Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three cases of disseminated intravascular coagulation following infusion of ascitic fluid from the peritoneal cavity to the vascular system are reported in patients with hepatic cirrhosis. One of these was treated with intermittent drainage and infusion, and in the other two a LeVeen shunt was used. Studies on the ascitic fluid indicate the presence of a procoagulant material which would appear to be an activator of factor X. Preactivated factor X (Xa) from the fluid and/or a tissue factor activator of factor VII are additional possibilities.
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PMID:Procoagulant activity of ascitic fluid in hepatic cirrhosis: in vivo and in vitro. 49 63

The regulatory mechanisms of microcirculation might differ in the liver from other organs, because macrophages are resident in the hepatic sinusoids and sinusoidal endothelial cells are unique in shape and function. Thrombomodulin expression in endothelial cells and tissue factor activity in isolated macrophages were studied in the liver and lung of rats. In normal rats, the thrombomodulin expression was minimal in hepatic sinusoids, but prominent in pulmonary capillaries, while the tissue factor activity in the presence of endotoxin was higher in pulmonary macrophages than in Kupffer cells, although the levels in the absence of endotoxin were comparable in both cells. The tissue factor activity in hepatic macrophages was increased after priming of the cells with Corynebacterium parvum or after induction of liver necrosis or cirrhosis with carbon tetrachloride. In the necrotic or cirrhotic liver, increased thrombomodulin expression was seen along capillaries extending in necrotic areas and regenerating nodules, but this increase was minimal in the Corynebacterium parvum-treated rat liver. Blood coagulation equilibrium in microcirculation regulated by endothelial cells and macrophages may differ between the liver and lung. Such equilibrium in the liver may vary depending on pathological status.
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PMID:Blood coagulation equilibrium in rat liver microcirculation as evaluated by endothelial cell thrombomodulin and macrophage tissue factor. 858 88

It is believed that perioperative hemorrhage, in the hepatoportal area, results from a coagulopathy. This study determined if this could be quantitated by a modified recalcification time (MRT) test developed in our laboratory. Unlike prothrombin (PT) and activated partial thromboplastin times (APTT), the MRT is performed with whole blood to ensure the role of blood cells and chemicals (particularly tissue factor, a potent procoagulant) in the coagulation process. Candidates for liver transplantation (n = 11) were studied. Samples (5 mL) of citrated venous blood were obtained from the patients. Aliquots (1 mL) from these samples were divided into groups of vials labeled C, S, and E. Groups C and S received 20 microL saline and group E, 20 microL of saline containing 10 micrograms of Escherichia coli endotoxin (055: B5W). Vial C was incubated for 10 minutes and vials S and E for 120 minutes, all at 37 degrees C. Then, the MRT was determined on 300 microL of blood from each vial after adding 40 microL of 0.1M calcium chloride. Mean MRT values (minutes +/- standard deviation) for C (MRTC), for S (MRTS), and for E (MRTE) were compared with like values from healthy controls (n = 29). Despite prolonged PT and APTT values, MRT values were shortened in patients with cirrhosis. This hypercoagulability detected by the MRT exonerates a hemorrhagic coagulopathy and possibly implicates widened and thinned gaps in the walls of the portal venous tributaries as the cause of perioperative hemorrhage.
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PMID:Deceptive prothrombin and activated partial thromboplastin times in alcoholic cirrhosis. 866 40

Clotting activation may occur in liver cirrhosis, but the pathophysiological mechanism has not been fully elucidated. Because a previous study demonstrated that lipid peroxidation is increased in cirrhosis, we analyzed whether there is a relationship between lipid peroxidation and clotting activation. Thirty cirrhotic patients (19 men and 11 women; age, 34 to 79 years) and 30 controls matched for sex and age were investigated. In all subjects, monocyte expression of tissue factor (TF) antigen and activity; plasma levels of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation; and urinary excretion of Isoprostane-F2alpha-III, a marker of lipid peroxidation, were measured. Furthermore, the above-reported variables were re-evaluated after 30 days of treatment with standard therapy (n = 5) or standard therapy plus 300 mg vitamin E twice daily (n = 9). In addition, we analyzed in vitro if vitamin E (50 micromol/L) influenced monocyte TF expression and F1+2 generation. Cirrhotic patients had higher values of Isoprostane-F2alpha-III (P <. 0001), F1+2 (P <.0001), and monocyte TF antigen (P <.0001) and activity (P <.03) than controls. Isoprostane-F2alpha-III was significantly correlated with F1+2 (Rho = 0.85; P <.0001) and TF antigen (Rho = 0.95; P <.0001) and activity (Rho = 0.94; P <.0001). After vitamin E treatment, Isoprostane-F2alpha-III (P =.008), F1+2 (P <.008), and monocyte TF antigen (P =.012) and activity (P =.008) significantly decreased; no changes of these variables were detected in patients not receiving vitamin E. In vitro, vitamin E significantly reduced the expression of monocyte TF antigen (-52%; P =.001) and activity (-55%; P =.003), as well as F1+2 generation (-51%; P =.025). This study shows that vitamin E reduces both lipid peroxidation and clotting activation and suggests that lipid peroxidation may be an important mediator of clotting activation in liver cirrhosis.
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PMID:Vitamin E reduces monocyte tissue factor expression in cirrhotic patients. 1021 89

