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)

Thrombopoietin (TPO) deficiency has been proposed as an important etiologic factor for thrombocytopenia in advanced-stage liver disease. To clarify the contributions of platelet production, platelet consumption, coagulation activation, and splenic sequestration to thrombocytopenia in liver disease, we studied TPO serum levels and markers of platelet production, platelet activation, and coagulation activation before and 14 days after orthotopic liver transplantation (OLT) in 18 patients with advanced liver cirrhosis. Thrombocytopenia before transplantation occurred with low-normal serum levels of TPO, normal levels of platelet and coagulation activation markers, and no increase in bone marrow production of platelets. TPO serum levels increased significantly on the first day after OLT, preceding the increase of reticulated platelets by 3 days and peripheral platelets by 5 days. Normalization of the peripheral platelet count occurred in most patients within 14 days of OLT, irrespective of the change in spleen size assessed by computed tomography volumetry. Normalization of platelet counts was not hampered by a certain degree of platelet activation observed during the steepest increase in the peripheral platelet count. Bone marrow production of platelets increased significantly within 2 weeks of transplantation. Low TPO serum levels with low platelet counts and without platelet consumption suggests low TPO production in end-stage liver disease. The rapid increase in TPO serum levels after transplantation induces an increase in the bone marrow production of platelets. Decreased TPO production in the cirrhotic liver is an important etiologic factor for thrombocytopenia in liver disease that is rapidly reversed by transplantation.
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PMID:Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production. 1064 88

Coagulopathy in patients with liver disease results from impairments in the clotting and fibrinolytic systems, as well as from reduced number and function of platelets. Parenteral vitamin K replacement corrects coagulopathy related to biliary obstruction, bacterial overgrowth, or malnutrition. Vitamin K is less effective for coagulopathy caused by severe parenchymal liver injury. Transfusion of fresh frozen plasma is the hallmark of treatment of significant coagulopathy in patients with liver disease and active bleeding. Transfusion of fresh frozen plasma also reverses moderate to severe coagulopathy of cirrhosis prior to invasive procedures. Cryoprecipitate is useful for severe coagulopathy with hypofibrinogenemia, especially when avoidance of volume overload is desired. Exchange plasmapheresis is useful in selected patients with coagulopathy due to liver disease, in whom fresh frozen plasma fails to correct coagulopathy or in patients who have coexistent severe fluid overload. Platelet transfusions, pooled or single donor, are useful in thrombocytopenic patients prior to performing invasive procedures or in the presence of significant bleeding, especially when the platelet count is below 50,000/mL. The use of recombinant factor VIIa and thrombopoietin therapy for correction of coagulopathy and thrombocytopenia, respectively, in patients with cirrhosis, is currently under investigation. Therapy with prothrombin complex concentrates, 1-deamino-8-d-arginine vasopressin and antithrombin III concentrates for the management of coagulopathy caused by liver disease can be hazardous and the use of these products is considered investigational at the present time.
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PMID:Coagulopathy of Liver Disease. 1109 2

Moderate thrombocytopenia is a frequent finding in cirrhosis of the liver and well tolerated in most instances. The pathophysiology of thrombocytopenia in liver disease has long been associated with the concept of hypersplenism, where portal hypertension was thought to cause pooling and sequestration of all corpuscular elements of the blood, predominantly thrombocytes in the enlarged spleen. The concept of hypersplenism was never proven beyond any doubt but was widely accepted for the lack of alternative explanations. With the discovery of the lineage-specific cytokine thrombopoietin (TPO) the missing link between hepatocellular function and thrombopoiesis was found. TPO is predominantly produced by the liver and constitutively expressed by hepatocytes. TPO production in humans is dependent on functional liver cell mass and is reduced when liver cell mass is severely damaged. This leads to reduced thrombopoiesis in the bone marrow and consequently to thrombocytopenia in the peripheral blood of patients with advanced-stage liver disease. With recombinant TPOs in development, patients with liver disease and TPO seem to be the ideal target population for this drug. Once the efficacy of thrombopoietin in patients with liver disease is proven, a potent yet safe drug may be available to treat cirrhotic patients undergoing invasive or surgical procedures, during bleeding episodes or when undergoing therapy with myelosuppressive drugs such as interferon-alpha.
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PMID:Thrombocytopenia in liver disease. 1111 Jun 14

Thrombopoietin (TPO) is primarily produced by hepatocytes and regulates the production and differentiation of megakaryocytes and platelets in the bone marrow. The endogenous TPO level is increased when the megakaryocyte count is low, and high in aplastic anaemia and after myeloablative chemotherapy. TPO is cloned and manufactured by a recombinant technique for clinical use. Treatment with recombinant human TPO (rhTPO) after intensive chemotherapy may reduce the need for platelet transfusions. Administration of granulocyte colony-stimulating factor in combination with rhTPO has enhanced the mobilisation and harvest product of haematopoietic stem cells. Whether rhTPO is effective in the treatment of the myelodysplastic syndrome, aplastic anaemia, and other conditions with bone marrow insufficiency (including AIDS) is not yet known. In liver cirrhosis, the endogenous TPO level rapidly increases after liver transplantation. Accordingly, substitution of rhTPO may be indicated in advanced liver failure complicated by thrombocytopenia and bleeding.
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PMID:[Clinical use of recombinant human thrombopoietin. Status and perspectives]. 1136 Mar 68

