RESUMEN
Detection and follow up of fibrogenesis in chronic hepatitis C (CHC) is mandatory for early treatment and risk stratification. The current study included 120 patients with CHC, of whom 30 had liver cirrhosis (LC) and 30 had hepatocellular carcinoma (HCC). 15 wedge liver biopsies, taken during laparoscopic cholecystectomy, were included as normal controls. Cases were subjected to laboratory investigations, serologic markers for viral hepatitis and assessment of circulating levels of hyaluronic acid (HA) and platelet-derived growth factor (PDGF). Immunohistochemical expression of connective tissue growth factor (CTGF), PDGF and transforming growth factor-ß1 (TGF-ß1) was also carried out. A significant increase (p < 0.01) in serum HA was noticed in CHC, LC and HCC compared to controls. Although, a significant decrease in serum PDGF was detected in CHC and LC compared to controls, HCC values were comparable. A significant up-regulation of CTGF was detected in CHC, LC and HCC (p < 0.01) in contrast to its limited mild expression in normal livers. Intense PDGF positive staining was noticed in CHC, LC and HCC compared to scattered faint expression in controls. The significant expression and marked intensity of PDGF staining matched the progress to tumorigenesis. A positive TGF-ß1 immunostaining was also noticed in CHC, LC and HCC. An intense and extensive cytoplasmic expression of TGF-ß1 was encountered in patients with LC revealing that CTGF, PDGF and TGF-ß1 act synergistically in LC. Data revealed that HA and CTGF may be implicated as important diagnostic parameters for assessment of hepatic fibrosis and PDGF for monitoring malignant transformation in CHC.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Matriz Extracelular/metabolismo , Hepatitis C Crónica/metabolismo , Cirrosis Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Lesiones Precancerosas/metabolismo , Adulto , Biomarcadores/sangre , Biomarcadores/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Estudios de Casos y Controles , Transformación Celular Neoplásica , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Femenino , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/patología , Humanos , Ácido Hialurónico/sangre , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Lesiones Precancerosas/patología , Lesiones Precancerosas/virología , Factor de Crecimiento Transformador beta1/metabolismo , Adulto JovenRESUMEN
The biological activity of blood coagulation factors II, V, VII, VIII, IX, X, XI and XII, fibrinogen and prekallikrein was assessed in 15 healthy subjects and 60 patients with endemic Egyptian hepatosplenomegaly. The degree of liver disease was graded according to the Child-Pugh classification, the intensity of S. mansoni infection was monitored by determination of circulating schistosome immune complexes (CSIC) level using a monoclonal antibody and hemostasis activation was detected by measurement of hemostatic markers D-dimer and prothrombin fragment 1 + 2 (F1+2). Functional activity of antithrombin III, alpha2-antiplasmin and protein C as well as quantitative determination of plasma concentrations of alpha1-antitrypsin, C1 activator inhibitor and alpha2-macroglobulin were also carried out. The progressive deterioration of liver function which matched the severity of the disease and the intensity of schistosomal infection led to a reduction in anticoagulant proteins (decreases in antithrombin III and protein C) resulting in hypercoagulability and thrombin generation (increased F1+2) subsequently followed by consumption (prolongation of coagulation screening tests, thrombocytopenia, hypofibrinogenemia and decreased factor VIII resulting in hypocoagulability and secondary fibrinolysis (increased D-dimer and decreased alpha2-antiplasmin). A significant decline in fibrinogen and factors VII, XII and prekallikrein was detected in bleeders compared with ascitic patients. The decline in factor XII was closely related to CSIC high titers in all disease groups, but was not correlated to D-dimer or F1+2 concentrations. This suggests that circulating schistosome immune complexes may exert an inhibitory effect on contact factor XII which should be taken into account when considering the reasons for schistosomal coagulopathy and bleeding in hepatosplenic schistosomiasis.
