scholarly journals Annual Incidence and Severity of Acute Episodes in Hereditary Thrombotic Thrombocytopenic Purpura

Blood ◽  
2021 ◽  
Author(s):  
Erika Tarasco ◽  
Lukas Bütikofer ◽  
Kenneth D. Friedman ◽  
James N George ◽  
Ingrid V Hrachovinova ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Premature Death ◽  
Annual Incidence ◽  
Prospective Data ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Survival Frequency ◽  
Overt Disease ◽  
Plasma Infusions

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in hTTP patients is largely lacking. This study reports prospective data of 87 patients from the Hereditary TTP Registry (ClinicalTrials.gov NCT01257269) for survival, frequency and severity of acute episodes from enrollment until December 2019. The 87 patients, followed for median 4.2 years (range 0.01-15), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and of 18 years (range 0.0-70 for both), respectively. Forty-three patients received regular plasma prophylaxis, while 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes of which 91 (69%) occurred in patients on regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95%CI 0.29-0.44) with and of 0.41 (95%CI 0.30-0.56) without regular plasma treatment. More than one third of acute episodes (n=51) were documented in children <10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients >40 years of age (1.18 [95% CI 0.88-1.55] vs. 0.14 [95% CI 0.08-0.23]). Prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, caregivers, patients and their guardians are reluctant to start regular plasma infusions, from which particularly children would benefit.

scholarly journals Insights from the Hereditary Thrombotic Thrombocytopenic Purpura Registry: Discussion of Key Findings Based on Individual Cases from Switzerland

2020 ◽  
Vol 40 (S 01) ◽  
pp. S5-S14
Author(s):  
Johanna A. Kremer Hovinga ◽  
Thomas R. Braschler ◽  
Florian Buchkremer ◽  
Stefan Farese ◽  
Heinz Hengartner ◽  
...  
Keyword(s):  
Cohort Study ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Onset ◽  
Myocardial Infarctions ◽  
Thrombocytopenic Purpura ◽  
Blood Disorder ◽  
A Disintegrin And Metalloproteinase ◽  
Systematic Collection ◽  
Plasma Infusions

AbstractThe Hereditary TTP Registry is an international cohort study for patients with a confirmed or suspected diagnosis of hereditary thrombotic thrombocytopenic purpura (hTTP) and their family members. Hereditary TTP is an ultra-rare blood disorder (prevalence of ∼1–2 cases per million), the result of autosomal-recessively inherited congenital ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency (ADAMTS13 activity <10% of the normal), and associated with yet many unanswered questions. Until December 2017, the Hereditary TTP Registry had enrolled 123 confirmed hTTP patients. Their median age at disease onset was 4.5 years (range: 0–70) and at clinical diagnosis 16.7 years (range: 0–69), a difference that highlights the existing awareness gap in recognizing hTTP. The systematic collection of clinical data of individual patients revealed their substantial baseline comorbidities, as a consequence of recurring TTP episodes in the past. Most notable was the high proportion of patients having suffered from premature arterial thrombotic events, mainly transient ischemic attacks, ischemic strokes, and to a lesser extent myocardial infarctions. At 40 to 50 years of age and above, more than 50% of patients had suffered from at least one such event, and many had experienced arterial thrombotic events despite regular plasma infusions every 2 to 3 weeks that supplements the missing plasma ADAMTS13. The article by van Dorland et al. (Haematologica 2019;104(10):2107–2115) and the ongoing Hereditary TTP Registry cohort study were recognized with the Günter Landbeck Excellence Award at the 50th Hemophilia Symposium in Hamburg in November 2019, the reason to present the Hereditary TTP Registry in more detail here.

scholarly journals A case of severe ADAMTS 13 deficiency presenting as thrombotic thrombocytopenic purpura in pregnancy

2012 ◽  
Vol 65 (9-10) ◽  
pp. 436-439 ◽  
Author(s):  
Marinos Nikolaou ◽  
Marina Karakantza ◽  
George Adonakis ◽  
George Theodorou ◽  
Nikolaos Zoumbos ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Prophylactic Treatment ◽  
Thrombocytopenic Purpura ◽  
Treatment And Prevention ◽  
Severe Deficiency ◽  
History Of ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Plasma Infusions

