Thrombopoietin Levels In Patients Research Articles

The Differences of Serum Thrombopoietin Levels Between Acquired Aplastic Anemia and Immune Thrombocytopenia in Pediatric Patients.

Thrombopoietin (TPO) is the critical regulator of platelet production. However, the role of TPO in pediatric patients with thrombocytopenic disorders has not been fully elucidated. In the present study, we attempted to investigate serum TPO levels in patients with acquired aplastic anemia (aAA) and immune thrombocytopenia (ITP). We analyzed the endogenous plasma concentration of TPO and platelet count at the time of TPO measurement in 166 patients with aAA and 280 patients with ITP retrospectively. We further observed a correlation between platelet counts and TPO. Serum TPO levels were significantly higher in aAA compared with ITP (1142 vs. 77.99pg/mL, P <0.001). In patients with aAA, an elevation for TPO levels in very severe AA (VSAA) was seen when compared with non-severe AA (NSAA) (1360 vs. 984.4pg/mL, P <0.05). In contrast, the circulating TPO levels with chronic ITP (CITP) showed a decrease than newly diagnosed ITP (NITP) and persistent ITP (PITP) (62.28 vs. 81.56pg/mL, P <0.01, 62.28 vs. 87.82pg/mL, P <0.05, respectively). There was a negative correlation between platelet counts and TPO levels in aAA (r s =-0.3325, P <0.001) as well as ITP (r s =-0.2570, P <0.001). Especially, TPO levels were inversely correlated with platelet counts in NSAA (r s =-0.3672, P <0.001) and NITP (r s =-0.3316, P <0.001). After grouping by age or sex, there were no statistical differences in aAA or ITP. Serum TPO levels were markedly elevated in pediatric patients with aAA compared with ITP. It was higher in VSAA and lower in CITP, suggesting that serum TPO level could play a role in classifying disease severity or clinical course in aAA and ITP.

The interplay between GPIb/IX antibodies, platelet hepatic sequestration, and TPO levels in patients with chronic ITP.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with an incompletely understood pathophysiology but includes platelet-clearance in the spleen and liver via T cells and/or platelet autoantibodies. Strikingly, thrombopoietin (TPO) levels remain low in ITP. Platelet-glycoprotein (GP)Ibα has been described to be required for hepatic TPO generation; however, the role of GPIb antibodies in relation to platelet hepatic sequestration and TPO levels, with consideration of platelet counts, remains to be elucidated. Therefore, we examined 53 patients with chronic and nonsplenectomized ITP for whom we conducted indium-labeled autologous platelet scintigraphy and measured platelet antibodies and TPO levels. Upon stratification toward the severity of thrombocytopenia, no negative association was observed between GPIb/IX antibodies and TPO levels, suggesting that GPIb/IX antibodies do not inhibit or block TPO levels. Surprisingly, we observed a positive association between GPIb/IX antibody levels and TPO levels and GPIb/IX antibodies and platelet hepatic sequestration in patients with severe, but not mild or moderate, thrombocytopenia. In addition, platelet hepatic sequestration and TPO levels were positively associated. This collectively indicates that GPIb/IX antibodies may be associated with increased platelet hepatic sequestration and elevated TPO levels in patients with severe thrombocytopenic ITP; however, further research is warranted to elucidate the pathophysiologic mechanisms.

Increase of Tpo Levels in Patients with Acute Inflammatory States

Thrombopoietin (TPO) is a growth factor for platelet/megakaryocytic lineage and may also have a protective effect in other cell types such as heart and neural cells (Li et al, Circulation, 2006). In this study, we investigated the changes of TPO levels in patients with acute inflammatory response disease of different etiologies. In the case-control study, 65 patients with acute inflammatory response disease were enrolled in the case group (15 patients with acute myocardial infarction, 15 patients with acute cerebral infarction, 25 patients with acute trauma and 10 patients with acute pneumonia), and 65 healthy subjects were selected as the control group. The levels of TPO in peripheral blood and blood cell counts between the case group and the control group were compared by Student's t test for examing whether the level of TPO in acute inflammation states was higher than that in healthy people. And, by using Kruskal-Wallis H test and Nemenyi test, subsequent subgroup comparison was performed to assess whether there was a difference in TPO levels under the condition of inflammation of different etiologies and at different levels. Compared with the control group, serum TPO levels in case group were significantly higher (181.11±35.38 vs 96.13± 9.7 pg/ml, P<0.001), and the white blood cell count in case group (9.64±3.43) ×109/L was higher than that in control group (7.35±1.49) ×109/L (P<0.001), but the platelet count in the case group was not statistically different from that in the control group (P=0.313). In the further subgroup analysis, it was found that changes in TPO levels were different in different levels of inflammation. The level of TPO in patients with inflammatory disease of high level (acute trauma, acute pneumonia) was greatly higher than that in patients with inflammatory disease of low level (acute myocardial infarction, acute cerebral infarction) (P <0.05), and there was no statistically significant difference in platelet count among subgroups. In acute inflammation states, serum TPO levels increase do not correlate with platelet counts but inflammation levels, and TPO may act as an acute response protein to protect the heart and neural cells. DisclosuresNo relevant conflicts of interest to declare.

