RESUMEN
BACKGROUND: CRISPR/Cas9 system to treat human-related diseases has achieved significant results and, even if its potential application in cancer research is improving, the application of this approach in clinical practice is still a nascent technology. MAIN BODY: CRISPR/Cas9 technology is not yet used as a single therapy to treat tumors but it can be combined with traditional treatment strategies to provide personalized gene therapy for patients. The combination with chemotherapy, radiation and immunotherapy has been proven to be a powerful means of screening, identifying, validating and correcting tumor targets. Recently, CRISPR/Cas9 technology and CAR T-cell therapies have been integrated to open novel opportunities for the production of more efficient CAR T-cells for all patients. GMP-compatible equipment and reagents are already available for several clinical-grade systems at present, creating the basis and framework for the accelerated development of novel treatment methods. CONCLUSION: Here we will provide a comprehensive collection of the actual GMP-grade CRISPR/Cas9-mediated approaches used to support cancer therapy highlighting how this technology is opening new opportunities for treating tumors.
Asunto(s)
Sistemas CRISPR-Cas , Neoplasias , Humanos , Edición Génica/métodos , Inmunoterapia , Inmunoterapia Adoptiva , Neoplasias/genética , Neoplasias/terapiaRESUMEN
We developed an innovative and efficient, feeder-free culture method to genetically modify and expand peripheral blood-derived NK cells with high proliferative capacity, while preserving the responsiveness of their native activating receptors. Activated peripheral blood NK cells were efficiently transduced by a retroviral vector, carrying a second-generation CAR targeting CD19. CAR expression was demonstrated across the different NK-cell subsets. CAR.CD19-NK cells display higher antileukemic activity toward CD19+ cell lines and primary blasts obtained from patients with B-cell precursor ALL compared with unmodified NK cells. In vivo animal model data showed that the antileukemia activity of CAR.CD19-NK cell is superimposable to that of CAR-T cells, with a lower xenograft toxicity profile. These data support the feasibility of generating feeder-free expanded, genetically modified peripheral blood NK cells for effective "off-the-shelf" immuno-gene-therapy, while their innate alloreactivity can be safely harnessed to potentiate allogeneic cell therapy.
Asunto(s)
Antígenos CD19/inmunología , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Inmunoterapia Adoptiva/métodos , Células Asesinas Naturales/trasplante , Leucocitos Mononucleares/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores Quiméricos de Antígenos/inmunología , Animales , Apoptosis , Proliferación Celular , Citotoxicidad Inmunológica/inmunología , Humanos , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL-15). We found that compared with CAR.19(+) T cells, iC9/CAR.19/IL-15(+) T cells had: (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (Annexin-V(+)/7-AAD(+) cells 10+/-6% for iC9/CAR.19/IL-15(+) T cells and 32+/-19% for CAR.19(+) T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells <15% for iC9/CAR.19/IL-15(+) T cells versus >40% for CAR.19(+) T cells); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL-15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies.
