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.

Clinical Features of Severe Acquired ADAMTS13 Deficiency in Thrombotic Thrombocytopenic Purpura: Second Report of the Korean TTP Registry.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2188-2188
Author(s):  
Doyeun Oh ◽  
Moon Ju Jang ◽  
Inho Kim ◽  
Soo-Mee Bang ◽  
Chul-Won Jung ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Serum Creatinine ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
Adamts13 Activity ◽  
Lower Serum ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

Abstract Abstract 2188 The clinical utility of ADAMTS13 activity for TTP has been extensively studied for last years. However, the clinical significance of ADAMTS13 activity for response to treatment, mortality rate, recurrence, and prognosis is still unclear. We previously reported the characteristics of severe ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) and patients with severe ADAMTS13 deficiency had lower serum creatinine levels than patients with non-severe ADAMTS13 deficiency using 66 patients enrolled from January 2005 to December 2008. (Jang MJ et al, Int J Hematol 2011;93:163–9). In this second report, we enrolled 65 additional patients from January 2009 to June 2012 and analyzed 131 TTP patients using same methods. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels (P=0.001), lower platelet counts (P<0.0001), and high total bilirubin levels (P=0.018) at presentation. However, as same as previous results, treatment outcomes did not differ significantly between severe and non-severe ADAMTS13 deficiency groups in response rate (82 vs. 65%, P = 0.256), remission rate (70 vs. 63%, P = 0.781), and mortality rate (23 vs. 18%, P = 0.820). After adjusting for clinical and laboratory features, multivariate analysis did not reveal any independent risk factors for TTP-associated mortality. In conclusion, although TTP with severe ADAMTS13 deficiency is a unique subgroup characterized by lower platelet count and relatively good renal function, the prognostic significance of ADAMTS13 is still unclear and further study would be required to clarify it. Disclosures: No relevant conflicts of interest to declare.

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.

FRETS-VWF73 rather than CBA assay reflects ADAMTS13 proteolytic activity in acquired thrombotic thrombocytopenic purpura patients

2014 ◽  
Vol 112 (08) ◽  
pp. 297-303 ◽  
Author(s):  
Ilaria Mancini ◽  
Carla Valsecchi ◽  
Luca Lotta ◽  
Louis Deforche ◽  
Silvia Pontiggia ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Proteolytic Activity ◽  
Binding Activity ◽  
Adamts13 Activity ◽  
Flow Conditions ◽  
Thrombocytopenic Purpura ◽  
Severe Deficiency ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryCollagen-binding activity (CBA) and FRETS-VWF73 assays are widely adopted methods for the measurement of the plasmatic activity of ADAMTS13, the von Willebrand factor (VWF) cleaving-protease. Accurately assessing the severe deficiency of ADAMTS13 is important in the management of thrombotic thrombocytopenic purpura (TTP). However, non-concordant results between the two assays have been reported in a small but relevant percentage of TTP cases. We investigated whether CBA or FRETS-VWF73 assay reflects ADAMTS13 proteolytic activity in acquired TTP patients with non-concordant measurements. Twenty plasma samples with non-concordant ADAMTS13 activity results, <10% using FRETS-VWF73 and ≥20% using CBA, and 11 samples with concordant results, <10% using either FRETS-VWF73 and CBA assays, were analysed. FRETS-VWF73 was performed in the presence of 1.5 M urea. ADAMTS13 activities were also measured under flow conditions and the VWF multimer pattern was defined in order to verify the presence of ultra-large VWF due to ADAMTS13 deficiency. In FRETS-VWF73 assay with 1.5 M urea, ADAMTS13 activity significantly increased in roughly 50% of the samples with non-concordant results, whereas it remained undetectable in all samples with concordant measurements. Under flow conditions, all tested samples showed reduced ADAMTS13 activity. Finally, samples with non-concordant results showed a ratio of high molecular weight VWF multimers higher than normal. Our results support the use of FRETS-VWF73 over CBA assay for the assessment of ADAMTS13 severe deficiency and indicate urea as one cause of the observed differences.

