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ConspectusAromatic esters are cost-effective, versatile, and commonly used scaffolds that are readily synthesized or encountered as synthetic intermediates. While most conventional reactions involving these esters are nucleophilic acyl substitutions or 1,2-nucleophilic additionsâwhere a nucleophile attacks the carbonyl group, decarbonylative transformations offer an alternative pathway by using the carbonyl group as a leaving group. This transition-metal-catalyzed process typically begins with oxidative addition of the C(acyl)-O bond to the metal. Subsequently, the reaction involves the migration of CO to the metal center, the reaction with a nucleophile, and reductive elimination to yield the final product. Pioneering work by Yamamoto on nickel complexes and the development of decarbonylative reactions (such as Mizoroki-Heck-type olefination) using aromatic carboxylic anhydrides catalyzed by palladium were conducted by de Vries and Stephan. Furthermore, reports have surfaced of decarbonylative hydrogenation of pyridyl methyl esters by Murai using ruthenium catalysts as well as Mizoroki-Heck-type reactions of nitro phenyl esters by Gooßen under palladium catalysis. Our group has been at the forefront of developing decarbonylative C-H arylations of phenyl esters with 1,3-azoles and aryl boronic acids using nickel catalysts. The key to this reaction is the use of phenyl esters, which are easy to synthesize, stabilize, and handle, allowing oxidative addition of the C(acyl)-O bond; nickel, which facilitates oxidative addition of the C(acyl)-O bond; and suitable bidentate phosphine ligands that can stabilize the intermediate. By modification of the nucleophiles, esters have been effectively utilized as electrophiles in cross-coupling reactions, encouraging the development of these nucleophiles among researchers. This Account summarizes our advancements in nucleophile development for decarbonylative coupling reactions, particularly highlighting the utilization of aromatic esters in diverse reactions such as alkenylation, intramolecular etherification, α-arylation of ketones, C-H arylation, methylation, and intramolecular C-H arylation for dibenzofuran synthesis, along with cyanation and reductive coupling. We also delve into reaction types that are distinct from typical decarbonylative reactions, including ester dance reactions, aromatic ring exchanges, and deoxygenative transformations, by focusing on the oxidative addition of the C(acyl)-O bond of the aromatic esters to the metal complex. For example, the ester dance reaction is hypothesized to undergo 1,2-translocation starting with oxidative addition to a palladium complex, leading to a sequence of ortho-deprotonation/decarbonylation, followed by protonation, carbonylation, and reductive elimination. The aromatic exchange reaction likely involves oxidative addition of complexes of different aryl electrophiles with a nickel complex. In deoxygenative coupling, an oxidative addition complex with palladium engages with a nucleophile, forming an acyl intermediate that undergoes reductive elimination in the presence of an appropriate reducing agent. These methodologies are poised to captivate the interest of synthetic chemists by offering unconventional and emerging approaches for transforming aromatic esters. Moreover, we demonstrated the potential to transform readily available basic chemicals into new compounds through organic synthesis.
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Thrombotic thrombocytopenic purpura (TTP) is a fatal thrombotic disease caused by a marked decrease in the activity of ADAMTS13, a von Willebrand factor cleaving protease. In congenital TTP, ADAMTS13 activity is decreased by an abnormality in ADAMTS13, and in acquired TTP, by anti-ADAMTS13 autoantibody. Death from thrombosis in the acute phase has been an issue with conventional treatment of acquired TTP by plasma exchange or immunosuppressive therapy. However, the advent of caplacizumab, an anti-VWF nanobody, has made it possible to suppress thrombus formation and is expected to improve survival rates. In addition, some case series have shown the efficacy of caplacizumab without plasma exchange for acquired TTP, and this approach is being investigated in clinical trials. Fresh-frozen plasma is transfused to supply ADAMTS13 for congenital TTP, but frequent transfusions over a long period of time can lead to problems such as infection and allergic reactions. Novel therapies such as recombinant ADAMTS13 products and gene therapy are now under development, and show promise for future clinical use.