Asunto(s)
Antígenos CD19/inmunología , Caspasa 9/inmunología , Interleucina-15/inmunología , Leucemia/prevención & control , Linfoma/prevención & control , Linfocitos T/inmunología , Animales , Presentación de Antígeno , Antígenos CD19/genética , Antígenos CD28/genética , Antígenos CD28/inmunología , Caspasa 9/genética , Vectores Genéticos , Humanos , Inmunofenotipificación , Interleucina-15/genética , Leucemia/genética , Leucemia/inmunología , Activación de Linfocitos , Linfoma/genética , Linfoma/inmunología , Ratones , Ratones SCID , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has a dismal prognosis. We prospectively evaluated minimal residual disease (MRD) by measuring BCR/ ABL levels with a quantitative real-time PCR procedure after induction and after consolidation in 45 adults with Ph+ ALL who obtained complete hematological remission after a high-dose daunorubicin induction schedule. At diagnosis, the mean BCR-ABL/GUS ratio was 1.55 +/- 1.78. A total of 42 patients evaluable for outcome analysis were operationally divided into two MRD groups: good molecular responders (GMRs; n = 28) with > 2 log reduction of residual disease after induction and > 3 log reduction after consolidation therapy, and poor molecular responders (PMRs; n = 14) who, despite complete hematological remission, had a higher MRD at both time points. In GMR, the actuarial probability of relapse-free, disease-free and overall survival at two years was 38, 27 and 48%, respectively, as compared to 0, 0 and 0% in PMR (P = 0.0035, 0.0076 and 0.0026, respectively). Salvage therapy induced a second sustained complete hematological remission in three GMR patients, but in no PMR patient. Our data indicate that, as already shown in children, adult Ph+ ALL patients have a heterogeneous sensitivity to treatment, and that early quantification of residual disease is a prognostic parameter in this disease.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Antibióticos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Asparaginasa/uso terapéutico , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/genética , Neoplasia Residual/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Valor Predictivo de las Pruebas , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vincristina/uso terapéuticoRESUMEN
BACKGROUND: Anti-phospholipid antibodies (aPLs) were associated with an ongoing prothrombotic state in patients with systemic lupus erythematosus (SLE). Because aPLs are able to shift endothelial function toward procoagulant activity in vitro, we investigated the relationship among aPLs, ongoing prothrombotic state, and endothelial perturbation in SLE patients. METHODS AND RESULTS: We measured aPLs, anti-EC antibodies, circulating levels of prothrombin fragment F1 + 2 (F1 + 2), tumor necrosis factor-alpha (TNF-alpha), tissue-type plasminogen activator (TPA), and von Willebrand factor (vWF) in 43 SLE patients and 25 healthy subjects. Patients positive for aPLs (n = 23) had a higher prevalence of anti-EC antibodies (P = .02) and higher levels of F1 + 2 (P = .003) than aPL(-) patients. Endothelial perturbation, defined by elevated plasma levels of both TPA and vWF, was significantly associated with aPL positivity (P = .001). F1 + 2 > 1 nmol/L (mean +/- 2 SD of controls) was detected in all but one patient in whom aPL positivity and endothelial perturbation coexisted and in no aPL(+) patient without endothelial perturbation (P = .0039). F1 + 2 was significantly correlated with vWF (rho = .6, P = .004) and TPA (114 = .70, P = .0006) only in aPL(+) patients. Endothelial perturbation was closely associated with high values of TNF-alpha (P = .0001), anti-phospholipid (P = .001), and anti-EC antibodies (P = .012). In 31 patients without a clinical history of thrombosis followed up for 3 years, aPL(+) patients with endothelial perturbation showed higher F1 + 2 and TNF-alpha values than aPL(+) patients without endothelial dysfunction. CONCLUSIONS: This study shows that in SLE patients, aPL positivity is associated with an ongoing prothrombotic state only in the presence of endothelial perturbation. Our findings also suggest that aPLs and TNF-alpha might cooperate in inducing endothelial perturbation.
