RESUMO
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.
Assuntos
Sistemas CRISPR-Cas , Neoplasias , Humanos , Edição de Genes/métodos , Imunoterapia , Imunoterapia Adotiva , Neoplasias/genética , Neoplasias/terapiaRESUMO
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.
Assuntos
Antígenos CD19/imunologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Leucócitos Mononucleares/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos Quiméricos/imunologia , Animais , Apoptose , Proliferação de Células , Citotoxicidade Imunológica/imunologia , Humanos , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Antibióticos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Asparaginase/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/genética , Neoplasia Residual/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Valor Preditivo dos Testes , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vincristina/uso terapêuticoRESUMO
The behaviour of aPTT, as assessed by standard or diluted phospholipid mixture, was investigated in 20 patients suffering from liver cirrhosis. Standard aPTT was prolonged in 13 but it was corrected by 1:1 mixture with normal plasma. Dilute aPTT performed in samples mixed 1:1 with normal plasma and calculated by the difference in time between 1:80 and 1:5 phospholipid mixture was prolonged in 9 patients, who had also significantly higher titre of anticardiolipin antibodies (p less than 0.005). Unlike patients' plasma with normal dilute aPTT, the addition of 0.05 M PC/PS liposomes to patient's plasma with prolonged dilute aPTT significantly shortened dilute aPTT (p less than 0.001). This study shows the presence of antiphospholipid antibodies in some patients with liver cirrhosis; this seems to be responsible for the prolongation of dilute aPTT.
Assuntos
Autoanticorpos/imunologia , Cirrose Hepática/imunologia , Fosfolipídeos/imunologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina ParcialRESUMO
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.
Assuntos
Antifibrinolíticos/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hemorragia Gastrointestinal/sangue , Cirrose Hepática/sangue , Ativadores de Plasminogênio/sangue , Ativador de Plasminogênio Tecidual/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Fibrinólise/fisiologia , Seguimentos , Hemorragia Gastrointestinal/etiologia , Humanos , Cirrose Hepática/complicações , Falência Hepática/sangue , Falência Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Estudos Retrospectivos , Fatores de RiscoRESUMO
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.
Assuntos
Antioxidantes/farmacologia , Dipiridamol/farmacologia , Lipoproteínas LDL/química , Lipoproteínas LDL/metabolismo , Apolipoproteínas B/química , Apolipoproteínas B/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Células Cultivadas , Cobre/química , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
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.
Assuntos
Aborto Espontâneo/imunologia , Inibidor de Coagulação do Lúpus/sangue , Lúpus Eritematoso Sistêmico/imunologia , Trombose/imunologia , Aborto Espontâneo/etiologia , Adolescente , Adulto , Autoanticorpos/análise , Testes de Coagulação Sanguínea , Cardiolipinas/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Gravidez , Sensibilidade e Especificidade , Trombose/etiologiaRESUMO
In 36 patients suffering from systemic lupus erythematosus (SLE), lupus anticoagulant (LA), as assessed by aPTT and diluted aPTT, and anticardiolipin antibodies (aCL) were studied. 14 patients, had a clinical history complicated by thrombosis and/or miscarriages. Among patients with thrombosis LA was positive in 42% and in 100% of patients when assessed by aPTT and diluted aPTT respectively; aCL were positive in 85.7% of patients. Among patients without a clinical history of thrombosis, 1 had prolonged aPTT, 3 had prolonged diluted aPTT and 5 had aCL positivity. Diluted aPTT was more sensitive than aPTT and aCL (p less than 0.01) to thrombosis and miscarriages; specificity to thrombosis and miscarriages ranged from 77.3% for aCL and 86.4% for diluted aPTT to 95.5% for aPTT but not significant differences were found. The study suggests that LA, as assessed by a sensitive test like diluted aPTT, is strongly associated to thrombosis and should therefore be considered an important risk factor.
