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.

Carboxiterminal pro-endothelin-1 as an endothelial cell biomarker in thrombotic thrombocytopenic purpura

2016 ◽  
Vol 115 (05) ◽  
pp. 1034-1043 ◽  
Author(s):  
György Sinkovits ◽  
Péter Farkas ◽  
Dorottya Csuka ◽  
Katalin Rázsó ◽  
Marienn Réti ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Acute Phase ◽  
Complement Activation ◽  
Endothelial Activation ◽  
Factor H ◽  
Healthy Controls ◽  
Activation Markers ◽  
Thrombocytopenic Purpura ◽  
Endothelin 1

SummaryThrombotic thrombocytopenic purpura (TTP) is characterised by the deficiency of the von Willebrand factor (VWF) cleaving protease (ADAMTS-13). Although several observations indicate an important role of endothelial activation in the pathogenesis of TTP, no reliable endothelial activation markers are available in the clinical management of TTP. Our aim was to investigate the presence of endothelial activation in TTP and to determine its connections with disease activity, therapy and complement activation. We enrolled 54 patients (median age 40.5; 44 females) and 57 healthy controls (median age 34; 30 females),VWF antigen, carboxiterminal-pro-endothelin-1 (CT-proET-1), complement Factor H and complement activation products (C3bBbP and SC5b-9) were measured. In both the acute and remission phase of TTP we found increased CT-proET-1 and VWF levels, while Factor H levels decreased compared with healthy controls. In remission, however, the elevated CT-proET-1 levels showed 22 % decrease when compared with the acute phase in paired samples (p=0.0031), whereas no changes for VWF and Factor H levels were observed. We also found positive correlations between CT-proET-1 levels and alternative pathway activation markers (C3bBbP; p=0.0360; r=0.4299). The data we present here demonstrate a role of endothelium activation in patients with acute TTP. The finding that CT-proET-1 levels decreased in remission compared with the acute phase further supports endothelial involvement. In addition, we show that endothelial activation also correlated with the activation of the alternative complement pathway. The data suggest that complement and endothelium activation jointly contribute to the development of TTP episodes in patients with predisposition to TTP.Supplementary Material to this article is available online at www.thrombosis-online.com.

Plasma Levels of Human Neutrophil Peptides and Complement Activation Markers in Patients with Acquired Autoimmune Thrombotic Thrombocytopenic Purpura

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1147-1147 ◽  
Author(s):  
Wenjing Cao ◽  
Huy Phu Pham ◽  
Lawrence A. Williams ◽  
Zheng Ping ◽  
Robin G. Lorenz ◽  
...  
Keyword(s):  
Complement Activation ◽  
Human Neutrophil ◽  
Plasma Levels ◽  
Alternative Pathway ◽  
Healthy Controls ◽  
Plasma Samples ◽  
Adamts13 Activity ◽  
Activation Markers ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

Abstract Acquired thrombotic thrombocytopenic purpura (TTP) is a potentially fatal syndrome, resulting from autoantibodies against the metalloprotease ADAMTS13. Autoantibodies bind and inhibit plasma ADAMTS13 activity, leading to exaggerated platelet agglutination and thrombus formation in small arteries and capillaries. However, plasma ADAMTS13 deficiency or the presence of anti-ADAMTS13 autoantibodies is not sufficient to cause the disease. Infection or inflammation often precedes the acute onset of TTP. We hypothesize that neutrophil activation or complement activation vial alternative pathway may be the trigger for TTP. In this study, plasma samples were collected prior to plasma exchange from 58 adult patients with acute TTP between 2006 and 2015 at the University of Alabama at Birmingham Medical Center. All patients were diagnosed having TTP on the basis of severe thrombocytopenia, microangiopathic hemolytic anemia, and severe deficiency of plasma ADAMTS13 activity (less than 10%) and the presence of ADAMTS13 inhibitors. All patients were treated by plasma exchange. Thirty plasma samples from healthy individuals were collected for controls. Plasma levels of human neutrophil peptides (HNP-1, -2, and -3) released from activated neutrophils and alternative pathway complement activation markers (iC3b, C4d, C5b-9, and Bb) were determined by enzyme-linked immunosorbent assays (ELISAs). We showed that plasma levels of HNP-1, -2, and -3 in TTP patients were elevated on average by 10-fold when compared with those in the healthy controls (44.12 ± 39.53 ng/ml vs. 3.54 ± 2.97 ng/ml, means ± SD) (p <0.0001). Whereas plasma levels of Bb and iC3b were only modestly increased in TTP patients (2.94 ± 1.82 µg/ml vs. 1.39 ± 0.34 µg/ml for Bb, p <0.0001, and 16.21 ± 9.71 µg/ml vs. 12.13 ± 3.07 µg/ml for iC3b, p =0.028). No significant difference was detected in the plasma levels of C4d and C5b-9 between TTP patients and healthy controls (p >0.05). To differentiate HNP-1 from HNP-2 or HNP-3, we developed a LC/MS mass spectrometric assay and showed that all subtypes of HNPs in TTP patients were significantly elevated when compared with those in the healthy controls (p<0.001). In general, there was good concordance between ELISA and LC/MS MS in the measurement of all three HNPs. These results demonstrate that innate immunity (i.e. activation of neutrophils) and to a lesser degree the activation of complements via alternative pathway may play a role in pathogenesis of TTP in light of severe ADAMTS13 deficiency. Our findings provide rationales for developing novel targeted therapies for acquired TTP. 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

