RESUMEN
OBJECTIVES: To preliminarily evaluate the feasibility of maintenance therapy with reduced dose of intravenous abatacept (ABT) to 250 mg/body/month after achieving remission or low disease activity (LDA). PATIENTS AND METHODS: RA patients treated with ABT at 13 sites were enrolled in this prospective interventional pilot study during the period between March 2013 and March 2015. Inclusion criteria were (1) age at 20 years or older, (2) under treatment with monthly intravenous ABT at approved doses, (3) DAS28-CRP lower than 2.7 at least for 6 months, (4) agreed to join this trial with written informed consent and (5) body weight under 125 kg. Enrolled patients were maintained with intravenous monthly ABT at a reduced dose of 250 mg/body (MATADOR protocol). The primary end point was the proportion of the patients continued with MATADOR protocol at week 48. MATADOR protocol was discontinued upon disease flare or other reasons such as patients' request or severe adverse event (AE). Disease activities and structural changes were also evaluated. RESULTS: Fifty-three patients fulfilled the entry criteria and were followed for 1-year. MATADOR protocol was continued for 1-year in 43 (81%) of the evaluated patients. Three patients experienced severe AEs. Mean DAS28-CRP and remission rate were 1.56 and 88% when ABT reduced and 1.80 and 81% at 1-year, respectively. Structural remission was achieved in 34 out of 42 evaluated patients. CONCLUSIONS: Reduced dose of intravenous ABT was proposed as a feasible choice for maintenance therapy for RA after achievement of remission/LDA, although further randomized trials would be awaited.
Asunto(s)
Abatacept/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Abatacept/administración & dosificación , Abatacept/efectos adversos , Adulto , Anciano , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Inducción de RemisiónRESUMEN
A 62-year-old woman developed B lymphoblastic leukemia (B-ALL) in April 2010, and achieved complete remission after hyper-CVAD/high-dose-MA therapy combined with rituximab. ALL recurred in December 2011, and remission was again achieved with the Japan Adult Leukemia Study Group (JALSG) ALL202 protocol combined with rituximab. Owing to a fever and rash that persisted from July 2012, the patient was examined again. On examination, redness was observed in the pharynx, and poorly defined oval erythemas were seen on the cheeks, posterior region of the neck, and upper arms. Blood test results showed high levels of ferritin, tumor necrosis factor (TNF)-α, an d C-reactive protein (CRP), and mild hepatosplenomegaly was identified on abdominal computed tomography (CT), indicative of an adult-onset Still's disease-like condition. Prednisolone therapy was initiated in August 2012, and remission was achieved. A second recurrence of ALL developed in September 2012, and although remission was again achieved using the JALSG ALL202 protocol, a third recurrence of ALL occurred in April 2013, and the patient could not be saved. In this case, adult-onset Still's disease-like erythema developed during the remission phase of ALL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Enfermedad de Still del Adulto/etiología , Resultado Fatal , Femenino , Humanos , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , RecurrenciaAsunto(s)
Hepatopatías/diagnóstico , Hígado/patología , Sarcoidosis/complicaciones , Adulto , Biopsia , Diagnóstico Diferencial , Femenino , Glucocorticoides/administración & dosificación , Humanos , Hepatopatías/tratamiento farmacológico , Hepatopatías/etiología , Metilprednisolona/administración & dosificación , Tomografía Computarizada por Tomografía de Emisión de Positrones , Prednisona/administración & dosificación , Sarcoidosis/diagnóstico , Sarcoidosis/tratamiento farmacológico , Tomografía Computarizada por Rayos XAsunto(s)
Amiloidosis/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Glomerulonefritis por IGA/tratamiento farmacológico , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Proteína Amiloide A Sérica/metabolismo , Anciano , Artritis Reumatoide/complicaciones , Femenino , HumanosRESUMEN
BACKGROUND: Tacrolimus (TAC) was approved in Japan in 2005 for rheumatoid arthritis (RA) patients having inadequate response to other disease-modifying anti-rheumatic drugs. As of May 2007, spontaneous reports identified twenty-seven cases of exacerbation or new development of interstitial pneumonia among RA patients given TAC in Japan. OBJECTIVE: To describe the clinical and radiological characteristics of TAC-induced pulmonary injury (TIPI). PATIENTS AND METHODS: Eleven RA patients diagnosed with de novo pulmonary injury or exacerbation of IP during treatment with TAC were identified. Clinical, radiological, and laboratory data of ten of these cases were retrospectively analyzed. RESULTS: Baseline data for the ten patients were a mean age of 69.7 years; gender, 70% female; mean RA disease duration, 9.1 years; and pulmonary comorbidities, 90%. Six cases were classified as presumptive TAC-induced pulmonary injury (TIPI) and four as probable TIPI. Among the six presumptive cases, TIPI developed at an average of 84 days after initiation of treatment (n = 5) or four days after reinstitution of TAC (n = 1). Five cases were an exacerbation of pre-existing interstitial pneumonia and one was a de novo pulmonary injury. Radiological patterns of thoracic computed tomography (CT) scans of patients in the presumptive TIPI cases were hypersensitivity pneumonia like-pattern (n = 3), ground-glass opacity (n = 2), and organizing pneumonia-pattern (n = 1). All patients with presumptive TIPI were treated with high dosage glucocorticosteroids and one received concomitant immunosuppressants. Two of the six presumptive TIPI patients died. CONCLUSION: Rheumatologists should be aware of this rare but potentially life-threatening adverse event in RA patients receiving TAC.