126 results on '"ADAMTS13 Protein"'
Search Results
2. Alemtuzumab-induced immune-mediated thrombotic thrombocytopenic purpura: A newly described drug-related autoimmune disease.
- Author
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Bourdin V, Fossé Q, Lambotte O, Joly B, Coppo P, Anguel N, and Labeyrie C
- Subjects
- Humans, Adult, Alemtuzumab adverse effects, Antibodies, Monoclonal therapeutic use, Plasma Exchange, ADAMTS13 Protein, Purpura, Thrombotic Thrombocytopenic chemically induced, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic therapy, Thrombotic Microangiopathies therapy, Autoimmune Diseases chemically induced, Autoimmune Diseases therapy
- Abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease that may result from drug exposure. We report a case of iTTP occurring in a 39-year-old patient, 45 months following introduction of the anti-CD52 lymphoid cell depleting monoclonal antibody alemtuzumab, to treat a relapsing-remitting multiple sclerosis. Treatment consisted in plasma exchange, corticosteroids and caplacizumab, allowing clinical remission 3 months after the diagnosis, attested by the absence of thrombocytopenia and recovery of ADAMTS-13 activity. As other autoimmune disorders, iTTP may occur following alemtuzumab. This diagnosis should be suspected in patients with features of thrombotic microangiopathy following this treatment., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
3. Cognitive decline in thrombotic thrombocytopenic purpura survivors: The role of white matter health as assessed by MRI.
- Author
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Hannan F, Hamilton J, Patriquin CJ, Pavenski K, Jurkiewicz MT, Tristao L, Owen AM, Kosalka PK, Deoni SCL, Théberge J, Mandzia J, Huang SHS, and Thiessen JD
- Subjects
- Humans, ADAMTS13 Protein, Purpura, Thrombotic Thrombocytopenic therapy, White Matter, Cognitive Dysfunction
- Abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare condition caused by severe ADAMTS13 deficiency, leading to platelet aggregation and thrombosis. Despite treatment, patients are prone to cognitive impairment and depression. We investigated brain changes in iTTP patients during remission using advanced magnetic resonance imaging (MRI) techniques, correlating these changes with mood and neurocognitive tests. Twenty iTTP patients in remission (30 days post-haematological remission) were compared with six healthy controls. MRI scans, including standard and specialized sequences, were conducted to assess white matter health. Increased T1 relaxation times were found in the cingulate cortex (p < 0.05), and elevated T2 relaxation times were observed in the cingulate cortex, frontal, parietal and temporal lobes (p < 0.05). Pathological changes in these areas are correlated with impaired cognitive and depressive scores in concentration, short-term memory and verbal memory. This study highlights persistent white matter damage in iTTP patients, potentially contributing to depression and cognitive impairment. Key regions affected include the frontal lobe and cingulate cortex. These findings have significant implications for the acute and long-term management of iTTP, suggesting a need for re-evaluation of treatment approaches during both active phases and remission. Further research is warranted to enhance our understanding of these complexities., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
4. Immune thrombotic thrombocytopenic purpura in older patients: Results from the Spanish TTP Registry (REPTT).
- Author
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Gómez-Seguí I, Francés Aracil E, Mingot-Castellano ME, Vara Pampliega M, Goterris Viciedo R, García Candel F, Pascual Izquierdo C, Del Río Garma J, Guerra Domínguez L, Vicuña Andrés I, Garcia-Arroba Peinado J, Zalba Marcos S, Vidan Estévez JM, González Arias E, Campuzano Saavedra V, García Gala JM, Ortega Sanchez S, Martínez Nieto J, Pardo Gambarte L, Solé Rodríguez M, Fernández-Docampo M, Avila Idrovo LF, Hernández L, Cid J, and de la Rubia Comos J
- Subjects
- Humans, Aged, Rituximab therapeutic use, Plasma Exchange, Registries, ADAMTS13 Protein, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic epidemiology, Purpura, Thrombotic Thrombocytopenic therapy, Purpura, Thrombocytopenic, Idiopathic therapy, Thrombosis therapy
- Abstract
Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare disease that seldom occurs in the elderly. Few reports have studied the clinical course of iTTP in older patients. In this study, we have analysed the clinical characteristics at presentation and response to therapy in a series of 44 patients with iTTP ≥60 years at diagnosis from the Spanish TTP Registry and compared them with 209 patients with <60 years at diagnosis from the same Registry. Similar symptoms and laboratory results were described in both groups, except for a higher incidence of renal dysfunction among older patients (23% vs. 43.1%; p = 0.008). Front-line treatment in patients ≥60 years was like that administered in younger patients. Also, no evidence of a difference in clinical response and overall survival was seen in both groups. Of note, 14 and 25 patients ≥60 years received treatment with caplacizumab and rituximab, respectively, showing a favourable safety and efficacy profile, like that observed in patients <60 years., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
5. Immune thrombotic thrombocytopenic purpura in patients over 60 years of age: Diagnostic pitfalls and treatment strategy.
- Author
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Lester W
- Subjects
- Humans, Middle Aged, Aged, Registries, ADAMTS13 Protein, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic therapy, Purpura, Thrombocytopenic, Idiopathic diagnosis, Purpura, Thrombocytopenic, Idiopathic therapy, Thrombosis
- Abstract
Real-world registry studies of older patients with iTTP highlight diagnostic difficulties in comparison to patients less than 60 years of age with greater risk of renal injury, atypical neurological features and less profound cytopenia, which can result in diagnostic delays. However, there is no clear signal of significantly increased toxicity from full active treatment. Commentary on: Gómez-Seguí et al. Immune thrombotic thrombocytopenic purpura in older patients: results from the Spanish TTP Registry (REPTT). Br J Haematol 2023;203:860-871., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
6. Caplacizumab: A game changer also in pregnancy-associated immune-mediated thrombotic thrombocytopenic purpura?
- Author
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Coppo P and Joly BS
- Subjects
- Humans, Pregnancy, Female, von Willebrand Factor, Adrenal Cortex Hormones therapeutic use, Plasma Exchange, ADAMTS13 Protein, Purpura, Thrombotic Thrombocytopenic drug therapy, Single-Domain Antibodies therapeutic use
- Abstract
Therapeutic options in immune-mediated thrombotic thrombocytopenic purpura (iTTP) during pregnancy are limited besides therapeutic plasma exchange (TPE) and corticosteroids. The report by Odetola et al. suggests that caplacizumab represents a reasonable option in iTTP during pregnancy, especially when the disease is not rapidly controlled with the standard TPE-corticosteroid association. Commentary on: Odetola et al. Safe and effective use of caplacizumab in pregnancy-related acquired thrombotic thrombocytopenic purpura. Br J Haematol 2023;202:879-882., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
7. A safe and effective use of caplacizumab in pregnancy-related acquired thrombotic thrombocytopenic purpura.
- Author
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Odetola O, Martin KA, Dreyer M, Rajan P, Zakarija A, and Stein BL
- Subjects
- Pregnancy, Infant, Newborn, Humans, Female, Hemorrhage therapy, Plasma Exchange, Adrenal Cortex Hormones therapeutic use, ADAMTS13 Protein, Purpura, Thrombotic Thrombocytopenic drug therapy
- Abstract
Thrombotic thrombocytopenic purpura (TTP) is not uncommonly seen in pregnancy, either with the first episode or with the exacerbation of known disease. The management of TTP in pregnancy can be challenging if there is refractoriness to the use of therapeutic plasma exchange (TPE) and high-dose corticosteroids. Caplacizumab, a vWF-directed humanized antibody fragment, is approved for the treatment of acquired TTP but there is sparse data on its use in pregnant patients. Antenatal and peripartum haemorrhage is a theoretical concern with the use of the medication in the obstetric population. However, as options for treatment of TTP in the patients who have refractory disease are significantly limited, off-label use of caplacizumab to achieve disease control and prevent maternofetal morbidity and mortality is a reasonable consideration. This article described the successful use of caplacizumab in a pregnant patient with acquired TTP and the associated favourable outcome. The patient suffered an exacerbation following initial TPE and became refractory to both plasma exchange and high-dose corticosteroids. Off-label use of caplacizumab resulted in hematologic recovery and successful delivery of a healthy neonate. This case represents a contribution to the sparse literature on the use of this effective medication in an often-challenging clinical situation., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
8. Anti-CD20 therapeutic options in immune-mediated thrombotic thrombocytopenic purpura
- Author
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Robert Maitta
- Subjects
Immunosuppression Therapy ,Purpura, Thrombocytopenic, Idiopathic ,Purpura, Thrombotic Thrombocytopenic ,ADAMTS13 Protein ,Humans ,Hematology ,Antigens, CD20 ,Rituximab - Abstract
Immunosuppression with rituximab in immune-mediated thrombotic thrombocytopenic purpura helps decrease production of autoantibody mediating ADAMTS13 clearance from circulation. Failure to respond to rituximab in a satisfactory way or made difficult by adverse events to the medication does not represent a reason to stop considering anti-CD20 therapies to control antibody production. Therefore, both of atumumab and obinutuzumab with specificity to CD20, represent potentially valuable therapeutic tools in patients who are not candidates for rituximab. Commentary on: Doyle et al. The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura. Br J Haematol. 2022;198:391-396.