Thrombocytopenia in liver diseases is considered to be due to splenic platelet pooling and accelerated destruction. Since thrombopoietin (TPO), a regulator of thrombopoiesis, is produced mainly in the liver, decreased production of TPO may account for thrombocytopenia in liver diseases. To address this issue, we measured serum TPO, using a sensitive sandwich ELISA, in 108 patients with chronic viral hepatitis, which included chronic hepatitis (CH) and liver cirrhosis (LC), and hepatocellular carcinoma (HCC), and in 29 normal controls. TPO mRNA in 78 liver samples was examined by reverse transcription (RT)-PCR. Platelet counts in CH, LC, HCC and controls were 176 +/- 15 x 10(9)/l, 81 +/- 8 x 10(9)/l, 99 +/- 7 x 10(9)/l and 234 +/- 9 x 10(9)/l respectively. Serum TPO levels in CH, LC and HCC were 2.79 +/- 0.4 fmol/ml, 1.49 +/- 0.2 fmol/ml and 1.97 +/- 0.2 fmol/ml, and were higher than those of controls. Serum TPO levels were positively correlated with prothrombin time and serum albumin (P < 0.05, in each case), and negatively correlated with Indocyanine Green test and Pugh score (P < 0.01 and P < 0.05 respectively). However, RT-PCR and immunohistochemistry showed that expression of TPO mRNA and protein were similar in the different liver diseases, suggesting that serum TPO is a reflection of the total mass of functional liver. Platelet counts were negatively correlated with spleen index, but not with serum TPO. These results suggest that thrombocytopenia in liver disease is not directly associated with serum TPO but is associated with hypersplenism.
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PMID:Thrombopoietin levels in serum and liver tissue in patients with chronic viral hepatitis and hepatocellular carcinoma. 1178 73

Thrombocytopenia is one of the major complications of liver cirrhosis. Except for hypersplenism associated with portal hypertension, it is not known which abnormalities of thrombopoiesis cause thrombocytopenia. To evaluate thrombopoiesis in liver cirrhosis, we analyzed thrombopoietin (TPO) and its receptor c-Mpl levels in cirrhotic patients. Expression of c-Mpl on platelets and the serum level of TPO were investigated from 38 patients with various stages of liver cirrhosis by flow-cytometric analysis and enzyme-immuno assay. Samples obtained from 22 individuals without evidence of liver disease were used as controls. Neither platelet counts nor TPO levels correlated with disease progression defined by the Child-Pugh classification. c-Mpl was constitutively expressed on the platelets of cirrhotic patients, and its expression level was reduced with disease progression defined by the Child-Pugh classification. In this study, serum TPO did not fluctuate according to the grade of cirrhosis. However, its receptor c-Mpl, which is expressed on platelets, was decreased significantly in severely cirrhotic patients with thrombocytopenia. Thus, a correlation between reduced c-Mpl expression and the progression of liver cirrhosis was demonstrated. We conclude that, in addition to hypersplenism, the reduced expression of c-Mpl may play a significant role in the thrombocytopenia observed in severe liver cirrhosis.
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PMID:Thrombopoietin receptor (c-Mpl) is constitutively expressed on platelets of patients with liver cirrhosis, and correlates with its disease progression. 1204 65

The aim of this study was to evaluate the relation between thrombopoietin (TPO) and thrombocytopenia in patients with liver cirrhosis and those with idiopathic portal hypertension (IPH) before and after partial splenic embolization (PSE). We examined changes in platelet counts, liver function, megakaryocyte function, and plasma TPO levels after PSE in 30 patients (20 with liver cirrhosis, and 10 with IPH). Platelet counts in both cirrhosis and IPH increased significantly 2 months after PSE (cirrhosis group, 4.0+/-1.9 vs. 7.5+/-4.4x10(4)/&mgr;l: P=0.0002; IPH group, 4.0+/-1.7 vs. 6.5+/-2.3x10(4)/&mgr;l: P=0.0042). Plasma TPO level and prothrombin time increased significantly and alanine aminotransferase level (ALT) and total bilirubin level decreased significantly 2 months after PSE in the cirrhosis group (plasma TPO level, 0.57+/-0.30 vs. 0.72+/-0.27 fmol/ml: P=0.024), but not in the IPH group (0.56+/-0.21 vs. 0.55+/-0.34 fmol/ml: P=0.94). Moreover, the score of megakaryocytes with platelet production, an index of platelet production by megakaryocytes in bone marrow, increased significantly in the cirrhosis group. TPO production in cirrhotic patients is restored after PSE, leading to the resolution of thrombocytopenia. But patients with IPH had no change in liver function, indicating that only decreased spleen volume was responsible for the improvement in platelet count.
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PMID:Restoration of thrombopoietin production after partial splenic embolization leads to resolution of thrombocytopenia in liver cirrhosis. 1219 74