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Proteína ADAMTS13 , Púrpura Trombocitopénica Trombótica , Púrpura Trombocitopénica Trombótica/terapia , Humanos , Proteína ADAMTS13/deficiencia , Intercambio Plasmático , Terapia Genética , Anticuerpos de Dominio Único/uso terapéuticoRESUMEN
INTRODUCTIONS: Patients with acquired thrombotic thrombocytopenic purpura (TTP) show no severe abnormalities in coagulation or fibrinolysis. However, the exact extent of the abnormalities is unclear. MATERIALS AND METHODS: This study analyzed 138 patients with acquired TTP and 46 patients with septic disseminated intravascular coagulation (DIC) who were included in a Japanese registry. Complete blood cell counts and 8 coagulation or fibrinolysis parameters were compared between the 2 groups. RESULTS: Platelet counts in the acquired TTP group were significantly lower than those in the septic DIC group (P < .001). The international normalized ratio of prothrombin time and the activated partial thromboplastin time in the septic DIC group were significantly higher and longer, respectively, than those in the acquired TTP group (P < .01). The antithrombin (AT) values were significantly lower in the septic DIC group than in the acquired TTP group (P < .001), the latter of which were almost normal. Although both groups revealed elevations of fibrinogen degradation product (FDP) and D-dimer, these levels were significantly higher in the septic DIC group than in the acquired TTP group (P < .001). Of 138 patients with acquired TTP, 25 (18.1%) were diagnosed with septic DIC by the diagnostic criteria of the Japanese Ministry Health, Labour and Welfare, and 78 (56.5%) by those of the Japanese Association of Acute Medicine. Receiver operating characteristic curve analysis showed that acquired TTP could be diagnosed based on severe thrombocytopenia (<20 × 109/L), normal AT level (>87%), and mildly elevated FDP (<23 µg/mL). CONCLUSIONS: Our results indicate that 3 routine laboratory tests could differentiate between acquired TTP and septic DIC.
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Coagulación Sanguínea , Coagulación Intravascular Diseminada , Fibrinólisis , Púrpura Trombocitopénica Trombótica , Antitrombinas/sangre , Diagnóstico Diferencial , Coagulación Intravascular Diseminada/sangre , Coagulación Intravascular Diseminada/diagnóstico , Humanos , Tiempo de Tromboplastina Parcial , Tiempo de Protrombina , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/diagnósticoRESUMEN
Because the coronavirus disease 2019 (COVID-19) pandemic is still rampant, vaccination is being promoted worldwide. However, the safety of various COVID-19 vaccines remains poorly understood. We herein report the case of a 37-year-old woman who experienced thrombocytopenia following BNT162b2 mRNA COVID-19 vaccination. The patient presented with purpura on the extremities 10 days after the first vaccination. She had marked thrombocytopenia and no thrombosis. Thrombocytopenia resolved spontaneously. Given the possibility of occurrence of post-vaccination thrombocytopenia, vaccinated persons should be instructed to consult a medical institution if they experience bleeding symptoms.
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COVID-19 , Púrpura Trombocitopénica , Adulto , Vacuna BNT162 , Vacunas contra la COVID-19 , Femenino , Humanos , ARN Mensajero , SARS-CoV-2 , Vacunación/efectos adversosRESUMEN
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease in which platelets are consumed and thrombotic microangiopathy develops in multiple organs due to a severe deficiency of the metalloproteinase, ADAMTS13. TTP should be suspected in any case associated with thrombocytopenia and hemolytic anemia; TTP can be diagnosed in cases of profound reduction in ADAMTS13 activity (to <10% of the normal level). Congenital TTP involves mutations in the ADAMTS13 gene, whereas acquired or autoimmune TTP results from the actions of inhibitory autoantibodies against the ADAMTS13 protein. Plasma exchange together with corticosteroids is an effective treatment for acquired TTP; plasma exchange removes autoantibodies and provides ADAMTS13 supplementation, whereas corticosteroids further suppress autoantibody generation. Rituximab was recently approved in Japan for use in refractory or relapsing TTP. Likewise, caplacizumab, an anti-von Willebrand factor, may contribute to disease control and overall survival by preventing ongoing thrombosis and acute end-organ damage.
