Thrombopoietin in acute liver failure

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.     

The role of thrombopoietin in the thrombocytopenia of patients with liver cirrhosis

OBJECTIVES: Thrombocytopenia is a common disorder among cirrhotics that has been traditionally explained by splenic platelet pooling and destruction. Thrombopoietin (TPO), the main stimuli for thrombopoiesis is produced primarily in the liver and degraded by circulating platelets, but its role in the thrombocytopenia of liver cirrhosis is not well understood. The main goal of this study is to clarify the role of TPO in the pathogenesis of thrombocytopenia in cirrhosis. METHODS: The relation among TPO, platelet count, spleen size, portal hypertension, and liver function was studied in 33 cirrhotic patients before and after either partial splenic embolization or liver transplantation. RESULTS: Cirrhotics with thrombocytopenia had lower serum TPO levels than healthy controls (median values (interquartile range: ICR) were 120.7 (42.0-191.6) vs 756.4 (527.0-965.1) pg/mL, respectively; p<0.001). Among cirrhotics with thrombocytopenia, serum TPO was related to spleen size (rho=-0.387, p=0.046), but not to platelet count as occurs physiologically. After partial splenic embolization, TPO and platelet count increased significantly and the physiological relation between TPO and platelet count was restored (rho=-0.665, p=0.026). Similar results were observed after liver transplantation. CONCLUSIONS: Our results suggest that besides impaired production in the failing liver, an increased TPO degradation by platelets sequestered in the congested spleen may contribute to thrombocytopenia in cirrhotic patients.     

Transient thrombopoietin peak after liver transplantation for end-stage liver disease

Knowledge about synthesis of thrombopoietin (TPO) by human liver cells is now well established and makes the study of TPO serum levels and interdependency with platelet concentrations important before and after liver transplantation. We followed these variables in 14 patients suffering from primary biliary cirrhosis (group A), 10 with hepatitis B (group B) and nine with hepatitis C (group C) infections, as well as 11 patients suffering from alcoholic cirrhosis (group D). In the pretransplant serum samples, TPO levels and platelet counts revealed median values (range) of 112.75 pg/ml (5.0-349.3) in group A, 67.8 pg/ml (14.8-249.9) in B, 68.6 pg/ml (31.4-147.3) in C and 57.9 pg/ml (25.2-264.2) in D for TPO, and 138 x 10(9)/l (36-243) in A, 48 x 10(9)/l (22-129) in B, 105 x 10(9)/l (32-176) in C and 109 x 10(9)/l (33-285) in D for platelets, the latter levels being abnormally reduced. Within 2-3 d of transplantation, the TPO levels started to increase to transient peaks of mostly 5-10 times baseline, which were followed by continuous correction of thrombocytopenia. Splenomegaly was identified to be an important co-factor of thrombocytopenia in groups A and D. We conclude that decreased TPO production in patients with end-stage liver diseases is reverted by orthotopic liver transplantation.     

Plasma thrombopoietin levels in liver cirrhosis and kidney failure

BACKGROUND: Recently, c-Mpl ligand (thrombopoietin, TPO) has been cloned by several groups and found to be a primary regulator of thrombopoiesis. Its mRNA expression has been detected in several organs including kidneys, bone marrow stroma cells, muscles, and is very strongly expressed in the liver. OBJECTIVE: To clarify thrombopoiesis and the regulation of TPO in severe liver and renal failure. DESIGN: We analysed plasma TPO levels in patients with biopsy verified liver cirrhosis (n = 18; mean platelet count 115 +/- 54 x 109 L-1), in patients on chronic haemodialysis as a result of end-stage renal failure (n = 20; mean platelet count 295 +/- 94 x 109 L-1), and in healthy individuals (n = 20; mean platelet count 250 +/- 40 x 109 L-1). Plasma was prepared from EDTA-anticoagulated whole blood and a commercially available ELISA kit was used for the analysis. RESULTS: The mean plasma TPO concentration amongst the normal individuals was 50 +/- 14 pg mL-1. In the patients with liver cirrhosis and in patients on haemodialysis the mean TPO levels were 62 +/- 19 pg mL-1 and 46 +/- 17 pg mL-1, respectively. The mean plasma TPO concentration for the cirrhotic patients was significantly higher than the mean recorded for the healthy volunteers (P = 0.031), whereas no statistically significant differences in plasma TPO were seen between the group of end-stage renal failure and normals. CONCLUSION: Our results suggest that TPO production is maintained in liver cirrhosis and in renal failure, and that the thrombocytopenia in liver cirrhosis is not due to an impaired TPO production.     