von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 778-785 ◽  
Author(s):  
Giuseppe Remuzzi ◽  
Miriam Galbusera ◽  
Marina Noris ◽  
Maria Teresa Canciani ◽  
Erica Daina ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Acute Phase ◽  
Von Willebrand Factor ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Uremic Syndrome ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Whether measurement of ADAMTS13 activity may enable physicians to distinguish thrombotic thrombocytopenic purpura (TTP) from hemolytic uremic syndrome (HUS) is still a controversial issue. Our aim was to clarify whether patients with normal or deficient ADAMTS13 activity could be distinguished in terms of disease manifestations and multimeric patterns of plasma von Willebrand factor (VWF). ADAMTS13 activity, VWF antigen, and multimeric pattern were evaluated in patients with recurrent and familial TTP (n = 20) and HUS (n = 29). Results of the collagen-binding assay of ADAMTS13 activity were confirmed in selected samples by testing the capacity of plasma to cleave recombinant VWF A1-A2-A3. Most patients with TTP had complete or partial deficiency of ADAMTS13 activity during the acute phase, and in some the defect persisted at remission. However, complete ADAMTS13 deficiency was also found in 5 of 9 patients with HUS during the acute phase and in 5 patients during remission. HUS patients with ADAMTS13 deficiency could not be distinguished clinically from those with normal ADAMTS13. In a subgroup of patients with TTP or HUS, the ADAMTS13 defect was inherited, as documented by half-normal levels of ADAMTS13 in their asymptomatic parents, consistent with the heterozygous carrier state. In patients with TTP and HUS there was indirect evidence of increased VWF fragmentation, and this occurred also in patients with ADAMTS13 deficiency. In conclusion, deficient ADAMTS13 activity does not distinguish TTP from HUS, at least in the recurrent and familial forms, and it is not the only determinant of VWF abnormalities in these conditions.

Preemptive Rituximab Infusions Efficiently Prevent Relapses In Acquired Thrombotic Thrombocytopenic Purpura. Experience Of The French Thrombotic Microangiopathies Reference Center

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 448-448
Author(s):  
Miguel HIE ◽  
Julie Gay ◽  
Lionel Galicier ◽  
Francois Provot ◽  
Sandrine Malot ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Median Number ◽  
Continuous Variables ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
History Of ◽  
Adamts13 Deficiency ◽  
Group 2 ◽  
Group 1

Context Acquired thrombotic thrombocytopenic purpura (TTP) results from a severe, antibody-mediated, deficiency in the von Willebrand factor-cleaving protease ADAMTS13. Rituximab is increasingly used in this indication in patients with a suboptimal response to plasma exchange. When severe acquired ADAMTS13 deficiency persists during remission, the estimated incidence rate is of 0.4/year. So far, it is still controversial whether preemptive rituximab efficiently prevents relapses in these patients. Patients and methods We defined two groups of patients with a history of acquired TTP who displayed a persistent severe ADAMTS13 deficiency during remission. Patients of group 1 were treated with preemptive infusions of rituximab. Patients of group 2 were managed in centers in which preemptive rituximab infusions were not the standard of care. The relapse incidence was evaluated and compared between both groups. Patients were treated according to National recommendations and enrolled from 12 French centers during a 12-year period. Patients were explored for ADAMTS13 activity and peripheral B-cell count every 3 months. Only patients with a > 12-month follow-up after rituximab administration are reported here. Median (25th - 75th percentile) was determined for all continuous variables. Wilcoxon’s test was used to compare continuous variables and the chi-square test or Fisher’s exact test to compare binary data. Relapse-free survival was compared between both groups using the Kaplan-Meier estimator with the corresponding 95% confidence interval. Results Forty-eight patients (20.6%) with a history of acquired TTP displayed a persistent severe ADAMTS13 deficiency on remission or experienced a subsequent severe ADAMTS13 deficiency (24 cases each) after a median follow-up of 17 months (12-29 months). Anti-ADAMTS13 antibodies concentration was 44 U/mL (24-59 U/mL). Thirty patients received preemptive infusions of rituximab (group 1), whereas 18 others had no therapeutical intervention (group 2). In group 1, 16 patients experienced a past history of TTP with a median number of 2 (1-3) episodes, corresponding to a relapse incidence of 0.22 (0-0.57)/year. Rituximab infusions were performed 14.5 months (6.5-27.4 months) after the last TTP episode. A median number of 4 (1-4) rituximab infusions were performed. The median follow-up between the first preemptive infusion of rituximab and the last ADAMTS13 evaluation is of 36 months (24-65 months). After preemptive rituximab administration, only 3 patients experienced a clinical relapse (0 [0] episode/year), corresponding to a significant reduction in the relapse incidence (P < .01). ADAMTS13 activity was 58.5% (30.5%-86.3%). Three months after the first rituximab infusion, ADAMTS13 activity was 46% (30-68); it further increased until the 12th month, and subsequently decreased. Accordingly, B-cell lymphocytes remained undetectable until the 6th month, and progressively increased at the 9th month to reach normal values at the 18th month. Nine patients (30%) required one (5 cases), two (2 cases), three (1 case) or ten (1 case) additional courses of rituximab for a further decrease or a persistent undetectable ADAMTS13 activity, which allowed to maintain a detectable ADAMTS13 activity in all but one patients. The time between two consecutive courses of rituximab was 26 months (5-59 months). At the end of follow-up, ADAMTS13 activity remained normal in 18 patients; 10 patients had a moderate ADAMTS13 deficiency, and 2 patients had a persistently undetectable ADAMTS13 activity. In four patients (13%), rituximab alone failed to increase durably ADAMTS13 activity, which required additional immunosuppressive drugs. In group 2, 14 patients relapsed after a 66-month follow-up (36-105 months), corresponding to a higher relapse incidence than in patients who received preemptive infusions of rituximab (0.23 [0.1-0.46] relapse/year, P<.01). Moreover, 2 patients died of TTP in group 2, whereas no fatal outcome was recorded in group 1. Relapse free survival over time was significantly longer in group 1 (Log-rank test: P = .049). Five patients experienced adverse effects including benign infections in 2 cases. Conclusion Rituximab efficiently prevents TTP relapses in most patients with a persistent acquired ADAMTS13 deficiency, with acceptable side effects. Disclosures: Off Label Use: Rituximab Rituximab may prevent relapses in acquired thrombotic thrombocytopenic purpura.