S2381 Evaluating Platelet Quantity in the Presence of Essential Thrombocythaemia With Cirrhosis

INTRODUCTION: Thrombocytopenia is normally a sequela of decompensated cirrhosis. Essential thrombocythaemia (ET), by contrast, is a myeloproliferative disorder involving an elevated platelet count that can manifest as thromboses of microvasculature. The rare concurrence of these two conditions is challenging for providers in that a normal platelet count may not be a proper indication of an adequate synthetic liver function, as a baseline value is unknown. CASE DESCRIPTION/METHODS: 66-year-old female with a history of ET and untreated chronic hepatitis B and C viral infections, who presented with intermittent left upper quadrant pain. On physical exam, the patient’s vital signs were within normal limits, and abdomen was non-tender on palpation. A complete metabolic panel was significant for elevated aminotransferases, with AST 78, ALT 78, and an alkaline phosphatase of 164. Additionally, a complete blood count was significant for thrombocytosis to 879 and hemoglobin of 10.6. Magnetic resonance imaging of the abdomen showed evidence of cirrhosis with sequelae of portal hypertension, including splenomegaly and upper abdominal varices, which were also seen on computed tomography of abdomen. She was diagnosed with new-onset cirrhosis secondary to chronic untreated viral hepatitis. Thrombopoietin (TPO) levels were not assessed as platelet count was markedly elevated. The patient was continued on her home hydroxyurea for continued management of ET. DISCUSSION: Platelet count is an important measure for patients with cirrhosis. Calculation like the AST to Platelet Ratio Index (APRI) score is used to predict disease severity. Assessing platelet production as an indicator of synthetic function in cirrhosis becomes difficult when treating patients with known ET. Prior cases have suggested that the thrombocytosis in ET may be attributed to an abnormality of the normal feedback inhibition responsible for platelet turnover. TPO levels are generally normal in ET and are notably reduced in decompensated cirrhosis. Providers, therefore, should consider direct measurement of TPO levels in patients with normal platelet counts who are diagnosed with ET and cirrhosis in order to assess whether synthetic liver function is impacted by liver disease. Furthermore, patients with cirrhosis have an increased risk of portal vein thrombosis (PVT); given that patients with both cirrhosis and ET may have an even higher risk of PVT, providers may consider prophylactically anticoagulating these patients to prevent such a complication.