- Published
- 2022
9. Performance of the <scp>PLASMIC</scp> score is improved with a positive score defined as ≥5 and with the inclusion of neurological symptoms
- Author
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Manasa S. Reddy, Natalie Newsom, Shunsuke Sakurai, So‐Youn Park, Joan Reisch, and Ravi Sarode
- Subjects
Purpura, Thrombotic Thrombocytopenic ,ADAMTS13 Protein ,Humans ,Hematology - Published
- 2022
10. Platelet factor 4 inhibits ADAMTS13 activity and regulates the multimeric distribution of von Willebrand factor
- Author
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Ishac Nazy, Donald M. Arnold, and Taylor D. Elliott
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_treatment ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Platelet Factor 4 ,Adamts13 activity ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,Von Willebrand factor ,hemic and lymphatic diseases ,Protein Interaction Mapping ,von Willebrand Factor ,medicine ,Humans ,Distribution (pharmacology) ,Thrombus ,Hemostasis ,Purpura, Thrombocytopenic, Idiopathic ,Protease ,biology ,Chemistry ,Thrombosis ,Hematology ,medicine.disease ,ADAMTS13 ,3. Good health ,Cell biology ,030220 oncology & carcinogenesis ,Proteolysis ,cardiovascular system ,biology.protein ,Protein Multimerization ,Platelet factor 4 ,Protein Binding ,circulatory and respiratory physiology ,030215 immunology - Abstract
The efficiency of von Willebrand factor (VWF) in thrombus formation is related to its multimeric size, which is controlled by the protease ADAMTS13. However, it is not clear what regulates ADAMTS13 activity. In this study, we investigated whether PF4 could bind to VWF and inhibit ADAMTS13 activity. We found that PF4 binds to VWF and protects against ADAMTS13 activity. We also found that VWF-PF4 complexes circulate in patients with thrombotic thrombocytopenic purpura (TTP). Our data provides the first evidence that PF4 may have a novel role in regulating VWF multimers during primary haemostasis and thrombosis.
- Published
- 2020
11. TTP: From empiricism for an enigmatic disease to targeted molecular therapies
- Author
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Nuno A. G. Graça, Bérangère S. Joly, Jan Voorberg, Karen Vanhoorelbeke, Nicolas Béranger, Agnès Veyradier, and Paul Coppo
- Subjects
Science & Technology ,FACTOR-CLEAVING PROTEASE ,Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,VON-WILLEBRAND-FACTOR ,FACTOR MULTIMERS ,PLASMA-EXCHANGE ,ADAMTS13 Protein ,ANTI-ADAMTS13 AUTOANTIBODIES ,Hematology ,UPSHAW-SCHULMAN SYNDROME ,HEMOLYTIC-UREMIC SYNDROME ,Humans ,THROMBOTIC THROMBOCYTOPENIC PURPURA ,Molecular Targeted Therapy ,Thiamine ,SEVERE ADAMTS13 DEFICIENCY ,Empiricism ,Life Sciences & Biomedicine ,INFLAMMATORY CYTOKINES - Abstract
The 100th anniversary of the first description of Thrombotic Thrombocytopenic Purpura (TTP) as a disease by Dr. Eli Moschcowitz approaches. For many decades, TTP remained mostly a mysterious fatal condition, where diagnosis was often post-mortem. Initially a pentad of symptoms was identified, a pattern that later revealed to be fallible. Sporadic observations led to empiric interventions that allowed for the first impactful breakthrough in TTP treatment, almost 70 years after its first description: the introduction of plasma exchange and infusions as treatments. The main body of knowledge within the field was gathered in the latest three decades: patient registries were set and proved crucial for advancements; the general mechanisms of disease have been described; the diagnosis was refined; new treatments and biomarkers with improvements on prognosis and management were introduced. Further changes and improvements are expected in the upcoming decades. In this review, we provide a brief historic overview of TTP, as an illustrative example of the success of translational medicine enabling to rapidly shift from a management largely based on empiricism to targeted therapies and personalized medicine, for the benefit of patients. Current management options and present and future perspectives in this still evolving field are summarized. ispartof: BRITISH JOURNAL OF HAEMATOLOGY vol:197 issue:2 pages:156-170 ispartof: location:England status: published
- Published
- 2021
12. Unusually high ADAMTS13 activity in a patient with congenital thrombotic thrombocytopenic purpura.
- Author
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Subhan MO, de Groot R, and Scully M
- Subjects
- Humans, ADAMTS13 Protein, Autoantibodies, Purpura, Thrombotic Thrombocytopenic diagnosis
- Published
- 2023
- Full Text
- View/download PDF
13. Bortezomib, a promising alternative for patients with refractory or relapsed thrombotic thrombocytopenic purpura after rituximab treatment.
- Author
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Yin J, Tian H, Kong D, Li Y, Gu C, Wang Z, Wu D, and Yu Z
- Subjects
- Humans, Rituximab adverse effects, Bortezomib adverse effects, ADAMTS13 Protein, Plasma Exchange, Purpura, Thrombotic Thrombocytopenic chemically induced, Purpura, Thrombotic Thrombocytopenic drug therapy
- Published
- 2022
- Full Text
- View/download PDF
14. Interrelationship between ADAMTS13 activity, von Willebrand factor, and complement activation in remission from immune‐mediated trhrombotic thrombocytopenic purpura
- Author
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Chenggong Han, Lauren Jay, Spero R. Cataland, Haiwa Wu, Shangbin Yang, Camila Masias, and Shili Lin
- Subjects
Male ,Purpura, Thrombocytopenic, Idiopathic ,Purpura, Thrombotic Thrombocytopenic ,biology ,business.industry ,Remission Induction ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Hematology ,medicine.disease ,Thrombocytopenic purpura ,Adamts13 activity ,Complement system ,Immune system ,Von Willebrand factor ,von Willebrand Factor ,Immunology ,medicine ,biology.protein ,Humans ,Female ,business ,Complement Activation ,Biomarkers - Published
- 2020
15. Performance of the PLASMIC score is improved with a positive score defined as ≥5 and with the inclusion of neurological symptoms.
- Author
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Reddy MS, Newsom N, Sakurai S, Park SY, Reisch J, and Sarode R
- Subjects
- ADAMTS13 Protein, Humans, Purpura, Thrombotic Thrombocytopenic diagnosis
- Published
- 2022
- Full Text
- View/download PDF
16. The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura.
- Author
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Doyle AJ, Stubbs MJ, Lester W, Thomas W, Westwood JP, Thomas M, Percy C, Prasannan N, and Scully M
- Subjects
- ADAMTS13 Protein, Antigens, CD20, Humans, Recurrence, Rituximab adverse effects, Serum Sickness chemically induced, Antibodies, Monoclonal, Humanized therapeutic use, Purpura, Thrombotic Thrombocytopenic drug therapy
- Abstract
Rituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanised anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the UK TTP Registry showed 15 patients received these drugs over 26 treatment episodes (eight obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity ≥30 iu/dl) after a median 15 days and 92% of episodes achieved complete remission (≥60 iu/dl). Seven patients required further treatment for disease relapse with a median relapse-free survival of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
17. Anti-CD20 therapeutic options in immune-mediated thrombotic thrombocytopenic purpura.
- Author
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Maitta RW
- Subjects
- ADAMTS13 Protein, Antigens, CD20, Humans, Immunosuppression Therapy, Rituximab therapeutic use, Purpura, Thrombocytopenic, Idiopathic drug therapy, Purpura, Thrombotic Thrombocytopenic drug therapy
- Abstract
Immunosuppression with rituximab in immune-mediated thrombotic thrombocytopenic purpura helps decrease production of autoantibody mediating ADAMTS13 clearance from circulation. Failure to respond to rituximab in a satisfactory way or made difficult by adverse events to the medication does not represent a reason to stop considering anti-CD20 therapies to control antibody production. Therefore, both of atumumab and obinutuzumab with specificity to CD20, represent potentially valuable therapeutic tools in patients who are not candidates for rituximab. Commentary on: Doyle et al. The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura. Br J Haematol. 2022;198:391-396.
1 ., (© 2022 The Author. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2022
- Full Text
- View/download PDF
18. The utility of a fast turnaround ADAMTS13 activity in the diagnosis and exclusion of thrombotic thrombocytopenic purpura
- Author
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Gary W. Moore, J A Cutler, Will Thomas, Beverley J Hunt, and Vickie McDonald
- Subjects
Male ,medicine.medical_specialty ,Thrombotic microangiopathy ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Hematology ,medicine.disease ,Adamts13 activity ,Gastroenterology ,ADAMTS13 ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Humans ,Medicine ,Female ,business ,030215 immunology - Published
- 2018
19. Mind and matter: The neurological complications of thrombotic thrombocytopenic purpura.
- Author
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Shaw RJ and Dutt T
- Subjects
- ADAMTS13 Protein, Humans, Purpura, Thrombotic Thrombocytopenic complications, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic therapy
- Abstract
Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal condition, with >90% mortality if untreated; deficiency of ADAMTS13 leads to widespread microvascular thromboses and organ injury particularly affecting organs with high shear stress, including the brain. The acute neurological complications have historically been those most feared by clinicians and synonymous with a poor prognosis. TTP, however, is no longer perceived as two extremes of acute presentation and remission, rather once diagnosed a chronic condition with the potential for a long-term symptom burden. Optimal neuroimaging timing and modality lacks consensus and as we learn more about the changes seen during the acute and chronic stages of TTP, there is scope for neuroimaging to play a greater role in guiding management and the secondary prevention of vascular disease. Reduced ADAMTS13 activity levels have been associated with increased thrombotic risk and novel therapies including caplacizumab and recombinant ADAMTS13 may offer a neuroprotective role. Given the increasing evidence of the neurocognitive and psychological disease in TTP, the importance of screening and timely intervention should not be underestimated. As more patients are surviving their initial TTP presentation, it is crucial for us to develop a greater understanding of the longer-term morbidity affecting these patients., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