scholarly journals The remarkable diversity of thrombotic thrombocytopenic purpura: a perspective

2018 ◽  
Vol 2 (12) ◽  
pp. 1510-1516 ◽  
Author(s):  
James N. George
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Immunosuppressive Treatment ◽  
Severe Thrombocytopenia ◽  
Adamts13 Activity ◽  
Long Term Outcomes ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Few Data ◽  
Autoimmune Etiology

Abstract Understanding the autoimmune etiology of acquired thrombotic thrombocytopenic purpura (TTP) has provided precision for the diagnosis and a rationale for immunosuppressive treatment. These advances have also allowed recognition of the remarkable clinical diversities of patients’ initial presentations and their long-term outcomes. These diversities are illustrated by the stories of patients from the Oklahoma TTP Registry. The initial presentation of TTP may be the discovery of unexpected severe thrombocytopenia in a patient with minimal or no symptoms. The patient may remain asymptomatic throughout treatment or may die suddenly before treatment can be started. ADAMTS13 activity may be reported as normal in a patient with characteristic clinical features of TTP, or the unexpected report of ADAMTS13 deficiency in a patient with another established disorder may lead to the discovery of TTP. ADAMTS13 activity during clinical remission is unpredictable. ADAMTS13 activity may recover and remain normal, it may remain severely deficient for many years, or it may become normal only many years after recovery. Our treatment of initial episodes and management of patients after recovery and during remission continue to change. The addition of rituximab to the treatment of acute episodes and preemptive rituximab for patients with severe ADAMTS13 deficiency during remission are reported to prevent relapse. Because TTP is uncommon, there are few data to guide these changes. Therefore our patients’ stories are profoundly influential. Their stories are the foundation of our experience, and our experience is the guide for our decisions.

Similar Levels of Complement Activation in Both Patients with Thrombotic Thrombocytopenic Purpura and Atypical Hemolytic Uremic Syndrome: The Report from the Korean TTP Registry

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4195-4195
Author(s):  
Doyeun Oh ◽  
Ji Young Huh ◽  
So Young Chong ◽  
In-Ho Kim ◽  
Soo-Mee Bang ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Complement Activation ◽  
Conflicts Of Interest ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Healthy Controls ◽  
Adamts13 Activity ◽  
Newly Diagnosed ◽  
Thrombocytopenic Purpura ◽  
Complement Pathways