Bayesian Analysis of TPO Levels in Immune Thrombocytopenia

Introduction: Thrombopoietin (TPO) is a haematopoietic growth factor that has a primary function in promoting the differentiation and maturation of megakaryocytes and the subsequent production of platelets. In patients with immune thrombocytopenia (ITP) TPO levels have been shown to be inappropriately low. The exact reasons for this are not well understood and are highly debated. The predominant hypothesis is that higher rates of platelet turnover in active ITP lead to an increased consumption of TPO through its binding to high-affinity receptors on the platelet cell membrane (the ‘sponge theory‘). To better understand the relationship between TPO and platelets in ITP we measured TPO levels in 67 patients with chronic ITP with a range of different platelet counts. For comparison we also measured TPO levels in 5 patients with aplastic anaemia as these patients are thrombocytopenic but lack direct immune-mediated platelet destruction. We used a Bayesian regression model to analyse the association between TPO and platelet counts, which has been shown to be more accurate with smaller sample sizes than classical gaussian regression models. We used this model to infer the probability distribution of TPO over a range of different platelet counts.Methods: Blood samples were collected in duplicate in sodium citrate vacutainer tubes, double spun and stored at -80°C within four hours of collection. TPO levels were measured using quantitative sandwich enzyme immunoassay technique. We used log-normalised TPO and platelet counts in a Bayesian regression model; with uninformative Gaussian prior distributions (mean 0.01, standard deviation 10). We used Gibbs sampling with 100,000 iterations to calculate posterior distributions from which we derived maximium a posteriori (MAP) estimates and 90% Bayesian Confidence intervals (BCI) for a range of platelet counts (1 to 200).Results: Of the 130 samples collected, 30 samples were excluded for failing to detect any TPO. All but 1 of these patients had a second positive sample. In the ITP group, median TPO levels was 43pg/ml (range 1.7 - 923.4pg/ml) with a median platelet count of 63 (range 3 - 328). 20% of this group were in remission at the time of sampling. In the aplastic anaemia cohort there were 9 samples with a median TPO of 1887.6pg/ml (range 9.4-4572.5pg/ml) and a median platelet count of 20 (range 4 - 102). The higher platelet counts (>35) in this aplastic group were from patients on tacrolimus therapy (n= 3). There was a clear non-linear relationship between platelet counts and TPO levels in both ITP and aplastic anaemia patients (FIGURE 1). At any given platelet count, MAP TPO estimates in our ITP cohort were approximately a tenth of that for patients with aplastic anaemia. 13% of the ITP patients were on TPO agonists, although a sensitivity analysis found this did not significantly influence model estimates. At a platelet count of 1 the MAP TPO estimate in ITP was 410pg/ml (BCI; 200-804pg/ml). This declined sharply to 100pg/ml as platelet counts increased to 10. The decline in TPO became increasingly shallow as platelet counts increased further, and at 100 it was 24pg/ml (BCI 18-29 pg/ml). In contrast, MAP TPO estimates in the aplastic anaemia group were >10000pg/ml at a platelet count of 1 and 221pg/ml (BIC 112 to 828pg/ml) at 100. This is approaching the normal range for a healthy individual (mean 120pg/ml, range 80 - 230pg/ml).Conclusion: This study shows that in patients with ITP and aplastic anaemia there is a non-linear correlation between platelet counts and TPO. The levels of TPO in patients with ITP were consistently lower than patients with aplastic anaemia at all platelet counts. This indicates that at all stages of disease activity, immune attack on platelets (and possibly megakaryocytes) in ITP and immune attack on the whole bone marrow in aplastic anaemia have differential effects on TPO levels. The findings also suggest that TPO in combination with platelet counts, when compared to modelled predictions, could be used as a diagnostic marker to differentiate between failure of platelet production and increased platelet destruction. Further work is needed to better understand the regulation of TPO in each disease. [Display omitted] DisclosuresCooper:Amgen, Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Characterization of Baseline Thrombopoietin Levels in Patients With Chronic Liver Disease: Results From 2 Pooled Clinical Studies in Patients With Thrombocytopenia and Liver Disease

Introduction: Patients with chronic liver disease (CLD) commonly develop thrombocytopenia (TCP). Thrombopoietin (TPO) is a cytokine that normally regulates megakaryocyte and platelet production, and is primarily produced in the liver. Because of the progressive destruction and regeneration of liver parenchyma that lead to fibrosis and cirrhosis, patients with liver disease have been shown to have decreased levels and/or activity of TPO. However, little is known about the correlation between TPO levels and the severity of TCP, the etiology of CLD, or the presence of hepatic decompensation. In this analysis, we focused on the Baseline TPO levels from 2 pooled studies evaluating the use of the TPO-receptor agonist avatrombopag in patients with CLD and TCP. Methods: Two randomized, double-blind, placebo-controlled Phase 3 trials (ADAPT-1 & ADAPT-2) enrolled adults with CLD and Baseline platelet counts (PC) <50x109/L, who were scheduled to undergo a procedure. Patients were divided into 2 cohorts based on Baseline PC (COHORT 1- PC<40x109/L [N=251]; COHORT 2- PC 40 to <50x109/L [N=184]). For this analysis, TPO levels reported at Baseline (pretreatment) were characterized for each cohort based on HCC status, MELD, CTP, and liver disease etiology. Results: For the overall population, Baseline TPO levels were 126.9 ng/L for COHORT 1 and 116.0 ng/L for COHORT 2. In COHORT 1, a trend towards lower TPO levels was observed in patients with worsening MELD scores. A similar trend was observed with worsening CTP class in COHORT 1. In COHORT 2, the higher Baseline PC cohort, no trend in TPO levels was observed with increasing MELD or worsening CTP class; the presence of HCC also did not impact TPO levels for either cohort. While differences in TPO levels were observed for the various etiologies of liver disease (alcoholic, chronic viral hepatitis, nonalcoholic steatohepatitis), no consistent trend was noted. Conclusion: The biology of TPO metabolism in advanced liver disease is complex and appears to be influenced by both platelet count and degree of liver failure. We hypothesize that the mechanism involves changes in feedback regulation of TPO levels in addition to impaired hepatic synthesis. When platelets are severely reduced (<40x109/L), TPO levels become almost entirely dependent on liver synthetic capacity and there is loss of TPO regulatory pathway activity.877 Figure 1 No Caption available.