Asunto(s)
Factores de Coagulación Sanguínea/metabolismo , Parasitosis Hepáticas/sangre , Fallo Hepático/parasitología , Esquistosomiasis mansoni/sangre , Enfermedades del Bazo/sangre , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Várices Esofágicas y Gástricas/complicaciones , Hemorragia Gastrointestinal/etiología , Humanos , Persona de Mediana Edad , Enfermedades del Bazo/parasitologíaRESUMEN
Some platelet alpha-granule contents were assessed in parallel with other markers of hemostatic imbalance in 50 patients with hepatosplenic schistosomiasis (15 patients with compensated hepatosplenomegaly, 15 patients with advanced hepatic fibrosis and ascites and 20 patients during an acute attack of hematemesis from ruptured esophageal varices). Platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), fibronectin (FN), prothrombin fragment 1 + 2, thrombin-antithrombin (TAT) complexes, fibrin degradation products (FbDP) and D-dimer were assessed in schistosomal patients compared to controls (15 healthy subjects). A significant increase in both thrombin (high TAT and prothrombin fragment 1 + 2 levels) and plasmin (high FbDP and D-dimer levels) generation was detected in decompensated patients establishing the presence of a steady state of low-grade disseminated intravascular coagulation, with and without overt bleeding, in these patients. A decrease in plasma FN concentration was found in diseased groups compared to controls. The reduction in plasma levels of FN paralleled the defective liver function and matched the relative decrease in tissue FN in liver specimens of decompensated patients suggesting that FN levels can be used to evaluate the pathological staging of the disease. A significant increase in beta-TG and PF4 levels was noted in decompensated patients with ascites and/or acute hematemesis compared both to controls and compensated patients reflecting platelet alpha-granule release and consequently increased in vivo platelet activation which may initiate and/or perpetuate the pathophysiological mechanisms of the hemostatic imbalance underlying the hemorrhagic diathesis in hepatosplenic schistosomiasis.
Asunto(s)
Fibronectinas/sangre , Hematemesis/sangre , Parasitosis Hepáticas/sangre , Factor Plaquetario 4/química , Esquistosomiasis mansoni/sangre , Enfermedades del Bazo/sangre , beta-Tromboglobulina/química , Enfermedad Aguda , Adolescente , Adulto , Femenino , Fibronectinas/fisiología , Hematemesis/etiología , Hematemesis/parasitología , Humanos , Parasitosis Hepáticas/patología , Masculino , Persona de Mediana Edad , Factor Plaquetario 4/fisiología , Esquistosomiasis mansoni/patología , Enfermedades del Bazo/parasitología , Enfermedades del Bazo/patología , beta-Tromboglobulina/fisiologíaRESUMEN
AIM: To evaluate the nature of accelerated fibrinolysis in hepatosplenic schistosomiasis. METHODS: The biological activity of plasminogen (Plg), plasminogen activators (PA), alpha 2-antiplasmin (alpha 2-AP) and plasminogen activator inhibitor-1 (PAI-1) was determined by photometric analysis in 15 compensated and 35 decompensated patients with endemic Egyptian hepatosplenomegaly. Quantitative measurement of plasma concentrations of tissue t-PA, t-PA-PAI-1 complex, alpha 2-antiplasmin-plasmin complex (alpha 2-APP), fibrinogen degradation products (FbDP), D-dimers (D-D), thrombin-antithrombin complex (TAT) and prothrombin fragment (F 1 + 2) complexes, using double antibody sandwich enzyme linked immunosorbent assays and grading of the degree of hepatic insufficiency according to the Child-Pugh classification, were also carried out. RESULTS: The progressive deterioration of liver function in schistosomal patients, which matched the severity of the disease, led to simultaneous defects in profibrinolytic (decreased Plg and increased PA and t-PA) and antifibrinolytic (decreased alpha 2-AP and PAI-1) factors-the latter defects being the most prominent-resulting in significant generation of plasmin (increased APP complexes) and therefore enhanced fibrinolysis (increased FbDP and D-dimer). The raised concentrations of FbDP, D-D, TAT and F 1 + 2 established its secondary nature. CONCLUSION: These findings suggest that the amount of PAI-1 available to bind and neutralise circulating t-PA may be a critical factor in the progress of hyperfibrinolysis observed in hepatosplenic schistosomiasis, and that the pronounced reduction in its plasma concentration may be regarded as a potential warning indicator of haemostatic imbalance in decompensated schistosomal patients at high risk of variceal bleeding.