Asunto(s)
Anticuerpos Antifosfolípidos/análisis , Endotelio Vascular/fisiopatología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/fisiopatología , Trombosis/etiología , Adulto , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Trombina/análisisRESUMEN
1. The oxidative modification of low density lipoprotein (LDL) is thought to be an important factor in the initiation and development of atherosclerosis. Natural and synthetic antioxidants have been shown to protect LDL from oxidation and to inhibit atherosclerosis development in animals. Synthetic antioxidants are currently being tested, by they are not necessarily safe for human use. 2. We have previously reported that dipyridamole, currently used in clinical practice, is a potent scavenger of free radicals. Thus, we tested whether dipyridamole could affect LDL oxidation at chemical and cellular level. 3. Chemically induced LDL oxidation was made by Cu(II), Cu(II) plus hydrogen peroxide or peroxyl radicals generated by thermolysis of 2,2'-azo-bis(2-amidino propane). Dipyridamole, (1-10 microM), inhibited LDL oxidation as monitored by diene formation, evolution of hydroperoxides and thiobarbituric acid reactive substances, apoprotein modification and by the fluorescence of cis-parinaric acid. 4. The physiological relevance of the antioxidant activity was validated by experiments at the cellular level where dipyridamole inhibited endothelial cell-mediated LDL oxidation, their degradation by monocytes, and cytotoxicity. 5. In comparison with ascorbic acid, alpha-tocopherol and probucol, dipyridamole was the more efficient antioxidant with the following order of activity: dipyridamole > probucol > ascorbic acid > alpha-tocopherol. The present study shows that dipyridamole inhibits oxidation of LDL at pharmacologically relevant concentrations. The inhibition of LDL oxidation is unequivocally confirmed by use of three different methods of chemical oxidation, by several methods of oxidation monitoring, and the pharmacological relevance is demonstrated by the superiority of dipyridamole over the naturally occurring antioxidants, ascorbic acid and alpha-tocopherol and the synthetic antioxidant probucol.
Asunto(s)
Antioxidantes/farmacología , Dipiridamol/farmacología , Lipoproteínas LDL/química , Lipoproteínas LDL/metabolismo , Apolipoproteínas B/química , Apolipoproteínas B/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Células Cultivadas , Cobre/química , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Humanos , Peroxidación de Lípido/efectos de los fármacos , Oxidación-Reducción , Espectrometría de Fluorescencia , Espectrofotometría Ultravioleta , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Cirrhotic patients with decompensated state and high serum levels of fibrin(ogen) degradation products are at high risk of bleeding. The aim of this study was to further analyse the relationship between hyperfibrinolysis and bleeding in cirrhosis by measuring plasma values of D-dimer and tissue plasminogen activator (t-PA) activity. One-hundred-twelve cirrhotic patients with oesophageal varices and without previous upper-gastrointestinal bleeding entered the study and were followed-up for 3 years. Patients were considered to have hyperfibrinolysis if they concomitantly had high values of D-dimer and t-PA activity. During the follow-up 34 (30%) patients bled. They had more severe liver failure (p = 0.0001) and variceal size (p = 0.0031) and higher prevalence of ascites (p = 0.0003), varices with red signs and hyperfibrinolysis (p = 0.0001) than patients who did not bleed. Multivariate analysis disclosed hyperfibrinolysis as the only marker predictive of bleeding (Hazard Ratio = 42.5, p < 0.001). Our findings suggest that screening for hyperfibrinolysis may be useful to identify cirrhotic patients at risk of bleeding.
Asunto(s)
Antifibrinolíticos/sangre , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Hemorragia Gastrointestinal/sangre , Cirrosis Hepática/sangre , Activadores Plasminogénicos/sangre , Activador de Tejido Plasminógeno/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Fibrinólisis/fisiología , Estudios de Seguimiento , Hemorragia Gastrointestinal/etiología , Humanos , Cirrosis Hepática/complicaciones , Fallo Hepático/sangre , Fallo Hepático/etiología , Masculino , Persona de Mediana Edad , Análisis de Regresión , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The aim of this study was to evaluate whether there is endothelial dysfunction in patients with cirrhosis and to detect the mechanism that may account for it. We measured plasma levels of von Willebrand factor (vWF), a marker of endothelial perturbation, and endotoxin, which releases vWF from endothelial cells in vitro, in 32 patients (18 men, 14 women, aged 39-70 years) with cirrhosis classified as mild (class A, n = 10), moderate (class B, n = 16), or severe (class C, n = 6) according to Child-Pugh's classification. vWF antigen (P < .0001) and endotoxemia (P < .0001) progressively increased from A to class C; but the increase of vWF antigen was not strictly related to liver failure, as shown by the lack of correlation between vWF and several indexes of liver protein synthesis. Analysis of the vWF subunit showed no sign of proteolytic fragmentation of the molecule. Multimeric analysis indicated intact vWF multimeric structure. In all patients, there was a strong correlation between vWF antigen and endotoxemia (rho = .92; P = .0001). In 20 selected patients, vWF antigen and endotoxemia were measured before and after 7 days of standard therapy (n = 10) or standard therapy plus nonabsorbable antibiotics. There was a significant decrease of vWF antigen (P < .02) concomitantly with the decrease of endotoxemia (P < .006) in patients taking nonabsorbable antibiotics. Human umbilical vein endothelial cells incubated in vitro with 125 to 500 pg/mL endotoxin released vWF antigen into the medium dose dependently. These results demonstrate that there is endothelial perturbation in cirrhosis and that endotoxemia may play a key role in its occurrence.