20. TTP: From empiricism for an enigmatic disease to targeted molecular therapies.
- Author
-
Graça NAG, Joly BS, Voorberg J, Vanhoorelbeke K, Béranger N, Veyradier A, and Coppo P
- Subjects
- ADAMTS13 Protein, Empiricism, Humans, Molecular Targeted Therapy, Plasma Exchange, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic therapy
- Abstract
The 100th anniversary of the first description of Thrombotic Thrombocytopenic Purpura (TTP) as a disease by Dr. Eli Moschcowitz approaches. For many decades, TTP remained mostly a mysterious fatal condition, where diagnosis was often post-mortem. Initially a pentad of symptoms was identified, a pattern that later revealed to be fallible. Sporadic observations led to empiric interventions that allowed for the first impactful breakthrough in TTP treatment, almost 70 years after its first description: the introduction of plasma exchange and infusions as treatments. The main body of knowledge within the field was gathered in the latest three decades: patient registries were set and proved crucial for advancements; the general mechanisms of disease have been described; the diagnosis was refined; new treatments and biomarkers with improvements on prognosis and management were introduced. Further changes and improvements are expected in the upcoming decades. In this review, we provide a brief historic overview of TTP, as an illustrative example of the success of translational medicine enabling to rapidly shift from a management largely based on empiricism to targeted therapies and personalized medicine, for the benefit of patients. Current management options and present and future perspectives in this still evolving field are summarized., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
21. Assessing the risk of refractory disease in iTTP
- Author
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Robert S. Makar and Pavan K. Bendapudi
- Subjects
medicine.medical_specialty ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,medicine ,Refractory Disease ,ADAMTS13 Protein ,Humans ,Therapeutic plasma exchange ,Hematology ,Rituximab ,Intensive care medicine ,business - Published
- 2020
22. Administration of immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) for persistent anti-ADAMTS13 antibodies in patients with thrombotic thrombocytopenic purpura in clinical remission
- Author
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Christian Kjellman, Matthew J. Stubbs, Sofia Järnum, Yvonne Stenberg, Elisabeth Sonesson, Chiara Vendramin, Mari Thomas, Charlotte Elfving, and Marie Scully
- Subjects
0301 basic medicine ,Male ,Streptococcus pyogenes ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,medicine.disease_cause ,Immunoglobulin G ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Autoantibodies ,Autoimmune disease ,biology ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,Remission Induction ,Hematology ,medicine.disease ,ADAMTS13 ,Clinical trial ,Purpura ,030104 developmental biology ,Immunology ,biology.protein ,Female ,medicine.symptom ,Antibody ,business ,030217 neurology & neurosurgery - Published
- 2018
23. The utility of ADAMTS13 in differentiating TTP from other acute thrombotic microangiopathies: results from the UK TTP Registry
- Author
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Sevda Hassan, Sylvia Benjamin, John-Paul Westwood, Marie Scully, Chris Laing, Debra Ellis, and Siobhan Mc Guckin
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,urologic and male genital diseases ,Gastroenterology ,Diagnosis, Differential ,Young Adult ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Thrombotic Microangiopathies ,heterocyclic compounds ,Platelet ,Registries ,Child ,neoplasms ,Aged ,Retrospective Studies ,Aged, 80 and over ,Creatinine ,Purpura, Thrombotic Thrombocytopenic ,Platelet Count ,business.industry ,Infant, Newborn ,Infant ,Retrospective cohort study ,Hematology ,Middle Aged ,respiratory system ,medicine.disease ,ADAMTS13 ,ADAM Proteins ,chemistry ,Child, Preschool ,Immunology ,Female ,Differential diagnosis ,Haemolytic-uraemic syndrome ,business ,Biomarkers - Abstract
Thrombotic microangiopathies (TMAs) are frequently difficult to differentiate clinically, and measurement of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) remains vital in thrombotic thrombocytopenic purpura (TTP) diagnosis. We retrospectively reviewed cases referred for ADAMTS13 testing, using UK TTP Registry screening data. Of a total 810 cases, 350 were confirmed as TTP. The 460 non-TTP cases comprised secondary TMAs (24·57%) and haemolytic uraemic syndrome (HUS) (27·17% aHUS, 2·83% Shiga-like toxin-producing E. coli [STEC]-HUS); the remainder were TMAs with no clear association, not TMAs, or had no confirmed diagnosis. ADAMTS13 levels were significantly lower in TTP than STEC-HUS, aHUS and other TMAs. TTP patients had significantly lower platelet count (15 × 10(9) /l; range 0-96) than aHUS (57 × 10(9) /l; range 13-145, P0·0001) or STEC-HUS (35 × 10(9) /l; range 14-106, P0·0001); they also had lower creatinine levels (92 μmol/l; range 43-374) than aHUS (255 μmol/l; range 23-941, P0·0001) and STEC-HUS (324 μmol/l; range 117-639, P0·0001). However, 12/34 (35·3%) aHUS patients had a platelet count30 × 10(9) /l and 26/150 (17·3%) of TTP patients had a platelet count30 × 10(9) /l; 23/150 (15·3%) of TTP patients had a creatinine level150 μmol/l. This study highlights the wide variety of TMA presentations, and confirms the utility of ADAMTS13 testing in TTP diagnosis.
- Published
- 2015
24. Impact of severe ADAMTS13 deficiency on clinical presentation and outcomes in patients with thrombotic microangiopathies: the experience of the Harvard TMA Research Collaborative
- Author
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Richard M. Kaufman, Christopher P. Stowell, Ang Li, Ayad Hamdan, Robert S. Makar, Pavan K. Bendapudi, Lynne Uhl, and Walter H. Dzik
- Subjects
Adult ,Male ,medicine.medical_specialty ,Thrombotic microangiopathy ,ADAMTS13 Protein ,macromolecular substances ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Thrombotic Microangiopathies ,Aged ,Disseminated intravascular coagulation ,Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,Hematology ,Length of Stay ,Middle Aged ,medicine.disease ,ADAMTS13 ,Surgery ,Transplantation ,ADAM Proteins ,Autoimmune thrombotic thrombocytopenic purpura ,Treatment Outcome ,Cohort ,Female ,Presentation (obstetrics) ,business - Abstract
The Harvard TMA Research Collaborative is a multi-institutional registry-based effort to study thrombotic microangiopathies (TMA). Laboratory and clinical parameters were recorded for 254 cases of suspected autoimmune thrombotic thrombocytopenic purpura (TTP). Patients with severe ADAMTS13 deficiency (activity ≤10%, N = 68) were more likely to be young, female and without a history of cancer treatment or transplantation. While all patients with severe deficiency were diagnosed with autoimmune TTP, those without severe deficiency frequently had disseminated intravascular coagulation, drug-associated TMA and transplant-related TMA. Patients with severe ADAMTS13 deficiency had superior overall survival at 360 d compared to those without severe deficiency (93·0% vs. 47·5%, P 0·0001). Almost all patients with severe deficiency received therapeutic plasma exchange (TPE), but the use of TPE in patients with ADAMTS13 activity10% varied significantly across the institutions in our consortium (13·2-63·8%, P 0·0001). Nevertheless, 90-d mortality was not different in patients with ADAMTS13 activity10% between the three hospitals (P = 0·98). Our data show that patients with severe ADAMTS13 deficiency represent a clinically distinct cohort that responds well to TPE. In contrast, TMA without severe ADAMTS13 deficiency is associated with increased mortality that may not be influenced by TPE.
- Published
- 2015
25. The p.R1819_C1948delinsS mutation makes von Willebrand factor ADAMTS13-resistant and reduces its collagen-binding capacity
- Author
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Margherita Morpurgo, Alessandra Casonato, Giovanni Barbon, Maria Grazia Cattini, Giorgia Saga, Elena Pontara, Giuseppe Zanotti, and Viviana Daidone
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,ADAMTS13 Protein ,VWF resistance to ADAMTS13 proteolysis ,Hemorrhage ,Plasma protein binding ,VWF gene mutation ,INDEL Mutation ,Von Willebrand factor ,hemic and lymphatic diseases ,von Willebrand Factor ,Von Willebrand disease ,medicine ,Disintegrin ,Humans ,Platelet ,Thrombospondin ,Metalloproteinase ,biology ,Chemistry ,Medicine (all) ,Hematology ,medicine.disease ,ADAMTS13 ,Molecular biology ,ADAM Proteins ,Immunology ,biology.protein ,VWF-ADAMTS13 binding ,Female ,Collagen ,Protein Binding ,circulatory and respiratory physiology - Abstract
Summary This report concerns abnormal ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) and collagen interactions coinciding with the p.R1819_C1948delinsS von Willebrand factor (VWF) mutation associated with the deletion of the C-terminus of the A3 domain (amino acids 1819–1947) in a patient with a history of bleeding. The von Willebrand disease (VWD) phenotype of the patient featured low plasma and platelet VWF, multimers with smears extending over the highest normal oligomers in plasma, but not platelets, and an impaired collagen-binding capacity. In vitro full-length p.R1819_C1948delinsS VWF expression showed impaired VWF release, increased cellular content with normally-multimerized VWF and impaired collagen binding. The recombinant p.R1819_C1948delinsS VWF fragment, extending from domains A2 to B3 (p.R1819_C1948delinsS A2-B3 VWF), was completely resistant to proteolysis by ADAMTS13 in the presence of 1·5 mol/l urea, unlike its normal counterpart. The defect stems from impaired ADAMTS13 binding to p.R1819_C1948delinsS A2-B3, analysed under static conditions. Partial deletion of the C-terminus of the A3 domain thus makes VWF resistant to ADAMTS13, interfering with ADAMTS13 binding to VWF, and impairing the collagen-binding capacity of VWF. The p.R1819_C1948delinsS mutation has both haemorrhagic features (defective collagen binding, reduced VWF levels) and prothrombotic (ADAMTS13 resistance) features, and the latter probably mitigate the patient's bleeding symptoms.