Asunto(s)
Fibrina/metabolismo , Fibrinólisis/fisiología , Parasitosis Hepáticas/metabolismo , Esquistosomiasis mansoni/metabolismo , Adolescente , Adulto , Ascitis/metabolismo , Ascitis/fisiopatología , Femenino , Fibrinolisina/metabolismo , Hematemesis/metabolismo , Hematemesis/fisiopatología , Hepatitis Viral Humana/complicaciones , Hepatitis Viral Humana/metabolismo , Hepatitis Viral Humana/fisiopatología , Humanos , Parasitosis Hepáticas/complicaciones , Parasitosis Hepáticas/fisiopatología , Masculino , Persona de Mediana Edad , Plasminógeno/metabolismo , Esquistosomiasis mansoni/complicaciones , Esquistosomiasis mansoni/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
Thrombin and plasmin generation were assessed in patients with endemic hepatosplenic schistomiasis (15 hepatosplenomegalic, 15 splenomegalic, 15 with advanced hepatic fibrosis and ascites and 15 hepatosplenic patients with hematemesis). Prolongation of prothrombin time, partial thromboplastin time and thrombin time, thrombocytopenia, hypofibrinogenemia, a decrease in antithrombin III and protein C and S levels and elevation in fibrinopeptide A, D-dimer and thrombin-antithrombin complex levels were detected in all groups. The deficit in hemostatic parameters was more pronounced with the advancement of the disease and was maximal in the hematemesis group. Our data demonstrate an increase in both thrombin and plasmin generation and indicate that low grade disseminated intravascular coagulation may occur in association with endemic Egyptian hepatosplenic schistosomiasis even in the steady state without overt bleeding.
Asunto(s)
Coagulación Intravascular Diseminada/etiología , Esquistosomiasis mansoni/complicaciones , Adulto , Ascitis , Biopsia , Factores de Coagulación Sanguínea/análisis , Pruebas de Coagulación Sanguínea , Enfermedad Crónica , Coagulación Intravascular Diseminada/sangre , Egipto/epidemiología , Várices Esofágicas y Gástricas/sangre , Várices Esofágicas y Gástricas/etiología , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Hepatomegalia/sangre , Hepatomegalia/etiología , Hepatomegalia/patología , Humanos , Hígado/patología , Cirrosis Hepática/sangre , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Esquistosomiasis mansoni/sangre , Esquistosomiasis mansoni/epidemiología , Esquistosomiasis mansoni/patología , Índice de Severidad de la Enfermedad , Esplenomegalia/sangre , Esplenomegalia/etiologíaRESUMEN
AIMS: To evaluate the role of bilharzial hepatic fibrosis--whether pure or combined with chronic hepatitis B virus infection--on the functional activity of vitamin K dependent coagulation proteins. METHODS: Coagulation screening using prothrombin time (PT), partial thromboplastin time (PTT), and thrombin time (TT) was carried out on 31 patients with endemic Egyptian hepatosplenomegaly and on 14 healthy controls. The functional activities of factors II, VII, IX and X and protein C were measured. Patients were classified as pure hepatosplenic schistosomiasis (n = 17) and schistosomiasis with concomitant chronic hepatitis B virus infection (n = 14). RESULTS: Prolongation of the PT and PTT were noticed in bilharzial patients compared with the controls. The increase in the TT remained within the upper range of normal. Factors II, VII, IX and X and protein C functional activities were significantly reduced in all groups studied. CONCLUSION: The decreased activity of vitamin K dependent coagulation factors might be partially offset by the reduced activity of circulating protein C which tends to establish a haemostatic balance at a lower level in endemic Egyptian hepatosplenomegaly. No significant difference could be shown between the pure and mixed cases. Schistosomal coagulopathy is therefore not necessarily aggravated by chronic hepatitis B virus infection.
Asunto(s)
Factores de Coagulación Sanguínea/fisiología , Hepatitis B/sangre , Cirrosis Hepática/parasitología , Esquistosomiasis/sangre , Vitamina K/metabolismo , Adolescente , Adulto , Pruebas de Coagulación Sanguínea , Niño , Egipto , Hepatomegalia , Humanos , Cirrosis Hepática/sangre , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Esquistosomiasis/complicaciones , EsplenomegaliaRESUMEN
Fibrinogen (Fg), plasminogen (Plg), alpha 2-antiplasmin (alpha 2-AP), plasminogen activator (PA), tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI), D-dimer (DD) and fibrin(ogen) degradation products (FDP) were studied in 60 subjects: 40 patients with endemic hepatosplenomegaly (20 during acute haematemesis from ruptured oesophageal varices, 20 with endemic hepatosplenomegaly assigned to the same grade of oesophageal varices but with no history of haematemesis) and 20 normal controls. All parameters were markedly altered in the disease groups. Reduced levels of Fg, Plg, alpha 2-AP and PAI were associated with increasing levels of PA, t-PA, DD and FDP. Alterations were most marked in the group complicated by acute bleeding. It was concluded that these patients have an enhanced fibrinolytic state. This was probably aggravated in the haematemesis group by an acute haemostatic imbalance that superimposed the low grade chronic DIC reported in cases of hepatosplenic schistosomiasis.