scholarly journals Relative incidence of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome in clinically suspected cases of thrombotic microangiopathy

2019 ◽  
Vol 13 (2) ◽  
pp. 208-216 ◽  
Author(s):  
Ulf Schönermarck ◽  
Wolfgang Ries ◽  
Bernd Schröppel ◽  
Lars Pape ◽  
Malgorzata Dunaj-Kazmierowska ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Haemolytic Uraemic Syndrome ◽  
Primary Objective ◽  
Adamts13 Activity ◽  
Cross Sectional ◽  
Thrombocytopenic Purpura ◽  
Relative Incidence ◽  
Severe Deficiency ◽  
Post Hoc

Abstract Background Data are lacking on the relative incidence of thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) caused by Shiga toxin–producing Escherichia coli (STEC) and atypical HUS (aHUS) in patients presenting with thrombotic microangiopathies (TMAs). Methods This was a prospective, cross-sectional, multicentre and non-interventional epidemiological study. Patients fulfilling criteria for TMAs (platelet consumption, microangiopathic haemolytic anaemia and organ dysfunction) were included in the study. The primary objective was to assess the relative incidence of TTP, STEC-HUS, aHUS and ‘other’ physician-defined diagnoses. The secondary objective was to develop an algorithm to predict a severe deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (≤10%) using routine laboratory parameters. A post hoc classification using the recent Kidney Disease: Improving Global Outcomes diagnostic criteria was then undertaken to further classify patient groups. Results aHUS was diagnosed with a relative incidence of 61%, whereas TTP, STEC-HUS and ‘other’ were diagnosed in 13, 6 and 20% of patients, respectively. In the post hoc analysis, 27% of patients with a TMA were classified as ‘primary aHUS’ and 53% as ‘secondary aHUS’. Multivariate analysis revealed that severe deficiency in ADAMTS13 activity (≤10%) was unlikely to underlie TMA if platelet and serum creatinine were above threshold values of 30 × 109/L and 1.8 mg/dL, respectively (negative predictive value of 92.3 and 98.1, respectively, if one or both values were above the threshold). Conclusions In this study, aHUS was the most common single diagnosis among patients presenting with a TMA. In the absence of an ADAMTS13 activity result, platelet count and serum creatinine may aid in the differential diagnosis.

Survival and relapse in patients with thrombotic thrombocytopenic purpura

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1500-1511 ◽  
Author(s):  
Johanna A. Kremer Hovinga ◽  
Sara K. Vesely ◽  
Deirdra R. Terrell ◽  
Bernhard Lämmle ◽  
James N. George
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Signs And Symptoms ◽  
Population Based ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Estimated Risk ◽  
Subsequent Relapse ◽  
Organ Dysfunctions

