Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 176
Filtrar
1.
Thromb Haemost ; 119(11): 1767-1772, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31587247

RESUMO

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy (TMA) characterized by the severe deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity (< 10%). Rapid ADAMTS13 testing is crucial for an early diagnosis and optimal management of acute TTP. We evaluated the performance of the HemosIL AcuStar ADAMTS13 activity assay (Instrumentation Laboratory, Bedford, Massachusetts, United States), a fully automated chemiluminescent immunoassay with an analytical time of 33 minutes. A method comparison study was performed on 176 samples from 49 healthy donors and 127 TMA patients (109 TTP, 7 atypical hemolytic uremic syndrome, 11 other TMAs), comparing this new assay with an in-house FRETS-VWF73 assay and a commercial enzyme-linked immunosorbent assay (ELISA) (TECHNOZYM ADAMTS-13 Activity, Technoclone GmbH, Vienna, Austria). Agreement between methods was assessed with focus on ADAMTS13 activity less than 10%, the medical decision level relevant for TTP diagnosis. The HemosIL AcuStar ADAMTS13 Activity showed good correlation with both the FRETS-VWF73 (r = 0.96) and ELISA (r = 0.96) methods. Slope of the Passing-Bablok regression was 1.05 for FRETS-VWF73 and 1.02 for ELISA, and absolute bias at the medical decision level was +0.1 and +0.3%, respectively. The study also revealed high agreement with FRETS-VWF73 (kappa 0.97) and ELISA (kappa 0.98) methods in classifying TTP patients with a severe deficiency of ADAMTS13 activity. Because of its short turnaround time and full automation, the HemosIL AcuStar ADAMTS13 activity assay might become the assay of choice to rapidly test ADAMTS13 activity in plasma and thus establish the diagnosis of acute TTP in emergency settings.


Assuntos
Proteína ADAMTS13/sangue , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Imunoensaio/métodos , Púrpura Trombocitopênica Trombótica/diagnóstico , Proteína ADAMTS13/deficiência , Síndrome Hemolítico-Urêmica Atípica/sangue , Síndrome Hemolítico-Urêmica Atípica/enzimologia , Automação Laboratorial , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Humanos , Medições Luminescentes , Valor Preditivo dos Testes , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/enzimologia , Reprodutibilidade dos Testes , Fatores de Tempo , Fluxo de Trabalho
2.
Haematologica ; 104(10): 2107-2115, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30792199

RESUMO

Congenital thrombotic thrombocytopenic purpura is an autosomal recessive inherited disease with a clinically heterogeneous course and an incompletely understood genotype-phenotype correlation. In 2006, the Hereditary TTP Registry started recruitment for a study which aimed to improve the understanding of this ultra-rare disease. The objective of this study is to present characteristics of the cohort until the end of 2017 and to explore the relationship between overt disease onset and ADAMTS13 activity with emphasis on the recurring ADAMTS13 c.4143_4144dupA mutation. Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles. By the end of 2017, 123 confirmed patients had been enrolled from Europe (n=55), Asia (n=52, 90% from Japan), the Americas (n=14), and Africa (n=2). First recognized disease manifestation occurred from around birth up to the age of 70 years. Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246 alleles. We found a larger proportion of compound heterozygous than homozygous carriers of ADAMTS13 c.4143_4144dupA with overt disease onset at < 3 months of age (50% vs 37%), despite the fact that ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous carriers. An evaluation of overt disease onset in all patients with an available sensitive ADAMTS13 activity assay (n=97) shows that residual ADAMTS13 activity is not the only determinant of age at first disease manifestation. Registered at clinicaltrials.gov identifier NCT01257269.


