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1.
Blood ; 135(26): 2413-2419, 2020 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-32253422

RESUMEN

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder caused by neutralizing anti-ADAMTS13 autoantibodies. In white individuals, HLA allele DRB1*11 is a predisposing factor for iTTP, whereas DRB1*04 is a protective factor. However, the role of HLA in Asians is unclear. In this study, we analyzed 10 HLA loci using next-generation sequencing in 52 Japanese patients with iTTP, and the allele frequency in the iTTP group was compared with that in a Japanese control group. We identified the following HLA alleles as predisposing factors for iTTP in the Japanese population: DRB1*08:03 (odds ratio [OR], 3.06; corrected P [Pc] = .005), DRB3/4/5*blank (OR, 2.3; Pc = .007), DQA1*01:03 (OR, 2.25; Pc = .006), and DQB1*06:01 (OR,: 2.41; Pc = .003). The estimated haplotype consisting of these 4 alleles was significantly more frequent in the iTTP group than in the control group (30.8% vs 6.0%; Pc < .001). DRB1*15:01 and DRB5*01:01 were weak protective factors for iTTP (OR, 0.23; Pc = .076; and OR, 0.23, Pc = .034, respectively). On the other hand, DRB1*11 and DRB1*04 were not associated with iTTP in the Japanese. These findings indicated that predisposing and protective factors for iTTP differ between Japanese and white individuals. HLA-DR molecules encoded by DRB1*08:03 and DRB1*11:01 have different peptide-binding motifs, but interestingly, bound to the shared ADAMTS13 peptide in an in silico prediction model.


Asunto(s)
Proteína ADAMTS13/fisiología , Pueblo Asiatico/genética , Antígenos HLA-DR/genética , Púrpura Trombocitopénica Trombótica/genética , Alelos , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Simulación por Computador , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/metabolismo , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Humanos , Japón/epidemiología , Masculino , Modelos Moleculares , Fragmentos de Péptidos/metabolismo , Conformación Proteica , Mapeo de Interacción de Proteínas , Púrpura Trombocitopénica Trombótica/etnología , Púrpura Trombocitopénica Trombótica/inmunología
2.
Curr Med Sci ; 43(5): 1043-1050, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37815743

RESUMEN

OBJECTIVE: Thrombotic thrombocytopenic purpura (TTP) is a rare and fatal disease caused by a severe deficiency in the metalloprotease ADAMTS13 and is characterized by thrombotic microangiopathy. The present study aimed to investigate the genes and variants associated with TTP in a Chinese population. METHODS: Target sequencing was performed on 220 genes related to complements, coagulation factors, platelets, fibrinolytic, endothelial, inflammatory, and anticoagulation systems in 207 TTP patients and 574 controls. Subsequently, logistic regression analysis was carried out to identify the TTP-associated genes based on the counts of rare deleterious variants in the region of a certain gene. Moreover, the associations between common variants and TTP were also investigated. RESULTS: ADAMTS13 was the only TTP-associated gene (OR = 3.77; 95% CI: 1.82-7.81; P=3.6×10È¡4) containing rare deleterious variants in TTP patients. Among these 8 variants, 5 novel rare variants that might contribute to TTP were identified, including rs200594025, rs782492477, c.T1928G (p.I643S), c.3336_3361del (p.Q1114Afs*20), and c.3469_3470del (p.A1158Sfs*17). No common variants associated with TTP were identified under the stringent criteria of correction for multiple testing. CONCLUSION: ADAMTS13 is the primary gene related to TTP. The genetic variants associated with the occurrence of TTP were slightly different between the Chinese and European populations.


Asunto(s)
Púrpura Trombocitopénica Trombótica , Humanos , Proteína ADAMTS13/genética , Pueblos del Este de Asia/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Púrpura Trombocitopénica Trombótica/etnología , Púrpura Trombocitopénica Trombótica/genética
3.
Transfusion ; 51(10): 2237-43, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21470236