Introduction. Thrombotic thrombocytopenic purpura is a rare lifethreatening disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia. It is caused by the absent or severe deficiency of the von Willebrand Factor-cleaving protease named ADAMTS13. Pregnancy is a well recognized factor precipitating the appearance of the disease both in women that had reduced levels of ADAMTS13 activity prior to gestation and in those with other inherited or acquired thrombophilic syndromes. Case Report. We report a 25-year old woman with severe ADAMTS13 deficiency presented early in her 1st pregnancy and relapsed in two subsequent gestations. This presentation is uncommon for thrombotic thrombocytopenic purpura is associated with pregnancy (ADAMTS13 deficiency <5%, without an inhibitor). In the first pregnancy she started with daily plasma exchange 1.5xvolume, corticosteroids and IV immunoglobulin and finally entered remission after 23 sessions and termination of pregnancy. In the second pregnancy she did not receive prophylactic treatment and relapsed in the 3rd trimester. Prophylactic treatment during the third pregnancy with plasma infusions proved also ineffective to prevent relapse. Discussion. Many issues regarding treatment and prevention of thrombotic thrombocytopenic purpura relapses in subsequent pregnancies are unclear. Proposed guidelines recommend that the same treatment should be performed on pregnant and non pregnant patients without modification of plasma replacement dose according to ADAMTS13 levels. In addition, many authors suggest that pregnant patients with history of thrombotic thrombocytopenic purpura and severe deficiency of ADAMTS13 levels should received prophylactic treatment for prevention of relapses in the subsequent pregnancies. Conclusion. Severe ADAMTS 13 deficiency may present as thrombotic thrombocytopenic purpura of pregnancy. Pregnant women with thrombotic thrombocytopenic purpura and especially with severe deficiency of ADAMTS13 levels require specific consideration regarding treatment and prophylaxis in subsequent pregnancies.

Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children

2009 ◽  
Vol 24 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Chantal Loirat ◽  
Jean-Pierre Girma ◽  
Céline Desconclois ◽  
Paul Coppo ◽  
Agnès Veyradier
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency

scholarly journals Beyond plasma exchange: novel therapies for thrombotic thrombocytopenic purpura

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 539-547 ◽  
Author(s):  
Kathryn Dane ◽  
Shruti Chaturvedi
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Relapse Prevention ◽  
Tissue Injury ◽  
Novel Therapies ◽  
Thrombocytopenic Purpura ◽  
Platelet Recovery ◽  
Adamts13 Deficiency ◽  
Prophylactic Use ◽  
Von Willebrand

Abstract The advent of plasma exchange has dramatically changed the prognosis of acute thrombotic thrombocytopenic purpura (TTP). Recent insights into TTP pathogenesis have led to the development of novel therapies targeting pathogenic anti-ADAMTS13 antibody production, von Willebrand factor (VWF)–platelet interactions, and ADAMTS13 replacement. Retrospective and prospective studies have established the efficacy of rituximab as an adjunct to plasma exchange for patients with acute TTP, either upfront or for refractory disease. Relapse prevention is a major concern for survivors of acute TTP, and emerging data support the prophylactic use of rituximab in patients with persistent or recurrent ADAMTS13 deficiency in clinical remission. Capalcizumab, a nanobody directed against domain A1 of VWF that prevents the formation of VWF–platelet aggregates, recently completed phase 2 (TITAN) and 3 (HERCULES) trials with encouraging results. Compared with placebo, caplacizumab shortened the time to platelet recovery and may protect against microthrombotic tissue injury in the acute phase of TTP, though it does not modify the underlying immune response. Other promising therapies including plasma cell inhibitors (bortezomib), recombinant ADAMTS13, N-acetyl cysteine, and inhibitors of the VWF–glycoprotein Ib/IX interaction (anfibatide) are in development, and several of these agents are in prospective clinical studies to evaluate their efficacy and role in TTP. In the coming years, we are optimistic that novel therapies and international collaborative efforts will usher in even more effective, evidence-based approaches to address refractory acute TTP and relapse prevention.

scholarly journals The HLA Variant rs6903608 Is Associated with Disease Onset and Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Caucasians

2020 ◽  
Vol 9 (10) ◽  
pp. 3379
Author(s):  
Ilaria Mancini ◽  
Elisa Giacomini ◽  
Silvia Pontiggia ◽  
Andrea Artoni ◽  
Barbara Ferrari ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Risk Allele ◽  
Absolute Risk ◽  
Disease Onset ◽  
Close Monitoring ◽  
Reference Allele ◽  
Thrombocytopenic Purpura ◽  
Immune Mediated ◽  
The Impact ◽  
Risk Of Relapse

