean-Pierre Girma ◽  
Céline Desconclois ◽  
Paul Coppo ◽  
Agnès Veyradier
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

scholarly journals Beyond plasma exchange: novel therapies for thrombotic thrombocytopenic purpura

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 539-547 ◽  
Author(s):  
Kathryn Dane ◽  
Shruti Chaturvedi
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Relapse Prevention ◽  
Tissue Injury ◽  
Novel Therapies ◽  
Thrombocytopenic Purpura ◽  
Platelet Recovery ◽  
Adamts13 Deficiency ◽  
Prophylactic Use ◽  
Von Willebrand

Abstract The advent of plasma exchange has dramatically changed the prognosis of acute thrombotic thrombocytopenic purpura (TTP). Recent insights into TTP pathogenesis have led to the development of novel therapies targeting pathogenic anti-ADAMTS13 antibody production, von Willebrand factor (VWF)–platelet interactions, and ADAMTS13 replacement. Retrospective and prospective studies have established the efficacy of rituximab as an adjunct to plasma exchange for patients with acute TTP, either upfront or for refractory disease. Relapse prevention is a major concern for survivors of acute TTP, and emerging data support the prophylactic use of rituximab in patients with persistent or recurrent ADAMTS13 deficiency in clinical remission. Capalcizumab, a nanobody directed against domain A1 of VWF that prevents the formation of VWF–platelet aggregates, recently completed phase 2 (TITAN) and 3 (HERCULES) trials with encouraging results. Compared with placebo, caplacizumab shortened the time to platelet recovery and may protect against microthrombotic tissue injury in the acute phase of TTP, though it does not modify the underlying immune response. Other promising therapies including plasma cell inhibitors (bortezomib), recombinant ADAMTS13, N-acetyl cysteine, and inhibitors of the VWF–glycoprotein Ib/IX interaction (anfibatide) are in development, and several of these agents are in prospective clinical studies to evaluate their efficacy and role in TTP. In the coming years, we are optimistic that novel therapies and international collaborative efforts will usher in even more effective, evidence-based approaches to address refractory acute TTP and relapse prevention.

Thrombotic Thrombocytopenic Purpura: A Paradigm Shift?

2000 ◽  
Vol 84 (10) ◽  
pp. 528-535 ◽  
Author(s):  
Barbara Konkle ◽  
Miha Furlan ◽  
Douglas Cines
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Paradigm Shift ◽  
Capillary Endothelium ◽  
Healthy Individuals ◽  
Thrombocytopenic Purpura ◽  
Autoimmune Attack ◽  
Sudden Appearance ◽  
Thrombotic Diseases ◽  
Insight Into ◽  
New Strategies

SummaryThe pathophysiology of thrombotic thrombocytopenic purpura (TTP) has fascinated hematologists for decades. What causes seemingly healthy individuals to suddenly develop widespread platelet-rich microthrombi in specific microvascular beds while sparing other vascular sites completely? Is the disorder caused by the sudden appearance of a novel platelet-agglutinating factor or do platelet-rich thrombi form as a consequence of insult to the capillary endothelium? Is the disease self-limiting, does plasma exchange fundamentally alter the pathophysiology of an autoimmune attack on a normal endothelium, or does the immune response develop to microvasculature that has been perturbed and, if so, by what? It has been thought by many of us that the answers to these questions will provide insight into how platelet-vessel wall interactions are normally regulated in the microvasculature and the differences that characterize the behavior of microvascular, arterial and venous systems in various organs. The corollary to these scientific issues is the anticipation that such answers would also lead to new strategies for intervention in other, more common thrombotic diseases.

Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 292-299 ◽  
Author(s):  
James T. B. Crawley ◽  
Marie A. Scully
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Therapeutic Strategies ◽  
Therapeutic Approaches ◽  
Thrombocytopenic Purpura ◽  
Vessel Injury ◽  
Adamts13 Deficiency ◽  
Flowing Blood ◽  
A Disintegrin And Metalloproteinase ◽  
Anti Cd20

