Retrospective Analysis of Patients Afflicted with Thrombotic Thrombocytopenic Purpura: A Single Institutional Experience.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2200-2200
Author(s):  
Manali K. Kamdar ◽  
Phillip Chae ◽  
Maria Javaid ◽  
Negin Mesaghian ◽  
Kevin O'Brien ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Blood Group ◽  
Conflicts Of Interest ◽  
Severe Thrombocytopenia ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Congenital Deficiency ◽  
Predominant Symptom ◽  
Threatening Condition

Abstract Abstract 2200 Introduction: Thrombotic Thrombocytopenic Purpura (TTP) is an acute life threatening condition characterized by thrombocytopenia, microangiopathic hemolytic anemia, with or without renal failure or neurologic abnormalities, and without another cause for thrombotic microangiopathy. The majority of cases of TTP are associated with a low ADAMTS13 activity which results from antibody to this enzyme. A minority of patients have TTP secondary to congenital deficiency of this enzyme. The mainstay of therapy for TTP is plasmapheresis (PEX) which has increased survival in affected patients from 10% to more than 75%. While TTP is considered as an uncommon disorder, at our institution we suspected that the diagnosis was made more commonly. Therefore we set out to perform a retrospective analysis of cases of TTP to evaluate cases diagnosed over the past 10 years. Methods: We performed a retrospective analysis of all cases of microangiopathy undergoing pheresis at our institution for presumed TTP from May 2007 to April 2012. A total of 112 patients had PEX initiated for presumed TTP however 11 of these were later determined to have some other etiology causing the constellation of symptoms and PEX was discontinued. The remaining 101 patients were entered into a database and further analyzed. Demographically, we captured patients from 30 of the 100 North Carolina counties because 3 other institutions in our state perform plasma exchange for TTP. ADAMTS13 activity and inhibitor levels were measured in 69 out of 101 patients. In our registry there were 80 patients with Idiopathic TTP and 21 patients with secondary TTP. Patients with idiopathic TTP were further divided based on the ADAMTS13 activity. Results: Discussion: Our analysis demonstrated that TTP was more common in females, African American population with a median age group in the mid forties with neurological symptoms being the predominant symptom of presentation. While hematocrit was higher in patients with idiopathic TTP these patients were noted to have increased incidence of ADAMTS13 levels less than 10% with inhibitors as compared to those with secondary TTP. Idiopathic TTP patients had more incidence of multiple relapses and required more Rituximab in addition to PEX. We compared our results with the results published from the Oklahoma registry. Similar to the Oklahoma registry results patients with ADAMTS13 levels less than 10% had more severe thrombocytopenia, renal dysfunction, required more sessions of PEX, had higher relapses and percentage of death compared to patients with idiopathic TTP with ADAMTS13 levels more than 10%. Patients with ADAMTS13 less than 10% required more Rituximab during first diagnosis of idiopathic TTP. In this group blood group A+ was seen more often whereas blood group O+ was prevalent in the group with ADAMTS more than 10%. Comparison amidst these groups brought out similarities between two distinct registries in the US. Our registry is another large registry of patients similar to the Oklahoma TTP registry. While many similarities are seen with the Oklahoma group there were a few differences as cited above. Disclosures: No relevant conflicts of interest to declare.

Evaluation of Clotting Factor Concentrates for Treatment of Thrombotic Thrombocytopenic Purpura.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3678-3678
Author(s):  
Tanja Falter ◽  
Mirjeta Qorraj ◽  
Sarah Steinemann ◽  
Thomas Vigh ◽  
Inge Scharrer
Keyword(s):  
Human Plasma ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Blood Group ◽  
Conflicts Of Interest ◽  
Blood Groups ◽  
Clotting Factor ◽  
Plasma Samples ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Clotting Factor Concentrates

