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

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura

Blood ◽

10.1182/blood-2012-02-408914 ◽

2012 ◽

Vol 119 (24) ◽

pp. 5888-5897 ◽

Cited By ~ 123

Author(s):

Marie Moatti-Cohen ◽

Céline Garrec ◽

Martine Wolf ◽

Pierre Boisseau ◽

Lionel Galicier ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

National Registry ◽

Cross Sectional ◽

Thrombocytopenic Purpura ◽

Severe Deficiency ◽

Specific Subgroup ◽

Life Threatening ◽

Adamts13 Deficiency ◽

Sectional Analysis

Abstract Pregnancy may be complicated by a rare but life-threatening disease called thrombotic thrombocytopenic purpura (TTP). Most cases of TTP are due to an acquired autoimmune or hereditary (Upshaw-Schulman syndrome [USS]) severe deficiency of a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13). In the present study, we performed a cross-sectional analysis of the national registry of the French Reference Center for Thrombotic Microangiopathies from 2000-2010 to identify all women who were pregnant at their initial TTP presentation. Among 592 adulthood-onset TTP patients with a severe ADAMTS13 deficiency, 42 patients with a pregnancy-onset TTP were included. Surprisingly, the proportion of USS patients (n = 10 of 42 patients [24%]; confidence interval, 13%-39%) with pregnancy-onset TTP was much higher than that in adulthood-onset TTP in general (less than 5%) and was mostly related to a cluster of ADAMTS13 variants. In the present study, subsequent pregnancies in USS patients not given prophylaxis were associated with very high TTP relapse and abortion rates, whereas prophylactic plasmatherapy was beneficial for both the mother and the baby. Pregnancy-onset TTP defines a specific subgroup of patients with a strong genetic background. This study was registered at www.clinicaltrials.gov as number NCT00426686 and at the Health Authority, French Ministry of Health, as number P051064.

Download Full-text

Clinical experience in treatment of thrombotic thrombocytopenic purpura - hemolytic uremic syndrome with 28 patients

Acta chirurgica iugoslavica ◽

10.2298/aci1301029v ◽

2013 ◽

Vol 60 (1) ◽

pp. 29-38

Author(s):

Dragica Vucelic ◽

Zoran Rajic ◽

Nebojsa Savic ◽

Danijela Mikovic ◽

Zivko Budisin ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

Thrombotic Thrombocytopenic Purpura ◽

Response Rate ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

Severe Deficiency ◽

Uremic Syndrome ◽

Design And Methods ◽

Thrombospondin Type 1 Repeats

Background: Neither optimal treatment nor significance of ADAMTS13 (A Desintegrin And Metalloprotease with ThromboSpondin type 1 repeats) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) have not been defined yet. The aim of the report is to analyze response to different volumes of plasma exchange (PE), and relationship to ADAMTS13. Design and methods: 28 patients clinically diagnosed with idiopathic TTP (n=18), secondary TTP (n=4), atypical HUS (n=3) and typical HUS (n=3) manifested 31 acute episodes. Patients were treated with PE in 26, and with plasma transfusion in 5 episodes with additional different therapies. Results: PE volumes were as follows: 1 in 7, 1.5 in 3, 2 in 14, and intensifying schedule (1 to 1.5) in 2 episodes. Procedure number was lower in patients treated with 2 and 1.5 (p=0.019) than in those treated with 1 volume exchange and PE intensifying, respectively (p=0.010). PE response rate was 25/26 (96.15%). Exacerbation frequency was higher in idiopathic TTP patients (3/19) treated with 1 compared with patients treated with >1 volume exchange (p=0.003). Survival rate was 25/28 (89.29%). ADAMTS13 activity was reduced in 22 with severe deficiency in 14 patients. Conclusion: Patients responded to different treatments regardless of ADAMTS13 activity, requiring less PEs with larger volume exchanges.

Download Full-text

ADAMTS13 activity in thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients

Blood ◽

10.1182/blood-2003-01-0193 ◽

2003 ◽

Vol 102 (1) ◽

pp. 60-68 ◽

Cited By ~ 465

Author(s):

Sara K. Vesely ◽

James N. George ◽

Bernhard Lämmle ◽

Jan-Dirk Studt ◽

Lorenzo Alberio ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Clinical Outcomes ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