Asunto(s)
Endotelio Vascular/fisiopatología , Endotoxinas/sangre , Endotoxinas/toxicidad , Cirrosis Hepática/sangre , Cirrosis Hepática/fisiopatología , Toxemia/sangre , Toxemia/fisiopatología , Factor de von Willebrand/metabolismo , Adulto , Anciano , Antibacterianos/uso terapéutico , Biomarcadores/sangre , Células Cultivadas , Femenino , Humanos , Cirrosis Hepática/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Toxemia/diagnóstico , Factor de von Willebrand/químicaRESUMEN
BACKGROUND & AIMS: Hyperfibrinolysis may complicate the clinical course of liver cirrhosis. The aim of this study was to evaluate if, in cirrhosis, hyperfibrinolysis is primary or secondary to intravascular clotting activation and if endotoxemia is associated with activation of clotting and/or the fibrinolytic system. METHODS: Clotting, fibrinolytic indexes, and endotoxemia were studied in 41 cirrhotic patients and 20 healthy subjects. RESULTS: Twenty-seven cirrhotic patients (66%) had high plasma levels of prothrombin fragment F1 + 2, a marker of thrombin generation. Nineteen patients had elevated values of D-dimer, a marker of fibrinolysis in vivo. All patients with high values of D-dimer also had high values of prothrombin fragment F1 + 2. Endotoxemia was elevated in patients with severe liver failure and significantly correlated to prothrombin fragment F1 + 2. Thirty patients were treated for 7 days either with standard therapy (n = 15) or with standard therapy plus nonabsorbable antibiotics (n = 15). Although standard therapy did not significantly change laboratory indexes, a significant reduction of endotoxemia, prothrombin fragment F1 + 2, and D-dimer was found in those patients who received the combined treatment. CONCLUSIONS: This study shows that, in cirrhotic patients, hyperfibrinolysis is not a primary phenomenon but occurs as a consequence of clotting activation and that endotoxemia might play a pathophysiological role.
Asunto(s)
Coagulación Intravascular Diseminada/complicaciones , Fibrinólisis , Cirrosis Hepática/sangre , Toxemia/complicaciones , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana EdadAsunto(s)
Anticuerpos Antifosfolípidos/inmunología , Trombosis/etiología , Aborto Habitual/etiología , Síndrome Antifosfolípido/complicaciones , Enfermedades Autoinmunes/complicaciones , Coagulación Sanguínea , Isquemia Encefálica/etiología , Enfermedad Coronaria/etiología , Susceptibilidad a Enfermedades/inmunología , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Masculino , Embarazo , Complicaciones del Embarazo/inmunología , Prevalencia , Estudios Prospectivos , Tromboflebitis/etiología , Trombosis/epidemiologíaRESUMEN
We have previously demonstrated that patients with cirrhosis may be positive for lupus anticoagulant and anticardiolipin antibodies. The prevalence and clinical value of antiphospholipid antibodies in cirrhosis have never been described. Besides, it has not yet been determined if serum levels of beta-2-glycoprotein I, which is synthesized by the liver and mediates the interaction between cardiolipin and anticardiolipin antibodies affects lupus anticoagulant detectability in