Abstract VWF is a multimeric plasma glycoprotein that specifically recruits platelets to sites of vessel injury. VWF multimeric size is central to this function, with larger multimers being more hemostatically active. Regulation of VWF multimeric size is mediated by the plasma metalloprotease ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, member 13). This enzyme can only recognize and cleave VWF when it is unraveled by rheological shear forces of the flowing blood. After the exposure of cryptic exosites, VWF recognition by ADAMTS13 involves multiple interactions that enable the protease to cleave VWF. Loss of VWF multimer size regulation caused by severe ADAMTS13 deficiency (either inherited or acquired) is associated with the microvascular thrombotic disorder thrombotic thrombocytopenic purpura (TTP). The sequelae associated with TTP are widely thought to be linked to hyperreactive circulating VWF that cause unwanted platelet aggregation in the high shear environment of the microvasculature. Diagnosis of TTP is primarily made through a combination of symptoms, analysis of plasma ADAMTS13 activity, and detection of inhibitory anti-ADAMTS13 antibodies. Current frontline treatments for TTP include plasma exchange, which serves to remove inhibitory antibodies (in acquired TTP) and provide a source of functional ADAMTS13, and steroids to treat the autoimmune component of acquired TTP. The use of anti-CD20 therapy has also exhibited encouraging results in the treatment of acquired TTP. Newer therapeutic strategies that are currently being explored or are in development include recombinant ADAMTS13, a hyperreactive ADAMTS13 variant, and anti-VWF therapy. This review discusses the basic biochemistry of VWF and ADAMTS13, their dysfunction in TTP, and therapeutic approaches for the amelioration of TTP.

scholarly journals Application of SELDI-TOF mass spectrometry in clinical evaluation of thrombotic thrombocytopenic purpura

2006 ◽  
Vol 20 (5-6) ◽  
pp. 219-227
Author(s):  
Haifeng M. Wu ◽  
Spero R. Cataland ◽  
Michael Bissell ◽  
Ming Jin
Keyword(s):  
Mass Spectrometry ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Rapid Determination ◽  
Correct Diagnosis ◽  
Thrombocytopenic Purpura ◽  
Autoimmune Antibodies ◽  
Adamts13 Deficiency ◽  
Rapid Purification ◽  
Von Willebrand

Surface Enhanced Laser Desorption/Ionization Time Of Flight (SELDI-TOF) mass spectrometry is characterized by integration of mass spectrometry with surface chemistry, which gives rise to rapid purification and subsequent determination of protein/peptide analytes. There are several surface matrices, named proteinChips, available for analyzing a particular analyte or a subset of biomolecules in biological samples. Each proteinChip has a unique surface property suitable for fractionation of a specific group of molecules. This article demonstrates the application of SELDI-TOF for the analysis of a cleaved peptide (Mr7739 daltons) from von Willebrand Factor by a metalloproteinase, ADAMTS13. Deficiency of ADAMTS13 is a known primary risk factor for the devastating hematological disorder, Thrombotic thrombocytopenic purpura (TTP). Rapid determination of ADAMTS13 activity helps clinicians tremendously in making the correct diagnosis and initiating timely therapy. Most patients with TTP are acquired cases who exhibit a production of autoimmune antibodies against ADAMTS13 protease. TTP's clinical course is critically controlled by the autoantibody's ability to inhibit ADAMTS13 function. Thus, a second SELDI-TOF based test has been devised to measure ADAMTS13 autoantibody activity for the evaluation of TTP disease activity. In conclusion, the unique features of SELDI-TOF which allow for the examination of the role of key proteases in disease processes have opened up new doors for the clinical application of mass spectrometer based techniques.

232-P: HLA-DRB1*11 is strongly associated with acquired severe ADAMTS13 deficiency-related idiopathic thrombotic thrombocytopenic purpura in Caucasian patients

2009 ◽  
Vol 70 ◽  
pp. S129
Author(s):  
Pascale Loiseau ◽  
Marc Busson ◽  
Agnes Veyradier ◽  
Karine Clabault ◽  
Alain Wynckel ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Caucasian Patients

Risk Factors for Recurrence of Thrombotic Thrombocytopenic Purpura.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1060-1060 ◽  
Author(s):  
Flora Peyvandi ◽  
Silvia Lavoretano ◽  
Roberta Palla ◽  
Hendrik B. Feys ◽  
Tullia Battaglioli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Relative Risk ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Recurrence ◽  
Acute Episode ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Neutralizing Activity ◽  
Adamts13 Deficiency