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30–50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (β −3.34, 95%CI −6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 292-299 ◽  
Author(s):  
James T. B. Crawley ◽  
Marie A. Scully
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Therapeutic Strategies ◽  
Therapeutic Approaches ◽  
Thrombocytopenic Purpura ◽  
Vessel Injury ◽  
Adamts13 Deficiency ◽  
Flowing Blood ◽  
A Disintegrin And Metalloproteinase ◽  
Anti Cd20

Abstract VWF is a multimeric plasma glycoprotein that specifically recruits platelets to sites of vessel injury. VWF multimeric size is central to this function, with larger multimers being more hemostatically active. Regulation of VWF multimeric size is mediated by the plasma metalloprotease ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, member 13). This enzyme can only recognize and cleave VWF when it is unraveled by rheological shear forces of the flowing blood. After the exposure of cryptic exosites, VWF recognition by ADAMTS13 involves multiple interactions that enable the protease to cleave VWF. Loss of VWF multimer size regulation caused by severe ADAMTS13 deficiency (either inherited or acquired) is associated with the microvascular thrombotic disorder thrombotic thrombocytopenic purpura (TTP). The sequelae associated with TTP are widely thought to be linked to hyperreactive circulating VWF that cause unwanted platelet aggregation in the high shear environment of the microvasculature. Diagnosis of TTP is primarily made through a combination of symptoms, analysis of plasma ADAMTS13 activity, and detection of inhibitory anti-ADAMTS13 antibodies. Current frontline treatments for TTP include plasma exchange, which serves to remove inhibitory antibodies (in acquired TTP) and provide a source of functional ADAMTS13, and steroids to treat the autoimmune component of acquired TTP. The use of anti-CD20 therapy has also exhibited encouraging results in the treatment of acquired TTP. Newer therapeutic strategies that are currently being explored or are in development include recombinant ADAMTS13, a hyperreactive ADAMTS13 variant, and anti-VWF therapy. This review discusses the basic biochemistry of VWF and ADAMTS13, their dysfunction in TTP, and therapeutic approaches for the amelioration of TTP.

scholarly journals Application of SELDI-TOF mass spectrometry in clinical evaluation of thrombotic thrombocytopenic purpura

2006 ◽  
Vol 20 (5-6) ◽  
pp. 219-227
Author(s):  
Haifeng M. Wu ◽  
Spero R. Cataland ◽  
Michael Bissell ◽  
Ming Jin
Keyword(s):  
Mass Spectrometry ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Rapid Determination ◽  
Correct Diagnosis ◽  
Thrombocytopenic Purpura ◽  
Autoimmune Antibodies ◽  
Adamts13 Deficiency ◽  
Rapid Purification ◽  
Von Willebrand

Surface Enhanced Laser Desorption/Ionization Time Of Flight (SELDI-TOF) mass spectrometry is characterized by integration of mass spectrometry with surface chemistry, which gives rise to rapid purification and subsequent determination of protein/peptide analytes. There are several surface matrices, named proteinChips, available for analyzing a particular analyte or a subset of biomolecules in biological samples. Each proteinChip has a unique surface property suitable for fractionation of a specific group of molecules. This article demonstrates the application of SELDI-TOF for the analysis of a cleaved peptide (Mr7739 daltons) from von Willebrand Factor by a metalloproteinase, ADAMTS13. Deficiency of ADAMTS13 is a known primary risk factor for the devastating hematological disorder, Thrombotic thrombocytopenic purpura (TTP). Rapid determination of ADAMTS13 activity helps clinicians tremendously in making the correct diagnosis and initiating timely therapy. Most patients with TTP are acquired cases who exhibit a production of autoimmune antibodies against ADAMTS13 protease. TTP's clinical course is critically controlled by the autoantibody's ability to inhibit ADAMTS13 function. Thus, a second SELDI-TOF based test has been devised to measure ADAMTS13 autoantibody activity for the evaluation of TTP disease activity. In conclusion, the unique features of SELDI-TOF which allow for the examination of the role of key proteases in disease processes have opened up new doors for the clinical application of mass spectrometer based techniques.

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