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Inmunosupresores/efectos adversos , Pulmón/efectos de los fármacos , Tacrolimus/efectos adversos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Pulmón/patología , Masculino , Persona de Mediana Edad , Radiografía Torácica , Tomografía Computarizada por Rayos XRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that has developed in late 2019 and 2020 is a serious threat to human health. With no vaccines or drugs approved for prevention and treatment until now, all efforts at drug design and/or clinical trials of already approved drugs are worthy and creditable. Using structure-based drug selection for identification of SARS-CoV-2 protease inhibitors, old drugs such as macrolides (MAC) were predicted to be effective for COVID-19. Lately, the anti-viral effects of macrolides have attracted considerable attention. Very recently, hydroxychloroquine in combination with azithromycin treatment was reported to be effective for COVID-19. We believe that treatments with macrolides alone or in combination with other drugs are promising and open the possibility of an international strategy to fight this emerging viral infection.
Asunto(s)
Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Macrólidos/farmacología , Neumonía Viral/tratamiento farmacológico , Antivirales/química , Antivirales/farmacología , Betacoronavirus/enzimología , Betacoronavirus/aislamiento & purificación , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Humanos , Macrólidos/química , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/virología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , SARS-CoV-2 , Relación Estructura-Actividad , Tratamiento Farmacológico de COVID-19RESUMEN
A 74-year-old woman with recurrent fever and multiple joint pain was admitted to Hokkaido University Hospital. Trans-esophageal echocardiogram revealed bacterial vegetation and destruction of the aortic valve. Although few bacteria grew in regular blood agar, Gram-positive coccobacillus was specifically grown in chocolate blood agar and Brucella agar, and it was identified to be Abiotrophia defectiva. Infectious endocarditis caused by Abiotrophia defectiva was diagnosed, she was treated with diuretics, penicillin G and gentamicin, and she immediately improved. Infectious diseases caused by Abiotrophia defectiva are extremely rare, and identification of this pathogen is important, as its bacterial characteristics require proper attention.
Asunto(s)
Endocarditis Bacteriana/etiología , Infecciones por Bacterias Grampositivas/complicaciones , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Antihipertensivos/uso terapéutico , Endocarditis Bacteriana/diagnóstico , Endocarditis Bacteriana/terapia , Femenino , Fiebre/etiología , Gentamicinas/uso terapéutico , Bacterias Grampositivas/efectos de los fármacos , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Hipertensión/complicaciones , Hipertensión/terapia , Penicilinas/uso terapéutico , Sulfonamidas/uso terapéutico , Torasemida , Resultado del TratamientoRESUMEN
Giant cell arteritis (GCA) is a granulomatous arteritis and it occurs older (more than 50 years) individuals. As GCA frequently involves temporal artery, this disease had been called as temporal arteritis. However, except for the temporal artery, GCA affects branches of the carotid arteries, as well as aorta and its major branches preferentially. Thus, this arteritis is collectively called as GCA from the characteristic histological findings. We systematically introduce the clinical pictures of GCA in the first half of this article. Because affected arteries of GCA are different in each patient, some patients do not present with classical clinical features, such as headache and tenderness of temporal artery. Recently, there are several variant forms of GCA have been recognized. Certain subtypes demonstrate organ dysfunction, such as visual loss or peripheral neuropathy with minimal or absent classical and systemic manifestations. This form of GCA is referred to as occult GCA. On the other hand, other form of GCA presents with a systemic inflammatory syndrome in the absence of focal ischemic symptoms. This is referred to as silent or masked GCA. In the latter half of this article, we introduce two patients presenting with such atypical presentations. One could be diagnosed as occult GCA, and the other was diagnosed as silent GCA with large vessel type. GCA is a heterogenous disease with more than a single clinical picture. This article can provide considerations of the wide spectrum of presentation of this characteristic systemic arteritis.