- Published
- 2015
26. Long-term cognitive impairments following recovery in the patients with immune-mediated thrombotic thrombocytopenic purpura.
- Author
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Sakai K
- Subjects
- ADAMTS13 Protein, Humans, Magnetic Resonance Imaging, Cognitive Dysfunction etiology, Purpura, Thrombotic Thrombocytopenic
- Published
- 2020
- Full Text
- View/download PDF
27. Assessing the risk of refractory disease in iTTP.
- Author
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Makar RS and Bendapudi PK
- Subjects
- ADAMTS13 Protein, Humans, Rituximab, Purpura, Thrombotic Thrombocytopenic
- Published
- 2020
- Full Text
- View/download PDF
28. Bortezomib in the treatment of refractory thrombotic thrombocytopenic purpura
- Author
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Siobhan McGuckin, Piers Blombery, Tina Dutt, Christopher J. Patriquin, Mari Thomas, John P. Westwood, Tanya Cranfield, and Marie Scully
- Subjects
Adult ,Male ,medicine.medical_specialty ,Thrombotic thrombocytopenic purpura ,Salvage therapy ,ADAMTS13 Protein ,030204 cardiovascular system & hematology ,Gastroenterology ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Aged ,Salvage Therapy ,Acquired Thrombotic Thrombocytopenic Purpura ,Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,Remission Induction ,Hematology ,Middle Aged ,medicine.disease ,ADAMTS13 ,Surgery ,Treatment Outcome ,Methylprednisolone ,030220 oncology & carcinogenesis ,Proteasome inhibitor ,Rituximab ,Female ,business ,medicine.drug - Abstract
Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening condition caused by autoantibody-mediated inhibition of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type-1 motif, 13). Therapeutic plasma exchange (TPE) improves survival, but disease may be refractory despite therapy. Management and treatment response of refractory TTP is variable, with rituximab and other immunosuppression often being used. Case reports have suggested a benefit of the proteasome inhibitor, bortezomib, possibly due to elimination of the autoreactive plasma cells producing anti-ADAMTS13 antibodies. We evaluated the effect of bortezomib in a series of primary refractory TTP patients unresponsive to intensive therapy. Bortezomib-treated patients were identified from consecutive cases managed at two UK referral centres. Demographic and clinical data were extracted from hospital records. ADAMTS13 activity was measured using a fluorescence resonance energy transfer VWF73 assay, and anti-ADAMTS13 IgG using enzyme-linked immunosorbent asssay. We identified six bortezomib-treated patients out of 51 consecutive cases of acute, acquired TTP. All patients received TPE, methylprednisolone and rituximab. Five of the six achieved complete remission with bortezomib, and one died of cardiac arrest due to underlying disease. No treatment-related adverse events were observed. Mean follow-up time after hospital discharge was 17 months (range: 3-33). Bortezomib appears effective in the treatment of a subgroup of cases with severe, refractory TTP. Prospective trials are required to further investigate this effect.
- Published
- 2015
29. Pregnancy-induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw-Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients
- Author
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Masamichi Hara, Hideo Wada, Toshiyuki Miyata, Kazuhiko Natori, Yutaka Imamura, Masako Seike, Teruhiko Kozuka, Nobu Akiyama, James N. George, Satoshi Higasa, Mitsuru Murata, Yasunobu Kuranishi, Kenji Soejima, Masanori Matsumoto, Junji Tomiyama, Yoshihiro Fujimura, Koichi Kokame, Ayami Isonishi, Yasuo Ikeda, and Nobumasa Inoue
- Subjects
Adult ,Male ,Risk ,Heterozygote ,medicine.medical_specialty ,Genotype ,Pregnancy Trimester, Third ,Blotting, Western ,DNA Mutational Analysis ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Congenital Thrombotic Thrombocytopenic Purpura ,Pregnancy ,hemic and lymphatic diseases ,Coagulopathy ,medicine ,Humans ,Genetic Predisposition to Disease ,Upshaw–Schulman syndrome ,Fetal Death ,Twin Pregnancy ,Purpura, Thrombotic Thrombocytopenic ,Obstetrics ,business.industry ,Pregnancy Complications, Hematologic ,Infant, Newborn ,Hematology ,medicine.disease ,ADAMTS13 ,Pedigree ,Surgery ,ADAM Proteins ,Pregnancy Trimester, Second ,Mutation ,Gestation ,Female ,business - Abstract
SummaryUpshaw–Schulman syndrome (USS) is a congenital thromboticthrombocytopenic purpura (TTP) due to mutations in the gene thatencodes for ADAMTS13 (ADAMTS13), but its clinical signs may be mild orabsent during childhood. We have identified 37 patients with USS (24females, 13 males) belonging to 32 families. The nine women from sixfamilies who were diagnosed during their first pregnancy are the focus of thisreport. Six of the nine women had episodes of thrombocytopenia duringchildhood misdiagnosed as idiopathic thrombocytopenic purpura.Thrombocytopenia occurred during the second–third trimesters in each oftheir 15 pregnancies, with 16 babies (one twin pregnancy), often followed byTTP. Of 15 pregnancies, eight babies were stillborn or died soon after birth,and the remaining seven were all premature except one, who was bornnaturally following plasma infusions to the mother that had started at8 weeks’ gestation. All nine USS women had severely deficient ADAMTS13activity. ADAMTS13 analyses demonstrated that eight women werecompound heterozygotes of Y304C/G525D (2 siblings), R125VfsX6/Q1302X (2 siblings), R193W/R349C (2 siblings), I178T/Q929X, andR193W/A606P; one woman was homozygous for R193W. Only the R193Wmutation has been previously reported. These observations emphasize theimportance of measuring ADAMTS13 activity in the evaluation ofthrombocytopenia during childhood and pregnancy.Keywords: Upshaw–Schulman syndrome, pregnancy, ADAMTS13 mutation,thrombocytopenia, haemolytic anaemia.
- Published
- 2009
30. Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis: a report of seven cases from a regional UK TTP registry
- Author
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Marie Scully, Michael Laffan, Vickie McDonald, David H. Bevan, Samuel J. Machin, and Sylvia Benjamin
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Gastroenterology ,Young Adult ,Von Willebrand factor ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,heterocyclic compounds ,Aged ,Autoantibodies ,Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,biology ,business.industry ,Autoantibody ,Immunosuppression ,Hematology ,respiratory system ,medicine.disease ,ADAMTS13 ,Surgery ,ADAM Proteins ,Purpura ,Treatment Outcome ,Pancreatitis ,Immunoglobulin G ,Acute Disease ,biology.protein ,Acute pancreatitis ,Female ,medicine.symptom ,business ,Follow-Up Studies - Abstract
Thrombotic thrombocytopenic purpura (TTP) may be idiopathic or secondary. We report seven TTP cases precipitated by pancreatitis. The patients were admitted with acute pancreatitis and at that time had no clinical or laboratory features of TTP. The median time to develop TTP after pancreatitis was 3 d. The patients had moderately reduced ADAMTS13 activity (mean activity 49%; normal range 66-126%) with no evidence of anti-ADAMTS13 inhibitory autoantibodies. The median number of plasma exchanges to remission was 10 (range 7-14) and no additional treatment with immunosuppression was required to maintain remission. There have been no relapses to date.
- Published
- 2009
31. Relationship between ADAMTS13 activity in clinical remission and the risk of TTP relapse
- Author
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Yu J. Li, Haifeng M. Wu, T. Charles Casper, Spero R. Cataland, Shili Lin, Ming Jin, and Melanie S. Kennedy
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Coagulopathy ,Humans ,Prospective Studies ,Prospective cohort study ,Aged ,Autoantibodies ,Hematology ,Purpura, Thrombotic Thrombocytopenic ,Vascular disease ,business.industry ,Age Factors ,Autoantibody ,Middle Aged ,medicine.disease ,ADAMTS13 ,ADAM Proteins ,Immunoglobulin G ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Immunology ,Female ,Caplacizumab ,business ,Biomarkers ,Follow-Up Studies - Abstract
Idiopathic thrombotic thrombocytopenic purpura (TTP) is characterized by frequent recurrences. Effective screening for relapses will enable intervention prior to overt episodes of TTP. The present study used a modified assay to detect ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, 13) activity as low as 0.5%. This analytical improvement permits adequate measurement of ADAMTS13 activity levels in 97% of remission samples used for statistical modelling. ADAMTS13 activity and ADAMTS13 antibody (IgG) were measured in 157 serial samples prospectively collected from 24 TTP patients during periods of clinical remission. These patients were followed-up quarterly for an average of 23 months, during which time nine episodes of TTP relapse occurred among six patients. Finally, logistic regression modelling was used to define the relationship between ADAMTS13 activity levels (0.5-100%) and the probability of TTP relapses. Our data demonstrated that lower ADAMTS13 activity and younger age were significantly associated with higher risk of relapse in the 3 months after specimens were taken. In contrast, ADAMTS13 antibody IgG levels were not predictive of TTP relapses. Identification of low ADAMTS13 activity during clinical remission as a key risk factor for TTP relapses provides a new screening strategy to identify patients who may benefit from prophylactic therapy prior to disease relapses.
