Thrombocytopenia In Liver Disease Research Articles

Thrombocytopenia and liver disease: pathophysiology and periprocedural management

Abnormal bleeding in patients with liver disease may result from elevated portal pressure and varix formation, reduced hepatic synthesis of coagulation proteins, qualitative platelet dysfunction, and/or thrombocytopenia. Major mechanisms of thrombocytopenia in liver disease include splenic sequestration and impaired platelet production due to reduced thrombopoietin production. Alcohol and certain viruses may induce marrow suppression. Immune thrombocytopenia (ITP) may co-occur in patients with liver disease, particularly those with autoimmune liver disease or chronic hepatitis C. Drugs used for the treatment of liver disease or its complications, such as interferon, immunosuppressants, and antibiotics, may cause thrombocytopenia. Periprocedural management of thrombocytopenia of liver disease depends on both individual patient characteristics and the bleeding risk of the procedure. Patients with a platelet count higher than or equal to 50 000/µL and those requiring low-risk procedures rarely require platelet-directed therapy. For those with a platelet count below 50 000/µL who require a high-risk procedure, platelet-directed therapy should be considered, especially if the patient has other risk factors for bleeding, such as abnormal bleeding with past hemostatic challenges. We often target a platelet count higher than or equal to 50 000/µL in such patients. If the procedure is elective, we prefer treatment with a thrombopoietin receptor agonist; if it is urgent, we use platelet transfusion. In high-risk patients who have an inadequate response to or are otherwise unable to receive these therapies, other strategies may be considered, such as a trial of empiric ITP therapy, spleen-directed therapy, or transjugular intrahepatic portosystemic shunt placement.

Thrombocytopenia and Hemostatic Changes in Acute and Chronic Liver Disease: Pathophysiology, Clinical and Laboratory Features, and Management.

Thrombocytopenia, defined as a platelet count <150,000/μL, is the most common complication of advanced liver disease or cirrhosis with an incidence of up to 75%. A decrease in platelet count can be the first presenting sign and tends to be proportionally related to the severity of hepatic failure. The pathophysiology of thrombocytopenia in liver disease is multifactorial, including (i) splenomegaly and subsequently increased splenic sequestration of circulating platelets, (ii) reduced hepatic synthesis of thrombopoietin with missing stimulation both of megakaryocytopoiesis and thrombocytopoiesis, resulting in diminished platelet production and release from the bone marrow, and (iii) increased platelet destruction or consumption. Among these pathologies, the decrease in thrombopoietin synthesis has been identified as a central mechanism. Two newly licensed oral thrombopoietin mimetics/receptor agonists, avatrombopag and lusutrombopag, are now available for targeted treatment of thrombocytopenia in patients with advanced liver disease, who are undergoing invasive procedures. This review summarizes recent advances in the understanding of defective but at low level rebalanced hemostasis in stable cirrhosis, discusses clinical consequences and persistent controversial issues related to the inherent bleeding risk, and is focused on a risk-adapted management of thrombocytopenia in patients with chronic liver disease, including a restrictive transfusion regimen.

Immunosuppressive Treatment Combined with Nucleoside Analogues Is Superior to Nucleoside Analogues Alone in the Treatment of Severe Thrombocytopenia in Patients with Cirrhosis-Associated with Hepatitis B in China: A Multicenter, Observational Study