Asunto(s)
Arteritis de Células Gigantes , Anciano , Ciclofosfamida/administración & dosificación , Diagnóstico por Imagen , Quimioterapia Combinada , Femenino , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/epidemiología , Arteritis de Células Gigantes/patología , Humanos , Inmunosupresores/administración & dosificación , Japón/epidemiología , Masculino , Metotrexato/administración & dosificación , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Prednisolona/administración & dosificación , Pronóstico , Quimioterapia por Pulso , Arterias Temporales/patologíaAsunto(s)
Artritis Reumatoide/tratamiento farmacológico , Varicela/inducido químicamente , Piperidinas/efectos adversos , Neumonía Viral/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Pirroles/efectos adversos , Anciano , Varicela/virología , Femenino , Herpesvirus Humano 3/efectos de los fármacos , Humanos , Neumonía Viral/virologíaRESUMEN
This is a case study of a patient diagnosed with microscopic polyangiitis (MPA) and complicated with deep vein thrombosis (DVT), who died of respiratory failure despite treatment. Autopsy revealed severe crescentic glomerulonephritis and massive alveolar hemorrhage. The thrombus contained abundant neutrophils. Although it is reported that patients with ANCA-associated vasculitis (AAV) have an increased risk of DVT, it remains elusive why they are prone to thrombosis. A recent study has demonstrated the presence of neutrophil extracellular traps (NETs), a newly recognized mode of neutrophil cell-death, in glomerular crescents of MPA patients. Interestingly, NETs were identified in the thrombus as well as in the glomerular crescents in the present case. When compared to other thrombi unrelated to MPA, the amount of NETs was significantly greater in the MPA patient. On the other hand, NETs are critically involved in thrombogenesis because histones within NETs can bind platelets and blood coagulants. Although this is important in regard to containment of microbes within NETs, excessive NETs could cause thrombosis. The collective findings suggest the possibility that thrombosis could be critically associated with MPA via NETs, and that NETs could be a therapeutic target in MPA patients.
RESUMEN
The cytotoxic function of CD178 (Fas ligand (FasL)) is critical to the maintenance of peripheral tolerance and immune-mediated tissue pathology. The active site of FasL resides at the FasL extracellular region (FasL(Ext)) and it functions through binding/cross-linking Fas receptor on target cells. In this study, we report that FasL(Ext)-mediated cytotoxicity is regulated by the FasL cytoplasmic tail (FasL(Cyt)). Deleting the N-terminal 2-70 aa (delta70) or N-terminal 2-33 aa (delta33) reduced the cytotoxic strength as much as 30- to 100-fold. By contrast, change in the cytotoxic strength was not observed with FasL deleted of the proline-rich domains (45-74 aa, delta PRD) in the FasL(Cyt). Our study identifies a novel function of FasL(Cyt) and demonstrates that FasL(2-33), a sequence unique to FasL, is critically required for the optimal expression of FasL(Ext)-mediated cytotoxicity.
Asunto(s)
Citotoxicidad Inmunológica , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/inmunología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Células COS , Línea Celular , Línea Celular Tumoral , Citoplasma/inmunología , ADN Complementario/genética , Proteína Ligando Fas , Humanos , Técnicas In Vitro , Células Jurkat , Glicoproteínas de Membrana/genética , Ratones , Datos de Secuencia Molecular , Células 3T3 NIH , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Eliminación de SecuenciaRESUMEN
OBJECTIVE: To study the capacity of butyrate to inhibit production of tumor necrosis factor alpha (TNFalpha) in macrophage-like synoviocytes (MLS) from patients with rheumatoid arthritis (RA), in human peripheral monocytes, and in murine RAW264.7 macrophages. METHODS: The concentrations of TNFalpha in culture supernatants of these cells were measured using enzyme-linked immunosorbent assay. The expression levels of various messenger RNAs (mRNA), such as those for TNFalpha, the mRNA-binding protein TIS11B, and luciferase, were measured using real-time quantitative polymerase chain reaction. The in vitro effects of butyrate on transcriptional regulation were evaluated by transfection with various reporter plasmids in RAW264.7 macrophages. The effects of TIS11B on TNFalpha expression were examined using an overexpression model of TIS11B in RAW264.7 cells. RESULTS: Butyrate suppressed TNFalpha protein and mRNA production in MLS and monocytes, but paradoxically enhanced transactivation of the TNFalpha promoter. Expression of the AU-rich element (ARE)-binding protein TIS11B was up-regulated by butyrate. Induction of TNFalpha mRNA by lipopolysaccharide was significantly inhibited when TIS11B was overexpressed. Butyrate facilitated the degradation of luciferase transcripts containing the 3'-untranslated region (3'-UTR) of TNFalpha, and this effect was dependent on the ARE in the 3'-UTR that is known to be involved in the regulation of mRNA degradation. CONCLUSION: These results indicate that butyrate suppresses TNFalpha expression by facilitating mRNA degradation mediated through a cis-acting ARE. Butyrate has the ability to regulate TNFalpha at the mRNA level and is therefore a potential therapeutic drug for RA patients.