AbstractSurvival of patients with thrombotic thrombocytopenic purpura (TTP) improved dramatically with plasma exchange treatment, revealing risk for relapse. The Oklahoma TTP Registry is a population-based inception cohort of all 376 consecutive patients with an initial episode of clinically diagnosed TTP (defined as microangiopathic hemolytic anemia and thrombocytopenia with or without signs and symptoms of ischemic organ dysfunctions) for whom plasma exchange was requested, 1989 to 2008. Survival was not different between the first and second 10-year periods for all patients (68% and 69%, P = .83) and for patients with idiopathic TTP (83% and 77%, P = .33). ADAMTS13 activity was measured in 261 (93%) of 282 patients since 1995. Survival was not different between patients with ADAMTS13 activity < 10% (47 of 60, 78%) and patients with 10% or more (136 of 201, 68%, P = .11). Among patients with ADAMTS13 activity < 10%, an inhibitor titer of 2 or more Bethesda units/mL was associated with lower survival (P = .05). Relapse rate was greater among survivors with ADAMTS13 activity < 10% (16 of 47, 34%; estimated risk for relapse at 7.5 years, 41%) than among survivors with ADAMTS13 activity of 10% or more (5 of 136, 4%; P < .001). In 41 (93%) of 44 survivors, ADAMTS13 deficiency during remission was not clearly related to subsequent relapse.

scholarly journals Diagnostic relevance of ADAMTS13 activity: Evaluation of 28 patients with thrombotic thrombocytopenic purpura - hemolytic uremic syndrome clinical diagnosis

2013 ◽  
Vol 141 (7-8) ◽  
pp. 466-474
Author(s):  
Dragica Vucelic ◽  
Danijela Mikovic ◽  
Zoran Rajic ◽  
Nebojsa Savic ◽  
Zivko Budisin ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Binding Activity ◽  
Adamts13 Activity ◽  
Activity Assay ◽  
Thrombocytopenic Purpura ◽  
Uremic Syndrome ◽  
Adamts13 Deficiency ◽  
A Disintegrin And Metalloproteinase ◽  
Thrombospondin Motif

Introduction. The significance of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif-13) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) is still a controversial issue. Objective. The aim of this report was to analyze the value of ADAMTS13 measurements in the diagnosis of TTP and HUS. Methods. At presentation, we analyzed patients with idiopathic TTP (n=18), secondary TTP (n=4), diarrhea positive HUS (n=3) and diarrhea negative HUS (n=3) treated in Belgrade, Serbia from 2004 to 2010. ADAMTS13 activity from acute phase samples was measured using the residual collagen binding activity assay at the Haemophilia and Thrombosis Centre, Milan, Italy. Results. There was a significant correlation between reduced ADAMTS13 activity and idiopathic TTP diagnosis (p=0.000) as well as between lower ADAMTS13 activities and higher reticulocytes (p=0.017) and lactate dehydrogenase levels (p=0.027). Significant correlation was also found between higher protease activity and diagnosis of HUS (p=0.000). There was a statistically significant correlation between higher ADAMTS13 activities and higher platelets count (p=0.002), blood urea nitrogen (p=0.000), and creatinine level (p=0.000). Conclusion. Severe ADAMTS13 deficiency points at the diagnosis of idiopathic TTP and it is present in the secondary TTP but not in HUS.

scholarly journals Complement Activation May Trigger the Onset of Thrombotic Thrombocytopenic Purpura in Patients with Severe ADAMTS13 Deficiency

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 600-600 ◽  
Author(s):  
Xiao-Hui Hu ◽  
Jialing Bao ◽  
Yoshiyasu Ueda ◽  
Takashi Miwa ◽  
Wenchao Song ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Complement Activation ◽  
Factor H ◽  
Severe Thrombocytopenia ◽  
Complement Factor ◽  
Healthy Controls ◽  
Adamts13 Activity ◽  
Activation Markers ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