Assuntos
Aborto Espontâneo/etiologia , Lúpus Eritematoso Sistêmico/complicações , Trombose/etiologia , Adulto , Autoanticorpos/sangue , Fatores de Coagulação Sanguínea/imunologia , Fatores de Coagulação Sanguínea/metabolismo , Cardiolipinas/imunologia , Feminino , Humanos , Inibidor de Coagulação do Lúpus , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Gravidez , Fatores de RiscoRESUMO
Anticardiolipin (aCL) antibodies were isolated from systemic lupus erythematosus serum using cardiolipin liposomes. In a sensitized activated partial thromboplastin time (aPTT) system, low concentrations of aCL were found to significantly prolong aPTT in a dose-dependent fashion. This effect was abolished by adding phosphatidylserine/phosphatidylcholine liposomes to the aPTT system, and could be significantly reduced by a monoclonal antibody against a cross-reacting idiotype of antiphospholipid antibodies (MoAb 5.2) previously incubated with aCL. These results suggest that the anticoagulant properties of aCL are mediated by an interaction with phospholipid components of the coagulation system. The functional block of this activity using monoclonal MoAb 5.2 antibody could be useful for investigating the mechanisms by which aCL is associated with clinical thrombosis.
Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Autoanticorpos/imunologia , Cardiolipinas/imunologia , Fosfolipídeos/imunologia , Anticorpos Monoclonais/imunologia , Fatores de Coagulação Sanguínea/imunologia , Reações Cruzadas , Humanos , Inibidor de Coagulação do Lúpus , Lúpus Eritematoso Sistêmico/imunologia , Tempo de Tromboplastina ParcialRESUMO
OBJECTIVE: To examine the relations among tissue plasminogen activator antigen, plasminogen activator inhibitor, the lupus anticoagulant, and anticardiolipin antibodies in patients with systemic lupus erythematosus. DESIGN: Prospective study of blood samples (a) from selected patients with systemic lupus erythematosus whose disease was and was not complicated by a history of thrombosis or recurrent abortions, or both, and (b) from a series of healthy controls with a similar age and sex distribution. SETTING: University based medical clinic. SUBJECTS: 23 Patients with definite systemic lupus erythematosus (American Rheumatism Association criteria), of whom 11 (eight women) aged 26-51 had a history of thrombosis or recurrent abortions, or both, and 12 (10 women) aged 23-53 had no such history. 15 Healthy subjects (10 women) aged 25-58 served as controls. MAIN OUTCOME MEASURES: Tissue plasminogen activator concentrations, plasminogen activator inhibitor activities, detection of the lupus anticoagulant, and values of anticardiolipin antibodies in the two groups of patients and in the patients with a history of thrombosis or abortions compared with controls. Other measurements included concentrations of proteins that are known to change during the acute phase of systemic lupus erythematosus--namely, fibrinogen, C3 and C4, and C reactive protein. RESULTS: Patients with a history of thrombosis or abortions, or both, had significantly higher values of tissue plasminogen activator and plasminogen activator inhibitor than patients with no such history. A significant correlation between tissue plasminogen activator and plasminogen activator inhibitor (r = 0.80) was found only in the patients with a history of complications of their disease. The lupus anticoagulant was detected in six of the 11 patients with a history of thrombosis or abortions when tested by measuring the activated partial thromboplastin time but was found in all 11 patients when tested by measuring the diluted activated partial thromboplastin time. Nine of these 11 patients had raised values of anticardiolipin antibodies. The findings showed no relation to the activity of the disease. CONCLUSIONS: A significant correlation between tissue plasminogen activator concentrations and plasminogen activator inhibitor activities was found only in patients whose systemic lupus erythematosus was complicated by a history of thrombosis or recurrent abortions. The findings show that these patients have raised plasminogen activator inhibitor activities, and the frequent association between these raised activities and the presence of the lupus anticoagulant suggests that the two may be linked.
Assuntos
Lúpus Eritematoso Sistêmico/enzimologia , Inativadores de Plasminogênio/sangue , Trombose/enzimologia , Ativador de Plasminogênio Tecidual/sangue , Aborto Habitual/enzimologia , Adulto , Autoanticorpos/análise , Fatores de Coagulação Sanguínea/análise , Fatores de Coagulação Sanguínea/imunologia , Cardiolipinas/imunologia , Complemento C3/análise , Complemento C4/análise , Feminino , Fibrinogênio/análise , Humanos , Inibidor de Coagulação do Lúpus , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Gravidez , Estudos Prospectivos , Trombose/complicaçõesRESUMO
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.