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Anemia Hemolítica , Púrpura Trombocitopénica Trombótica , Humanos , Japón , Intercambio Plasmático , Factor de von WillebrandRESUMEN
A 71-year-old male developed plasmacytoma on September 2015. He received radiotherapy, followed by posterior spinal fusion, at Th5 and L3 and was subsequently administered lenalidomide plus dexamethasone (Ld) from January 2016. After the 9th course of Ld, the patient complained of epigastric discomfort and papules on the face. FDG-PET showed duodenum 3rd potion and indicated nodular lesions with high glucose uptake on the lower lobe of the right lung and third portion of the duodenum. Biopsy of the skin, duodenum, and lung revealed Grocott's stain positive circular bodies, and the patient was subsequently diagnosed with disseminated cryptococcosis. Although disseminated cryptococcosis often causes encephalomeningitis, gastrointestinal involvement is rarely reported. The underlying conditions of disseminated cryptococcosis include AIDS, hematological malignancies, and steroid and immunosuppressant use. The sites of infections are the esophagus, stomach, small intestine, and colon. Disseminated cryptococcosis is diagnosed by abdominal pain, bloody stool, and gastrointestinal perforation. However, disseminated cryptococcosis may be asymptomatic; therefore, it is imperative that there is no delay in its diagnosis.
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Criptococosis , Plasmacitoma , Anciano , Biopsia , Humanos , Intestino Delgado , Masculino , Plasmacitoma/terapia , Tomografía de Emisión de PositronesAsunto(s)
COVID-19 , Púrpura Trombocitopénica Trombótica , Proteína ADAMTS13 , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Humanos , Japón/epidemiología , Púrpura Trombocitopénica Trombótica/epidemiología , Púrpura Trombocitopénica Trombótica/genética , ARN Mensajero , Sistema de Registros , Vacunas de ARNmRESUMEN
The allergic inflammatory effects of particulate matter (PM) 2.5, collected with the cyclone system in Yokohama city in Japan, were investigated in NC/Nga mice, which are hypersensitive to mite allergens. PM2.5 with alum was injected intraperitoneally for sensitization. Five days later, 200 µg of PM2.5 in 25 µL of saline was administered to mice intranasally five times for further sensitization. On the 11th day, PM2.5 was administered as a challenge. On the 12th day, mice were examined for airway hyperresponsiveness (AHR), the bronchoalveolar lavage fluid (BALF) cell count, mRNA expression of Th1 , Th2 cytokines, and metallothioneins in lung tissue, and histopathology. PM2.5 increased AHR, total cell numbers including eosinophils in BALF, and mRNA levels of IL-5, IL-22, eotaxin, eotaxin 2, and metallothionein 3. In PM2.5-induced lungs, inflammation was observed around the bronchus. These results demonstrate that PM2.5 alone, collected with the cyclone system in Yokohama city in Japan, induces asthma-like airway inflammation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1047-1054, 2017.