Asunto(s)
Butiratos/farmacología , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , Membrana Sinovial/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Regiones no Traducidas 3'/efectos de los fármacos , Animales , Artritis Reumatoide , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/metabolismo , Lipopolisacáridos/farmacología , Luciferasas/genética , Luciferasas/metabolismo , Macrófagos/metabolismo , Ratones , Monocitos/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Membrana Sinovial/citología , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Tristetraprolina , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Soluble CD95 (Fas) ligand (sFasL) is known to be deficient in transducing signals upon engagement with membrane Fas. Here we report that sFasL tranduces, in synergy with non-cytotoxic anti-Fas monoclonal antibody (mAb), signals for apoptosis and nuclear translocation of the NF-kappaB (p65/p50) heterodimer. Activation of the specific signaling pathways correlates with target Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein expression. Synergy with anti-Fas mAb was demonstrated with a trimeric unit of sFasL bearing a single binding site for Fas trimer. In contrast, membrane-bound FasL as expressed on cell-derived vesicles was fully competent in transducing Fas-mediated signals for apoptosis and NF-kappaB nuclear translocation. We propose a model in which the trimeric sFasL signaling requires target expression of a high focal density of Fas, which is induced by the signaling-incompetent anti-Fas mAb. Membrane-bound FasL induces powerful Fas-mediated signals because it possesses both Fas-focusing and signal-transducing functions.
Asunto(s)
Anticuerpos Monoclonales/fisiología , Apoptosis/inmunología , FN-kappa B/metabolismo , Transducción de Señal/fisiología , Receptor fas/fisiología , Células 3T3 , Transporte Activo de Núcleo Celular , Animales , Secuencia de Bases , Cartilla de ADN , Sinergismo Farmacológico , Humanos , Cinética , Ratones , Sondas de Oligonucleótidos , Transcripción Genética , Células Tumorales Cultivadas , Receptor fas/inmunologíaRESUMEN
The Jo2 anti-mouse CD95 monoclonal antibody induces lethality in mice characterized by hepatocyte death and liver hemorrhage. Mice bearing a defect in Fas expression or in the Fas-mediated apoptotic pathway are resistant to Jo2. Here we show that FcgammaRII knockout mice or mice with monoclonal antibody-blocked FcgammaRII are also resistant to Jo2. The critical FcgammaRII(+) cells are radioresistant and could not be reconstituted with splenic cells. Death of sinusoidal lining cells and destruction of sinusoids were observed, consistent with the characteristic liver hemorrhage and the selective FcgammaRII expression in sinusoidal lining cells but not hepatocytes. Hemorrhage developed coincident with hepatocyte death and the sharp rise of serum alanine aminotransferase and alanine aminotransferase. Invariably, moribund mice showed severe liver hemorrhage and destruction of sinusoids. The data demonstrate a novel mechanism by which the destruction of liver sinusoids, induced by the Jo2-mediated co-engagement of Fas and FcgammaRII, leads to severe hemorrhage and lethal fulminant hepatitis.