Abstract The introduction of plasma exchange therapy in early 1970s significantly reduced the rate of mortality in patients affected by thrombotic thrombocytopenic purpura (TTP), a disease characterized by thrombocytopenia and microangiopathic hemolytic anemia. A similar improvement was never achieved in the prevention of the disease recurrence. Still, 20–50% of patients, who survived the fatal disease, experience a relapse one month or even years after the acute episode of TTP. There is no pathognomic marker or laboratory test that can be used for the surveillance of TTP during remission and predict which patients will relapse. We have retrospectively analyzed for the first time at remission the role of ADAMTS13, anti-ADAMTS13 autoantibodies and von Willebrand Factor (VWF) in 109 patients who survived the acute episode of TTP. ADAMTS13 activity and ADAMTS13 antigen levels were measured as described by Gerritsen et al (TH 1999) and Feys HB et al. (JTH 2006), respectively. The total anti-ADAMTS13 autoantibodies (with and without neutralizing activity) were measured by western blot analysis and the presence of neutralizing anti-ADAMTS13 autoantibodies was checked according to Gerritsen et al (TH 1999). VWF antigen was measured using an ELISA assay and VWF multimers analysis was carried out using low-resolution SDS-agarose gel electrophoresis and exposing gels to human anti-VWF antibodies labeled with I125 for autoradiography (Ruggeri & Zimmerman, Blood 1981). All variables have been statistically analyzed in 2 subgroups of patients with or without TTP recurrence, in order to understand the role of each variable as a potential predictor marker for recurrence. Univariate and multivariate analysis were carried out to evaluate adjusted and unadjusted odds ratios (Ors) with 95% confidence intervals (CI) as a measure of the relative risk of relapse associated with the risk factors under investigation. Our data showed that the median value of ADAMTS13 activity and antigen levels at remission were significantly lower in patients with recurrent TTP than in patients with no relapse (ADAMTS13 activity: 12% vs. 41%; p=0.007; ADAMTS13 antigen: 36% vs 58%; p=0.003). Furthermore, the prevalence of patients with severe ADAMTS13 deficiency (≤10%) was significantly higher in the group of patients who relapsed (OR=2.9 CI95% 1.3–6.8, p=0.01). The prevalence of anti-ADAMTS13 autoantibodies (with or without neutralizing activity) resulted to be significantly higher in patients with recurrent TTP (OR= 3.1 CI 95% 1.4–7.3, p=0.006). A higher VWF antigen levels or the presence of ultralarge VWF (ULVWF) multimers at remission did not increase the risk of recurrence (p=0.4 for VWF:Ag and p=0.7 for ULVWF multimers). In conclusion, our data showed that the association of severe ADAMTS13 deficiency and the presence of anti-ADAMTS13 autoantibodies is a negative prognostic marker at remission and increases the relative risk of TTP recurrence by 3.6 times (OR=3.6 CI95% 1.4–9). Therefore our results would suggest that our efforts should go in the direction of maintenance therapy which aims at reducing or abolishing the presence of antibodies during remission and increasing the level of ADAMTS13 in plasma in order to prevent the recurrence of TTP.

Clinical Characteristics of Thrombotic Thrombocytopenic Purpura with Severe ADAMTS13 Deficiency

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4666-4666
Author(s):  
Moon Jang ◽  
So Young Chong ◽  
Inho Kim ◽  
Chul W. Jung ◽  
Doyeun Oh
Keyword(s):  
Mortality Rate ◽  
Serum Creatinine ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Clinical Significance ◽  
Sodium Dodecyl ◽  
Prognostic Significance ◽  
Adamts13 Activity ◽  
Lower Serum ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

Abstract Abstract 4666 The clinical significance of ADAMTS13 activity for response to treatment, mortality rate, recurrence, and prognosis is unclear. Therefore, we investigated the characteristics of severe ADAMTS13 deficiency and evaluated its clinical significance in Thrombotic thrombocytopenic purpura (TTP). The Korean TTP Registry includes 66 patients from 13 teaching hospitals in Korea who received the diagnosis of TTP from January 2005 to December 2008. Blood samples obtained upon admission were sent for ADAMTS13 analysis (multimer analysis by sodium dodecyl sulfate electrophoresis and/or ELISA) to a central laboratory along with patient clinical information. After 6 months, patient data regarding treatment, response, and prognosis were collected on standardized report forms. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels (P=0.001) and WBC counts (P=0.050) than patients with non-severe ADAMTS13 deficiency. Although severe ADAMTS13 deficiency was associated with better response rate (75% vs 53%, P=0.145), remission rate (81% vs 61%, P=0.209), and mortality rate (19% vs 31%, P=0.508) than non-severe ADAMTS13 deficiency, treatment outcomes did not differ significantly between groups. After adjusting for clinical and laboratory features, multivariate analysis did not reveal any independent risk factors for TTP-associated mortality. Patients with severe ADAMTS13 deficient had lower serum creatinine levels and WBC counts at presentation but Severe ADAMTS13 activity deficiency at TTP diagnosis does not appear to have prognostic significance. Disclosures: No relevant conflicts of interest to declare.

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