Clinical Significance of Serum Thrombopoietin Levels in Patients with Aplastic Anaemia

To evaluate the clinical significance of thrombopoietin (TPO) level in diagnosis of pateints with aplastic anaemia (AA). The TPO levels in sera from 54 AA patients and 119 healthy controls were examined. A total of 92 samples were collected from AA patients including 43 samples harvested at diagnosis, 23 samples in the cytopenic period after treatment, and 26 samples of patients in partial (n=10) or complete remission (n=16) following immunosuppressive treatment. Serum TPO levels were assessed by a sandwich-antibody ELISA that utilized a polyclonal rabbit antiserum for both capture and signal. Serum samples from normal donors revealed a mean TPO level of 95.3±54.0 pg/ml, the mean TPO levels in AA sera collected at diagnosis and before onset of treatment were 2728±1074 pg/ml (P<0.001) compared with normal controls; mean platelet count at that time: 27×109/L). Serum TPO levels of AA patients in partial or complete remission after immunosuppressive treatment were significantly lower than TPO levels at diagnosis (P<0.001). However, despite normal platelet counts (mean 167×109/L), TPO levels remained significantly elevated in complete remission (mean TPO 1009±6590 pg/ml (P<0.001) compared with normal controls. There was a significant negative correlation between serum TPO levels and platelet counts in AA patients (coefficient of correlation r=-0.70, P<0.001). TPO levels are highly elevated in sera of patients with AA. Thrombopoietin did not return to normal levels in remission, indicating normal platelet count in remission of AA needs sustained high level of TPO.

Changes of Thrombopoietin Levels in Patients with Acute Inflammatory Disease and Its Significance

To investigate the changes of TPO levels in patients with acute inflammatory response disease of different etiologies. In the case -control study, 65 patients with acute inflammatory response disease were enrolled in the case group (15 patients with acute myocardial infarction, 15 patients with acute cerebral infarction, 25 patients with acute trauma and 10 patients with acute pneumonia), and 42 healthy subjects were selected as the control group. The levels of TPO in peripheral blood and blood cell counts between the case group and the control group were compared by Student's t test for examing whether the level of TPO in acute inflammation states was higher than that in healthy people. And, by using Kruskal-Wallis H test and Nemenyi test, subsequent subgroup compaison was performed to assess whether there was a difference in TPO levels under the condition of inflammation of different etiologies and at different levels. Compared with the control group,serum TPO levels in case group were significantly higher (181.11±35.38 vs 96.13±9.7 pg/ml)(P<0.001), and the white blood cell count in case group (9.64±3.43)×109/L was higher than that in control group(7.35±1.49)×109/L(P<0.001), but the platelet count in the case group was not statistically different from that in the control group (P=0.313). In the further subgroup analysis, it was found that changes in TPO level were different in different levels of inflammation. The level of TPO in patients with inflammatory disease of high level(acute trauma, acute pneumonia) was greatly higher than that in patients with inflammatory disease of low level(acute myocardial infarction, acute cerebral infarction) (P<0.05), and there was no statistically significant difference in platelet count among subgroups. In acute inflammation states, the increase of serum TPO levels does not correlate with platelet counts, but correlates with inflammation levels, and TPO may act as an acute response protein to protect the body.

Persistent elevated bone marrow plasma levels of thrombopoietin in patients with aplastic anemia

Acquired aplastic anemia (AA) is an immune-mediated bone marrow (BM) failure syndrome. Plasma thrombopoietin (TPO) levels are elevated in AA patients with reduced blood counts. However, whether elevated TPO can recover to normal level in AA patients in complete remission (CR) after efficient immunosuppressive therapy (IST) is unknown. We measured TPO levels of BM plasma in a large cohort of AA patients with focusing on patients in CR after IST. Our data showed that BM plasma TPO levels were still high in patients who had reached normal blood counts levels for a long time. We speculate that downregulated expression of MPL (TPO receptor) in HSPC (hematopoietic stem and progenitor cells) may be related to the upregulated TPO in AA.