肝硬化患者血小板计数与血小板生成素及脾脏指数间的关系

目的 研究肝硬化患者外周血血小板计数、血清血小板生成素(TPO)水平及脾脏指数间的关系,以明确肝硬化患者血小板减少的原因。方法 血清TPO水平采用酶联吸附法检测,脾脏指数由同一医生在相同的条件下用彩色多普勒超声仪测量。结果 健康对照组与肝硬化组外周血小板计数分别为(169.63±26.60)×10~(12)/L、(109.20±53.39)×10~(12)/L,t=3.630,P<0.05;血清TPO水平分别为(412.63±132.80)pg/ml、(436.42±258.97)pg/ml,t=0.272,P>0.05。随着肝脏损伤的加重,血清TPO水平依次下降,Child-Pugh A级、B级、C级分别为(526.13±317.44)pg/ml、(445.22±214.90)pg/ml、(311.45±182.66)pg/ml,A级与C级之间差异有显著性,而其它指标(血小板计数、脾脏指数、门静脉宽度)A级与B级、C级之间差异有显著性。血小板正常组(35例)与血小板减少组(36例)血清TPO水平分别为(529.43±282.64)pg/ml、(351.27±228.25)pg/ml,t=-2.926,P<0.01;而两组间脾脏指数分别为(19.65±12.00)cm~2、(36.35±12.68)cm~2,t=1.891,P>0.05。结论 血清TPO水平降低可能是肝硬化患者血小板减少的原因之一,脾脏在血小板减少中的作用有待进一步研究。     

Impaired liver function and retroviral activity are risk factors contributing to HIV-associated thrombocytopenia. Swiss HIV Cohort Study.

OBJECTIVE: To investigate the relationship between thrombopoetin (TPO) serum levels and HIV-associated thrombocytopenia. DESIGN AND METHODS: The relationship between TPO levels and severity of HIV-associated thrombocytopenia was investigated. Thirty-eight patients (19 patients with 30-96x10(9) platelets/l and 19 patients with <10x10(9) platelets/l) were matched with 38 HIV-positive non-thrombocytopenic patients (>150x10(9) platelets/l). RESULTS: HIV-positive patients with normal platelet counts had a median TPO serum level of 137 pg/ml. Patients with 30-96x10(9) platelets/l had decreased TPO levels with a median of 90 pg/ml (P = 0.016), and were more likely to have elevated serum aspartate-transferase levels (P<0.001) and hepatomegaly by palpation or ultrasound imaging (P = 0.005). The median TPO serum level of HIV-infected patients with severe thrombocytopenia was 110 pg/ml (non-significant). All patients with severe thrombocytopenia were positive for antibodies against hepatitis B virus core antigen, compared with 80% of HIV-infected persons without thrombocytopenia. Patients with severe thrombocytopenia were more likely to have high HIV replication compared to patients with normal platelet counts (P = 0.02), and reduction of plasma HIV-1 RNA levels was associated with increasing platelet counts. Severe thrombocytopenia was not associated with liver disease. CONCLUSIONS: Liver disease predisposes for low TPO serum levels and mild thrombocytopenia. High retroviral activity predisposes for severe, immune thrombocytopenic purpura-like thrombocytopenia. At least two distinct categories of severe HIV-associated thrombocytopenia exist, one responsive to antiretroviral treatment and one non-responsive to antiretroviral treatment.     