Introduction: Thrombocytopenia is a frequent manifestation of liver cirrhosis (LC) related to the hepatitis B virus (HBV). Severe thrombocytopenia is associated with bleeding events that increase morbidity and mortality in patients with LC. No effective treatment has been identified for patients with composited liver cirrhosis associated with HBV and severe thrombocytopenia. The pathogenesis of thrombocytopenia in liver diseases has not been well established. It has been suggested that autoantibody-mediated platelet destruction might contribute, at least in part, to hepatitis B cirrhotic thrombocytopenia. We aimed to explore the effectiveness and safety of low dose prednisone or low dose cyclosporine combined with a nucleoside analogue in patients with severe thrombocytopenia associated with HBV-related LC.Methods: In this observational cohort study, we included 145 consecutive compensated HBV-associated LC patients with severe thrombocytopenia (PLT<30,000 per cubic millimeter, accompanied by a tendency towards bleeding) between January 1, 2006 and December 31, 2013. We divided the patients into three groups by treatment strategy, including NA alone (n=57), NA plus prednisone (n=46), and NA plus cyclosporine (CsA) (n=42). Prednisone was given at a dosage of 0.5 mg/kg/d for 4 weeks until a response was observed or until the side effects became intolerable. The cyclosporine regimen consisted of oral CsA at a dosage of 1 mg/kg/d given in two divided doses. The dose of prednisone or CsA was then slowly tapered in the patients who responded to the drugs. We analyzed the platelet counts, bleeding events, liver function, replication of HBV, and outcomes in each group. The platelet counts following the treatments were estimated using mixed-effects linear models that included all available platelet counts after treatment. These models were adjusted by age, sex, the Child-Pugh score, other systemic complications, platelet transfusion, and research center. Cox proportional hazards analyses were performed to examine the factors related to bleeding events. Data was analyzed using IBM SPSS Statistics version 19.0 (SPSS Inc., an IBM company). P values less than 0.05 were considered significant. This study is registered with ClinicalTrials.gov under number NCT01987791.Results: At all time points during this observation, platelet counts in the prednisone plus NA and CsA plus NA groups were higher than those in the NA group. In the group receiving prednisone plus NA, 35 of the 46 patients (76.1%) had platelet counts of 50,000 per cubic millimeter or greater during this observation. As in the CsA plus NA group, 30 of the 42 patients (71.4%) had platelet counts of 50,000 per cubic millimeter or greater. Only 4 of the 57 patients (7.0%) in the NA treatment group had platelet counts that were higher than 50,000 per cubic millimeter. The cumulative bleeding events in the three treatment groups were 67.0% in the NA only group, 56.9% in the prednisone group and 62.2% in the CsA group. The cumulative rates of bleeding events were significantly different among the three groups (p=0.001). The platelet counts, treatment with prednisone plus NA and treatment with CsA plus NA were factors associated with bleeding events in the multivariate analysis. After treatment, serum alanine transaminase levels were significantly lower than those before treatment in all groups. The differences in the HBV-DNA negative rates, HBV-DNA elevated rates, normal serum alanine transaminase rates, serum alanine transaminase rates that elevated more than two times the baseline rate, and HBeAg seropositive conversion ratios among the groups did not reach statistical significance. Levels of the platelet-associated anti-GPIIb-IIIa antibodies after the 4-week treatment were lower than those at baseline in the prednisone group and CsA group; no difference was observed in the NA alone group. The adverse events in our study were mild in general and balanced among the three treatment groups.Conclusions: Treatment with low dose prednisone or low dose CsA plus NA could elevate the platelet count and reduce the risk of bleeding events in HBV LC patients with severe thrombocytopenia; the treatment had no obvious adverse effects on liver function and HBV DNA replication. DisclosuresNo relevant conflicts of interest to declare.

Use of eltrombopag in thrombocytopenia of liver disease

Second generation thrombopoietin agonists including eltrombopag and romiplostim act on the thrombopoietin receptor to increase the megakaryocyte production. These agents were needed as use of first generation recombinant products was associated with formation of autoantibodies. Eltrombopag is an oral thrombopoietin agonist found effective in raising platelet counts in patients with immune thrombocytopenia. The drug has now been found to be useful in raising platelet counts in thrombocytopenia related to liver disease including cirrhosis and chronic viral hepatitis. Although the drug may help enable adequate interferon therapy in patients with HCV infection and help carry out invasive procedures in patients with cirrhosis, concerns have been raised of possible thrombotic complications including portal vein thrombosis. Randomized trials have shown that use of eltrombopag concomitant with pegylated interferon and ribavirin increased the chances of sustained virologic response while decreasing the dose reductions of interferon. The data on use of romiplostim in these clinical indications is also emerging. However, in the future, availability of interferon free regimens is likely to decrease the use of eltrombopag for enabling antiviral therapy. The review discusses the role of eltrombopag in management of liver disease related thrombocytopenia in wake of recent data as also the dosage, precautions and adverse effects associated with its use.

Use of Thrombopoietic Agents for the Thrombocytopenia of Liver Disease

Thrombocytopenia can be a sign of advanced liver disease. This complicates the management of these patients, as patients with advanced liver disease frequently need therapeutic interventions, which are associated with an increased risk of bleeding. Thrombocytopenia may even be more pronounced in patients with hepatitis C virus (HCV) infection. This can limit current and future treatments for HCV, which remains based on interferon therapy, and this therapy can worsen thrombocytopenia. Thus, the ability to increase platelets to higher and safer levels would be desirable, but no treatment has yet been proven effective and safe in this setting. The small molecule thrombopoietin mimetic, eltrombopag, has demonstrated a dose-response increase in platelet counts in a phase II study in HCV patients without significant side effects, allowing initiation and completion of a 12-week course of pegylated interferon plus ribavirin in 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, or 75 mg eltrombopag daily, respectively, compared to only 6% in the placebo arm. A current phase III study is currently evaluating whether this treatment allows successful outcomes and sustained viral eradication.