Assuntos
Proteína ADAMTS13 , Alelos , Heterozigoto , Homozigoto , Mutação , Púrpura Trombocitopênica Trombótica , Proteína ADAMTS13/sangue , Proteína ADAMTS13/genética , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/genética
3.
Hematology Am Soc Hematol Educ Program ; 2018(1): 530-538, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504354

RESUMO

Thrombotic thrombocytopenia purpura (TTP) is a rare, life-threatening disease with an incidence of approximately 2 persons per million per year. It is characterized by severe deficiency of the von Willebrand cleaving protease, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), leading to formation of platelet-rich thrombi in the microvasculature. Prompt initiation of appropriate therapy, particularly plasma exchange, may be life-saving. Diagnosis of TTP is challenging because of its diverse clinical manifestations, overlap in clinical presentation with other thrombotic microangiopathies, and limited availability of ADAMTS13 testing. Clinical prediction scores have been developed to estimate the pretest probability of severe ADAMTS13 deficiency and may be used as an adjunct to clinical judgment to guide initial management decisions. An ADAMTS13 activity level of less than 10% supports the diagnosis of TTP in appropriate clinical contexts, but many centers do not offer testing in-house and must send out the test to a reference laboratory with a turnaround time of several days. In such instances, initial management decisions must be made without the benefit of laboratory testing. In patients with TTP, inhibitor tests may be useful for distinguishing immune-mediated from congenital TTP. In this article, we review the epidemiology, natural history, and clinical presentation of TTP and laboratory assays for TTP including ADAMTS13 activity and inhibitor assays. We also describe an evidence-based approach to the evaluation of a patient with suspected TTP that integrates clinical and laboratory assessment.


Assuntos
Técnicas de Laboratório Clínico/métodos , Púrpura Trombocitopênica Trombótica/diagnóstico , Proteína ADAMTS13/deficiência , Humanos , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/patologia
4.
Arterioscler Thromb Vasc Biol ; 38(11): 2731-2743, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354235

RESUMO

Objective- ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) cleaves VWF (von Willebrand factor). This process is essential for hemostasis. Severe deficiency of plasma ADAMTS13 activity, most commonly resulting from autoantibodies against ADAMTS13, causes thrombotic thrombocytopenic purpura. Therapeutic plasma exchange is the standard of care to date, which removes autoantibodies and replenishes ADAMTS13. However, such a therapy is often ineffective to raise plasma ADAMTS13 activity, and in-hospital mortality rate remains as high as 20%. Approach and Results- To overcome the inhibition by autoantibodies, we developed a novel approach by delivering rADAMTS13 (recombinant ADAMTS13 ) using platelets as vehicles. We show that both human and murine platelets can uptake rADAMTS13 ex vivo. The endocytosed rADAMTS13 within platelets remains intact, active, and is stored in α-granules. Under arterial shear (100 dyne/cm2), the rADAMTS13 in platelets is released and effectively inhibits platelet adhesion and aggregation on a collagen-coated surface in a concentration-dependent manner. Transfusion of rADAMTS13-loaded platelets into Adamts13-/- mice dramatically reduces the rate of thrombus formation in the mesenteric arterioles after FeCl3 injury. An ex vivo transfusion of rADAMTS13-loaded platelets to a reconstituted whole blood containing plasma from a patient with immune-mediated thrombotic thrombocytopenic purpura and the cellular components (eg, erythrocytes and leukocytes) from a healthy individual, as well as a fresh whole blood obtained from a patient with congenital or immune-mediated thrombotic thrombocytopenic purpura also dramatically reduces the rate of thrombus formation under arterial flow. Conclusions- Our results demonstrate that transfusion of rADAMTS13-loaded platelets may be a novel and potentially effective therapeutic approach for arterial thrombosis, associated with congenital and immune-mediated thrombotic thrombocytopenic purpura.


Assuntos
Proteína ADAMTS13/sangue , Arteriopatias Oclusivas/prevenção & controle , Plaquetas/enzimologia , Transfusão de Plaquetas , Púrpura Trombocitopênica Trombótica/terapia , Trombose/prevenção & controle , Lesões do Sistema Vascular/terapia , Proteína ADAMTS13/deficiência , Proteína ADAMTS13/genética , Proteína ADAMTS13/imunologia , Animais , Arteriopatias Oclusivas/sangue , Arteriopatias Oclusivas/enzimologia , Arteriopatias Oclusivas/genética , Autoanticorpos/sangue , Modelos Animais de Doenças , Endocitose , Humanos , Camundongos Knockout , Adesividade Plaquetária , Agregação Plaquetária , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/genética , Trombose/sangue , Trombose/enzimologia , Trombose/genética , Lesões do Sistema Vascular/sangue , Lesões do Sistema Vascular/enzimologia , Lesões do Sistema Vascular/genética
5.
Blood ; 132(9): 903-910, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30006329