Thrombopoietin (TPO) Levels in Hepatic Patients with Thrombocytopenia

Thrombocytopenia is a common problem complicating the course of liver disease. One of the postulated mechanisms in chronic liver disease is impaired production of the hormone, thrombopoietin (TPO). The aim of present study was to evaluate the role of TPO on the occurrence of thrombocytopenia. Serum TPO levels was determined by ELISA in 40 patients with liver disease (11 seropositive with hepatitis C; 10 with mixed liver cirrhosis; 19 with bilharzial hepatic fibrosis), plus 14 normal healthy subjects as a control group. The sTPO levels were unevenly distributed among the liver disease subgroups being the highest in the group with HCV (median 1232.0, range 154.7-2042.0 pg/ml) followed by the mixed cirrhosis group (556.5; 342.0-1497.0 pg/ml) and lowest among the bilharzial hepatic fibrosis group (130.0; 22.0-204.0 pg/ml) ( P <0.01). While sTPO levels in HCV and cirrhotic group were significantly higher when compared to the control group (97.0; 19.0-377.0 pg/ml), those in the Bilharzial hepatic fibrosis group were not significantly elevated ( P > 0.05). There is significant negative correlation between sTPO levels and spleen size ( R =?0.3, P =0.043); but there was no correlation with platelet count ( R =0.09, P >0.05). In addition, sTPO levels were significantly higher in patients with platelet counts ≥60×10 9 /l as compared to those with platelet counts <60×10 9 /l ( P =0.04). Using the receiver operating curve (ROC) at sTPO cut off value ≥ vs. < 368 ng/ml, most of HCV and cirrhotic patients had higher sTPO levels (81.8 and 80.0%, respectively), while all Bilharzial hepatic fibrosis group (100%) had lower sTPO levels. In conclusion, sTPO levels had no role in the occurrence of thrombocytopenia in liver disease patients and other factors appear to be more important. It also appears that the mechanism controlling sTPO levels might be different in cirrhotic patients compared to Bilharzial hepatic fibrosis patients.     

Thrombopoietin (TPO) levels in hepatic patients with thrombocytopenia

Thrombocytopenia is a common problem complicating the course of liver disease. One of the postulated mechanisms in chronic liver disease is impaired production of the hormone, thrombopoietin (TPO). The aim of present study was to evaluate the role of TPO on the occurrence of thrombocytopenia. Serum TPO levels was determined by ELISA in 40 patients with liver disease (11 seropositive with hepatitis C; 10 with mixed liver cirrhosis; 19 with bilharzial hepatic fibrosis), plus 14 normal healthy subjects as a control group. The sTPO levels were unevenly distributed among the liver disease subgroups being the highest in the group with HCV (median 1232.0, range 154.7-2042.0 pg/ml) followed by the mixed cirrhosis group (556.5; 342.0-1497.0 pg/ml) and lowest among the bilharzial hepatic fibrosis group (130.0; 22.0-204.0 pg/ml) (P<0.01). While sTPO levels in HCV and cirrhotic group were significantly higher when compared to the control group (97.0; 19.0-377.0 pg/ml), those in the Bilharzial hepatic fibrosis group were not significantly elevated (P>0.05). There is significant negative correlation between sTPO levels and spleen size (R=-0.3, P=0.043); but there was no correlation with platelet count (R=0.09, P>0.05). In addition, sTPO levels were significantly higher in patients with platelet counts >or=60x10(9)/l as compared to those with platelet counts <60x10(9)/l (P=0.04). Using the receiver operating curve (ROC) at sTPO cut off value >or= vs. <368 ng/ml, most of HCV and cirrhotic patients had higher sTPO levels (81.8 and 80.0%, respectively), while all Bilharzial hepatic fibrosis group (100%) had lower sTPO levels. In conclusion, sTPO levels had no role in the occurrence of thrombocytopenia in liver disease patients and other factors appear to be more important. It also appears that the mechanism controlling sTPO levels might be different in cirrhotic patients compared to Bilharzial hepatic fibrosis patients.     

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.     

Usefulness of thrombopoietin in the diagnosis of peripheral thrombocytopenias.