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Hiperreactividad Bronquial/inducido químicamente , Material Particulado/toxicidad , Neumonía/inducido químicamente , Neumonía/fisiopatología , Animales , Asma/inducido químicamente , Asma/patología , Asma/fisiopatología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Hiperreactividad Bronquial/fisiopatología , Líquido del Lavado Bronquioalveolar/química , Citocinas/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos , Tamaño de la Partícula , Neumonía/inmunología , Neumonía/patologíaRESUMEN
Oxidative stress is widely known to play a role in asthma. However, the contribution of xanthine oxidoreductase (XOR) as a source of the superoxide anion radical (O2ï¼) in oxidative stress associated with asthma has not yet been examined in detail. Here we investigated pathophysiological changes in XOR in an experimental model of asthma induced by the house dust mite Dermatophagoides farinae (Df). In the lungs of Df-treated mice, the production of O2 ï¼ from XOR increased and the nitrite concentrations decreased, whereas the protein expression of XOR remained unchanged. Moreover, the protein expression levels of XOR and the hydrogen peroxide (H2O2) concentrations in bronchoalveolar lavage fluid (BALF) were higher in the Df-treated mice than in saline-treated mice. Immunohistochemically, although XOR was highly localized in the bronchial epithelial cells of the saline-treated mice, immunostaining for XOR was absent in the bronchial epithelium of Df-treated mice. These results suggest that oxidative stress is up-regulated by increases in the conversion of the dehydrogenase form (xanthine dehydrogenase; XDH) of XOR to the oxidase form (xanthine oxidase; XOD).
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Antígenos Dermatofagoides/inmunología , Asma/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Xantina Deshidrogenasa/metabolismo , Animales , Líquido del Lavado Bronquioalveolar , Peróxido de Hidrógeno , Pulmón/química , Masculino , Ratones , Nitratos/química , Nitratos/metabolismo , Nitritos/química , Nitritos/metabolismo , Ácido Úrico/químicaRESUMEN
Allergic asthma caused by continuous allergen exposure evokes allergen-specific Th2 responses and is characterized by chronic airway inflammation and hyperresponsiveness. A previous report showed that rebamipide improved asthmatic symptoms in an ovalbumin/trypsin mice model. However, it is still unclear how rebamipide exerts its effects in asthma. In this study, rebamipide improved the asthmatic responses induced by mite exposure in NC/Nga mice, revealing the mechanism of this therapeutic effect. Rebamipide suppressed the infiltration of eosinophils into the airways and lung as well as attenuating the production of reactive oxygen species in tissues. In addition to these anti-inflammatory effects, rebamipide inhibited the production of IL-33, a member of the IL-1 family that drives the subsequent production of Th2-associated cytokines. These observations identify the point where rebamipide exerts its suppressive action on asthma and suggest that rebamipide has therapeutic potential in preventing mite-induced asthma.
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Alanina/análogos & derivados , Asma/tratamiento farmacológico , Quinolonas/uso terapéutico , 8-Hidroxi-2'-Desoxicoguanosina , Alanina/uso terapéutico , Alérgenos/administración & dosificación , Animales , Antígenos Dermatofagoides/administración & dosificación , Antioxidantes/uso terapéutico , Asma/etiología , Asma/patología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Quimiocina CCL11/genética , Quimiocina CCL11/metabolismo , Quimiocina CCL24/genética , Quimiocina CCL24/metabolismo , Citocinas/genética , Citocinas/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Modelos Animales de Enfermedad , Interleucina-33/genética , Interleucina-33/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/fisiopatología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Hipersensibilidad Respiratoria/tratamiento farmacológicoRESUMEN
Changes in l-arginine metabolism, including increased arginase levels and decreased nitric oxide production, are involved in the pathophysiology of asthma. In this study, using an intranasal mite-induced NC/Nga mouse model of asthma, we examined whether administration of l-arginine ameliorated airway hyperresponsiveness and inflammation by altering l-arginine metabolism. Experimental asthma was induced in NC/Nga mice via intranasal administration of mite crude extract (50 µg/day) on 5 consecutive days (days 0-4, sensitization) and on day 11 (challenge). Oral administration of l-arginine (250 mg/kg) was performed twice daily on days 5-10 for prevention or on days 11-13 for therapy. On day 14, we evaluated the inflammatory airway response (airway hyperresponsiveness, the number of cells in the bronchoalveolar lavage fluid, and the changes in pathological inflammation of the lung), arginase expression and activity, l-arginine bioavailability, and the concentration of NOx, the end products of nitric oxide. Treatment with l-arginine ameliorated the mite-induced inflammatory airway response. Furthermore, l-arginine administration attenuated the increases in arginase expression and activity and elevated the NOx levels by enhancing l-arginine bioavailability. These findings indicate that l-arginine administration may contribute to the improvement of asthmatic symptoms by altering l-arginine metabolism.