- Published
- 2008
32. The clinical utility of ADAMTS13 activity, antigen and autoantibody assays in thrombotic thrombocytopenic purpura
- Author
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G Purdy, Richard D. Starke, Marie Scully, Ian J. Mackie, and Samuel J. Machin
- Subjects
Male ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Enzyme-Linked Immunosorbent Assay ,Immunoglobulin G ,Von Willebrand factor ,Antigen ,Pregnancy ,hemic and lymphatic diseases ,von Willebrand Factor ,Humans ,Medicine ,Platelet ,Autoantibodies ,Purpura, Thrombotic Thrombocytopenic ,biology ,business.industry ,Pregnancy Complications, Hematologic ,Autoantibody ,Hematology ,medicine.disease ,ADAMTS13 ,ADAM Proteins ,Immunology ,biology.protein ,Female ,Antibody ,Epidemiologic Methods ,business ,Biomarkers - Abstract
Thrombotic thrombocytopenic purpura (TTP) has been linked to a severe deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) activity. Since the identification of ADAMTS13, and its target cleavage sequence in von Willebrand factor (VWF), several novel ADAMTS13 activity, antigen and autoantibody assays have been developed. Our aim was to evaluate the potential use of these novel assays. ADAMTS13 activity and inhibitors were measured by overnight incubation of patient plasma with pure VWF followed by multimer or collagen binding analysis. ADAMTS13 activity (Rapid peptide assay), antigen and immunoglobulin G anti-ADAMTS13 were measured by enzyme-linked immunosorbent assay. 118 samples from seven TTP patients (six adult idiopathic, one congenital) were studied longitudinally during episodes of TTP, their treatment and prophylaxis. ADAMTS13 antigen levels varied considerably between patients and sample times, but in new cases of acute TTP, rapid assays of ADAMTS13 antigen, on serial samples, maybe helpful in confirming the diagnosis. The rapid peptide ADAMTS13 activity assay showed good concordance of results with the older activity assay methods. The change in ADAMTS13 activity mirrored the autoantibody level and in 5/6 acquired TTP cases, a fall in antibody appeared to predict a rise in ADAMTS13 activity, potentially allowing modification of patient management based on autoantibody levels.
- Published
- 2007
33. An evaluation of ciclosporin and corticosteroids individually as adjuncts to plasma exchange in the treatment of thrombotic thrombocytopenic purpura
- Author
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Eric H. Kraut, Amy K. Ferketich, Haifeng M. Wu, James N. George, Spero R. Cataland, Melanie S. Kennedy, and Ming Jin
- Subjects
Adult ,Male ,medicine.medical_specialty ,Exacerbation ,medicine.drug_class ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Gastroenterology ,Adrenal Cortex Hormones ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Coagulopathy ,Humans ,Prospective Studies ,Autoantibodies ,Hematology ,Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,Vascular disease ,Remission Induction ,Middle Aged ,Ciclosporin ,medicine.disease ,ADAMTS13 ,Surgery ,ADAM Proteins ,Chemotherapy, Adjuvant ,Immunoglobulin G ,Cyclosporine ,Corticosteroid ,Female ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Summary We present the results of two consecutively performed cohort studies that evaluated the clinical effects of corticosteroids or ciclosporin as an adjunct to plasma exchange (PE) for the treatment of an acute episode of thrombotic thrombocytopenic purpura (TTP). In comparing 12 corticosteroid-treated patients with eight ciclosporin-treated patients, none of the ciclosporin-treated patients suffered an exacerbation or recurrence of TTP in the first 30 d after discontinuing PE compared with 6/10 (60%) of the corticosteroid-treated patients (P = 0·042). These data suggest that ciclosporin may have advantages over corticosteroids as an adjunct to PE therapy in the initial treatment of idiopathic TTP.
- Published
- 2007
34. Prospective study on the behaviour of the metalloprotease ADAMTS13 and of von Willebrand factor after bone marrow transplantation
- Author
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Simona Maria Siboni, D. Lambertenghi Deliliers, Flora Peyvandi, P. Mannuccio Mannucci, G. Lambertenghi Deliliers, B. Moroni, N. De Fazio, and Silvia Lavoretano
- Subjects
Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Graft vs Host Disease ,Gastroenterology ,Von Willebrand factor ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,von Willebrand Factor ,Humans ,Medicine ,Platelet ,Prospective Studies ,Prospective cohort study ,Aged ,Bone Marrow Transplantation ,Hematology ,Purpura, Thrombotic Thrombocytopenic ,biology ,business.industry ,Vascular disease ,Middle Aged ,medicine.disease ,ADAMTS13 ,ADAM Proteins ,medicine.anatomical_structure ,Hematologic Neoplasms ,Immunology ,biology.protein ,Female ,Bone marrow ,business - Abstract
Summary Thrombotic microangiopathies (TMAs) are rare but serious complications of bone marrow transplantation (BMT). Clinical manifestations are similar to those of thrombotic thrombocytopenic purpura (TTP), but prognosis is generally poorer despite plasma exchange. The enzymatic activity of the plasma metalloprotease ADAMTS13, which cleaves ultralarge thrombogenic multimers of von Willebrand factor (VWF) derived from activated endothelial cells, is very low or undetectable in patients with classic TTP, and protease deficiency is thought to play a mechanistic role in the formation of platelet thrombi in the microcirculation. This is the first prospective study to evaluate the incidence of TMA in 46 consecutively recruited patients undergoing autologous or allogeneic BMT and explore in parallel the behaviour of ADAMTS13, VWF antigen and VWF multimer size. The incidence of post-BMT TMA was 6% (three of 46); all cases occurred after allogeneic BMT. Compared with baseline values plasma ADAMTS13 activity was significantly reduced in patients undergoing BMT, particularly after the conditioning regimen (mean values: 50 ± 22 vs. 77 ± 32%; P
- Published
- 2006
35. Homozygous C2362F von Willebrand factor induces intracellular retention of mutant von Willebrand factor resulting in autosomal recessive severe von Willebrand disease
- Author
-
Giancarlo Castaman, Jeroen Eikenboom, Rogier M. Bertina, H. L. Vos, and P. Tjernberg
- Subjects
Heterozygote ,congenital, hereditary, and neonatal diseases and abnormalities ,Vasopressin ,medicine.medical_specialty ,Mutant ,Mutation, Missense ,ADAMTS13 Protein ,Genes, Recessive ,medicine.disease_cause ,Hemostatics ,Von Willebrand factor ,hemic and lymphatic diseases ,Internal medicine ,von Willebrand Factor ,medicine ,Von Willebrand disease ,Coagulopathy ,Humans ,Missense mutation ,Deamino Arginine Vasopressin ,Mutation ,Factor VIII ,biology ,Chemistry ,Homozygote ,Hematology ,medicine.disease ,ADAMTS13 ,ADAM Proteins ,von Willebrand Diseases ,Endocrinology ,cardiovascular system ,biology.protein ,Half-Life ,circulatory and respiratory physiology - Abstract
Summary The missense mutation of cysteine 2362 to a phenylalanine in von Willebrand factor (VWF) has been detected in several Italian families with autosomal recessive, severe von Willebrand disease. We investigated how this amino acid change in VWF may lead to a predominantly quantitative defect. This mutation was studied in vitro by transient expression of the full-length mutant VWF-C2362F protein and in vivo by analysis of plasma VWF after infusion of 1-deamino-8-d-arginine vasopressin (DDAVP) in a patient homozygous for this mutation. Single transfections of pSVHVWF-C2362F and cotransfections of mutant and wild-type constructs resulted in 8% and 50% VWF antigen, respectively, in conditioned medium. These reduced levels are in accordance with observations in homozygous and heterozygous carriers of the mutation. In addition, VWF-C2362F was retained intracellularly. Similar results were obtained for C2362F and C2362A. After infusion of DDAVP in a homozygous patient, a twofold decrease in half-life of plasma VWF-C2362F was observed. This was not explained by increased susceptibility of recombinant VWF-C2362F to ADAMTS13. It was concluded that VWF-C2362F causes reduced VWF plasma levels due to impaired secretion and intracellular retention. Furthermore, it is the loss of cysteine 2362 rather than the introduction of the bulky amino acid side chain that causes these effects.
- Published
- 2006
36. The prevalence of the cysteine1584 variant of von Willebrand factor is increased in type 1 von Willebrand disease: co-segregation with increased susceptibility to ADAMTS13 proteolysis but not clinical phenotype
- Author
-
R. Campbell Tait, Will Lester, Jonathon T. Wilde, Derrick John Bowen, Frank Hill, Kate Khair, A. M. Cumming, K. John Pasi, Peter William Collins, Pamela Grundy, Paula H. B. Bolton-Maggs, Steven Keeney, David Keeling, and Saad M. Enayat
- Subjects
Male ,Heterozygote ,congenital, hereditary, and neonatal diseases and abnormalities ,ADAMTS13 Protein ,Enzyme-Linked Immunosorbent Assay ,Haemophilia ,ABO Blood-Group System ,Cohort Studies ,Von Willebrand factor ,Polymorphism (computer science) ,hemic and lymphatic diseases ,ABO blood group system ,medicine ,Von Willebrand disease ,Coagulopathy ,Humans ,Genetic Predisposition to Disease ,Cysteine ,Polymorphism, Genetic ,biology ,business.industry ,ADAMTS ,Metalloendopeptidases ,Hematology ,medicine.disease ,ADAMTS13 ,Pedigree ,ADAM Proteins ,von Willebrand Diseases ,Phenotype ,Immunology ,biology.protein ,Female ,business - Abstract
The molecular pathogenesis of type 1 von Willebrand disease (VWD) is uncertain in most patients. We examined 30 type 1 VWD families in the UK Haemophilia Centre Doctors' Organization study. Heterozygosity for Y/C1584 was present in eight of 30 (27%) families and 19 of 76 (25%) individuals with type 1 VWD recruited into the study. Eighteen (95%) of these 19 individuals were blood group O. C1584 did not co-segregate with VWD in four families, and co-segregated in one family; the results were equivocal in three families. In all families increased susceptibility of von Willebrand factor (VWF) to a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) 13 proteolysis co-segregated with C1584 in affected and unaffected individuals. These data show that C1584, associated with blood group O, is prevalent among patients with type 1 VWD but not necessarily causative of disease and should not be used in isolation to diagnose VWD. Increased susceptibility of C1584 VWF to ADAMTS13 proteolysis may be physiologically significant and increase an individual's risk of bleeding and presenting with VWD.