BACKGROUND AND OBJECTIVE: Thrombocytopenia of peripheral origin is basically due to platelet destruction or splenic sequestration. Thrombopoietin (TPO) regulates platelet production stimulating megakaryocyte proliferation and maturation. The evaluation of TPO levels may be a useful tool in the diagnosis of thrombocytopenias of unknown origin. We tried to determine the value of TPO levels in some thrombocytopenias classically considered as peripheral. DESIGN AND METHODS: Serum TPO levels and platelet counts were measured in 32 thrombocytopenic patients with liver cirrhosis (LC) and 23 with chronic hepatitis C (CHC) viral infection, in 54 patients with a clinical and serological diagnosis of autoimmune thrombocytopenic purpura (AITP), and in 88 patients infected with the human immunodeficiency virus (HIV). RESULTS: Patients with LC, AITP and HIV had lower platelet counts than patients with CHC. The degree of thrombocytopenia did not, however, correlate with the TPO levels. HIV infected patients (246+/-304 pg/mL) and AITP patients (155+/-76 pg/mL) had higher TPO levels than controls (121+/-58 pg/mL). TPO levels in patients with CHC (125+/-40 pg/mL) did not differ from those in control subjects, but were slightly decreased in patients with LC (104+/-56 pg/mL). INTERPRETATION AND CONCLUSIONS: Reduced TPO production could be involved in the development of thrombocytopenia in LC patients, but not in patients with early stages of CHC viral infection. HIV and AITP patients had slightly raised levels of TPO. As TPO levels are normal or slightly increased in most peripheral thrombocytopenias, these data alone are not sufficient to distinguish the different types of peripheral thrombocytopenia. They may, however, be a useful tool for differentiating some central and peripheral thrombocytopenias.     

Expression of hepatic thrombopoietin mRNA in primary cultured hepatocytes and in rats with acute liver injury or bone marrow suppression with or without cirrhosis

BACKGROUND AND AIMS: The main causes of thrombocytopenia in cirrhosis are thought to be platelet destruction and the reduction of thrombopoietin (TPO) expression in the liver. The mechanisms by which levels of TPO mRNA are regulated in cirrhosis have not been elucidated. In this study, we investigated some possible mechanisms. METHODS: We used three experimental models: bone marrow suppression, acute liver injury and primary cultured hepatocytes. We used northern blots to assess the kinetics of TPO mRNA expression in the livers of irradiated rats (with and without cirrhosis) in acute liver injury and in primary cultured hepatocytes treated with hepatotoxin or cytokines. RESULTS: Although the bone marrow was hypocellular, there was no apparent enhancement of TPO mRNA expression in the irradiated rats with cirrhotic livers compared with the unirradiated rats with cirrhotic livers. There were no conspicuous changes in hepatic TPO mRNA expression between the livers of the control rats and the three models of acute liver injury. There were no conspicuous changes in the levels of TPO mRNA between control hepatocytes and hepatocytes treated with hepatotoxin or cytokines. CONCLUSIONS: Our results suggest that bone marrow is not a regulator of hepatic TPO production in cirrhosis. The reduced TPO mRNA expression found in cirrhotic rats may not result merely from serious cellular damage; it may be associated with cirrhosis-specific regulatory mechanisms for the expression of the TPO gene. Further studies are needed to search for other factors that may induce reduced TPO expression.     

Thrombopoietic cytokines and reversal of thrombocytopenia after liver transplantation

OBJECTIVES: 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. DESIGN: Measurement of thrombopoietic cytokines before and for 14 days post liver transplantation in a cohort of thrombocytopenic liver transplant patients. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Role of elevated platelet-associated immunoglobulin G and hypersplenism in thrombocytopenia of chronic liver diseases

