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

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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Clinical Characteristics of Thrombotic Thrombocytopenic Purpura with Severe ADAMTS13 Deficiency

Blood ◽

10.1182/blood.v116.21.4666.4666 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4666-4666

Author(s):

Moon Jang ◽

So Young Chong ◽

Inho Kim ◽

Chul W. Jung ◽

Doyeun Oh

Keyword(s):

Mortality Rate ◽

Serum Creatinine ◽

Thrombotic Thrombocytopenic Purpura ◽

Clinical Significance ◽

Sodium Dodecyl ◽

Prognostic Significance ◽

Adamts13 Activity ◽

Lower Serum ◽

Thrombocytopenic Purpura ◽

Adamts13 Deficiency

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

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Risk Factors for Recurrence of Thrombotic Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v108.11.1060.1060 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1060-1060 ◽

Cited By ~ 1

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.

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

Blood ◽

10.1182/blood.v116.21.4661.4661 ◽

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.

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Thrombotic Thrombocytopenic Purpura Misdiagnosed As Autoimmune Cytopenia: Causes of Diagnostic Errors and Consequence on Outcome. Experience of the French Thrombotic Microangiopathies Reference Centre

Blood ◽

10.1182/blood.v128.22.3730.3730 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3730-3730

Author(s):

Maximilien Grall ◽

Ygal Benhamou ◽

Elie Azoulay ◽

Eric Mariotte ◽

Lionel Galicier ◽

...

Keyword(s):

Organ Failure ◽

Thrombotic Thrombocytopenic Purpura ◽

Conflicts Of Interest ◽

Diagnostic Errors ◽

Hemoglobin Level ◽

Thrombocytopenic Purpura ◽

Platelet Recovery ◽

Reference Centre ◽

Adamts13 Deficiency ◽

The Impact

Abstract Introduction: Thrombotic thrombocytopenic purpura (TTP) is a life threatening disease defined by the association of a hemolytic mechanical anemia, a profound thrombopenia and organ failure with a severe ADAMTS13 deficiency. A rapid diagnosis represents a major goal and sources of misdiagnosis need to be identified to avoid diagnostic wandering and delayed adapted treatment that may translate in increased morbi-mortality. The main objective of this study is to describe the characteristics of TTP initially misdiagnosed and analyse the impact of a late diagnosis on patient's outcomes. Methods: From May 2000 to May 2014, all patients with acquired TTP and severe ADAMTS13 deficiency enrolled prospectively in the French TMA Reference Centre registry were included. A misdiagnosis was retained if initial diagnosis was not TTP and if patients did not receive TPE as initial treatment. Results: Among the 423 studied patients, 84 (20%) were initially misdiagnosed and not received plasma exchange. Main diagnostic errors were attributed to an Evans syndrome and an auto-immune thrombopenic purpura in 51% and 37% of cases respectively. Median time to diagnosis was longer in the misdiagnosed group than in the accurately diagnosed (5 [IQR, 2-8] vs. 1 [IQR, 0-3] days, P=.008). At admission, compared to the accurately diagnosed patients, misdiagnosed patients had a higher rate of low or undetectable schizocytosis (57.5% vs. 32%, P=.001), higher hemoglobin level (8.4 [IQR, 6.7-9.7] g/dl vs. 7.7 [IQR, 6.5-9.1] g/dl, P=.008) and rate of positive DAT (18% vs. 4%, P=.008). Anti-nuclear antibodies (65% vs. 51%, P=.045) and an associated auto-immune disease (24% vs. 13%, P=.017) were also more frequent. In multivariate analysis, a positive DAT and hemoglobin level were retained as risk factor (OR= 8.71, 95% CI [1.759-43.181], P=.008 and OR= 1.27, 95% CI [1.002-1.602], P=.048), respectively. Platelet count recovery over time was significantly longer in the misdiagnosed group (log-rank test: P=.041) without any consequence on overall mortality, exacerbation and relapse. However, specific causes of death probably differed between groups: in the accurately diagnosed group, patients died more frequently on early stage from a fulminant form of TTP within the first week, whereas in the misdiagnosed group patients died later (13 [IQR, 3-20] vs. 6 [IQR, 2-9] days; P=.023), had less organ involvement at early diagnosis (49% vs.64%, P=.019) and received more salvage therapies (80% vs. 35%, P=.009), suggesting that prognosis could have been improved with an earlier treatment. Conclusion: TTP is frequently misdiagnosed with auto-immune cytopenias and usual biological parameters may be initially absent. In a context of hemolysis and thrombocytopenia, a low or undetectable rate of schizocytosis at admission, and a positive DAT should not rule out the diagnosis of TTP, especially when associated with organ failure. A rapid accurate diagnosis of TTP may result in a shorter time to platelet recovery and could improve prognosis. Disclosures No relevant conflicts of interest to declare.

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

Thrombosis and Haemostasis ◽

10.1160/th13-08-0688 ◽

2014 ◽

Vol 112 (08) ◽

pp. 297-303 ◽

Cited By ~ 13

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

Blood ◽

10.1182/blood-2001-12-0166 ◽

2002 ◽

Vol 100 (3) ◽

pp. 778-785 ◽

Cited By ~ 144

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.

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

Blood ◽

10.1182/blood.v116.21.3678.3678 ◽

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.

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

Blood ◽

10.1182/blood.v120.21.2200.2200 ◽

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.

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

Blood ◽

10.1182/blood.v122.21.448.448 ◽

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.

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

Clinical Kidney Journal ◽

10.1093/ckj/sfz066 ◽

2019 ◽

Vol 13 (2) ◽

pp. 208-216 ◽

Cited By ~ 1

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.

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