RESUMEN

BACKGROUND: It has been postulated that blood group O subjects may be partially protected against thrombotic thrombocytopenic purpura (TTP) because they have lower plasma levels of von Willebrand factor. STUDY DESIGN AND METHODS: The Oklahoma TTP Registry enrolled 301 consecutive patients from November 13, 1995 (when systematic ADAMTS13 measurements began), through 2009; 281 (93%) patients had ADAMTS13 measurements. Patients were designated as having severe ADAMTS13 deficiency when the activity measurement by either method was less than 10%. ABO blood group was determined in all 281 patients. The observed frequency of blood group O was compared to the expected frequency. The association between severe ADAMTS13 deficiency and blood group, race, sex, and age were analyzed by logistic regression. RESULTS: The frequency of blood group O was unexpectedly and significantly greater than the race-ethnicity-adjusted expected frequency in 65 patients with severe ADAMTS13 deficiency (60.0% vs. 47.4%, p = 0.042) but not in 216 patients without severe ADAMTS13 deficiency (44.9% vs. 46.5%, p = 0.639). Blood group O and race-ethnicity were independently associated with severe ADAMTS13 deficiency among patients with TTP. The probability for severe ADAMTS13 deficiency was 45.8% with O and 32.1% with non-O blood groups for black patients and 24.1% with O and 15.1% with non-O blood groups for white patients. CONCLUSION: Among patients with TTP and severe ADAMTS13 deficiency the relative frequency of patients with blood group O was greater than expected, suggesting that blood group O may be a risk factor for TTP associated with severe ADAMTS13 deficiency.


Asunto(s)
Sistema del Grupo Sanguíneo ABO , Proteínas ADAM/deficiencia , Negro o Afroamericano , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/etnología , Proteína ADAMTS13 , Adolescente , Adulto , Factores de Edad , Anciano , Asiático , Femenino , Hispánicos o Latinos , Humanos , Indígenas Norteamericanos , Masculino , Persona de Mediana Edad , Oklahoma/epidemiología , Estudios Prospectivos , Factores de Riesgo , Factores Sexuales , Población Blanca , Adulto Joven
4.
Am J Med Sci ; 337(5): 373-6, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19322066

RESUMEN

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) has a high mortality rate if undiagnosed and untreated. Although recent literature supports the role of ADAMTS13 (a disintegrin-like metalloproteinase with thrombospondin type 1 repeats), the von Willebrand factor cleaving protease, in the pathogenesis of the disease, many aspects of the disease remain a mystery. Various drugs and autoimmune conditions, such as systemic lupus erythematosus and the antiphospholipid syndrome, have been observed in association with TTP. Adult onset Still's disease (AOSD) has been reported less frequently in association with TTP. PRESENTATION: We report the case of a 43-year-old African American man who initially presented with fever and joint pain and was later diagnosed with TTP. He responded initially to plasma exchange, but never achieved complete remission. He eventually required splenectomy for complete resolution of symptoms of TTP, but the arthritis never resolved, resulting in several admissions for joint pain. The arthritis was eventually diagnosed as AOSD. DISCUSSION: Literature review shows that the autoimmune diseases usually associated with TTP include systemic lupus erythematosus and the antiphospholipid syndrome. Eight reports of AOSD with TTP have been reported, but our case is unique in several aspects. Previous case reports have described TTP occurring in patients with known AOSD; here, we describe TTP preceding or coinciding with the onset of AOSD. Interestingly, the patient's AOSD-associated arthritis responded to plasma exchange, but did not resolve after splenectomy. The coincident onset of AOSD and TTP in this patient lead us to suspect a common pathophysiologic pathway in the pathogenesis for both of these diseases.


Asunto(s)
Púrpura Trombocitopénica Trombótica/complicaciones , Púrpura Trombocitopénica Trombótica/diagnóstico , Enfermedad de Still del Adulto/complicaciones , Enfermedad de Still del Adulto/diagnóstico , Proteínas ADAM/sangre , Proteínas ADAM/inmunología , Proteína ADAMTS13 , Adulto , Antígenos CD36/sangre , Antígenos CD36/inmunología , Hematología/métodos , Humanos , Masculino , Intercambio Plasmático , Púrpura Trombocitopénica Trombótica/etnología , Púrpura Trombocitopénica Trombótica/terapia , Inducción de Remisión , Esplenectomía , Enfermedad de Still del Adulto/etnología , Enfermedad de Still del Adulto/terapia , Resultado del Tratamiento
5.
J Thromb Haemost ; 5(1): 62-9, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17038160