Differential Diagnosis of Hereditary and Acquired Thrombocytopenia By the Immature Platelet Fraction and Thrombopoietin Levels

Introduction: The differential diagnosis of hereditary and acquired thrombocytopenias can be challenging, especially when between immune thrombocytopenia (ITP) and less well characterized hereditary thrombocytopenias (HT) such as MYH9-related disorders. Fundamental differences in the management of these two conditions add clinical relevance to the search for novel parameters that differentiate these conditions. The immature platelet count (IPF) represents the fraction of platelets with higher RNA content, and in analogy to the reticulocyte count for erythropoiesis is a biomarker of thrombopoietic activity. In a recent report (Miyazaki et al, 2015), IPF values that were more than 5-fold higher than those observed in ITP patients were reported in a population of 15 patients with HT. However, whether this increased values represented a real increase in thrombopoietic activity, or reflected a technical limitation of IPF determination in large platelets could not be clarified. Here, we aimed to evaluate the role of IPF determination in the differential diagnosis between HT and several forms of acquired thrombocytopenia in a larger and more diverse population of patients. We also evaluated thrombopoietin (TPO) levels in HT compared to ITP, to further investigate the mechanisms by which extremely large IPF values are observed in HT.Methods: IPF and mean platelet volume (MPV) were prospectively determined using a Sysmex XE5000 hematologic analyzer (as part of the complete blood count) in a cohort of patients with post-chemotherapy thrombocytopenia (n=56), bone marrow failure (myelodysplastic syndromes and aplastic anemia; n=22), ITP (ITP; n=105) and inherited thrombocytopenias (n=27). The latter population consists of a well-defined cohort of individuals with HT thrombocytopenia characterized by clinical, familial, laboratory and molecular data. TPO levels were determined by ELISA (R&D Systems) in 21 HT patients and 22 ITP patients matched for platelet count and age. A group of 178 healthy volunteers were used to determine normal IPF and MPV values.Results: Median platelet counts were similar in post-chemotherapy patients (CTx) (32.0*109/L), bone marrow failure (BMF) (33.5*109/L), ITP (52.0*109/L) and HT (52.0*109/L) (P=0.15). Similar IPF levels were observed in CTx and BMF patients (5.6%; IQR 3.4-8.8% and 6.5%; IQR 3.5-13.7%. Compared to these two groups, higher IPF values were observed in both ITP (12.3%; 7.0-21.0%) and HT patients (29.8%; 17.5-56.4%) (both P values < 0.05). In addition, IPF were significantly higher in HT compared to ITP (Kruskall-Wallis test and Dunn's post test,P=0.001). MPV values were different between HT and CTx/BMF groups, but could not differentiate ITP from HT. TPO levels. The accuracy of IPF to discriminate HT from all other causes of thrombocytopenia estimated by ROC analysis was 0.88 (CI95%0.8-0.96, p<0.0001). Similar TPO levels were observed in platelet count-matched ITP, HT patients and healthy volunteers without thrombocytopenia. Interestingly, TPO presented marked correlations with both platelet count (Rs = - 0.61, P=0.002) and IPF (Rs= 0.59, P=0.003), even with TPO levels in the same range of healthy individuals. In contrast, no significant correlation could be observed between TPO and IPF or platelet count in HT patients.Conclusions: IPF represents an informative biomarker for the differential diagnosis of hereditary and acquired thrombocytopenias, and accurately differentiates ITP from the most common HT. As expected, TPO levels in patients with ITP were not higher than in individuals with normal platelets counts. The inverse correlation between TPO and platelet count in these patients confirm a blunted TPO response to thrombocytopenia in these patients. Similarly, patients with HT did not present increased TPO levels compared to healthy individuals. Accordingly, increased IPF levels in these patients cannot be attributed to higher TPO levels. DisclosuresNo relevant conflicts of interest to declare.