Assuntos
Antígenos CD19/imunologia , Caspase 9/imunologia , Interleucina-15/imunologia , Leucemia/prevenção & controle , Linfoma/prevenção & controle , Linfócitos T/imunologia , Animais , Apresentação de Antígeno , Antígenos CD19/genética , Antígenos CD28/genética , Antígenos CD28/imunologia , Caspase 9/genética , Vetores Genéticos , Humanos , Imunofenotipagem , Interleucina-15/genética , Leucemia/genética , Leucemia/imunologia , Ativação Linfocitária , Linfoma/genética , Linfoma/imunologia , Camundongos , Camundongos SCID , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Fatores de Coagulação Sanguínea/imunologia , Cirrose Hepática/imunologia , Autoanticorpos/análise , Fatores de Coagulação Sanguínea/análise , Cardiolipinas/imunologia , Humanos , Cirrose Hepática/sangue , Inibidor de Coagulação do Lúpus , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Fosfolipídeos/imunologiaAssuntos
Cirrose Hepática/complicações , Inibidor de Coagulação do Lúpus/sangue , Veias Mesentéricas , Veia Porta , Trombose/etiologia , Adulto , Idoso , Feminino , Humanos , Cirrose Hepática/sangue , Masculino , Veias Mesentéricas/diagnóstico por imagem , Pessoa de Meia-Idade , Veia Porta/diagnóstico por imagem , Trombose/sangue , Trombose/diagnóstico por imagem , UltrassonografiaRESUMO
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)
Assuntos
Glicoproteínas/sangue , Cirrose Hepática/sangue , Inibidor de Coagulação do Lúpus/sangue , Adulto , Idoso , Anticorpos Anticardiolipina/análise , Apolipoproteínas/sangue , Feminino , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Falência Hepática/complicações , Falência Hepática/fisiopatologia , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Tromboflebite/complicações , beta 2-Glicoproteína IRESUMO
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.
Assuntos
Fibrinolíticos/farmacologia , Inativadores de Plasminogênio/sangue , Polidesoxirribonucleotídeos/farmacologia , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Administração Oral , Idoso , Testes de Coagulação Sanguínea , Transtornos Cerebrovasculares/sangue , Doença das Coronárias/sangue , Método Duplo-Cego , Feminino , Fibrinolíticos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/sangue , Polidesoxirribonucleotídeos/administração & dosagem , Ativador de Plasminogênio Tecidual/sangueRESUMO
In patients with chronic liver disease (CLD), several clotting changes can be observed. The most frequent abnormality is the reduced synthesis of many clotting factors, including vitamin-K-dependent and vitamin-K-independent ones. A low platelet count is another frequent feature of patients with CLD, which, however, is not always associated with the prolongation of bleeding time. Hyperfibrinolytic syndrome is usually seen in patients with decompensated state, and may further deteriorate the clotting abnormalities and favor bleeding complications. The assessment of the clotting system may be a useful approach to evaluate liver function and predict prognosis of patients with CLD.
Assuntos
Transtornos da Coagulação Sanguínea/etiologia , Hepatopatias/complicações , Testes de Coagulação Sanguínea , Transtornos Plaquetários/etiologia , Doença Crônica , Fibrinólise , Hemorragia/etiologia , Humanos , Hepatopatias/sangue , Contagem de Plaquetas , Fatores de Risco , Trombocitopenia/etiologiaRESUMO
Defibrotide, an antithrombotic drug, was previously shown to activate fibrinolysis. In order to elucidate the relationship between defibrotide treatment and fibrinolysis, ten atherosclerotic patients were given 1200 mg/day defibrotide intravenously for 7 days and then 400 mg/day intramuscularly for another 20 days. t-PA antigen assessed before and after venous occlusion was not affected by the treatment. Tissue PAI activity significantly decreased and t-PA activity, measured after venous occlusion, increased after 8 and 28 days of treatment; both these changes disappeared after defibrotide was discontinued. No particular side effects were detected throughout the investigation. The study suggests that defibrotide increases t-PA activity by reducing PAI activity.