BACKGROUND AND AIM: Thrombocytopenia typically worsens with the progression of liver disease and can become a major clinical complication. Several mechanisms that contribute to thrombocytopenia have been proposed, including hypersplenism accompanied by increased platelet sequestration, platelet destruction mediated by platelet-associated immunoglobulins (PAIgG), and diminished platelet production stimulated by thrombopoietin (TPO). The purpose of the present study was to evaluate the role of each of these mechanisms in patients with liver disease-associated thrombocytopenia. METHODS: Twenty-nine patients with liver cirrhosis (LC), 20 of whom were hepatitis C virus (HCV)-seropositive, 29 chronic hepatitis (CH) patients, 24 of whom were HCV-seropositive, and 16 control patients without liver or hematopoetic disease were enrolled in this study. Serum TPO levels, PAIgG, and liver-spleen volumes were determined and correlation analyses were performed. RESULTS: No differences in serum TPO levels were observed among the three groups. The PAIgG levels were significantly elevated in CH and LC patients (mean +/- SD: 56.5 +/- 42.3 and 144.6 +/- 113.6 ng/107 cells, respectively) compared with the controls (18.9 +/- 2.5 ng/107 cells, P < 0.001 for both). Spleen volume was significantly higher only in LC (428 +/- 239) compared with CH (141 +/- 55) and control (104 +/- 50 cm3) (P < 0.001), while liver volume was not significantly different between the three groups. Correlation analyses demonstrated a significant negative correlation between platelet count with PAIgG (r = - 0.517, P < 0.001) and spleen volume (r = - 0.531, P < 0.001), and no relationship between platelet count and serum TPO level (r = 0.076). CONCLUSIONS: Serum TPO level may not be directly associated with thrombocytopenia in patients with chronic hepatitis and liver cirrhosis. In contrast, spleen volume and PAIgG are associated with thrombocytopenia in such patients, suggesting that hypersplenism and immune-mediated processes are predominant thrombocytopenic mechanisms.     

Serum thrombopoietin levels are linked to liver function in untreated patients with hepatitis C virus-related chronic hepatitis

BACKGROUND: Thrombocytopenia can be found in patients with chronic hepatitis related to hepatitis C virus (HCV). Both hypersplenism and decreased liver production of thrombopoietin (TPO) have been hypothesized as mechanisms responsible for thrombocytopenia. AIMS: To assess the presence of relationships among platelet count, spleen size, TPO serum levels, liver histology, and liver function in a group of patients with HCV-related chronic hepatitis. METHODS: Platelet count, TPO serum levels, and spleen size were assessed in 25 untreated HCV positive chronic hepatitis patients undergoing liver biopsy. These parameters were correlated to liver histology and liver function as evaluated by means of [(13)C]aminopyrine breath test (ABT). RESULTS: Both platelet counts (146 +/- 48 vs. 202 +/- 56 x 10(9)/1, P < 0.03) and TPO serum levels (103 +/- 24 vs. 158 +/- 7 1 pg/ml, P < 0.02) were lower among patients with high fibrosis scores as compared to patients with low fibrosis scores. Patients with thrombocytopenia as well as patients with high fibrosis scores had lower ABT results as compared to patients with normal platelet counts and patients with no or mild fibrosis, respectively. TPO serum levels were correlated to platelet count (r(s) = 0.493, P = 0.016), and negatively correlated to fibrosis stage (r(s) = -0.545, P = 0.008). Lastly, low TPO serum levels were associated to a decrease in liver function. CONCLUSIONS: Our study showed that in patients with chronic hepatitis related to HCV infection serum TPO levels are correlated to liver functional impairment and to the degree of liver fibrosis.     

Serum Thrombopoietin Levels and Its Relationship With Thrombocytopenia in Patients With Cirrhosis

Background:

Patients with cirrhosis usually have thrombocytopenia in discrete levels. The mechanism of thrombocytopenia is thought as splenic sequestration and destruction of platelets, impaired bone marrow generation and diminished hepatic thrombopoietin synthesis.

Objectives:

The aim of this study was to evaluate serum thrombopoietin levels and its relationship with thrombocytopenia at patients with cirrhosis.

Patients and Methods:

Ninety–two cirrhotic patients and 45 healthy controls without history or findings of pathologies that can effect thrombopoietin levels were enrolled by simple random sampling to patient and control groups of this case control study performed at Eskisehir-Turkey. Thrombopoietin was measured in serum samples with a solid phase enzyme-linked immune absorbent assay. Additionally, spleen size and volume index were determined.