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We examined the relationships between dietary carbohydrate, protein, fat, and the ratio of n6/n3 fatty acid intakes with the predicted 10-year coronary heart disease (CHD) risk in a general Japanese population. We used the Framingham risk score to determine the 10-year CHD risk of the subjects, who were employees of 6 companies in a single prefecture in Japan. After excluding the subjects who reported any history of angina pectoris, myocardial infarction, diabetes, or cancer, and those with missing data resulting in the inability of estimation of 10-year CHD risk and food intakes, the final data analysis was carried out for 809 subjects. The logistic regression models revealed a significantly increased odds ratio of 10-year CHD risk in the subjects with the highest tertile of carbohydrate intake (% energy) (odds ratio 3.64, 95% CI, 2.07-6.40); after adjustment for other variables, the odds ratio for the 10-year CHD risk was also higher in the subjects with the highest tertile of carbohydrate intake (odds ratio 1.72, 95% CI, 0.70-4.25). We also found that fat intake and the ratio of n6/n3 fatty acids were inversely associated with the predicted 10-year CHD risk (p for trend<0.01). The present findings added evidence of a positive association of dietary carbohydrate and inverse associations of total fat and n6/n3 fatty acid ratio with the predicted 10-year CHD risk in a general Japanese population.
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Enfermedad Coronaria/epidemiología , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Adolescente , Adulto , Anciano , Pueblo Asiatico/etnología , Femenino , Humanos , Japón/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
To evaluate the allergic effect of airborne particulate matter (PM) on the airway, separated soluble supernatant (Sup) and insoluble precipitate (Pre) in suspended PM were inoculated into NC/Nga mice with a high sensitivity for mite allergens. Sup, Pre, or both Sup and Pre with or without pronase treatment were inoculated via the nasal route five times for sensitization and a challenge inoculation on the 11th day in NC/Nga mice. On the 14th day, mice were examined for airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF) cell count, mRNA expression of Th1 and Th2 cytokines in the lung tissue, and histopathology. Synergistic effects of Sup and Pre were observed as increases in AHR and a histopathological change of Periodic acid-Schiff (PAS) staining. Increases in neutrophils, macrophages, and lymphocytes of BALF cells were dependent on Pre. The expression of IL-4 mRNA was increased by Sup, and those of IL-5 mRNA and Il-13 mRNA was increased by Sup and Pre. Augmented AHR, mRNA expression of IL-4, peribronchial inflammation, and PAS staining by Sup plus Pre were attenuated by treatment of Sup with pronase to digest proteins. These results suggest that some proteins of ambient PM may be important environmental factors for AHR and airway inflammation with the aid of insoluble particulates, although some soluble factors such as endotoxins cannot be ruled out.