RESUMO

ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) is a metalloprotease responsible for cleavage of ultra-large von Willebrand factor (VWF) multimers. Severely deficient activity of the protease can trigger an acute episode of thrombotic thrombocytopenic purpura (TTP). Our understanding of the pathophysiology of TTP has allowed us to grasp the important role of ADAMTS13 in other thrombotic microangiopathies (TMAs) and thrombotic disorders, such as ischemic stroke and coronary artery disease. Through its action on VWF, ADAMTS13 can have prothrombotic and proinflammatory properties, not only when its activity is severely deficient, but also when it is only moderately low. Here, we will discuss the biology of ADAMTS13 and the different assays developed to evaluate its function in the context of TTP, in the acute setting and during follow-up. We will also discuss the latest evidence regarding the role of ADAMTS13 in other TMAs, stroke, and cardiovascular disease. This information will be useful for clinicians not only when evaluating patients who present with microangiopathic hemolytic anemia and thrombocytopenia, but also when making clinical decisions regarding the follow-up of patients with TTP.


Assuntos
Proteína ADAMTS13/sangue , Anemia Hemolítica/enzimologia , Anemia Hemolítica/terapia , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/terapia , Proteína ADAMTS13/genética , Anemia Hemolítica/genética , Humanos , Púrpura Trombocitopênica Trombótica/genética
6.
Ann Clin Lab Sci ; 48(3): 373-376, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29970443

RESUMO

ADAMTS13 testing plays a critical role in confirming the clinical diagnosis of acquired idiopathic thrombotic thrombocytopenic purpura (TTP) and distinguishing it from other forms of thrombotic microangiopathies (TMA). Serial measurements of ADAMTS13 activity and inhibitor levels are also helpful in determining response to treatment and/or subsequent relapses. Numerous ADAMTS13 assays have been developed recently, including some with rapid turnaround times. Despite the good inter-assay correlation of different ADAMTS13 methodologies in published case studies, discrepancies have been shown to occur. Here we present a case where discrepant results were obtained using two different assays, posing a clinical treatment dilemma.


Assuntos
Proteína ADAMTS13/sangue , Biomarcadores/sangue , Técnicas de Laboratório Clínico/métodos , Púrpura Trombocitopênica Trombótica/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/terapia
9.
J Thromb Haemost ; 16(4): 618-629, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29356300

RESUMO

Thrombotic microangiopathies are rare disorders characterized by the concomitant occurrence of severe thrombocytopenia, microangiopathic hemolytic anemia, and a variable degree of ischemic end-organ damage. The latter particularly affects the brain, the heart, and the kidneys. The primary forms, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), although their clinical presentations often overlap, have distinctive pathophysiologies. TTP is the consequence of a severe ADAMTS-13 deficiency, either immune-mediated as a result of circulating autoantibodies, or caused by mutations in ADAMTS-13. HUS develops following an infection with Shiga-toxin producing bacteria, or as the result of excessive activation of the alternative pathway of the complement system because of mutations in genes encoding complement system proteins.


Assuntos
Proteína ADAMTS13 , Via Alternativa do Complemento , Proteínas do Sistema Complemento , Síndrome Hemolítico-Urêmica/fisiopatologia , Púrpura Trombocitopênica Trombótica/fisiopatologia , Escherichia coli Shiga Toxigênica/patogenicidade , Proteína ADAMTS13/sangue , Proteína ADAMTS13/deficiência , Proteína ADAMTS13/genética , Proteína ADAMTS13/imunologia , Autoanticorpos/imunologia , Via Alternativa do Complemento/genética , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Predisposição Genética para Doença , Síndrome Hemolítico-Urêmica/genética , Síndrome Hemolítico-Urêmica/imunologia , Síndrome Hemolítico-Urêmica/microbiologia , Humanos , Mutação , Prognóstico , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/imunologia , Fatores de Risco
10.
J Thromb Haemost ; 16(1): 164-169, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29064619