- Published
- 2005
37. Ticlopidine-associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (SONAR)
- Author
-
Constance Danielson, X. Long Zheng, Masanori Matsumoto, Thomas L. Ortel, Sony Jacob, Ravindra Sarode, Richard J. Ablin, Gail Rock, Hau C. Kwaan, June M. McKoy, Peter Georgantopoulos, Nicholas Bandarenko, William F. Clark, Joseph E. Kiss, Patricia M. Carey, Thomas J. Raife, Jeffrey L. Winters, Jametta Magwood, Zaina P. Qureshi, Brianne L. Dunn, Yoshihiro Fujimura, and Charles L. Bennett
- Subjects
medicine.medical_specialty ,Ticlopidine ,Thienopyridine ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Gastroenterology ,Article ,Japan ,Von Willebrand factor ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Disseminated intravascular coagulation ,Purpura, Thrombotic Thrombocytopenic ,biology ,business.industry ,Hematology ,Microangiopathic hemolytic anemia ,medicine.disease ,ADAMTS13 ,Schistocyte ,Enzyme Activation ,ADAM Proteins ,Immunology ,biology.protein ,business ,medicine.drug - Abstract
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder. The classic TTP ‘pentad’ is thrombocytopenia, microangiopathic hemolytic anemia (MAHA), renal impairment, neurological symptoms, and fever (Amorosi & Ultmann, 1966). Laboratory studies identified deficiency of plasma ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13) activity (ADAMTS13:AC) among some TTP patients (Furlan et al, 1998; Tsai & Lian, 1998). ADAMTS13 cleaves the peptide bond between Thy1605 and Met1606 in the A2 domain of von Willebrand factor (VWF) subunit. VWF is released into the plasma as unusually large VWF multimers (UL-VWFMs), which are degraded into smaller size VWF multimers by ADAMTS13. In the late 1990's, studies in the United States identified 117 cases of TTP that developed after initiation of the thienopyridine, ticlopidine; although at that time, ADAMTS13 activity levels were not widely available (Bennett et al, 1999; Steinhubl et al, 1999). A study of seven patients in the United States with ticlopidine-associated TTP found that all seven had severe deficiency of ADAMTS13 activity and five had detectable antibodies to ADAMTS13 activity (Tsai et al, 2000). We now report on 22 individuals from Japan with ticlopidine-induced TTP and compare these findings to those from the United States. Ticlopidine was the primary anti-platelet agent in Japan from 1989 to 2006. Since 1998, our laboratory at Nara Medical University has been a nationwide referral centre in Japan for thrombotic microangiopathies (TMAs), including TTP (Fujimura & Matsumoto, 2010). The study protocol was approved by the Ethics Committee of Nara Medical University Hospital. TTP diagnostic criteria were: microangiopathic haemolytic anaemia (haemoglobin ≤ 120 g/l), Coombs test negative, undetectable serum haptoglobin (
- Published
- 2013
38. The use of ADAMTS13 activity, platelet count, and serum creatinine to differentiate acquired thrombotic thrombocytopenic purpura from other thrombotic microangiopathies
- Author
-
Spero R. Cataland, Shangbin Yang, and Haifeng M. Wu
- Subjects
Adult ,Male ,medicine.medical_specialty ,ADAMTS13 Protein ,Adamts13 activity ,Gastroenterology ,Diagnosis, Differential ,chemistry.chemical_compound ,Internal medicine ,Humans ,Medicine ,Thrombotic Microangiopathies ,Platelet ,Creatinine ,Acquired Thrombotic Thrombocytopenic Purpura ,Purpura, Thrombotic Thrombocytopenic ,Platelet Count ,business.industry ,Hematology ,ADAMTS13 ,ADAM Proteins ,chemistry ,Female ,business - Published
- 2012
39. ADAMTS13 deficiency in severe postpartum HELLP syndrome
- Author
-
Fabrice Pierre, Olivier Pourrat, and Rémi Coudroy
- Subjects
medicine.medical_specialty ,HELLP Syndrome ,Thrombotic microangiopathy ,HELLP syndrome ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Gastroenterology ,Diagnosis, Differential ,Pregnancy ,Internal medicine ,Medicine ,Humans ,Aspartate Aminotransferases ,Hematuria ,L-Lactate Dehydrogenase ,Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,Platelet Count ,Hematology ,Puerperal Disorders ,medicine.disease ,ADAMTS13 ,Schistocyte ,ADAM Proteins ,Creatinine ,Female ,business ,Biomarkers - Published
- 2013
40. Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP)
- Author
-
Cynthia J. Rutherford, Yu-min P Shen, Ravi Sarode, Neil P. Shah, and Karen Matevosyan
- Subjects
Adult ,Male ,medicine.medical_specialty ,Thrombotic microangiopathy ,Adolescent ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Adamts13 activity ,Diagnosis, Differential ,Antibodies, Monoclonal, Murine-Derived ,Young Adult ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Thrombotic Microangiopathies ,Humans ,Platelet ,In patient ,Child ,Aged ,Retrospective Studies ,Aged, 80 and over ,Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,Disease Management ,Metalloendopeptidases ,Hematology ,Middle Aged ,Haemolysis ,medicine.disease ,ADAMTS13 ,Surgery ,ADAM Proteins ,Female ,business ,Rituximab - Abstract
The clinical presentation of thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies (TMAs) can often be similar. The role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in diagnosing TTP is accepted by most researchers but continues to be debated in a few studies. We report the experience of our single-centre academic institution, where ADAMTS13 is used to diagnose TTP and guide plasma exchange (PLEX). Patients presenting to our institution with thrombotic microangiopathy (60 patients) between January 2006 and December 2012 were divided into two groups based on ADAMTS13 activity and clinical history. Patients with ADAMTS13 activity10% were included in the TTP (n = 30) cohort while patients with activity11% were classified as 'other microangiopathies' (TMA, n = 30). PLEX was only initiated in patients with a high likelihood of TTP and discontinued when the baseline ADAMTS13 activity was11%. Patients with severe ADAMTS13 deficiency (TTP group) showed significant presenting differences: lower platelet counts, less renal dysfunction, higher presence of neurological abnormalities, and greater haemolysis markers as compared to non-deficient patients (TMA group). Most importantly, patients without severe ADAMTS13 deficiency were safely managed without increased mortality despite receiving no PLEX or discontinuing PLEX after a short course (upon availability of ADAMTS13 results). In conclusion, ADAMTS13 can be used to diagnose TTP and guide appropriate PLEX therapy.