Initial Management ◽

Severe Deficiency ◽

Uremic Syndrome ◽

Adamts13 Deficiency

Abstract Initial management of patients with thrombotic thrombocytopenic purpura—hemolytic uremic syndrome (TTP-HUS) is difficult because of lack of specific diagnostic criteria, high mortality without plasma exchange treatment, and risks of plasma exchange. Although severe ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) deficiency may be specific for TTP, the role of ADAMTS13 activity measurements for initial management decisions is unknown. ADAMTS13 was measured before beginning plasma exchange treatment in 142 (88%) of 161 consecutive patients with clinically diagnosed TTP-HUS with assignment to 1 of 4 categories: less than 5% (severe deficiency), 5% to 9%, 10% to 25%, and more than 25%. Eighteen (13%) of 142 patients had severe ADAMTS13 deficiency. Among 6 predefined clinical categories (stem cell transplantation, pregnant/postpartum, drug association, bloody diarrhea, additional/alternative disorder, idiopathic), severe deficiency occurred only among pregnant/postpartum (2 of 10) and idiopathic (16 of 48) patients. The presenting features and clinical outcomes of the 16 patients with idiopathic TTP-HUS who had severe ADAMTS13 deficiency were variable and not distinct from the 32 patients with idiopathic TTPHUS who did not have severe ADAMTS13 deficiency. Many patients in all ADAMTS13 activity categories apparently responded to plasma exchange treatment. Therefore, severe ADAMTS13 deficiency does not detect all patients who may be appropriately diagnosed with TTP-HUS and who may respond to plasma exchange treatment. (Blood. 2003;102:60-68)

Download Full-text

Platelets: Thrombotic Thrombocytopenic Purpura

Hematology ◽

10.1182/asheducation-2002.1.315 ◽

2002 ◽

Vol 2002 (1) ◽

pp. 315-334 ◽

Cited By ~ 43

Author(s):

James N. George ◽

J. Evan Sadler ◽

Bernhard Lämmle

Keyword(s):

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Clinical Approach ◽

Adamts13 Activity ◽

Extensive Experience ◽

Thrombocytopenic Purpura ◽

Severe Deficiency ◽

Adamts13 Deficiency ◽

And Function ◽

Von Willebrand

Abstract Abnormalities of plasma von Willebrand factor (VWF) have been recognized to be associated with thrombotic thrombocytopenic purpura (TTP) for over 20 years. Patients with chronic, relapsing TTP have VWF multimers that are larger than normal, similar in size to those secreted by cultured endothelial cells. Recent observations have documented that a deficiency of a VWF-cleaving protease (termed ADAMTS13) may be responsible for the presence of these unusually large VWF multimers. Multiple mutations of the ADAMTS13 gene can result in ADAMTS13 deficiency and cause congenital TTP; autoantibodies neutralizing ADAMTS13 protease activity have been associated with acquired TTP. In Section I, Dr. Evan Sadler reviews the structure, biosynthesis, and function of the ADAMTS13 protease. He describes the mutations that have been identified in congenital TTP and describes the relationship of ADAMTS13 deficiency to the development of both congenital and acquired TTP. Dr. Sadler postulates that the development of TTP may be favored by conditions that combine increased VWF secretion, such as during the later stages of pregnancy, and decreased ADAMTS13 activity. In Section II, Dr. Bernhard Lämmle describes the assay methods for determining ADAMTS13 activity. Understanding the complexity of these methods is essential for understanding the difficulty of assay performance and the interpretation of assay data. Dr. Lämmle describes his extensive experience measuring ADAMTS13 activity in patients with TTP as well as patients with acute thrombocytopenia and severe illnesses not diagnosed as TTP. His data suggest that a severe deficiency of ADAMTS13 activity (< 5%) is a specific feature of TTP. However, he emphasizes that, although severe ADAMTS13 deficiency may be specific for TTP, it may not be sensitive enough to identify all patients who may be appropriately diagnosed as TTP and who may respond to plasma exchange treatment. In Section III, Dr. James George describes the evaluation and management of patients with clinically suspected TTP, as well as adults who may be described as having hemolytic-uremic syndrome (HUS). Dr. George presents a classification of TTP and HUS in children and adults. Appropriate evaluation and management are related to the clinical setting in which the diagnosis is considered. A clinical approach is described for patients in whom the diagnosis of TTP or HUS is considered (1) following bone marrow transplantation, (2) during pregnancy or the postpartum period, (3) in association with drugs which may cause TTP either by an acute immune-mediated toxicity or a dose-related toxicity, (4) following a prodrome of bloody diarrhea, (5) in patients with autoimmune disorders, and (6) in patients with no apparent associated condition who may be considered to have idiopathic TTP. Patients with idiopathic TTP appear to have the greatest frequency of ADAMTS13 deficiency and appear to be at greatest risk for a prolonged clinical course and subsequent relapse. Management with plasma exchange has a high risk of complications. Indications for additional immunosuppressive therapy are described.