RESUMO

Essentials Severe ADAMTS-13 deficiency is key to thrombotic thrombocytopenic purpura (TTP) diagnosis. PLASMIC score predicts ADAMTS-13 deficiency in suspected TTP with high discrimination. PLASMIC score is more generalizable with fewer missing data than alternative clinical scores. PLASMIC score identifies a subgroup of patients lacking significant response to plasma exchange. SUMMARY: Background The PLASMIC score was recently published to distinguish patients with severe ADAMTS-13 deficiency from those without for early identification of thrombotic thrombocytopenia purpura (TTP). Objective We performed an independent external validation of the PLASMIC score for clinical prediction of severe ADAMTS-13 deficiency. Patients/Methods We studied an independent cohort of 112 consecutive hospitalized patients with suspected thrombotic microangiopathy and appropriate ADAMTS-13 testing (including 21 patients with TTP diagnosis). Results The PLASMIC score model predicted severe ADAMTS-13 deficiency with a c statistic of 0.94 (0.88-0.98). When dichotomized at high (score 6-7) vs. low-intermediate risk (score 0-5), the model predicted severe ADAMTS-13 deficiency with positive predictive value of 72%, negative predictive value of 98%, sensitivity of 90% and specificity of 92%. In the low-intermediate risk group (score 0-5) there was no significant improvement in overall survival associated with plasma exchange. Conclusions The PLASMIC score model had excellent applicability, discrimination and calibration for predicting severe ADAMTS-13 deficiency. The clinical algorithm allowed identification of a subgroup of patients who lacked a significant response to empiric treatment.


Assuntos
Proteína ADAMTS13/sangue , Técnicas de Apoio para a Decisão , Troca Plasmática , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/terapia , Proteína ADAMTS13/deficiência , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/enzimologia , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Resultado do Tratamento
11.
J Thromb Haemost ; 16(2): 378-388, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29222940

RESUMO

Essentials Conformational changes in ADAMTS-13 are part of its mode-of-action. The murine anti-ADAMTS-13 antibody 1C4 discriminates between folded and open ADAMTS-13. ADAMTS-13 conformation is open in acute acquired thrombotic thrombocytopenic purpura (TTP). Our study forms an important basis to fully elucidate the pathophysiology of TTP. SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (aTTP) is an autoimmune disorder characterized by absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies. Recently, it was shown that ADAMTS-13 adopts a folded or an open conformation. Objectives As conformational changes in self-antigens play a role in the pathophysiology of different autoimmune diseases, we hypothesized that the conformation of ADAMTS-13 changes during acute aTTP. Methods Antibodies recognizing cryptic epitopes in the spacer domain were generated. Next, the conformation of ADAMTS-13 in 40 healthy donors (HDs), 99 aTTP patients (63 in the acute phase versus 36 in remission), 12 hemolytic-uremic syndrome (HUS) patients and 63 sepsis patients was determined with ELISA. Results The antibody 1C4 recognizes a cryptic epitope in ADAMTS-13. Therefore, we were able to discriminate between a folded and an open ADAMTS-13 conformation. We showed that ADAMTS-13 in HDs does not bind to 1C4, indicating that ADAMTS-13 circulates in a folded conformation. Similar results were obtained for HUS and sepsis patients. In contrast, ADAMTS-13 of acute aTTP patients bound to 1C4 in 92% of the cases, whereas, in most cases, this binding was abolished during remission, showing that the conformation of ADAMTS-13 is open during an acute aTTP episode. Conclusions Our study shows that, besides absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies, an open ADAMTS-13 conformation is also a hallmark of acute aTTP. Demonstrating this altered ADAMTS-13 conformation in acute aTTP will help to further unravel the pathophysiology of aTTP and lead to improved therapy and diagnosis.