- Published
- 2013
41. Complement activation in thrombotic microangiopathies
- Author
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Leticia Nolasco, Michael H. Kroll, Joel L. Moake, Shuju Feng, and Vahid Afshar-Kharghan
- Subjects
Male ,medicine.medical_specialty ,Thrombotic microangiopathy ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Gastroenterology ,Article ,Von Willebrand factor ,hemic and lymphatic diseases ,Internal medicine ,Atypical hemolytic uremic syndrome ,medicine ,Humans ,Platelet activation ,Complement Activation ,biology ,business.industry ,Thrombotic Microangiopathies ,Hematology ,Complement System Proteins ,medicine.disease ,Hemolysis ,Complement system ,ADAM Proteins ,Immunology ,Alternative complement pathway ,biology.protein ,Female ,business - Abstract
The thrombotic microangiopathies (TMA) are a group of disorders defined by the presence of microangiopathic hemolytic anemia and thrombocytopenia. The most common of these is thrombotic thrombocytopenic purpura (TTP), which is a systemic disorder of microvascular thromboses due to deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). A less common TMA is the atypical hemolytic uremic syndrome (aHUS), which is a renal vascular TMA caused by complement dysregulation. Despite overlapping clinical and pathologic manifestations, TTP and aHUS have distinct etiologies. TTP is often caused by a deficiency of ADAMTS-13 that is the result of gene mutations or acquired autoantibodies (Tsai, 2006). Atypical HUS is caused by defects of regulation and/or excessive activation of the alternative complement pathway (Kavanagh & Goodship, 2010). The mechanism by which complement dysregulation contributes to aHUS is not precisely defined, although complement-mediated glomerular endothelial injury and enhanced complement-mediated platelet activation are probably involved (Stahl et al, 2008). Similarly, triggers and co-factors directing systemic platelet deposition in TTP are not completely understood. Evidence that complement activation might play a role in TTP (Noris et al, 1999; Ruiz-Torres et al, 2005; Reti et al, 2012) raises the possibility of a cross-talk between ADAMTS-13/ultra-large von Willebrand factor (ULVWF) and the complement system. We studied plasma samples of 81 patients diagnosed with TMA according to clinical criteria for functional abnormalities in both ADAMTS-13 and complement regulation. Citrated platelet-poor plasma samples were obtained for testing before the initial plasma infusion or exchange procedures. All patients had microangiopathic hemolytic anemia and thrombocytopenia without an alternative cause, and treated with either plasma infusion or plasma exchanges. None of our patients had acute renal failure. Samples for analysis of DNA were not obtained/stored from this group of patients. All human subject studies were conducted according to the approved institutional review board protocols in the Rice University and University of Texas M.D. Anderson Cancer Center. ADAMTS-13 activity was measured by: (1) the rate of cleavage of a substrate that contains 73 amino acids of the A2 domain of VWF with fluorescence resonance energy transfer (FRET) tags on either side of the cleavage site for ADAMTS-13 (FRETS-VWF73), according to the manufacturer’s protocol (GTi Diagnostics); and (2) cleavage of urea-treated ULVWF multimers (obtained from human umbilical vein endothelial cell supernatant) by citrated patient plasma, followed by VWF multimeric analysis using SDS-1% agarose electrophoresis and Western-blotting with anti-VWF antibody. This is a modification of the method described by Furlan, et al. (Furlan et al, 1998). The presence or absence of ADAMTS-13 inhibitors was determined by measuring cleavage of urea-treated ULVWF multimers before and after mixing normal citrated plasma with an equal volume of patient citrated plasma (Furlan et al, 1998). Complement activity was measured by the hemolysis of sheep erythrocytes after incubation with human serum or plasma according to modified techniques from Sanchez-Corral, et al. (Sanchez-Corral et al, 2004). Factor H-depleted plasma causes complement-induced lysis of sheep erythrocytes with the visually apparent release of hemoglobin. Pooled normal plasma or serum caused 7% and 8% hemolysis of sheep erythrocytes, respectively. Optimal dilution of plasma or serum for the assay was determined to be between 4/100 to 6/100, and optimal incubation time was 10 min. Sixty percent (49/81) of TMA patients had severe ADAMTS-13 deficiency (less than 10% activity). Eighty percent (65/81) of our patients’ plasma samples caused little to no hemolysis of sheep erythrocytes (median of 10%; range of 0–15%). In contrast, 20% (16/81) of the patients’ samples showed significant hemolysis (median of 60% hemolysis; range of 23–89%) (Figure 1). Sixteen percent (8/49) of plasma samples from TTP patients with severe ADAMTS-13 deficiency caused increased hemolysis. Only one of the 8 patients with concurrent excessive complement-induced hemolysis and severe ADAMTS-13 deficiency had detectable antibody (in low titer) against ADAMTS-13 (Table 1). Twenty-five percent (8/32) of plasma samples from patients who did not have severe ADAMTS-13 deficiency also caused increased hemolysis. Figure 1 Sheep erythrocyte hemolysis assay in plasma samples from patients with thrombotic microangiopathy Table 1 Patients with a clinical diagnosis of TTP and decreased complement regulation. Severe deficiency of functional ADAMTS-13 is associated with TTP; however, many patients with a TTP-like syndrome have normal ADAMTS-13 levels, as did 40% (32/81) of the patients in our study. There are several reports of patients with reduced ADAMTS-13 function who either did not develop TTP, or did so later in life (Noris et al, 2005). These observations raise the possibility of the presence of additional factors besides ADAMTS-13 deficiency involved in the pathophysiology of TTP (Ruiz-Torres et al, 2005; Reti et al, 2012; Noris et al, 2005; Chapin et al, 2012). Activation of the complement system in both familial (Noris et al, 1999) and acquired TTP (Reti et al, 2012) has been reported, based on the lower concentration of C3 and elevated levels of complement activation products (C3a and sC5b-9) in the sera of patients with acute TTP, and deposition of C3 and C5b-9 on endothelial cell exposed to TTP sera (Ruiz-Torres et al, 2005). We studied activity of the alternative complement pathway in 81 patients with the clinical diagnosis of TTP-like TMA requiring plasma infusion and/or plasma exchange. Some patients with severe ADAMTS-13 deficiency (8/49; 16%) or TTP-like TMA (8/32; 25%), had elevated plasma complement activity. We did not detect an increased titer of ADAMTS-13 inhibitor in ADAMTS-13 deficient TTP patients with complement dysregulation, and the majority of these patients (5/8; 68%) had a history of familial or recurrent TTP (Table 1). Our data suggest that the complement system may be an important co-factor involved in the pathogenesis of TMA. Excessive alternative pathway activity occurred in a significant number of TTP patients indicating that concurrent defects in ADAMTS-13 and complement regulation may occur more frequently than previously reported (Noris et al, 2005; Chapin et al, 2012). In addition, our findings indicate that excessive alternative pathway activity can be associated with a TTP-like TMA in some patients who do not have severe deficiencies of ADAMTS-13. Further genetic studies of patients with the clinical diagnosis of TTP may be informative.
- Published
- 2012
42. Multiple in silico tools predict phenotypic manifestations in congenital thrombotic thrombocytopenic purpura
- Author
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Evi Struble, Estelle Russek-Cohen, Andrew Wu, Chava Kimchi-Sarfaty, Tal Schiller, Zachary A. Hing, and Nobuko Hamasaki-Katagiri
- Subjects
Male ,Adolescent ,In silico ,DNA Mutational Analysis ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Congenital Thrombotic Thrombocytopenic Purpura ,Biology ,medicine.disease_cause ,Cohort Studies ,hemic and lymphatic diseases ,medicine ,Humans ,Amino Acid Sequence ,Phosphorylation ,Child ,Codon ,Genetic Association Studies ,Genetics ,Mutation ,Purpura, Thrombotic Thrombocytopenic ,Genetic disorder ,Infant, Newborn ,Infant ,Hematology ,medicine.disease ,Phenotype ,ADAM Proteins ,Codon usage bias ,Child, Preschool ,Female ,Age of onset - Abstract
Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare, recessively inherited genetic disorder with varying clinical presentation that is caused by ADAMTS13 mutations. Several studies have found limited associations between ADAMTS13 mutations and cTTP phenotype. The use of in silico tools that examine multiple mutation characteristics may better predict phenotype. We analysed 118 ADAMTS13 mutations found in 144 cTTP patients reported in the literature and examined associations of several mutation characteristics, including N-terminal proximity, the evolutionary conservation of the affected amino acid position, as well as amino acid charge/phosphorylation and genetic codon usage to disease phenotype. Structure-altering mutations were examined for their impact on ADAMTS13 function based on existing ADAMTS13 crystallographic data (AA 77-685). Our in silico data indicate that: (i) The position of the mutation in the N- or C-terminus, (ii) evolutionary conservation and (iii) codon usage of the affected mutation position are associated with disease parameters, such as age of onset, organ damage and fresh frozen plasma prophylaxis. In conclusion, the usage of multiple in silico tools presents a promising strategy in refining predictions for the diverse presentation of cTTP. Enhancing our utilization of in silico tools to find genotype-phenotype associations will create better-tailored approaches for individual patient treatment.
- Published
- 2012
43. Ten years of prophylactic treatment with fresh-frozen plasma in a child with chronic relapsing thrombotic thrombocytopenic purpura as a result of a congenital deficiency of von Willebrand factor-cleaving protease
- Author
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Marisol Guerra, Maria Sameiro Barreirinho, Elísio Costa, José Barbot, Pratima Isvarlal, Miha Furlan, Helena E. Gerritsen, Rodolfo Robles, and Bernhard Lämmle
- Subjects
Hemolytic anemia ,Fresh-frozen plasma ,Adolescent ,medicine.medical_treatment ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Congenital Thrombotic Thrombocytopenic Purpura ,Plasma ,Infusion therapy ,Von Willebrand factor ,Recurrence ,hemic and lymphatic diseases ,medicine ,Humans ,Chronic haemolytic anemia ,Platelet ,Thrombotic thrombo-cytopenic purpura ,Protease ,Purpura, Thrombotic Thrombocytopenic ,biology ,Platelet Count ,business.industry ,Metalloendopeptidases ,Hematology ,medicine.disease ,Pedigree ,ADAM Proteins ,Chronic Disease ,Immunology ,VWF - cleaving protease ,biology.protein ,Deficiency ,Female ,Fresh frozen plasma ,business ,Follow-Up Studies - Abstract
We report the results of 10 years of prophylactic fresh-frozen plasma (FFP) infusion therapy in a 14-year-old girl with chronic relapsing thrombotic thrombocytopenic purpura (TTP), in whom a severe congenital von Willebrand factor (VWF)-cleaving protease deficiency has been documented. Severe haemolytic crises triggered by infections were prevented and her present renal and neurological functions have been preserved. Sequential measurements of protease activity and platelet count after FFP infusion led us to conclude tentatively that 5% may be sufficient to degrade very large and adhesive VWF multimers.
- Published
- 2001
44. Microangiopathic haemolytic anaemia in metastasizing malignant tumours is not associated with a severe deficiency of the von Willebrand factor-cleaving protease
- Author
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Stefano Fontana, Miha Furlan, Helena E. Gerritsen, Bernhard Lämmle, and J. A. Kremer Hovinga
- Subjects
Male ,Hemolytic anemia ,Anemia, Hemolytic ,medicine.medical_specialty ,Lung Neoplasms ,Immunoblotting ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Bone Neoplasms ,Breast Neoplasms ,Malignancy ,Autoantigens ,Gastroenterology ,Pathogenesis ,Von Willebrand factor ,hemic and lymphatic diseases ,Internal medicine ,von Willebrand Factor ,Humans ,Medicine ,Platelet ,Aged ,biology ,business.industry ,Vascular disease ,Liver Neoplasms ,Microangiopathy ,Metalloendopeptidases ,Prostatic Neoplasms ,Hematology ,Middle Aged ,medicine.disease ,ADAM Proteins ,Immunology ,biology.protein ,Female ,business ,circulatory and respiratory physiology - Abstract
Complete deficiency of von Willebrand factor-cleaving protease (VWF-cp) has recently been identified as a pathogenetically important factor for thrombotic thrombocytopenic purpura (TTP). Microangiopathic haemolytic anaemia (MAHA) with thrombocytopenia in patients with metastasizing neoplasms is clinically similar to TTP, however, the pathogenesis of the condition is unclear. Partial deficiency of VWF-cp in metastasizing malignancy has recently been reported in patients without MAHA. Our study shows normal or subnormal VWF-cp activity in four patients with metastasizing neoplasia-associated MAHA but, in contrast to classical TTP, no complete deficiency of VWF-cp despite the full clinical picture of MAHA.