Liver cirrhosis is associated with alterations of the coagulation system commonly causing bleeding as well as thromboembolic complications. The potential pathophysiological roles of tissue factor (TF) (the initiator of the extrinsic coagulation pathway) and thrombomodulin (TM) (an initiator of the anticoagulatory protein C pathway) are unknown. We therefore measured plasma concentrations of TF and TM in 111 patients with liver diseases who were evaluated for liver transplantation. We could demonstrate that the levels of both molecules increased with the Child's class of liver cirrhosis, independently of aetiology. TM was significantly elevated in Child A, B and C patients compared with patients without cirrhosis; TF only in Child C patients. The plasma TM and TF concentrations correlated with prothrombin time, activated partial thromboplastin time, and inversely with factor VII activity, cholinesterase serum activity, and serum albumin concentration. TM was elevated in patients with a bleeding tendency, but TM and TF did not differ between patients with or without prior thrombotic events. Further studies are warranted to clarify the underlying mechanisms that raise TM and TF plasma levels in liver disease with possible clinical consequences.
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PMID:Tissue factor and thrombomodulin levels are correlated with stage of cirrhosis in patients with liver disease. 1168 41

Pro-hemostatic therapy aims at an improvement of hemostasis, which may be achieved by amelioration of primary hemostasis, stimulation of fibrin formation or inhibition of fibrinolysis. These treatment strategies may be applied to specifically correct a defect in one of the pathways of coagulation, but have in some situations also been shown to be effective in reducing bleeding in patients without a primary defect in coagulation. Besides the transfusion of platelets in case of thrombocytopenia or severe platelet disorders, a pharmacological improvement of primary hemostasis may be achieved by the administration of desmopressin. The administration of DDAVP results in a marked increase in the plasma concentration of Von Willebrand factor (and associated coagulation factor VIII) and (also by yet unexplained additional mechanisms) a remarkable potentiation of primary hemostasis as a consequence. DDAVP is used for the prevention and treatment of bleeding in patients with von Willebrand disease or mild hemophilia A, and further in patients with an impaired function of primary hemostasis, such as in patients with uremia, liver cirrhosis or in patients with aspirin-associated bleeding. Based on the current insight that activation of coagulation in vivo predominantly proceeds by the tissue factor/factor VII(a) pathway, recombinant factor VIIa has been developed as a prohemostatic agent and has recently become available for clinical use. Indeed, in uncontrolled clinical studies this compound has been shown to exert a potent procoagulant activity and appeared to be highly effective in the prevention and treatment of bleeding, although most experience so far has been obtained in patients with severe and complicated coagulation defects. At present, a more general use of this agent for bleeding patients without an apparent coagulation defect is the subject of a number of ongoing clinical trials. Agents that exert anti-fibrinolytic activity are aprotinin and the group of lysine analogues. The pro-hemostatic effect of these agents proceeds not only by the inhibition of fibrinolysis (thereby shifting the procoagulant/anticoagulant balance towards a more procoagulant state), but also due to a protective effect on platelets, as has been demonstrated at least for aprotinin. The mechanism of this platelet-protective effect has, besides a potential prevention of plasmin-mediated loss of platelet receptors not been elucidated. Whether the pro-hemostatic effect of the anti-fibrinolytic agents will eventually result in a higher incidence of thromboembolic complications is still a matter of debate (see further), however, this has so far not been shown in straightforward clinical trials.
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PMID:Management of bleeding disorders by prohemostatic therapy. 1243 Sep 14

Individuals with chronic hepatitis C (CHC) progress to cirrhosis and hepatic cancer. Individuals with advanced CHC are coagulopathic and can manifest fibrinolysis. The coagulopathy is a consequence of hepatocytic dysfunction. The fibrinolysis represents a response to local endothelial cell injury, and is of a low-grade. Based upon this hypothesis, the effect of the infusion of recombinant human factor VIIa (rh-FVIIa) on endothelial cell inflammatory integrins and measures of endothelial stress were determined in 17 individuals with advanced CHC. Immediately prior to the infusion of rh-FVIIa, the plasma levels of tissue factor (TF), Thrombomodulin (TM), human soluble ICAM-1 (hs-ICAM-1), human soluble VCAM-1 (hs-VCAM-1), human soluble L-Selectin (hs-L-Selectin), the prothrombin time and the activated partial thromboplastin time were determined. The same parameters were assayed at 5, 10, 30, 120, 240 and 360 min after infusion. TF and TM levels were very high at baseline consistent with a vascular endothelial stress response. Similarly hs-ICAM-1, hs-VCAM-1 as well as L-Selectin levels were increased. Thirty minutes after the infusion, a marked reduction in ICAM-1 and VCAM-1 and to a lesser degree L-Selectin levels was observed. This reduction persisted for 360 min. No change in measures of fibrinolysis [plasminogen activator inhibitor-1 (PAI-1), total tissue factor pathway inhibitor (t-TFPI), activated tissue factor pathway inhibitor (TFPIa), d-dimers (DD), FSP and fibrinogen levels] occurred. In addition, no change in plasma Annexin-V was observed. Based upon these data it can be concluded that: (1) rh-FVIIa corrects the coagulopathy seen in advanced CHC; (2) reduces endothelial cell injury and/or stress as evidenced by the TF, TM, hs-ICAM-1 and hs-VCAM-1 levels in plasma; (3) these changes in coagulation occurred without inducing a propagated vascular thrombosis.
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PMID:Modulation of endothelial cell inflammatory integrins and stress markers with rh-factor VIIa in patients with advanced chronic hepatitis C. 1282 99