RESUMEN

BACKGROUND: Human fibrinogen gamma chain variants, termed gamma' chains, contain a unique 20-residue sequence after gamma chain residue 407 that ends at gamma'427, and is designated gamma'(427L). Full-length (FL) gamma'(427L) chains are constituents of a fibrin-dependent thrombin inhibitory system known as antithrombin I, whereas a gamma' chain processed in vivo, termed gamma'(423P), lacks the C-terminal tetrapeptide EDDL, and does not bind thrombin. Together, the gamma'(423P) and gamma'(427L) chains comprise the total plasma fibrinogen gamma' chain content. OBJECTIVES: Lowered plasma gamma' chain content (i.e. gamma' chain-containing fibrinogen/total fibrinogen ratio) has been shown to correlate with susceptibility to venous thrombosis, thus prompting this study on the total and FL gamma' chain content in 45 subjects with thrombotic microangiopathy (TMA), a disorder characterized by microvascular thrombosis. METHODS: We measured by enzyme-linked immunosorbent assay the total gamma' chain-containing fibrinogen/total fibrinogen (Total gamma'-fgn/Total fgn) ratio and the FL gamma' chain-containing fibrinogen/total fibrinogen (FL gamma'-fgn/Total fgn) ratio in these plasmas and in healthy subjects (n = 87). RESULTS: In healthy subjects, the mean Total gamma'-fgn/Total fgn ratio was 0.127, whereas the FL gamma'-fgn/Total fgn ratio was somewhat lower at 0.099 (P < 0.0001), a difference reflecting the presence of gamma'(423P) chains. In TMA plasmas, both the Total gamma'-fgn and FL gamma'-fgn/Total fgn ratios (0.099 and 0.084, respectively) were lower than those of their healthy subject counterparts (P < 0.0001). CONCLUSIONS: These findings in TMA suggest that reductions in the gamma' chain content indicate reduced antithrombin I activity that may contribute to microvascular thrombosis in TMA.


Asunto(s)
Fibrinógeno/metabolismo , Púrpura Trombocitopénica Trombótica/sangre , Trombosis/sangre , Proteínas ADAM/sangre , Proteína ADAMTS13 , Adulto , Negro o Afroamericano , Anciano , Anciano de 80 o más Años , Anemia Hemolítica/sangre , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibrina/metabolismo , Fibrinógeno/genética , Haplotipos , Humanos , Modelos Lineales , Masculino , Microcirculación/fisiopatología , Persona de Mediana Edad , Polimorfismo Genético , Púrpura Trombocitopénica Trombótica/etnología , Púrpura Trombocitopénica Trombótica/fisiopatología , Valores de Referencia , Síndrome , Trombosis/etnología , Trombosis/fisiopatología , Población Blanca
6.
J Thromb Haemost ; 4(5): 955-62, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16689741

RESUMEN

BACKGROUND: The recently discovered plasma enzyme ADAMTS-13 cleaves the A2-domain of von Willebrand factor (VWF). A defective cleaving protease results in unusually large VWF multimers, which cause thrombotic thrombocytopenic purpura (TTP). AIM: Analysis of the ADAMTS-13 antigen levels in TTP patients compared with normal donors. METHODS: An antigen ELISA test was built, based on high affinity anti-ADAMTS-13 monoclonal antibodies, which were generated using genetic immunization. RESULTS: Specificity of the ADAMTS-13 antigen test was confirmed, as (i) plasma from a patient with acquired TTP but presenting without inhibitor did not contain antigen and (ii) the binding of recombinant ADAMTS-13 was inhibited by increasing amounts of normal plasma. The assay is sensitive as it can detect antigen levels as low as 1.6% of normal. The concentration in normal pooled human plasma was determined (1.03 +/- 0.15 microg mL(-1)) and arbitrarily set to 1 U mL(-1). The antigen levels in congenital TTP samples (34 +/- 21 mU mL(-1), n = 2), as well as in samples from patients with acquired TTP (231 +/- 287 mU mL(-1), n = 11), were clearly reduced when compared with normal Caucasian donors (951 +/- 206 mU mL(-1), n = 16). Remarkably, normal Chinese donors have a significantly lower antigen titer (601 +/- 129 mU mL(-1), n = 15), when compared with normal Caucasians. CONCLUSIONS: Our results show that acquired TTP patients suffer mainly from ADAMTS-13 antigen depletion, thereby indicating the importance of ADAMTS-13 antigen determination in diagnosis and patient follow-up.