cirrhosis. We evaluated the prevalence of lupus anticoagulant in 63 patients with cirrhosis and related it to beta-2-glycoprotein I serum levels. We also analyzed whether lupus anticoagulant and anticardiolipin antibodies were associated with previous thrombotic complications. Eleven patients (18%) were lupus anticoagulant positive; 14 (22%) had high values of anticardiolipin antibodies. Fourteen patients had a previous history of splanchnic venous thrombosis (n = 9) or thrombophlebitis (n = 5). A significant association between lupus anticoagulant (p = 0.0001), anticardiolipin antibodies (p = 0.0001) and venous thrombosis was found. Patients with severe liver failure had significantly lower beta-2-glycoprotein I levels than those with moderate (p < 0.01) or low (p < 0.001) hepatic insufficiency. Among 14 anticardiolipin antibodies positive patients, six with severe liver failure were lupus anticoagulant negative and had beta-2-glycoprotein I values below 100 micrograms/ml. In four of these, basal values of dilute activated partial thromboplastin time were not modified by the addition of 50 micrograms/ml of exogenous beta-2-glycoprotein I. This study shows that antiphospholipid antibodies are relatively frequent in cirrhosis and that beta-2-glycoprotein I levels are not so low as to affect lupus anticoagulant detectability.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glicoproteínas/sangre , Cirrosis Hepática/sangre , Inhibidor de Coagulación del Lupus/sangre , Adulto , Anciano , Anticuerpos Anticardiolipina/análisis , Apolipoproteínas/sangre , Femenino , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/inmunología , Fallo Hepático/complicaciones , Fallo Hepático/fisiopatología , Masculino , Registros Médicos , Persona de Mediana Edad , Tromboflebitis/complicaciones , beta 2 Glicoproteína IAsunto(s)
Cirrosis Hepática/complicaciones , Inhibidor de Coagulación del Lupus/sangre , Venas Mesentéricas , Vena Porta , Trombosis/etiología , Adulto , Anciano , Femenino , Humanos , Cirrosis Hepática/sangre , Masculino , Venas Mesentéricas/diagnóstico por imagen , Persona de Mediana Edad , Vena Porta/diagnóstico por imagen , Trombosis/sangre , Trombosis/diagnóstico por imagen , UltrasonografíaRESUMEN
BACKGROUND AND PURPOSE: Our purpose was to assess the presence of lupus anticoagulant and fibrinolytic system abnormalities in young patients with stroke. METHODS: We studied 33 consecutive ischemic patients aged < 50 years. Lupus anticoagulant was screened by four different coagulation tests, and the fibrinolytic system was studied by analyzing tissue plasminogen activator antigen and plasminogen activator inhibitor activity. RESULTS: Six patients (18%), two of whom were affected by systemic lupus erythematosus, had lupus anticoagulant. Plasminogen activator inhibitor activity was significantly higher in those positive for lupus anticoagulant than in those negative for lupus anticoagulant and control subjects (p < 0.001). CONCLUSIONS: In young patients with stroke, lupus anticoagulant is associated with an imbalance of the fibrinolytic system as a result of higher levels of plasminogen activator inhibitor.