Abstract Thrombotic thrombocytopenic purpura (TTP), a potential fatal syndrome, is often associated with severe deficiency of plasma ADAMTS13 activity, either resulting from ADAMTS13 mutations or acquired anti-ADAMTS13 autoantibodies that inhibit plasma ADAMTS13 activity. Patients with severe ADAMTS13 do not always have TTP signs and symptoms, which often occur following infections or inflammatory responses. The mechanism of TTP flare is not fully understood. In the present study, complement activation markers (iC3b, C5b, Bb, and C4b) were determined by enzyme-linked absorbent assays (ELISA) in the initial plasmas (prior to plasma exchange) of 20 patients with acquired TTP with severe ADAMTS13 deficiency (less than 20% of normal) and plasmas from 20 healthy controls. Of 20 TTP patients, 19 exhibited positive inhibitor in the 50:50 mixing study. Plasma levels of iC3b (1,000 ± 1,062 ng/ml), sC5b-9 (1,342±867 ng/ml), and Bb (38.2±47.7 ng/ml), as well as C4b (74.3±49.5 ng/ml) in acquired TTP patients were significantly higher than those in healthy controls (p value less than 0.01) These results indicate that complement activation in both classic and alternative pathways is a common phenomenon in patients with acquired autoimmune TTP. To demonstrate the causative effect of complement activation in TTP, we turned to our Adamts13 null mice. C57BL/6 (Adamts13-/-) mice are resistant to the development of spontaneous and Shigatoxin-induced TTP syndrome. When injected with a murine specific monoclonal antibody against complement factor H (CFH) (800 micro grams/mouse), which inhibits binding of circulating CFH to endothelial cells and C3b, Adamts13-/- mice (C57BL/6) developed more severe thrombocytopenia and anemia than wild type mice did within 6 days without additional challenge. However, renal insufficiency manifested by the increase of plasma BUN concentration was similar in both groups (Fig. 1). These results indicate that complement activation through an alternative pathway, following antibody-mediated inhibition of CFH or other complement regulatory components, may trigger the onset of TTP in light of severe ADAMTS13 deficiency. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Clinical and Outcomes Findings for Thrombotic Thrombocytopenic Purpura among 467 Persons with Severely Versus Not Severely Deficient ADAMTS-13 Levels.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2088-2088 ◽  
Author(s):  
Charles L. Bennett ◽  
Thanh Ha Luu ◽  
Anaadriana Zakarija ◽  
Hau C. Kwaan ◽  
Nicholas Bandarenko ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Neutralizing Antibodies ◽  
Clinical Laboratory ◽  
Survival Rates ◽  
Outcome Data ◽  
Severe Thrombocytopenia ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

Abstract Background: Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that presents with microangiopathic hemolytic anemia and thrombocytopenia, fevers, renal insufficiency and neurologic features. We reviewed clinical, laboratory, and outcome data for TTP cases with severely deficient versus non-severely deficient ADAMTS13 activity levels. Methods: Mean and median data were from the Surveillance, Epidemiology and Risk Factors for TTP (SERF-TTP) study group for idiopathic TTP cases, the Canadian Apheresis Group (CAG), and five published series (Zheng 2004, Raife 2004, Vesely 2003 (Oklahoma TTP-HUS Registry), Matsumoto 2004 (Japan Referral Center), Bennett 2007). Results: Compared to TTP cases with near-normal ADAMTS13 activity levels (n= 282), TTP cases with severe ADAMTS13-deficiency (n=185) were more likely to have severe thrombocytopenia, normal renal function and neutralizing ADAMTS13 antibodies. Severe ADAMTS13 deficient TTP cases have better overall survival after therapeutic plasma exchange (TPE) but are more likely to relapse. TTP patients with severe ADAMTS13 deficiency were primarily categorized as idiopathic or ticlopidine-associated, while TTP patients with non-severely deficient ADAMTS13 activity levels were frequently categorized as idiopathic, secondary to drugs (clopidogrel, quinine), stem cell transplantation, or cancer. Conclusions: Severe ADAMTS13 deficiency is most commonly idiopathic, has better survival following TPE, and a 35–40% spontaneous relapse rate. By contrast, non-ADAMTS13 deficient TTP cases are usually associated with an underlying disorder or external insults. Amongst this cohort, four series have 47–62% survival rates and three series, which contain mostly idiopathic cases, have 83–90% survival rates following TPE. From this, we propose that TTP may occur by three possible mechanism; ADAMTS13-deficient (antibody-mediated), an immunologic mediated pathway independent of ADAMTS13 (i.e. quinine) that is responsive to TPE, and endothelial injury related TTP that is unresponsive to TPE. Platelet count mean (x10^9/L) Creatinine mean (mg/dl) ADAMTS13 neutralizing antibodies (%) Survival % Relapse % * &lt;15% ADAMTS13 activity cutoff Severe ADAMTS13 Deficiency (&lt;10–15%) SERF-TTP (n=30) 19 1.3 83 97 41 Zheng (n=16) 19 1.6 44 81 38 Bennett (n=26) 15 85 Oklahoma (n=18) 12 1.8 94 81 38 Raife (n=50) * 13 1.2 92 35 Japan (n=34) 35 91 Canada (n=11) 16 2.4 82 Not Severely Deficient ADAMTS13 Activity (&gt; 15%) SERF-TTP (n=22) 57 3.9 35 90 0 Raife (n=57) * 44 2.7 83 9 Canada (n=17) 57 4.1 88 Zheng (n=13) 40 3.0 0 54 Bennett (n=13) 62 Japan (n=66) 9 62 Oklahoma (n=94 ) 23 47 3

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