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Hiperreactividad Bronquial/patología , Inflamación/patología , Pulmón/patología , Material Particulado/efectos adversos , Animales , Hiperreactividad Bronquial/inmunología , Líquido del Lavado Bronquioalveolar/citología , Citocinas/metabolismo , Interleucina-13/inmunología , Interleucina-4/inmunología , Interleucina-5/inmunología , Pulmón/inmunología , Linfocitos/citología , Macrófagos/citología , Glicoproteínas de Membrana , Ratones , Neutrófilos/citología , Receptores de Interleucina-1RESUMEN
ABSTRACT: For patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP), caplacizumab, a nanobody against von Willebrand factor A1 domain, has become crucial. Delayed normalization of ADAMTS13 activity during caplacizumab therapy has been identified. In a retrospective analysis, we compared platelet count, ADAMTS13 activity, its inhibitor, and anti-ADAMTS13 immunoglobulin G (IgG) levels in acute iTTP cases treated with caplacizumab (n = 14) or without it (n = 16). The median time from initial therapeutic plasma exchange (TPE) to the first rituximab administration was 12 days in the caplacizumab group (n = 11) and 10 days in the group without caplacizumab (n = 13). We evaluated ADAMTS13-related parameters at onset and once a week until day 28 after the first TPE. The number of days until the platelet counts reached ≥150 × 109/L was significantly shorter in the caplacizumab group than in the non-caplacizumab group. The median ADAMTS13 activity levels on days 14, 21, and 28 were significantly lower in the caplacizumab group. The median titers of the ADAMTS13 inhibitor and anti-ADAMTS13 IgG on the same days were significantly higher in the caplacizumab group. Furthermore, the median number of days from the first TPE until finally achieving an ADAMTS13 activity of ≥10% was significantly longer in the caplacizumab group than in the non-caplacizumab group (42 vs 23 days, P = .014). We observed delayed ADAMTS13 activity recovery and continued inhibitor and anti-ADAMTS13 IgG detection in patients with acute iTTP on caplacizumab, possibly because of the decreased number of TPEs and delayed frontline rituximab.
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Proteína ADAMTS13 , Púrpura Trombocitopénica Trombótica , Anticuerpos de Dominio Único , Humanos , Proteína ADAMTS13/metabolismo , Anticuerpos de Dominio Único/uso terapéutico , Anticuerpos de Dominio Único/farmacología , Masculino , Femenino , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Púrpura Trombocitopénica Trombótica/terapia , Estudios Retrospectivos , Adulto , Anciano , Inmunoglobulina G/sangre , Recuento de Plaquetas , Japón , Rituximab/uso terapéutico , Rituximab/farmacología , Resultado del Tratamiento , Intercambio Plasmático , Pueblos del Este de AsiaRESUMEN
Serum ceruloplasmin (CP), a marker relevant to copper metabolism, is one of famous inflammation markers with a reduction in Wilson's disease, whereas serum ferritin is a marker relevant to iron metabolism. Recently, ferritin is pointed out to be related with oxidative stress. However, there is still no population research which showed the relation of CP and ferritin. Therefore, we investigated the relationship between CP and ferritin including oxidative stress biomarkers among healthy Japanese (n = 389). We measured serum CP, ferritin, Fe, high-sensitivity C-reactive protein (hs-CRP), and urinary oxidative stress biomarkers [H2O2, 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-isoprostane] and so on. Subjects showed that age; 41.7 ± 10.0 (year), CP; 31.9 ± 6.8 (mg/dl), ferritin; 123.5 ± 121.0 (ng/ml), hs-CRP; 0.89 ± 2.53 (mg/l), 8-OHdG; 10.2 ± 4.4 [ng/mg creatinine (Cre)] and H2O2; 6.5 ± 10.9 (µM/g Cre), (All data mentioned above were expressed as mean ± SD). CP was significantly and positively correlated with hs-CRP and inversely correlated with ferritin, Fe and 8-OHdG. By a multiple logistic regression analysis, odds ratio of CP according to quartiles of hs-CRP was 4.86, and according to quartiles of 8-OHdG was 0.39 after adjusting for age and other confounding factors. In conclusion, our findings suggest that CP was an antioxidative biomarker which controls oxidative stress, whereas ferritin was a marker which may participate in the generation of oxidative stress.