Asunto(s)
Trastornos Cerebrovasculares/sangre , Fibrinólisis , Inhibidor de Coagulación del Lupus/sangre , Adulto , Trastornos Cerebrovasculares/etiología , Femenino , Fibrinógeno/análisis , Humanos , Masculino , Persona de Mediana Edad , Péptidos/sangre , Inactivadores Plasminogénicos/sangre , Factores de Riesgo , Antígeno Polipéptido de TejidoRESUMEN
This study explored the relationship between clotting activation and tissue plasminogen activator and its inhibitor in cirrhotic patients with different degrees of liver failure. Sixty-seven patients (40 men, 27 women; age = 31-77 yr) with cirrhosis diagnosed by liver biopsy were divided into three subgroups (A, B and C) on the basis of Child-Pugh classification. Tissue plasminogen activator antigen and activity, plasminogen activator inhibitor antigen and activity, fibrin/fibrinogen degradation products, and D-dimer were measured in each patient. Forty-two patients with normal levels of fibrin/fibrinogen degradation products and D-dimer showed significant progressive decreases of plasminogen activator inhibitor antigen levels (p < 0.01) and activity (p < 0.0001) from class A to class C. This decrease was significantly related to prothrombin time (p < 0.003). Tissue plasminogen activator values were not different in the three Child classes. Twenty-five patients (7 class B and 18 class C) with high circulating values of fibrin/fibrinogen degradation products and D-dimer had higher values of tissue plasminogen activator antigen (20.0 +/- 10.1 ng/ml vs. 5.9 +/- 3.0 ng/ml; p < 0.0001) and activity (6.9 +/- 2.2 U/ml vs. 2.1 +/- 1.3 U/ml; p < 0.0001) and lower values of plasminogen activator inhibitor antigen (6.9 +/- 4.1 ng/ml vs. 14.8 +/- 5.6 ng/ml; p < 0.0001) and activity (4.1 +/- 2.8 U/ml vs. 9.8 +/- 3.7 U/ml; p < 0.0001) than did patients with normal values of fibrin/fibrinogen degradation products and D-dimer.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Coagulación Sanguínea , Fibrinólisis , Cirrosis Hepática/sangre , Adulto , Anciano , Femenino , Humanos , Cirrosis Hepática/complicaciones , Fallo Hepático/etiología , Fallo Hepático/fisiopatología , Masculino , Persona de Mediana Edad , Inactivadores Plasminogénicos/sangre , Análisis de Regresión , Activador de Tejido Plasminógeno/sangreRESUMEN
The relation between coagulation indexes and survival rate was studied and analyzed in 46 patients with advanced liver cirrhosis (grade B and C Child-Pugh Classification), during a follow-up of 1 year. Twenty-four patients (52%) died of liver failure or fatal haemorrhage within 12 months of follow-up. Prothrombin activity, fibrinogen, fibrin(ogen) degradation products, prekallikrein and factor VII, serum bilirubin, and the degree of liver insufficiency, scored by Child-Pugh classification, proved to be significantly correlated with survival by univariate analysis. A multivariate survival analysis (Cox regression model) disclosed two variables, prekallikrein and factor VII, that predicted survival. The rate ratios of death increased to 2.8 and 7.6 with values of prekallikrein < 26% and factor VII < 39%, respectively. This study shows that some simple laboratory tests exploring the clotting system may identify patients with poor prognosis in severe liver failure.
Asunto(s)
Pruebas de Coagulación Sanguínea/normas , Cirrosis Hepática/sangre , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Hospitales Universitarios , Humanos , Italia/epidemiología , Cirrosis Hepática/mortalidad , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Análisis de Supervivencia , Tasa de SupervivenciaRESUMEN
Sixty-one patients with different degrees of liver failure, 23 with Child-Pugh class B and 38 with Child-Pugh class C, were studied and observed for 3 yr. Coagulation index analysis showed significantly lower values of prothrombin activity, more prolonged activated partial thromboplastin time, higher bilirubin and fibrinogen degradation products values in class C patients. Among all patients, 28 had fibrinogen degradation products values greater than 10 micrograms/ml, and in these patients a hyperfibrinolytic state was confirmed by higher values of circulating plasminogen activator antigen (17.3 +/- 8.7 ng/ml vs. 5.41 +/- 1.9 ng/ml; p less than 0.0001) and activity (6.6 +/- 2.1 IU/ml vs. 1.92 +/- 1.12 