Thrombocytopenia is commonly seen in patients with cirrhosis. Both splenomegaly and inadequate thrombopoietin (TPO) production by the cirrhotic liver are responsible for thrombocytopenia. In addition, thrombocytopenia is frequently observed in chronic hepatitis patients who received interferon therapy, and may even lead to the discontinuation of treatment. The aim of this study is to evaluate the clinical significance of the changes of platelet counts and serum TPO levels in chronic hepatitis C patients treated with different doses of consensus interferon (CIFN). Data from 75 chronic hepatitis C patients who received subcutaneous injection of either CIFN 9 (25 patients) or 3 &mgr;g (26 patients) or placebo (24 patients), three times a week for 24 weeks, were analyzed from a randomized controlled study. All patients received a 24-week observation period after the end of the treatment. The results showed a significantly higher degree of decrease in platelet counts and elevated serum TPO in patients receiving CIFN 9 or 3 &mgr;g as compared with placebo at week 12 and week 24 of treatment, respectively. These changes were more obvious in patients receiving CIFN 9 &mgr;g than in patients receiving CIFN 3 &mgr;g. However, both the decrease of platelet counts and elevated serum TPO levels returned to the baseline values after stopping CIFN therapy. Lower hepatic fibrosis score, lower pretreatment serum HCV RNA level, genotype non-1b infection and patients with sustained response to CIFN were manifested with higher degree of serum TPO elevation in response to the CIFN-induced thrombocytopenia. Multivariate logistic regression analysis showed that an age of less than 45 years and a serum TPO level elevation greater than 50% of baseline level at week 12 of CIFN treatment were significantly independent predictors associated with the sustained response to the CIFN treatment. In conclusion, the changes of platelet counts and serum TPO levels in chronic hepatitis C patients during CIFN therapy were reversible, and the degree of changes were more prominent in higher doses of CIFN treatment. The serum TPO response to CIFN-induced thrombocytopenia may serve as a marker for the degree of liver fibrosis, and also as a parameter for predicting therapeutic response.
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PMID:Clinical significance of the changes of platelet counts and serum thrombopoietin levels in chronic hepatitis C patients treated with different doses of consensus interferon. 1239 25

To clarify the thrombopoietin (TPO) production in patients with end-stage liver cirrhosis and uremia under hemodialysis, plasma TPO levels in patients with liver cirrhosis (n = 15), uremia under hemodialysis (n = 20) and healthy controls (n = 40) were measured by using a sandwich enzyme linked immunosorbent assay. Relationship between megakaryocytopoiesis and plasma TPO levels was analysed by linear regression. The results showed that the mean plasma TPO concentration in the uremic patients was significantly lower than that in the healthy volunteers, whereas plasma TPO level in end-stage liver cirrhosis was not significantly different from that of normal controls; plasma TPO levels in liver cirrhosis and uremic patients did not significantly influence megakaryocytopoiesis. It is concluded that end-stage liver cirrhosis patients maintained normal plasma TPO levels, but the production of TPO was significantly reduced in renal failure patients. Thrombocytopenia in liver cirrhosis appears to be not related to plasma TPO levels.
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PMID:[Plasma thrombopoietin level and its influence on megakaryocytopoiesis in end-stage liver cirrhosis and uremia patients]. 1251 30

Thrombopoietin (TPO) is the primary regulator of platelet production. TPO is produced in the liver and levels are low in patients with cirrhosis. Because thrombocytopenia is common in patients with acute liver failure (ALF), we measured TPO concentrations (normal TPO range, 31 to 136 pg/mL) in 51 patients with ALF to determine if low levels were associated with thrombocytopenia. TPO levels from hospital day 2 were elevated in 43% of patients, normal in 47%, and decreased in 10% of patients. Levels were higher in acetaminophen-induced than in non-acetaminophen-induced ALF, 160 (12 to 549) pg/mL versus 73 (18 to 563) pg/mL, respectively, P =.031. TPO levels did not correlate with platelet count and were not related with survival or infection. We analyzed daily TPO levels for the first week of hospitalization in 12 patients with acetaminophen-induced ALF and observed a gradual increase from a median admission level of 50 (5 to 339) pg/mL to a median peak level of 406 (125 to 1,081) pg/mL occurring on day 5 (3 to 6). Platelets were reduced in 11 of the 12 patients with a nadir platelet count of 52 (19 to 156) x 10(9) cells/L occurring on day 5.5 (1 to 6). The peak TPO level did not correlate with the nadir platelet count (P =.43). In conclusion, the normal inverse relationship between platelet count and TPO levels was not observed in ALF. Despite severe hepatic dysfunction, serum TPO levels were initially normal and increased during hospitalization in acetaminophen-induced ALF, but did not prevent the development of thrombocytopenia.
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PMID:Thrombopoietin in acute liver failure. 1260 53


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