Assuntos
Proteína ADAMTS13/química , Púrpura Trombocitopênica Trombótica/enzimologia , Proteína ADAMTS13/sangue , Proteína ADAMTS13/imunologia , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Mapeamento de Epitopos , Epitopos , Humanos , Ligação Proteica , Conformação Proteica , Dobramento de Proteína , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/imunologia , Relação Estrutura-Atividade
12.
Rinsho Ketsueki ; 58(10): 2081-2086, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28978852

RESUMO

Although thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease, appropriate diagnosis and treatment result in the higher survival rate of >80%. TTP is usually suspected with thrombocytopenia and hemolytic anemia and is confirmed by a reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) <10%. TTP is classified as acquired if a patient tests positive for anti-ADAMTS13 autoantibodies, and as congenital if ADAMTS13 gene abnormalities are identified. In patients with congenital TTP, fresh frozen plasma (FFP) transfusion for the supplementation of ADAMTS13 is performed. On the other hand, in patients with acquired TTP, plasma exchange therapy using FFP is conducted to supplement ADAMTS13 and remove anti-ADAMTS13 autoantibodies. Besides, corticosteroid therapy is often administered in conjunction with plasma exchange to suppress autoantibody production. In 2017, we aim to provide "diagnostic and treatment guidelines for TTP 2017 in Japan". In this review, we describe new developments in diagnosis and management of TTP, which are not discussed in the guidelines.


Assuntos
Púrpura Trombocitopênica Trombótica/terapia , Proteína ADAMTS13/metabolismo , Ensaios Clínicos como Assunto , Humanos , Terapia de Alvo Molecular , Guias de Prática Clínica como Assunto , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/enzimologia
13.
Rinsho Ketsueki ; 58(8): 933-937, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28883277

RESUMO

Congenital thrombotic thrombocytopenic purpura (TTP) is a rare hereditary deficiency of ADAMTS13 (von Willebrand factor-cleaving protease) characterized by thrombocytopenia and microangiopathic hemolytic anemia. The spectrum of the clinical phenotype is wide, ranging from asymptomatic episodes of thrombocytopenia to life-threatening multiorgan failure. Reportedly, some patients develop isolated thrombocytopenia during childhood. We herein report sibling cases of congenital TTP. An 11-year-old boy with thrombocytopenia accompanied by influenza virus infection was referred to our hospital. He had a history of severe neonatal jaundice. His 15-year-old brother also had recurrent thrombocytopenia with approximately 10 episodes of recurrence since 3 years of age. Their ADAMTS13 activities were low and ADAMTS13 inhibitors were negative, and a gene analysis confirmed the diagnosis of congenital TTP. Notably, congenital TTP should be included in the differential diagnosis, and it is essential to determine the ADAMTS13 activity for pediatric patients with thrombocytopenia of unknown etiology.


Assuntos
Proteína ADAMTS13/genética , Púrpura Trombocitopênica Trombótica/congênito , Púrpura Trombocitopênica Trombótica/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Púrpura Trombocitopênica Trombótica/enzimologia , Irmãos
15.
Arterioscler Thromb Vasc Biol ; 37(5): 836-844, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28254814

RESUMO

OBJECTIVE: Severe deficiency in the von Willebrand factor-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) because of mutations in the ADAMTS13 gene can lead to acute episodes of congenital thrombotic thrombocytopenic purpura (TTP), requiring prompt treatment. Current treatment consists of therapeutic or prophylactic infusions of fresh frozen plasma. However, lifelong treatment with plasma products is a stressful therapy for TTP patients. Here, we describe the use of the nonviral sleeping beauty (SB) transposon system as a gene therapeutic approach to realize lifelong expression of ADAMTS13 and subsequent protection against congenital TTP. APPROACH AND RESULTS: We demonstrated that hydrodynamic tail vein injection of the SB100X system expressing murine ADAMTS13 in Adamts13-/- mice resulted in long-term expression of supraphysiological levels of transgene ADAMTS13 over a period of 25 weeks. Stably expressed ADAMTS13 efficiently removed the prothrombotic ultralarge von Willebrand factor multimers present in the circulation of Adamts13-/- mice. Moreover, mice stably expressing ADAMTS13 were protected against TTP. The treated mice did not develop severe thrombocytopenia or did organ damage occur when triggered with recombinant von Willebrand factor, and this up to 20 weeks after gene transfer. CONCLUSIONS: These data demonstrate the feasibility of using SB100X-mediated gene therapy to achieve sustained expression of transgene ADAMTS13 and long-term prophylaxis against TTP in Adamts13-/- mice.