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- 2001
45. Different clinical severity of first episodes and recurrences of thrombotic thrombocytopenic purpura
- Author
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Luca A, Lotta, Mariagabriella, Mariani, Dario, Consonni, Ilaria, Mancini, Roberta, Palla, Alberto, Maino, Dragica, Vucelic, Michele, Pizzuti, Pier M, Mannucci, and Flora, Peyvandi
- Subjects
Adult ,Male ,ADAM Proteins ,Purpura, Thrombotic Thrombocytopenic ,Platelet Count ,Recurrence ,ADAMTS13 Protein ,Humans ,Female ,Registries ,Middle Aged ,Nervous System Diseases ,Prognosis - Abstract
The clinical course of thrombotic thrombocytopenic purpura (TTP) is characterized by recurrent disease episodes in up to 50% of cases. The clinical presentation and severity of different TTP episodes have not been systematically compared. Laboratory and clinical information from 51 patients with recurrent disease, derived from 136 patients with TTP included in the Milan TTP registry (URL: http://www.ttpdatabase.org), were used to compare mortality, symptoms and disease-related laboratory measurements in different disease episodes. The prevalence of severe neurological symptoms (coma, seizures, and focal neurological defects) was significantly lower in recurrences than in the first episode. Platelet counts and haemoglobin levels at presentation were higher in recurrences than in the first disease episode, and lactate dehydrogenase levels were lower. Also, mortality tended to be lower in the second and third disease episodes than in the first. Recurrences of TTP are generally milder than first episodes. These differences in severity should be taken into account in clinical research on TTP and in patient management.
- Published
- 2010
46. The difficult distinction between antiphospholipid syndrome and thrombotic thrombocytopenic purpura
- Author
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Jecko Thachil
- Subjects
medicine.medical_specialty ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Hematology ,medicine.disease ,Antiphospholipid Syndrome ,Dermatology ,Immune thrombocytopenia ,ADAMTS13 ,Diagnosis, Differential ,ADAM Proteins ,Antiphospholipid syndrome ,Immunology ,medicine ,Coagulopathy ,Humans ,Platelet ,business ,Biomarkers - Published
- 2010
47. ADAMTS13 cleavage efficiency is altered by mutagenic and, to a lesser extent, polymorphic sequence changes in the A1 and A2 domains of von Willebrand factor
- Author
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Lee A. O'Brien, Cynthia M. Pruss, David Lillicrap, Colleen Notley, and Carol Hegadorn
- Subjects
Proteolysis ,ADAMTS13 Protein ,Biology ,Cleavage (embryo) ,Polymorphism, Single Nucleotide ,law.invention ,Von Willebrand factor ,law ,hemic and lymphatic diseases ,von Willebrand Factor ,Von Willebrand disease ,medicine ,Humans ,DNA Cleavage ,Thrombospondin ,Metalloproteinase ,medicine.diagnostic_test ,Hematology ,medicine.disease ,Molecular biology ,Recombinant Proteins ,ADAMTS13 ,Protein Structure, Tertiary ,ADAM Proteins ,Mutagenesis ,Recombinant DNA ,biology.protein - Abstract
Summary The multimeric plasma protein von Willebrand factor (VWF) is regulated in size by its protease, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13). Y1605-M1606 cleavage site mutations and single nucleotide polymorphisms (SNPs) in the VWF A1 and A2 domains were examined for alteration in ADAMTS13-mediated cleavage of VWF. Recombinant human full-length VWF (rVWF) was digested with recombinant human ADAMTS13 (rADAMTS13) using a dialysis membrane method with 1·5 mol/l urea, and analyzed via multimer migration distance. The glutathione-S-transferase (GST) and histidine-tagged construct, E1554-R1668 of VWF (VWF115) was assayed via enzyme-linked immunosorbent assay: VWF115 was bound to anti-GST coated plates, digested with rADAMTS13, and intact VWF115 detected via horseradish peroxidase-labelled anti-histidine tag antibody. All alterations examined in the Y1605-M1606 cleavage site greatly reduced the cleavability of VWF by ADAMTS13 in the rVWF assay. Greatest cleavage resistance in both assays was observed in Y1605A/M1606A. In contrast, Y1605H and M1606L show a loss of cleavability only in the rVWF assay, suggesting that an aromatic ring at 1605 is critical for ADAMTS13 recognition. Additionally, under our rVWF assay conditions, the G1643S polymorphism showed increased cleavage, suggesting a Type 2A VWD phenotype, while D1472H, Q1571H and P1601T showed slightly decreased ADAMTS13 cleavage. Our two complementary assay conditions show that A-domain changes in VWF alter ADAMTS13-mediated proteolysis.
- Published
- 2008
48. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features
- Author
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Beverley J. Hunt, Ri Liesner, Sylvia Benjamin, Samuel J. Machin, Helen Yarranton, Jamie Cavenagh, Marie Scully, Ian J. Mackie, and David H. Bevan
- Subjects
Hemolytic anemia ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Internal medicine ,medicine ,Coagulopathy ,Humans ,Registries ,Child ,Aged ,Aged, 80 and over ,Hematology ,Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,Vascular disease ,business.industry ,ADAMTS ,Infant, Newborn ,Infant ,Metalloendopeptidases ,Middle Aged ,medicine.disease ,Surgery ,ADAM Proteins ,England ,Child, Preschool ,Immunoglobulin G ,Rituximab ,Female ,Caplacizumab ,business ,medicine.drug - Abstract
Thrombotic thrombocytopenic purpura (TTP) is an acute, rare, life-threatening disorder. This report presents the South East (SE) England registry for TTP, from April 2002 to December 2006, which included 176 patients and 236 acute episodes; 75% of patients were female and 25% were male, overall median age at presentation was 42 years. Mortality was 8.5%, most cases died before treatment was instigated. The main ethnic groups were Caucasian (64%) and Afro Caribbean (27%). Seventy-seven percent of cases were idiopathic, 5% were congenital and the remaining cases had a defined precipitant. Neurological features were the most prevalent, but cardiac involvement accounted for 42% of presenting features. The overall median number of plasma exchanges (PEXs) to remission was 15; between April 2002 and December 2003, the median number of PEXs was 19 and it was 12 between January 2004 and December 2006 (P < 0.0001). In the latter period, adjuvant therapies were reduced, but Rituximab was increased. ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was
- Published
- 2008
49. Sporadic bloody diarrhoea-associated thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome: an adult and paediatric comparison
- Author
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Bernhard Lämmle, Xiaoning Li, Sara K. Vesely, Deirdra R. Terrell, Johanna A. Kremer Hovinga, James N. George, and Charity A. Karpac
- Subjects
Hemolytic anemia ,Adult ,Diarrhea ,Male ,Pediatrics ,medicine.medical_specialty ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Escherichia coli O157 ,Recurrence ,hemic and lymphatic diseases ,medicine ,Coagulopathy ,Humans ,Registries ,Child ,Escherichia coli Infections ,Aged ,Aged, 80 and over ,Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,Acute kidney injury ,Age Factors ,Hematology ,Acute Kidney Injury ,Middle Aged ,medicine.disease ,ADAMTS13 ,Surgery ,Bloody ,ADAM Proteins ,Hemolytic-Uremic Syndrome ,Female ,medicine.symptom ,business ,Gastrointestinal Hemorrhage ,Kidney disease ,Follow-Up Studies - Abstract
Although diarrhoea-associated haemolytic uremic syndrome (HUS) in children is well described, the clinical features of bloody diarrhoea-associated thrombotic thrombocytopenic purpura (TTP)-HUS in adults are not documented. Twenty-one adults, 6.5% of the 322 adults in The Oklahoma TTP-HUS Registry, 1989-2006, have presented with bloody diarrhoea. There were no case clusters. Escherichia coli O157:H7 was identified in five patients, but many patients did not have appropriate studies. The annual incidence was 0.68/10(6), 10-fold less than the incidence of diarrhoea-associated HUS in children in Oklahoma. Two (13%) of 16 patients in whom ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) was measured had
- Published
- 2008
50. ADAMTS 13 in non-thrombotic thrombocytopaenic purpura conditions
- Author
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C. Burgess, Samuel J. Machin, AS Lawrie, Marie Scully, and Ri Liesner
- Subjects
Adult ,Male ,medicine.medical_specialty ,MEDLINE ,ADAMTS13 Protein ,law.invention ,law ,Reference Values ,Internal medicine ,von Willebrand Factor ,medicine ,Humans ,Child ,Hematology ,business.industry ,ADAMTS ,Infant, Newborn ,Middle Aged ,Dermatology ,Intensive care unit ,Thrombocytopaenic purpura ,Purpura ,ADAM Proteins ,Purpura, Thrombocytopenic ,Reference values ,Immunology ,Female ,medicine.symptom ,business - Published
- 2008
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