Thrombopoietin and thrombocytopenia in anorexia nervosa with severe liver dysfunction

Patients with anorexia nervosa (AN) display various physical complications. One such problem is thrombocytopenia. However, no studies have investigated links between AN and thrombopoietin (TPO), which is the primary regulator of megakaryocyte and platelet production produced mainly in the liver, although TPO has been recently reported to play a role in thrombocytopenia in liver diseases. We therefore clarified temporal relationships between platelet counts and TPO level in a woman with AN and severe liver dysfunction in whom platelet count decreased to 53 x 10⁹/L. While international normalized ratio (INR) was low, serum TPO level was relatively low despite low platelet counts. After INR and liver enzymes improved in conjunction with improved nutritional status, a rapid increase in TPO was observed and platelet count began to rise. These findings thus suggest that decreased TPO production accompanying liver dysfunction may be related to thrombocytopenia besides myelosuppression in AN with malnutrition.

Thrombocytopenia in liver disease

To evaluate recent findings in the multifaceted pathophysiological mechanisms underlying thrombocytopenia in patients with chronic liver disease and to assess its therapeutic management. Antiplatelet antibodies, despite being observed rather frequently in patients with chronic viral liver disease, have minimal relevance in the determinism of thrombocytopenia, and antiviral treatment of the underlying liver disease does not seem to significantly affect their prevalence. Translational application of the results of studies evaluating coagulation disorders associated with liver disease seems to suggest that these may be improved by treating thrombocytopenia. Both splenectomy and partial splenic embolization are still part of the therapeutic approach to thrombocytopenia. As far as this latter technique is concerned, patient selection is fundamental, and its success likely depends upon thrombopoietin-mediated mechanisms. Eltrombopag is a promising thrombopoietic drug that proved to be able to safely increase platelet counts in patients with viral liver disease and allows the initiation of antiviral treatment. New insights into the pathophysiological mechanisms of thrombocytopenia in patients with liver disease have provided interesting clinical reflex. In these patients, novel therapies for treating thrombocytopenia seem promising, although it remains to be established whether treating thrombocytopenia may help improve liver disease-associated coagulopathy.

Thrombopoietin levels in serum and liver tissue in patients with chronic viral hepatitis and hepatocellular carcinoma

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±15×109/l, 81±8×109/l, 99±7×109/l and 234±9×109/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 &lt; 0.05, in each case), and negatively correlated with Indocyanine Green test and Pugh score (P &lt; 0.01 and P &lt; 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.

Thrombopoietin levels in serum and liver tissue in patients with chronic viral hepatitis and hepatocellular carcinoma

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.

Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production

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.

Thrombocytopenia in liver disease.

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.

Thrombopoietic cytokines and reversal of thrombocytopenia after liver transplantation.

Thrombopoietin (TPO), the key regulator of platelet production, is mainly produced by the liver and reduced expression of TPO could cause thrombocytopenia in liver cirrhosis. Reversal of thrombocytopenia by orthotopic liver transplantation seems to be mediated through an increase in TPO plasma levels after transplantation, but other cytokines with thrombopoietic activity could augment the actions of TPO on post transplant platelet recovery. Measurement of thrombopoietic cytokines before and for 14 days post liver transplantation in a cohort of thrombocytopenic liver transplant patients. TPO, interleukin-3 (IL-3), IL-6, and IL-11 plasma levels as well as peripheral platelet count were analysed in thrombocytopenic patients with liver disease undergoing orthotopic liver transplantation (17 patients) and followed for 14 days after the intervention. Before liver transplantation, TPO plasma levels were undetectable and IL-3, IL-6, and IL-11 levels were normal. Sixteen out of 17 patients showed a significant rise of TPO levels within 2 days after transplantation, with a peak between days 4 and 6, while IL-3 and IL-6 levels did not show a significant rise. IL-11 levels remained normal. Platelet counts were significantly higher than pretransplantation levels by day 14 post transplantation. Restitution of normal TPO production by liver replacement seems to be of key importance for reversal of thrombocytopenia in liver disease. The early acting thrombopoietic factor IL-3 and the late acting factors IL-6 and IL-11 do not play a major role for recovery of peripheral platelet count after orthotopic liver transplantation.

In thrombocytopenia in liver failure dependent on an inadequate synthesis of thrombopoietic stimulating factor by the liver?

Thrombocytopenia in liver diseases has been considered secondary to portal hypertension or to a consumption mechanism associated with fibrinolytic disorders. Several conflicting clinical reports and evidence from experimental models justify the above mentioned mechanisms only in part. We propose that thrombocytopenia may be consequent to an inadequate synthesis of a factor stimulating trombopoiesis produced by the liver.