Abstract Background: Uncontrolled complement activation has a major role in the pathogenesis of atypical HUS (aHUS) and the restraint of this process by eculizumab is life saving. However, the evidence of complement dysregulation in the pathogenesis of Thrombotic Thrombocytopenic Purpura (TTP) is still unclear. In this study we examined the presence of complement activation biomarkers in patients with aHUS and TTP and the levels were compared to normal healthy controls . Patients and Methods: Patients with thrombotic microangiopathic thrombocytopenia diagnosed either as TTP with low ADAMTS13 activity less than 10% or aHUS with impaired renal function, Cr> 2mg/dL and normal ADAMTS13 activity were chosen from the Korean TTP registry from February 2012 to June 2014. Prospective plasma and serum samples prior to intervention were collected from newly diagnosed patients with TTP (n=20), aHUS (n=20), and 20 healthy controls and frozen at -700C. Complement activation products (C3a, Bb as alternative pathway; C4d as classic pathway; C5a, C5b-9; terminal pathway) were measured by ELISA. Results: Significantly increased levels of Bb and C5b-9 were observed in TTP (median [range], ng/mL; Bb, 1220 [540.0 – 16560], p=0.048; C5b - 9, 390.1 [238.5 - 938.7], p<0.0001) when compared with controls (Bb, 870.0 [630.0 - 2070]; C5b - 9, 190.8 [77.96 - 458.9]). Increased levels of C3a, C5a, C5b - 9, and Factor Bb were observed in HUS (C3a, 231.3 [80.70 - 791.8], p<0.0001; C5a, 21.38 [5.590 - 34.96], p= 0.006; C5b - 9, 0.49 [0.21 - 1.41], p<0.0001; Bb, 1490 [540.0 – 11800], p= 0.0003) as compared with controls (C3a, 108.7 [30.98 - 425.1]; C5a, 8.620 [2.660 - 26.93]; C5b - 9, 0.49 [0.21 - 1.41]; Bb, 870.0 [630.0 - 2070]). These suggested alternative and terminal complement pathways were activated in initial episodes of TTP or HUS. However levels of C4d were not different in HUS and TTP as compared with controls which suggested classic complement pathways were not important in this process. There were no significant differences in complement levels between TTP and HUS although levels of C3a, C4d, C5b - 9 in HUS (C3a, 231.3 [80.70 - 791.8]; C4d, 2140 [10.00 - 960.0]; C5b - 9, 488.4 [212.7 – 1414]) tended to be increased as compared with TTP (C3a, 134.5 [61.97 - 378.4]; C4d, 1330 [2.000 - 699.0]; C5b - 9, 390.1 [238.5 - 938.7]). Conclusion: Complement biomarkers are activated to a similar level in both newly diagnosed cases of TTP and aHUS. Complement activation product levels did not differentiate aHUS from TTP. Disclosures No relevant conflicts of interest to declare.

scholarly journals Exome Sequencing Identifies Glycosylation Defects As a Probable Cause of Immune Thrombotic Thrombocytopenic Purpura

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 217-217
Author(s):  
Felipe Massicano ◽  
Elizabeth M. Staley ◽  
Konstantine Halkidis ◽  
Nicole K. Kocher ◽  
Lance A. Williams ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Potential Contribution ◽  
Severe Thrombocytopenia ◽  
Adamts13 Activity ◽  
Genomic Alterations ◽  
Autoantibody Production ◽  
Thrombocytopenic Purpura ◽  
Long Term Outcome ◽  
Clinical Presentations

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal syndrome, resulting primarily from autoantibodies against ADAMTS13. However, the mechanism underlying the autoantibody formation and the contribution of other genomic alterations to the pathogenesis of iTTP are largely unknown. Methods: Whole exome sequencing (WES) and bioinformatic analyses were performed to determine the genetic variations in 40 patients with iTTP who had ADAMTS13 activity &lt;10 IU/dL and a positive inhibitor or an elevated anti-ADAMTS13 IgG in concordance with clinical presentations of severe thrombocytopenia and microangiopathic hemolytic anemia with various degrees of organ injury. WES was also performed at the same time in fifteen age-, gender-, and ethnicity- matched individuals who did not have a history of iTTP or other hematological disorders as controls. Results: WES identified variants or mutations in the genes involving in glycosylation, including O-linked glycosylation, to be the major pathway affected in patients with iTTP. We propose that the altered glycosylation may be responsible for the development of autoantibodies against ADAMTS13 which impair the proteolytic cleavage of von Willebrand factor, accelerate the clearance of ADAMTS13 from circulation, and result in severe thrombocytopenia platelets in patients with iTTP. We also identified defects in ankyrin repeat containing protein ANKRD36C, a protein with hitherto unknown function, as the most statistically significant genomic alterations associated with iTTP (p &lt; 10-5). Moreover, candidate gene analysis revealed that various genes involving in hemostasis, complement activation, platelet function and signaling pathway, and inflammation were all affected in patients with iTTP, which may contribute to the onset, progress, severity, and long-term outcome of iTTP. Finally, we also identified two patient subgroups where the disease mechanism might be different. Conclusion: Our findings provide novel insight into the pathogenic mechanism underlying ADAMTS13 autoantibody production and the potential contribution of other genetic abnormalities in modifying the iTTP clinical presentations in the individuals with severe deficiency of plasma ADAMTS13 activity. Disclosures Zheng: Alexion: Speakers Bureau; Ablynx/Sanofi: Consultancy, Speakers Bureau; Shire/Takeda: Research Funding; Clotsolution: Other: Co-Founder.

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.

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.

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