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Thrombotic thrombocytopenic purpura (TTP) is a fatal disease in which platelet-rich microthrombi cause end-organ ischemia and damage. TTP is caused by markedly reduced ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity. Hereditary or congenital TTP (cTTP) is caused by ADAMTS13 gene mutations. In acquired or immune TTP (iTTP), ADAMTS13 activity is reduced by anti-ADAMTS13 autoantibodies. TTP is characterized by thrombocytopenia, hemolytic anemia, fever, renal dysfunction, and neuropsychiatric symptoms. Therapeutic plasma exchange (TPE) and immunosuppressive therapy are the mainstays of treatment. As untreated TTP has a high mortality rate, immediate initiation of TPE is recommended when TTP is suspected. Conventionally, corticosteroids have been used for immunosuppressive therapy. Current drug therapies include rituximab, an anti-CD20 antibody that is effective in newly diagnosed cases and refractory cases, as well as for relapse prevention, and caplacizumab, an anti- von Willebrand factor (VWF) nanobody that inhibits the binding of platelets to VWF and prevents microthrombi formation. Recombinant human ADAMTS13 is a promising treatment for cTTP. Although these therapeutic advances have improved the outcomes of TTP, early diagnosis and prompt initiation of appropriate therapy are necessary to achieve these outcomes.
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Anemia Hemolítica , Púrpura Trombocitopénica Trombótica , Humanos , Factor de von Willebrand/metabolismo , Rituximab/uso terapéutico , Autoanticuerpos , Anemia Hemolítica/tratamiento farmacológico , Intercambio Plasmático , Proteína ADAMTS13RESUMEN
BACKGROUND: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare autoimmune disorder caused by autoantibodies against ADAMTS13. A strong association of DRB1∗11 with iTTP and DRB1∗11-restricted T-cell epitopes in ADAMTS13 have been reported in Europeans, whereas we previously found DRB1∗08:03 as a susceptible allele in Japanese. OBJECTIVES: The limited information is available regarding a susceptible allele and its T-cell epitopes in Japanese patients with iTTP. MATERIALS AND METHODS: We conducted a reanalysis on iTTP-predisposing alleles using 3 distinct Japanese control groups. Subsequently, a novel human leukocyte antigen (HLA)-peptide expression assay (MHC-density assay) was used to identify the presentation of 24 ADAMTS13-derived peptides, including the regions that were identified previously by MHC-peptidome analysis and/or T-cell assays or predicted by NetMHCIIpan-4.0, to DRB1∗08:03 and DRB1∗11:01. RESULTS: We reconfirmed the strong association of DRB1∗08:03 with iTTP, as well as the absence of the secondary risk alleles and protective alleles in Japanese iTTP, which altogether reveal that the HLA association pattern is completely different between the European and Japanese iTTP. MHC-density assay found the 3 ADAMTS13-derived peptides in the spacer domain as a potential strong binder to DRB1∗08:03. Moreover, 6 peptides in the metalloprotease, spacer, sixth thrombospondin-1 repeat, and CUB domains in ADAMTS13 showed increased presentation by both DRB1∗08:03 and DRB1∗11:01. CONCLUSION: Altogether, the findings of distinct HLA-DR association with iTTP across populations and the presentation of common peptides by DRB1∗08:03 and DRB1∗11:01 suggest that the same ADAMTS13-derived peptides might be presented and trigger the activation of autoreactive CD4+ T cells, leading to production of anti-ADAMTS13 autoantibodies by autoreactive B cells.