IU/ml; p less than 0.0001) and significantly lower plasminogen activator inhibitor antigen (6.4 +/- 3.5 ng/ml vs. 15.8 +/- 5.6 ng/ml; p less than 0.0001) and activity (3.6 +/- 2.2 IU/ml vs. 8.5 +/- 3.9 IU/ml; p less than 0.0001). Patients with positive fibrinogen degradation products had higher serum bilirubin (6 +/- 4 mg/dl vs. 2 +/- 2 mg/dl; p less than 0.0001) and lower fibrinogen (156 +/- 52 mg/dl vs. 194 +/- 62 mg/dl; p less than 0.02) than patients without hyperfibrinolysis. During the follow-up period, 41 patients died, 22 from fatal gastrointestinal hemorrhage and 19 from liver failure. Thirty patients experienced fatal (22 patients) and nonfatal (8 patients) gastrointestinal hemorrhage. Patients with positive fibrinogen degradation products or class C had a higher risk of gastrointestinal bleeding than patients with negative fibrinogen degradation products (odds ratio = 8) or class B (odds ratio = 3.5), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Fibrinólisis , Hemorragia Gastrointestinal/etiología , Cirrosis Hepática/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Estudios de Seguimiento , Humanos , Cirrosis Hepática/mortalidad , Masculino , Persona de Mediana Edad , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
AIMS: To examine the sensitivity and specificity to past thrombotic events of four different coagulation tests, which screen for lupus anticoagulant (LA), and of anticardiolipin antibodies in patients with systemic lupus erythematosus. METHODS: Fifty three consecutive patients with systemic lupus erythematosus were studied of whom three males and 21 females, aged 21-60 years, had a history of venous and arterial thrombosis, or miscarriage, or both. Activated partial thromboplastin time (aPTT), dilute Russell's viper venom time (dRVVT), kaolin clotting time (KCT), dilute aPTT and the circulating titre of anticardiolipin antibodies were investigated in the two groups of patients and in 20 healthy control subjects. RESULTS: The prolonged dilute aPTT was more sensitive to thromboses or miscarriages, or both than dRVVT (p less than 0.05), KCT (p less than 0.01), and aPTT (p less than 0.001). No significant differences in specificity were found among aPTT (100%), dRVVT (93%), KCT (93%) and dilute aPTT (86.2%); but aPTT and dRVVT were significantly more specific (p less than 0.01, p less than 0.05, respectively) than anticardiolipin antibodies. CONCLUSIONS: The study shows a strong association between lupus anticoagulant and thrombosis when a very sensitive test such as the dilute aPTT is used. The combination of this assay with a very specific test such as dRVVT might enable patients with SLE at high risk of thrombosis to be identified.
Asunto(s)
Aborto Espontáneo/inmunología , Inhibidor de Coagulación del Lupus/sangre , Lupus Eritematoso Sistémico/inmunología , Trombosis/inmunología , Aborto Espontáneo/etiología , Adolescente , Adulto , Autoanticuerpos/análisis , Pruebas de Coagulación Sanguínea , Cardiolipinas/inmunología , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Masculino , Persona de Mediana Edad , Embarazo , Sensibilidad y Especificidad , Trombosis/etiologíaRESUMEN
Defibrotide, a polydeoxyribonucleotide of mammalian origin, has been shown to reduce the blood level of the plasminogen activator inhibitor, and so to increase the activity of tissue plasminogen activator without any adverse effect. A randomized, double-blind, placebo-controlled study has been done in 22 patients, 14 with peripheral vascular disease, 6 with coronary heart disease and 2 with cerebrovascular disease. Patients were given defibrotide 400 mg b.d. or identical placebo for 30 days and the parameters of fibrinolysis were evaluated before and after the treatment. A significant increase in tissue plasminogen activator activity at rest and after venostasis was observed after defibrotide; tissue plasminogen activator antigen at rest and after venostasis was not affected by either treatment. Defibrotide significantly reduced plasminogen activator inhibitor activity and antigen at rest. Only one patient complained of gastric pain after placebo treatment. The study shows that defibrotide has profibrinolytic property and that it could be used to explore the role of plasminogen activator inhibitor in venous and arterial thrombosis.