Abstract Abstract 3678 Introduction: Thrombotic thrombocytopenic purpura (TTP) is characterized by microthrombi, hemolytic anemia as well as thrombocytopenia. These symptoms are caused by a decreased activity of the protease ADAMTS13 which cleaves the von Willebrand Factor (VWF), due to mutation of the ADAMTS13-gene or autoantibodies. At the moment, the only available immediate therapy is plasmapheresis with Fresh Frozen Plasma (FFP) which may induce side effects. Therefore an alternative therapy might be the treatment with clotting factor concentrates. Methods: 40 plasma samples were tested, consisting of FFP and solvent/detergent treated plasma, four batches of each blood group; VWF/VIII concentrates (Wilate®; Wilfactin®; Haemate®P; Immunate®; Kogenate®, Beriate®). In all samples ADAMTS13 activity, antigen and autoantibodies against ADAMTS13 were investigated. Additionally, the samples were tested for the presence of ultralarge VWF multimers. The BCS method according to Böhm, two ELISAs (Technozym®ADAMTS13 and Actifluor™ADAMTS13) and the electrophoresis on a SDS gel were used. Results: ADAMTS13 activity was found in all VWF)VIII concentrates, which are produced from human plasma, but only with a very low activity (Wilate® 5.6%; Wilfactin® 2.8%; Haemate®P 13%; Immunate® 3.7%). ADAMTS13 activity was not detectable in the factor VIII concentrates (Kogenate® <2%; Beriate® <2%). Usual FFP and solvent/detergent treated plasma samples, contained much higher ADAMTS13 activity and antigen values than concentrates (FFP 78.6%, solvent/detergent treated plasma 77.6%). However a difference of activity between individual blood groups was evident in FFP samples (blood group A 69.4%; B 64.9%; AB 98.1%; 0 82.0%). Ultralarge VWF multimers could be demonstrated in VWF containing concentrates, less in VIII concentrate from human plasma and not in FFP and solvent/detergent treated plasma samples. As expected recombinant-produced VIII concentrate contained no traces of ultralarge VWF. In all analyzed samples antibodies were negative. Conclusion: For therapy of TTP clotting factor concentrates cannot be used as an alternative to the usual FFP and solvent/detergent treated plasma, because their ADAMTS13 activity values are too low. In addition, the VWF/VIII concentrates contain higher quantities of ultralarge VWF multimers, which are contraindicated for TTP patients. The differences of ADAMTS13 activity in FFP samples varies between the individual blood groups and batches. Solvent/detergent treated plasma shows less variation in ADAMTS13 activity due to the manufacturing process involving plasma pooling. Disclosures: No relevant conflicts of interest to declare.

Residual Plasmatic Activity of ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura Correlates with Disease Phenotype

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2219-2219
Author(s):  
Luca A Lotta ◽  
Haifeng M Wu ◽  
Marie A Scully ◽  
Marina Noris ◽  
Agnes Veyradier ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Conflicts Of Interest ◽  
Limit Of Detection ◽  
Clinical Phenotype ◽  
Disease Onset ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Congenital Deficiency ◽  
Disease Episode ◽  
Congenital Thrombotic Thrombocytopenic Purpura

Abstract Abstract 2219 ABSTRACT Congenital thrombotic thrombocytopenic purpura (TTP) (OMIM #274150) is a rare, recessively inherited thrombotic microangiopathy characterized by the congenital deficiency of ADAMTS13 due to mutations in the corresponding gene. The clinical phenotype of congenital TTP is variable, encompassing neonatal-onset disease and adult-onset disease, forms with a single disease episode and chronic-relapsing forms. A review of the ∼100 published cases of congenital TTP showed similar age of first disease episode in patients carrying the same ADAMTS13 gene suggesting that different ADAMTS13 mutations might influence the severity of clinical phenotype, conceivably by determining different patterns of residual plasmatic activity of ADAMTS13. However, the quantification of residual ADAMTS13 activity in severely deficient patients was blunted by the relatively high limit of detection (LOD) of commonly used ADAMTS13 activity assays (varying between 3% and 6%). We report 29 cases of congenital TTP from 4 European cohorts, with 32 mutations of ADAMTS13 including 8 not previously published. To assess if residual ADAMTS13 activity was detectable in these patients and correlated with their clinical history, ADAMTS13 activity was measured by SELDI-TOF mass spectrometry (LOD=0.5%). ADAMTS13 activity above 0.5% was measurable in 26 (90%) patients, and lower levels of activity correlated with an earlier age of disease onset (r=0.51; p=0.006) and with the need for regular fresh frozen plasma prophylaxis (2.24% vs 3.88%; p=0.03). Mutations at the highly conserved N-terminal domains of the protein were associated with lower residual ADAMTS13 activity (1.48% vs 4.89%, p=0.02) and earlier disease onset (3.2 years vs 24.2 years, p=0.003). Our results show that residual ADAMTS13 activity correlates with the severity of clinical phenotype in congenital TTP and provide insights into genotype-phenotype correlations. 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.

Investigation of Side Effects of Plasmaexchange In the Treatment of Thrombotic Thrombocytopenic Purpura

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4661-4661
Author(s):  
Sarah Steinemann ◽  
Tanja Falter ◽  
Mirjeta Qorraj ◽  
Thomas Vigh ◽  
Inge Scharrer
Keyword(s):  
Side Effects ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Side Effect ◽  
Conflicts Of Interest ◽  
Allergic Reactions ◽  
Adamts13 Activity ◽  
Plasma Therapy ◽  
Thrombocytopenic Purpura ◽  
Wide Range ◽  
Von Willebrand