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Epítopos de Linfocito T , Púrpura Trombocitopénica Trombótica , Humanos , Proteína ADAMTS13/metabolismo , Autoanticuerpos , Susceptibilidad a Enfermedades , Péptidos/química , Cadenas HLA-DRB1/inmunologíaRESUMEN
Background: Both immune-mediated thrombotic thrombocytopenic purpura (iTTP) and septic disseminated intravascular coagulation (DIC) are life-threatening disorders developed by platelet-consuming microvascular thrombi and necessitate immediate therapeutic interventions. Although severe deficiencies of plasma haptoglobin in iTTP and factor XIII (FXIII) activity in septic DIC have been reported, few studies have focused on the possibility of using these markers to distinguish between iTTP and septic DIC. Objectives: We investigated whether the plasma levels of haptoglobin and FXIII activity could be helpful for differential diagnosis. Methods: Thirty-five patients with iTTP and 30 with septic DIC were enrolled in the study. Patient characteristics, coagulation, and fibrinolytic markers were collected from the clinical data. Plasma haptoglobin and FXIII activities were measured using chromogenic Enzyme-Linked Immuno Sorbent Assay and an automated instrument, respectively. Results: The median plasma haptoglobin level was 0.39 mg/dL and 54.20 mg/dL in the iTTP and septic DIC groups, respectively. The median plasma FXIII activities were 91.3% and 36.3% in the iTTP and septic DIC groups, respectively. In the receiver operating characteristic curve analysis, the cutoff level of plasma haptoglobin was 2.868 mg/dL and the area under the curve was 0.832. The cutoff level for plasma FXIII activity and the area under the curve were 76.0% and 0.931, respectively. The thrombotic thrombocytopenic purpura (TTP)/DIC index was defined by FXIII activity (percentage) and haptoglobin (milligrams per decilitre). Laboratory TTP was defined as an index ≥60 and laboratory DIC <60. The sensitivity and specificity of the TTP/DIC index were 94.3% and 86.7%, respectively. Conclusion: The TTP/DIC index, composed of plasma levels of haptoglobin and FXIII activity, is useful in differentiating iTTP from septic DIC.
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A 63-year-old woman with adult T-cell leukemia (ATL) lymphomatous type developed a mild dry cough. Computed tomography revealed lung lesions with a tree-in-bud appearance during intensive chemotherapy. Antibodies against Mycobacterium avium complex were positive. Bronchoalveolar lavage culture showed growth of M. abscessus complex. Finally, M. abscessus subsp. massiliense was also identified. Sequential use of antimicrobials, including macrolides, was introduced during intensive chemotherapy, and the patient successfully underwent allogeneic hematopoietic stem cell transplantation (AHSCT). This is the first case report of a patient with ATL complicated by M. massiliense lung infection, who was successfully treated with haploidentical AHSCT using various combinations of antimicrobials.
RESUMEN
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultrarare thrombotic disease caused by autoantibody-induced ADAMTS13 deficiency. Open ADAMST13 conformation, induced by autoantibodies, was identified as a novel biomarker for iTTP. Determining immunoprofiles in patients with iTTP has been shown to guide the development of novel targeted therapies. However, these studies were done in mainly Caucasian iTTP cohorts. To validate those findings across other ethnic cohorts, we investigated 195 acute TTP plasma samples from the Japanese iTTP registry. Seventy-six of the 195 samples had detectable ADAMTS13 antigen levels, of which 94.7% were shown to have an open ADAMTS13 conformation. A positive correlation was observed between ADAMTS13 inhibitor titers (a diagnostic parameter in Japan) and anti-ADAMTS13 immunoglobulin G autoantibody titers. Studying anti-M, anti-DT, anti-CS, anti-T2-T5, anti-T6-T8, anti-CUB1-2 autoantibodies and the corresponding immunoprofile showed that 73% of the patients had anti-CS autoantibodies and 25.8% had anti-M autoantibodies, with the latter being higher than in Caucasians. Stratifying patients according to their immunoprofiles revealed that the profile with only anti-CS autoantibodies was the most common immunoprofile similar to that in Caucasians (28.9%). Although this profile did not affect the 1-year TTP-related mortality rate, patients with autoantibodies against all 6 ADAMTS13 fragments had a higher risk for TTP-related death than other patients (P = .02). We here validated open ADAMTS13 as a novel biomarker for acute iTTP and determined the dominant immunoprofiling in the Japanese cohort, contributing to setting up the diagnosis and managing guidelines across different ethnic cohorts and developing ADAMTS13 variants that do not bind to the anti-CS autoantibodies.