Download Full-text

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

Blood ◽

10.1182/blood.v120.21.2188.2188 ◽

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.

Download Full-text

Exome Sequencing Identifies Glycosylation Defects as a Probable Cause of Immune-Mediated Thrombotic Thrombocytopenic Purpura

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqz112.037 ◽

2019 ◽

Vol 152 (Supplement_1) ◽

pp. S19-S20

Author(s):

Malay Kumar Basu ◽

Elizabeth Staley ◽

Konstantine Halkidis ◽

Jingrui (Jean) Sui ◽

Nicole K Kocher ◽

...

Keyword(s):

Exome Sequencing ◽

Thrombotic Thrombocytopenic Purpura ◽

Potential Contribution ◽

Healthy Controls ◽

Adamts13 Activity ◽

Autoantibody Production ◽

Thrombocytopenic Purpura ◽

Long Term Outcome ◽

Immune Mediated ◽

Severe Deficiency

Abstract Background Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal syndrome, resulting from autoantibodies against ADAMTS13. However, the mechanism underlying autoantibody formation is not known. Neither is known about the other genetic abnormality in the setting of severe deficiency of plasma ADAMTS13 activity. Methods Whole-exome sequencing (WES) was performed in 40 patients with iTTP who had plasma ADAMTS13 activity <10% and a positive inhibitor or elevated anti-ADAMTS13 IgG. Fifteen age- and ethnicity-matched subjects who never had iTTP were recruited as healthy controls. Results WES identified mutations in the genes involved in glycosylation, including O-linked glycosylation to be the major pathway affected in patients with iTTP. Mass spectrometry confirmed the changes in plasma levels of various glycoproteins in patients with acute iTTP when compared with those in the healthy controls. The altered glycosylation in glycoproteins may be responsible for the development of autoantibodies, susceptibility of von Willebrand factor to proteolysis by ADAMTS13, and the clearance of platelets in iTTP patients. Moreover, candidate gene analysis revealed that various genes involving in hemostasis, complement activation, platelet number and function, and inflammation were all affected in patients with iTTP, which may contribute to the onset, progress, severity, and long-term outcome of iTTP. Conclusions Our findings provide novel insight into a pathogenic mechanism underlying autoantibody production and the potential contribution of other genetic abnormalities in pathogenesis of iTTP in the individuals with severe deficiency of plasma ADAMTS13 activity. Future Direction Further studies are warranted to determine the specific glycosylation patterns of various plasma and cellular proteins in patients with iTTP and to determine the synergistic role of various gene mutations and severe ADAMTS13 deficiency in the pathogenesis of iTTP.

Download Full-text

How I treat patients with thrombotic thrombocytopenic purpura: 2010

Blood ◽

10.1182/blood-2010-07-271445 ◽

2010 ◽

Vol 116 (20) ◽

pp. 4060-4069 ◽

Cited By ~ 290

Author(s):

James N. George

Keyword(s):

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Immunosuppressive Agents ◽

Adamts13 Activity ◽

Microangiopathic Hemolytic Anemia ◽

Thrombocytopenic Purpura ◽

Severe Deficiency ◽

Adamts13 Deficiency ◽

The Common ◽

Renal Abnormalities

Abstract Thrombotic thrombocytopenic purpura (TTP) is the common name for adults with microangiopathic hemolytic anemia, thrombocytopenia, with or without neurologic or renal abnormalities, and without another etiology; children without renal failure are also described as TTP. The diagnosis of TTP is an indication for plasma exchange treatment, but beginning treatment requires sufficient confidence in the diagnosis to justify the risk of plasma exchange complications. Documentation of a severe deficiency of plasma ADAMTS13 activity, defined as less than 10% of normal, is not essential for the diagnosis of TTP. Some patients without severe ADAMTS13 deficiency may benefit from plasma exchange treatment; in addition, some patients with severe ADAMTS13 deficiency may subsequently be diagnosed with another cause for their clinical features. However, severe acquired ADAMTS13 deficiency does define a subgroup of patients who appear to benefit from treatment with corticosteroids and other immunosuppressive agents in addition to plasma exchange but who have a high risk for relapse. Approximately 80% of patients survive their acute episode, a survival rate that has not changed since the introduction of plasma exchange treatment. Although recovery may appear to be complete, many patients have persistent minor cognitive abnormalities. More effective as well as safer treatment for TTP is needed.

Download Full-text