Abstract Abstract 4661 Introduction: Thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia, hemolytic anemia and microthrombi. A deficiency of the metalloprotease ADAMTS 13, which cleaves a Tys1605-Met1606 bond in the A2 subunit of von Willebrand factor (VWF), leads to formation of ultra large von Willebrand multimers (UL-VWF) and can cause platelet aggregation and mircovascular thrombosis. Treatment of choice is the substitution of plasma with plasmaexchange. There are two different plasma types available: Fresh Frozen Plasma (FFP) and solvent/detergent (s/d) treated plasma. This treatment may carry significant risks and side effects for the patients. Therefore we investigated the side effects of the therapy and furthermore the ADAMTS13 activity of the two plasma types. Methods: A questionnaire was send to 66 TTP patients of the Department of Hematology to evaluate different side effects of the therapy. 20 batches of FFP and 4 batches of s/d plasma of all blood groups were investigated on ADAMTS13 activity. The ADAMTS13 activity was detected with BCS-Method according to Böhm and two commercial FRET assays. Results: So far 34 patients were inquired about age, weight and suspected trigger situations that might have caused their TTP manifestation. The mean age of the patients was 34 years with a mean weight of 70kg. A previous infection caused TTP manifestation in 42% of the patients; drug therapy (22%) and pregnancy (17%) were other mentioned triggers. 94% of the patients suffered from an acquired TTP and only 6% had a hereditary TTP. The patients had 2.88 relapses and were treated with 16.27 plasmaexchanges. 56% had an additional therapy with Rituximab to achieve a faster remission of the disease. These patients needed less plasmaexchanges for recovery, which proofed to be significant at 2% level in a one sided t-test. Tingling (64.7%) and shivering (51%) were the most often mentioned side effects and simultaneously described as the strongest. Shivering was significantly correlated to tachycardia (p<0.01). Headaches were significantly correlated to hot flushes, tingling and collapse (p< 0.05). Side effects and allergic reactions occurred in the therapy with FFP as well as with s/d plasma. Another side effect was the complication that came along with infection of the venous access. Most patients had a central venous catheter (72%) and described infections and pruritus (60%), 50% of them mentioned this complication more than once. We found in usual FFP slightly higher ADAMTS13 activity levels (696.97 ng/ml) than in s/d virus inactivated plasma (643.86 ng/ml). The ADAMTS13 activity varied between the different assays (normal range: 666 ± 135ng/ml). Conclusion: Our investigation demonstrated that plasmaexchange therapy is still associated with a wide range of side effects. Side effects of plasmaexchange that were most frequently described by patients were tingling and shivering. Headaches also occurred in various cases. Patients suffered generally from more than one side effect at the same time during the treatment. Allergic reactions to the plasma therapy were mentioned by 65% of the patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Factors Associated with Mortality in Patients Experiencing First Episodes of Acquired Thrombotic Thrombocytopenic Purpura (aTTP). Results of the Spanish TTP Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1082-1082
Author(s):  
Julio del Rio-Garma ◽  
Sabela Bobillo ◽  
Javier De La Rubia ◽  
Maria Cristina Pascual Izquierdo ◽  
Faustino García-Candel ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Laboratory Data ◽  
Complete Information ◽  
Biological Factor ◽  
First Episode ◽  
Severe Thrombocytopenia ◽  
Adamts13 Activity ◽  
International Consensus ◽  
Thrombocytopenic Purpura ◽  
The Impact

Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, but life-threatening, hematological disorder characterized by severe thrombocytopenia, hemolytic microangiopathic anemia, and frequent organ damage. The underlying pathophysiology of aTTP is a functional deficiency of plasma ADAMTS13 activity caused by antibodies directed against the ADAMTS13 protease. Despite plasma exchange (PEX) and immunosuppression with corticosteroids, and, more recently, rituximab, which achieve remission in most patients with aTTP, 10-20% of patients are refractory to treatment and die as a result of disease progression. Most of such deaths occur during first episodes of aTTP, as subsequent relapses tend to be milder. These patients would probably benefit from new therapies aimed at temporarily halting the microvascular thrombosis. This study was aimed at identifying predictive factors of mortality during a first episode of aTTP. Methods: We searched the Spanish TTP Registry (REPTT, Registro Español de la Purpura Trombocitopénica Trombótica) for patients with a clinical diagnosis of TTP (n = 345) with ADAMTS13 activity <10%, and anti-ADAMTS13 inhibitors in plasma (n = 143). Among these, we selected 103 patients with complete information on their first episode of aTTP. The patients were diagnosed between 2004 and 2018, and all were treated with daily PEX and corticosteroids. Additional treatments (rituximab, vincristine, etc.) were used at the discretion of the attending hematologist. Clinical and laboratory data of the episodes were analyzed at diagnosis and during the course of the treatment. The impact of refractoriness, exacerbations (as defined by the international consensus; DOI: 10.1111/jth.13571) and platelet transfusions on mortality was also studied. Results: The 103 patients examined suffered a total of 111 episodes of aTTP (103 with a first episode and 8 with a relapse). Eight deaths (7.7%) took place during an initial episode of aTTP and none during relapses. The time elapsed from the diagnosis to the events of death ranged from a few hours to 36 days (Figure). One patient died before starting the treatment. In the multivariate analysis, stupor or coma at diagnosis was the only clinical and biological factor associated with mortality, as 6 out of 18 patients with stupor or coma died vs. 2 out of 85 without these symptoms (OR: 21.95% CI: 4-114; p = 0.001). Persistently low platelet counts during PEX (i.e. refractoriness) were also strong predictors of subsequent mortality, with a platelet count <20 x109/L after 6 PEX procedures yielding the highest positive and negative values (Table). Exacerbation of aTTP while on treatment occurred in 44 of the 95 patients, all of whom eventually achieved remission with no events of death. Patients with exacerbations required a higher number of PEX procedures to achieve clinical remission (23, IQR: 19-31 vs. 12, IQR: 8-16; p <0.001) and were more likely to receive rituximab (39% vs. 9%; p = 0.001). Platelets were transfused into 16 patients, including 2 patients who died a few days later and 14 survivors. Conclusions: Stupor or coma at diagnosis and lack of response to PEX by the 6th-7th day in patients experiencing first episodes of aTTP are strong predictors of mortality. These patients are candidates for new treatments aimed at controlling the microvascular thrombotic phenomena until effective immunosuppression is achieved. Disease exacerbation does not seem to increase mortality but requires a more intensive treatment. Disclosures De La Rubia: Celgene Corporation: Consultancy; AbbVie: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy.