Asunto(s)
Proteínas ADAM/sangre , Antígenos/inmunología , Etnicidad , Púrpura Trombocitopénica Trombótica/inmunología , Proteína ADAMTS13 , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Secuencia de Bases , Western Blotting , Cartilla de ADN , Electroforesis en Gel de Poliacrilamida , Humanos , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/etnología
7.
PLoS One ; 11(7): e0156679, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27383202

RESUMEN

Black people are at increased risk of thrombotic thrombocytopenic purpura (TTP). Whether clinical presentation of TTP in Black patients has specific features is unknown. We assessed here differences in TTP presentation and outcome between Black and White patients. Clinical presentation was comparable between both ethnic groups. However, prognosis differed with a lower death rate in Black patients than in White patients (2.7% versus 11.6%, respectively, P = .04). Ethnicity, increasing age and neurologic involvement were retained as risk factors for death in a multivariable model (P < .05 all). Sixty-day overall survival estimated by the Kaplan-Meier curves and compared with the Log-Rank test confirmed that Black patients had a better survival than White patients (P = .03). Salvage therapies were similarly performed between both groups, suggesting that disease severity was comparable. The comparison of HLA-DRB1*11, -DRB1*04 and -DQB1*03 allele frequencies between Black patients and healthy Black individuals revealed no significant difference. However, the protective allele against TTP, HLA-DRB1*04, was dramatically decreased in Black individuals in comparison with White individuals. Black people with TTP may have a better survival than White patients despite a comparable disease severity. A low natural frequency of HLA-DRB1*04 in Black ethnicity may account for the greater risk of TTP in this population.


Asunto(s)
Población Negra/genética , Negro o Afroamericano/genética , Púrpura Trombocitopénica Trombótica/etnología , Púrpura Trombocitopénica Trombótica/genética , Adulto , Alelos , Femenino , Frecuencia de los Genes , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/mortalidad , Sistema de Registros , Factores de Riesgo , Resultado del Tratamiento , Población Blanca/genética
8.
J Thromb Haemost ; 11(7): 1399-406, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23621748

RESUMEN

BACKGROUND: An East Asian-specific P475S polymorphism in the gene encoding ADAMTS-13 causes an approximately 16% reduction in plasma ADAMTS-13 activity. OBJECTIVES: To demonstrate the impact of this dysfunctional polymorphism by characterizing the structure and activity of the P475S mutant protein. METHODS: We determined the crystal structure of the P475S mutant of ADAMTS-13-DTCS (DTCS-P475S, residues 287-685) and compared it with the wild-type structure. We determined the enzymatic parameters of ADAMTS-13-MDTCS (residues 75-685) and MDTCS-P475S, and further examined the effects of denaturants and reaction temperature on their activity. We also examined the cleavage of shear-treated von Willebrand factor (VWF) by MDTCS-P475S. RESULTS: MDTCS-P475S showed a reaction rate similar to that of wild-type MDTCS, but showed two-fold lower affinity for the peptidyl substrate, indicating that the Pro475-containing V-loop (residues 474-481) in the CA domain is a substrate-binding exosite. Structural analysis showed that the conformation of the V-loop was significantly different in DTCS-P475S and the wild type, where no obvious interactions of Ser475 with other residues were observed. This explains the higher susceptibility of the enzymatic activity of MDTCS-P475S to reaction environments such as denaturants and high temperature. MDTCS-P475S can moderately cleave shear-treated VWF. CONCLUSIONS: We have provided structural evidence that the P475S polymorphism in ADAMTS-13 leads to increased local structural instability, resulting in lowered affinity for the substrate without changing the reaction rate. The moderate activity of ADAMTS-13-P475S for shear-treated VWF is sufficient to prevent thrombotic thrombocytopenic purpura (TTP) onset.


Asunto(s)
Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Pueblo Asiatico/genética , Polimorfismo Genético , Púrpura Trombocitopénica Trombótica/enzimología , Púrpura Trombocitopénica Trombótica/genética , Proteínas ADAM/química , Proteína ADAMTS13 , Animales , Células CHO , Cricetinae , Cricetulus , Estabilidad de Enzimas , Predisposición Genética a la Enfermedad , Humanos , Cinética , Modelos Moleculares , Fenotipo , Conformación Proteica , Desnaturalización Proteica , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/etnología , Púrpura Trombocitopénica Trombótica/prevención & control , Relación Estructura-Actividad , Temperatura , Transfección , Factor de von Willebrand/metabolismo
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