Assuntos
Proteína ADAMTS13/deficiência , Elementos de DNA Transponíveis , Terapia Genética/métodos , Púrpura Trombocitopênica Trombótica/prevenção & controle , Transposases/genética , Proteína ADAMTS13/genética , Animais , Modelos Animais de Doenças , Estudos de Viabilidade , Predisposição Genética para Doença , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/genética , Fatores de Tempo , Fator de von Willebrand
16.
Lancet Haematol ; 4(4): e157-e164, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28259520

RESUMO

BACKGROUND: Among the syndromes characterised by thrombotic microangiopathy, thrombotic thrombocytopenic purpura is distinguished by a severe deficiency in the ADAMTS13 enzyme. Patients with this disorder need urgent treatment with plasma exchange. Because ADAMTS13 activity testing typically requires prolonged turnaround times and might be unavailable in resource-poor settings, a method to rapidly assess the likelihood of severe ADAMTS13 deficiency is needed. METHODS: All consecutive adult patients presenting to three large academic medical centres in Boston, MA, USA, with thrombotic microangiopathy and a possible diagnosis of thrombotic thrombocytopenic purpura between Jan 8, 2004, and Dec 6, 2015, were included in an ongoing multi-institutional registry (the Harvard TMA Research Collaborative). Univariate analysis was used to identify covariates for a logistic regression model predictive of severe ADAMTS13 deficiency (≤10% activity). A clinical point score was generated, and its diagnostic performance was assessed using internal and external validation cohorts and compared to clinical assessment alone. FINDINGS: 214 patients with thrombotic microangiopathy were included in the derivation cohort. A seven-component clinical prediction tool, termed the PLASMIC score, was developed and found to reliably assess the pretest probability of severe ADAMTS13 deficiency (C statistic 0·96, 95% CI 0·92-0·98). Our diagnostic model was reproducibly accurate in both the internal (0·95, 0·91-0·98) and external (0·91, 0·85-0·95) validation cohorts. The scoring system also more consistently diagnosed thrombotic microangiopathy due to severe ADAMTS13 deficiency than did standard clinical assessment, as measured by C statistic (0·96, 95% CI 0·92-0·98 for PLASMIC vs 0·83, 0·77-0·88 for clinical assessment; p<0·0001) and mean Brier score (0·065 for PLASMIC vs 0·111 for clinical assessment; mean paired difference 0·05, 95% CI 0·01-0·08; p<0·0001). When utilised in addition to clinical assessment, the PLASMIC score contributed significant discriminatory power (integrated discrimination improvement 0·24, 95% CI 0·11-0·37). INTERPRETATION: We have developed and validated a clinical prediction tool-the PLASMIC score-to stratify patients with thrombotic microangiopathy according to their risk of having severe ADAMTS13 deficiency. We have shown that this scoring system is superior to standard clinical assessment in addressing the diagnostic challenge presented by thrombotic microangiopathy. Its use, together with clinical judgment, may facilitate treatment decisions in patients for whom timely results of ADAMTS13 activity testing are unavailable. FUNDING: The Luick Family Fund of Massachusetts General Hospital.


Assuntos
Proteína ADAMTS13/deficiência , Microangiopatias Trombóticas/diagnóstico , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/enzimologia , Microangiopatias Trombóticas/enzimologia
18.
Medicine (Baltimore) ; 95(24): e3712, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27310951

RESUMO

In the pathogenesis of thrombotic thrombocytopenic purpura (TTP), reductions in the enzyme activity of ADAMTS13, which cuts ultralarge von Willebrand multimers, generates shear stress on the microvascular endothelium, leading to platelet aggregation and the formation of a thrombus. ADAMTS13 activity is markedly decreased in typical TTP, but is only mildly reduced in secondary TTP, which concomitantly develops with primary disease. The latter develops with septic disseminated intravascular coagulation (DIC) and often causes organ failure. Recombinant thrombomodulin (rTM) is a drug that is used to treat DIC and may also remit TTP because it improves vascular endothelial dysfunction. Therefore, we herein investigated the efficacy of rTM in patients treated for the pathology of secondary TTP. Patients who were admitted to the Emergency and Critical Care Center of our hospital and met the following conditions were extracted and retrospectively analyzed: hemolytic anemia accompanied by fragmented red blood cells (Hb < 12 g/dL or lower); thrombocytopenia (<100 × 10/µL); and ADAMTS13 activity <50%. Sixteen patients were included and accompanied by Kidney Disease: Improving Global Outcomes (KDIGO) stage 2 or more severe nephropathy and DIC. Eleven and 5 patients treated with and without rTM (the rTM and non-rTM treatment groups, respectively) were compared, and no significant difference was noted in their basic characteristics, such as background disease and severity. No significant difference was observed in survival rates; however, the platelet count, which is an important outcome of treatments for TTP, significantly increased in the rTM treatment group: 3.3 ±â€Š2.6→11.3 ±â€Š14.6 versus 3.5 ±â€Š3.7→5.7 ±â€Š3.9 (×1000/µL) (P = 0.034). Thrombotic thrombocytopenic purpura originally requires invasive treatments and its prognosis is not favorable. Blood thrombomodulin levels also markedly increase due to vascular endothelial dysfunction, whereas rTM alleviates vascular endothelial dysfunction in TTP patients with high blood TM levels, suggesting the importance of administering rTM. Thus, rTM may be effective for secondary TTP and may be adopted as adjuvant therapy.