Asunto(s)
Antígenos CD/metabolismo , Fallo Hepático/metabolismo , Receptores de IgG/metabolismo , Receptor fas/metabolismo , Alanina Transaminasa/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Antígenos CD/química , Apoptosis , Muerte Celular , Relación Dosis-Respuesta a Droga , Hepatocitos/metabolismo , Hepatocitos/patología , Lipopolisacáridos/metabolismo , Hígado/metabolismo , Hígado/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de IgG/químicaRESUMEN
During thymic selection 'mis-selected' CD8(+) T cells exit to the periphery where they are deleted by a Fas/FasL-mediated mechanism, presumably as a result of activation by self-antigens. In the absence of functional FasL, as is the case in autoimmune gld mice, these 'mis-selected' T cells develop into unique Thy1(+)CD4(-)CD8(-) TCRalphabeta(+)B220(+) lymphocytes [abnormal double negative T (DN T) cells]. Using bioactive FasL-bearing vesicles [FasL vesicle preparation (FasL VP)], we were able to induce acute apoptosis in freshly isolated lymphocytes and to demonstrate that peripheral lymphocytes of gld mice become more sensitive to the FasL-mediated apoptosis as they age. Furthermore, flow cytometric analyses indicated that within this peripheral lymphocyte population, the abnormal DN T cells were preferentially eliminated. The exquisite sensitivity of these abnormal DN T cells is attributed to their increased membrane Fas expression with a concomitant reduction of cytosolic FLIP(L). Our data support the hypothesis that specific components of the Fas-mediated apoptotic pathway are modulated in favor of the elimination of auto-reactive T cells as well as those CD8(+) T cells that are 'mis-selected' in the thymus and escape to the periphery.
Asunto(s)
Apoptosis/inmunología , Enfermedades Autoinmunes/inmunología , Supresión Clonal , Glicoproteínas de Membrana/farmacología , Subgrupos de Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales de Origen Murino , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Proteína Ligando Fas , Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/genética , Antígenos Comunes de Leucocito/análisis , Ganglios Linfáticos/citología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Mutantes , Proteínas/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , ARN Mensajero/análisis , Bazo/citología , Timo/citología , Proteína bcl-XRESUMEN
Fas ligand ((FasL) CD178), a type II transmembrane protein, induces apoptosis of cells expressing the Fas receptor. It possesses a unique cytoplasmic tail (FasLCyt) of 80 aa. As a type II transmembrane protein, the early synthesis of FasLCyt could affect FasL translation by impacting FasL endoplasmic reticulum translocation and/or endoplasmic reticulum retention. Previous studies suggest that the proline-rich domain (aa 43-70) in FasLCyt (FasLPRD) inhibits FasL membrane expression by retaining FasL in the secretory lysosomes. This report shows that deletion of aa 2-33 of FasLCyt dramatically increased total FasL levels and FasL cell surface expression. This negative regulator of FasL expression is dominant despite the presence of FasLPRD. In addition, retention of proline-rich domain-containing FasL in the cytoplasm was not observed. Moreover, we demonstrated that FasLCyt regulates FasL expression by controlling the rate of de novo synthesis of FasL. Our study demonstrated a novel negative regulator of FasL expression in the FasLCyt region and its mechanism of action.
Asunto(s)
Citoplasma/metabolismo , Lisosomas/metabolismo , Glicoproteínas de Membrana/biosíntesis , Biosíntesis de Proteínas , Secuencia de Aminoácidos , Animales , Células COS , Proteína Ligando Fas , Glicoproteínas de Membrana/análisis , Glicoproteínas de Membrana/química , Ratones , Datos de Secuencia Molecular , Células 3T3 NIH , RatasRESUMEN
BEta(2)-glycoprotein I (beta(2)-GPI) is proteolytically cleaved by plasmin in domain V (nicked beta(2)-GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked beta(2)-GPI were detected in patients with massive plasmin generation and fibrinolysis turnover. In this study, we report higher prevalence of elevated ratio of nicked beta(2)-GPI against total beta(2)-GPI in patients with ischemic stroke (63%) and healthy subjects with lacunar infarct (27%) when compared to healthy subjects with normal findings on magnetic resonance imaging (8%), suggesting that nicked beta(2)-GPI might have a physiologic role beyond that of its parent molecule in patients with thrombosis. Several inhibitors of extrinsic fibrinolysis are known, but a negative feedback regulator has not been yet documented. We demonstrate that nicked beta(2)-GPI binds to Glu-plasminogen with K(D) of 0.37 x 10(-6) M, presumably mediated by the interaction between the fifth domain of nicked beta(2)-GPI and the fifth kringle domain of Glu-plasminogen. Nicked beta(2)-GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact beta(2)-GPI lacks these properties. These data suggest that beta(2)-GPI/plasmin-nicked beta(2)-GPI controls extrinsic fibrinolysis via a negative feedback pathway loop.