The mechanisms leading to the hemostatic changes of acute liver injury are poorly understood. To study these further we have assessed coagulation and immune changes in patients with acute paracetamol overdose and compared the results to patients with chronic cirrhosis and normal healthy controls. The results demonstrate that in paracetamol overdose coagulation factors (F)II, V, VII and X were reduced to a similar degree and were significantly lower than FIX and FXI (mean levels 0.28, 0.16, 0.13, 0.19, 0.51 and 0.72 IU mL(-1), respectively). In cirrhosis, by contrast, FII, FV, FVII, FIX and FX were equally reduced whilst FXI was lower than the other factors (mean levels 0.64, 0.69, 0.62, 0.60, 0.66 and 0.40 IU mL-1, respectively). FVIII was raised in paracetamol overdose patients but normal in those with cirrhosis (mean levels 1.95 and 1.01 IU mL(-1), respectively). Interleukin-6 and tumor necrosis factor-alpha levels were raised in both patient groups, but higher levels were found in paracetamol overdose, compared to cirrhosis. Thrombin-antithrombin and soluble tissue factor levels were higher in those with acute liver injury but normal in cirrhosis. Antithrombin levels were reduced in both acute liver injury and cirrhosis. From these data we put forward a novel mechanism for the coagulation changes in acute paracetamol induced liver injury. We propose that immune activation leads to tissue factor-initiated consumption of FII, FV, FVII and FX, but that levels of FIX and FXI are better preserved because antithrombin inhibits the thrombin induced positive feedback loop that activates these latter factors.
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PMID:Effects of acute liver injury on blood coagulation. 1287 12

P-selectin is a leukocyte receptor and platelet activation marker that has been shown to be involved in thrombogenesis as well as bleeding disorders and may represent a possible link between inflammation and thrombosis. In animal models, high plasma levels correlated with a procoagulant tendency. In acute liver damage models such as hepatic ischaemia-reperfusion-injury, P-selectin was found to be a key mediator of liver injury. In order to investigate the clinical and pathogenetic role of P-selectin in chronic liver diseases, plasma P-selectin levels were measured in 111 patients with chronic liver diseases. P-Selectin was significantly elevated in patients (median 56 ng/ml, range 0-180) compared with controls (n = 38, median 20 ng/ml, range 3.3-42, P < 0.001). Current clinical bleeding symptoms were common, whereas thrombotic events occurred rarely. P-selectin levels were not associated with haemorrhagic or thromboembolic complications. P-selectin correlated with platelet and white-blood-cell counts, but not with endothelial injury markers thrombomodulin and tissue factor or coagulation factors. Interestingly, P-selectin levels were not associated with Child's stage of cirrhosis or disease aetiology, but were generally elevated in chronic liver diseases. Severe hepatic leukocyte infiltration in liver histology was associated with a tendency towards higher P-selectin levels. In line with its role in acute liver damage, P-selectin elevation in chronic liver disease may suggest a possible pathogenetic role in the course of liver cirrhosis.
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PMID:Plasma P-selectin levels are elevated in patients with chronic liver disease. 1294 72

The precise mechanisms leading to the coagulopathy of acute liver injury are unclear. To study this further, coagulation and immune changes have been compared in patients with acute liver injury secondary to paracetamol overdose, with chronic cirrhosis, and normal healthy controls. In acute liver injury, coagulation factors II, V, VII and X were reduced to a similar degree, and were significantly lower than factors IX and XI. In cirrhosis, by contrast, these coagulation factors were reduced to similar levels. Factor VIII increased in acute liver injury, but was normal in cirrhosis. Interleukin-6 and tumour necrosis factor-alpha levels increased in both patient groups, but were higher in paracetamol overdose. Thrombin-antithrombin and soluble tissue factor levels increased in those with acute liver injury, but were normal in patients with cirrhosis. Functional antithrombin was reduced in both acute liver injury and cirrhosis. It is hypothesized that in acute paracetamol-induced liver injury, immune activation leads to tissue factor-initiated consumption of factors II, V, VII and X, but that levels of factors IX and XI are better preserved because of inhibition of the thrombin-induced amplification phase of coagulation. These findings have implications for appropriate coagulation factor support for patients with acute liver injury.
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PMID:New insights into haemostasis in liver failure. 1456 36


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