Assuntos
Proteína ADAMTS13/sangue , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Trombomodulina/administração & dosagem , Idoso , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Púrpura Trombocitopênica Trombótica/enzimologia , Proteínas Recombinantes , Estudos Retrospectivos , Resultado do Tratamento
19.
Clin J Gastroenterol ; 9(2): 104-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26905311

RESUMO

Recent successive reports on acute pancreatitis-induced thrombotic thrombocytopenic purpura (TTP) have revealed that TTP-related microvascular damage is an aggravating factor of acute pancreatitis. Here, we report the case of a 26-year-old man diagnosed with acute pancreatitis due to high alcohol consumption. The patient was unconscious as he had taken an overdose of medication, and presented with fever and renal failure due to acute pancreatitis on admission. Although the pancreatitis subsequently improved, the symptoms were still observed; on the next day, he exhibited hemoglobinuria, anemia, and thrombocytopenia. Moreover, general blood examinations indicated the presence of schistocytes and reduced activity of ADAMTS13 (a disintegrin-like metalloproteinase with thrombospondin type 1 motif 13) to 47 %. Thus, the patient was diagnosed with TTP, and plasma exchange was performed. After the development of TTP, the acute pancreatitis recurred, but a severe pathogenesis was prevented by plasma exchange. Thus, ADAMTS13 activity may be useful for predicting a severe pathogenesis of acute pancreatitis. In ADAMTS13-deficient cases, plasma exchange may be an effective technique for preventing aggravation of acute pancreatitis.


Assuntos
Pancreatite/complicações , Púrpura Trombocitopênica Trombótica/complicações , Proteínas ADAM/deficiência , Doença Aguda , Adulto , Humanos , Masculino , Pancreatite/enzimologia , Troca Plasmática , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/terapia , Recidiva
20.
Gan To Kagaku Ryoho ; 43(1): 133-6, 2016 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-26809542

RESUMO

A 71-year-old male patient began FOLFOX6 plus panitumumab treatment for unresectable recurrent rectal cancer. He developed thrombocytopenia after 2 courses of treatment and therefore a platelet transfusion was performed. The day after transfusion, the patient developed jaundice and hematuria. His lactate dehydrogenase levels had increased and a peripheral blood smear review revealed the presence of schistocytes. Anti-ADAMTS13 antibodies were present, and there was a reduction in ADAMTS13 activity. The patient was diagnosed with thrombotic thrombocytopenic purpura and treated with a plasma exchange. The day after the plasma exchange, his clinical condition rapidly worsened and he died. Thrombocytopenia due to chemotherapy often appears as myelosuppression. If conditions such as jaundice, indirect bilirubinemia, or hematuria appear during the course of chemotherapy, this condition must be considered as a differential diagnosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Púrpura Trombocitopênica Trombótica/complicações , Neoplasias Retais/tratamento farmacológico , Proteínas ADAM/metabolismo , Proteína ADAMTS13 , Idoso , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Progressão da Doença , Evolução Fatal , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Compostos Organoplatínicos/administração & dosagem , Panitumumabe , Troca Plasmática , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/terapia , Neoplasias Retais/complicações , Neoplasias Retais/patologia , Recidiva
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...