Results:

Platelet counts were lower in patients with cirrhosis (97000 ± 8000/mm³) than in healthy subjects (240000 ± 51000/mm³, P < 0.001). Significant difference was determined for platelet counts among child A, B and C stages (Child A vs. Child B P < 0.05 Child A vs. Child C P < 0.001–Child B vs. Child C P < 0.05). Serum TPO concentration was higher (69 ± 12 pg/mL) in cirrhotic group than healthy controls (49 ± 9 pg/ml) (P < 0.05). No significant difference in TPO levels were found among the Child A, B and C stages (64 ± 11 pg/mL, 75 ± 13 pg/mL and 68 ± 10 pg/mL, respectively). Spleen size and SVI was significantly higher in the cirrhotic patients than healthy controls (148 ± 14 mm vs. 98 ± 11 mm, P < 0.001-9167 ± 287 cm² vs. 4118 ± 123 cm²). Significant difference was determined for spleen size and spleen index among child A, B and C stages (Child A vs. Child B P < 0.05 Child A vs. Child C P < 0.001–Child B vs. Child C P < 0.05). TPO levels were significantly different between cirrhotic patients with platelet levels below 50.000/mm³ (n = 16, plt-count: 41000 ± 8300/mm³, TPO levels: 73 ± 7 pg/mL) and above 50.000/mm³ (n = 76, plt-count: 105000 ± 9500/mm³, TPO levels: 65 ± 10 pg/mL) (P < 0.01). In correlation analysis, there was a strong negative correlation between platelet count-spleen size (P < 0.001, r = -0.74) and platelet count–serum TPO levels (P < 0.001, r = -0.71).

Conclusions:

Our results suggest that liver cirrhosis does not cause impaired thrombopoietin production even in the late stage of disease. Thrombopoietin has no contribution for the occurrence of thrombocytopenia in cirrhosis; splenic sequestration seems to be the main factor.     

Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction

Thrombopoietin (TPO), the ligand for c-mpl, stimulates proliferation of committed megakaryocytic progenitors and induces maturation of megakaryocytes. To better understand factors regulating TPO levels, we measured blood levels of TPO in patients with impaired platelet production due to aplastic anemia (AA) and with platelet destructive disorders, including idiopathic thrombocytopenic purpura (ITP), posttransfusion purpura (PTP), drug purpura (DP), and X-linked thrombocytopenia (XLTP). The TPO receptor capture enzyme immunoassay (EIA) used had a detection limit of integral of approximately-150 to 200 pg/mL. TPO was undetectable in 88 of 89 normal individuals. Eighteen of 19 patients with AA and a mean platelet count (MPC) of 18,000/microliters (2,000 to 61,000/microliters) had markedly elevated TPO levels (mean, 1,467 pg/mL; range, 597 to 3,834 pg/mL). Eight AA patients who responded to immunosuppressive therapy with their MPC increasing to 140,000/microliters (92,000 to 175,000/microliters) had substantial decreases in TPO (mean, 440 pg/mL; range, 193 to 771 pg/mL). Initial TPO levels did not differ significantly between responders and nonresponders. In contrast, all 21 patients with ITP and an MPC of 16,000/microliters (1,000 to 51,000 /microliters) had undetectable TPO levels, as did 6 patients with acute PTP or DP and 2 patients with XLTP. Megakaryocyte mass, reflected in the rate of platelet production, appears to be the major determinant of TPO levels in thrombocytopenic patients rather than circulating platelet levels per se. Measurement of serum TPO may be useful in differentiating thrombocytopenias due to peripheral destruction from those due to thrombopoietic failure.     

Acoustic radiation force impulse (ARFI) elastography in acute liver failure: necrosis mimics cirrhosis

Acoustic radiation force Impulse (ARFI) technology correlates shear-wave velocity with fibrosis. It can differentiate between advanced fibrosis and normal tissue in chronic liver disease. However, specificity is impaired by cholestasis, inflammation or oedema in acute hepatitis. In patients with acute liver failure (ALF) necessitating liver transplantation ARFI has not been evaluated yet. We investigated 3 patients with ALF and compared their ARFI results to those of healthy controls (n = 33) and cases with liver cirrhosis (n = 21). In the 3 ALF patients shear-wave velocities were 3.0, 2.5, and 2.7 m/s, respectively. These results were significantly increased compared to those of healthy controls (median: 1.13 m/s; p < 0.001) and similar to those of cirrhotic individuals (median: 2.93 m/s). Two individuals underwent liver transplantation. Explants showed massive necrosis, but no signs of chronic liver disease. Patient 3 recovered spontaneously and showed decreasing ARFI results during follow-up. In conclusion, hepatic necrosis can mimic liver cirrhosis at ARFI evaluation in ALF patients and this impairs the specificity of ARFI.