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

Inhibition of ADAMTS13 Activity By Human Neutrophil Peptide 1 (HNP-1): Potential Link Between Inflammation, Onset of Thrombotic Thrombocytopenic Purpura, and Other Thrombosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 599-599 ◽  
Author(s):  
Jialing Bao ◽  
Khalil Bdeir ◽  
Don L. Siegel ◽  
Douglas B. Cines ◽  
X. Long Zheng
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Human Neutrophil ◽  
Conflicts Of Interest ◽  
Human Monoclonal Antibody ◽  
Amino Acid Sequences ◽  
Dependent Manner ◽  
Adamts13 Activity ◽  
Single Chain ◽  
Concentration Dependent Manner ◽  
Thrombocytopenic Purpura

Abstract Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal syndrome associated with severe deficiency of plasma ADAMTS13 activity resulting from either mutations or autoantibodies. However, patients with severe ADAMTS13 deficiency do not always develop TTP. Rather, a trigger, such as infection or inflammation, often precedes the onset of the TTP syndrome. We hypothesized that antimicrobial human neutrophil peptides 1-3 (HNPα1-3) or α-defensins, the most abundant proteins in the granules of neutrophils, which are released at site of inflammation, activate platelets, and inhibit fibrinolysis, might help to initiate TTP. This question arose because we noted that the amino acid sequences of HNPα1-3, which are nearly identical except for one residue at the N-terminus, all contain a motif (RRY) similar to exosite 3 (659RRYGEEY665) in the spacer domain of ADAMTS13 (Fig. 1) that was shown to be critical for recognition of von Willebrand factor (VWF). Here, we found that both purified and synthetic HNPα1 bind to FRETS-VWF73 and plasma-derived VWF and inhibit proteolytic cleavage of these substrates in a concentration-dependent manner. At the final concentrations of 10 micro mol/L and 150 micro mol/L, HNPα1 completely abolished the cleavage of FRETS-VWF73 (IC50=3.5 micro mol/L) (Fig. 2) and VWF (IC50=75 micro mol/L) (not shown), respectively. Such concentrations are readily attained locally after systemic infection. Deletion or alanine substitution within the RRY motif of HNPα1 completely abolished its ability to inhibit ADAMTS13 activity assessed by FRETS-VWF73 and VWF multimer analysis. This suggests that an interaction of the RRY motif in HNPα1 with the central A2 domain of VWF is required to mediate its inhibition. In support of this hypothesis, HNPα1 interacts with a human monoclonal antibody against ADAMTS13 scFv (the single chain fragment of variable region) designated 4-20, but not scFv3-1, both isolated by phage display from patients with acquired autoimmune TTP. Hydrogen-deuterium exchange mass spectrometry has shown that the binding site for scFv4-20, but not scFv3-1, contains the RRY sequence. These results suggest that HNPα1-3 released from neutrophils following infection or inflammation may inhibit residual plasma ADAMTS13 activity in vivo similar to anti-ADAMTS13 autoantibodies by interfering with its interaction with VWF, thereby triggering the onset of hereditary and acquired autoimmune TTP. Our findings suggest a potential novel link between systemic inflammation and the pathogenesis of TTP and possibility other thrombotic sequelae. Figure 2 Figure 2. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

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.

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