Thrombopoietin levels in patients with disorders of platelet production: Diagnostic potential and utility in predicting response to TPO Receptor agonists

Thrombopoietin (TPO) is the major regulator of megakaryopoiesis. Measurement of serum TPO levels may help distinguish between various causes of thrombocytopenia and predict treatment response to TPO receptor agonists. Serum TPO levels from 118 healthy volunteers and 88 patients with abnormal platelet counts were measured using a quantitative ELISA assay. The mean (range) TPO level in healthy volunteers was 39 (7-99) pg/mL. TPO values were correlated with the patient's diagnosis, platelet count, and response to TPO receptor agonists. 88 patients with history of consumptive thrombocytopenia (39) or hypoproliferative thrombocytopenia (49) were analyzed. Median (interquartile range) TPO level for consumptive thrombocytopenia patients was 63 (48-98) pg/mL with a corresponding median (interquartile range) platelet count of 73 (28-146) × 10(9) /L. In contrast, hypoproliferative thrombocytopenia patients had platelet counts [59 (30-117) × 10(9) /L] comparable with consumptive thrombocytopenia patients, but significantly higher serum TPO levels [706 (358-1546) pg/mL, P < 0.0001]. Analysis of 21 ITP patients treated with TPO receptor agonists demonstrated that a TPO level >95 pg/mL was associated with lack of clinical response (P < 0.002). TPO levels may have diagnostic utility in discriminating between patients with hypoproliferative and consumptive thrombocytopenia. Elevated TPO levels in ITP patients may predict a poor clinical response to treatment with TPO receptor agonists.

Increased plasma levels of thrombopoietin in patients with severe acute pancreatitis

The aim of this study was to evaluate the accuracy of thrombopoietin (TPO) plasma levels as a biomarker of clinical severity in patients with acute pancreatitis (AP). TPO is a humoral growth factor that stimulates megakaryocyte proliferation and differentiation [1]. Furthermore, it favors platelet aggregation and polymorphonuclear leukocyte activation [2]. Elevated plasmatic concentrations of TPO have been shown in patients with critical diseases, including ACS, burn injury and sepsis [2]. In particular, clinical severity is the major determinant of elevated TPO levels in patients with sepsis [3]. AP is a relatively common disease whose diagnosis and treatment are often difficult, especially in the clinical setting of the emergency department (ED). About 20% of patients with AP develop a severe form of the disease. In order to early identify those patients affected by severe AP, several biomarkers have been studied. No data regarding TPO plasma levels in patients with AP are currently available.

Increased plasma thrombopoietin levels in patients with myelodysplastic syndrome: a reliable marker for a benign subset of bone marrow failure

Although myelodysplastic syndromes are heterogeneous disorders comprising a benign subset of bone marrow failure similar to aplastic anemia, no laboratory test has been established to distinguish it from bone marrow failures that can evolve into acute myeloid leukemia. Plasma thrombopoietin levels were measured in 120 patients who had myelodysplastic syndrome with thrombocytopenia (< 100 × 10(9)/L) to determine any correlation to markers associated with immune pathophysiology and outcome. Thrombopoietin levels were consistently low for patients with refractory anemia with excess of blasts, while patients with other myelodysplatic syndrome subsets had more variable results. Patients with thrombopoietin levels of 320 pg/mL and over had increased glycosylphosphatidylinositol-anchored protein-deficient blood cells (49.1% vs. 0%), were more likely to have a low International Prognostic Scoring System (IPSS) score (≤1.0, 100% vs. 65.5%), a higher response rate to immunosuppressive therapy (84.2% vs. 14.3%), and a better 5-year progression-free survival rate (94.1% vs. 63.6% for refractory cytopenia with unilineage dysplasia; 100.0% vs. 44.4% for refractory cytopenia with multilineage dysplasia). In conclusion, increased plasma thrombopoietin levels were associated with a favorable prognosis of bone marrow failure and could, therefore, represent a reliable marker for a benign subset of myelodysplastic syndrome.

Analyses of plasma thrombopoietin levels in patients with thrombocytopenia

Analyses of plasma thrombopoietin levels in patients with thrombocytopenia

Thrombopoietin Levels May Predict Responsiveness to Therapy with Thrombopoietin Agonists Among Patients with Immune Thrombocytopenic Purpura,

Abstract 3288▪▪This icon denotes a clinically relevant abstract INTRODUCTION:Thrombopoietin (TPO) is the major regulator of platelet production. In prior clinical studies, thrombopoietin levels have been shown to vary inversely with circulating platelet mass and with the rate of platelet production. Thus, TPO levels may help distinguish between the various disorders of thrombocytopenia. In addition, the introduction of TPO agonists has created an interest in predicting the response of patients to these agents. Determining TPO levels may help predict such treatment responses. METHODS:Sera from 121 patients with a history of abnormal platelet counts were tested using a novel, commercially available ELISA assay that measures TPO levels. The TPO assay detected TPO levels as low as 7 pg/mL and was linear for levels up to 2000 pg/mL. The coefficient of variation ranged from 27% near the lower limit of detection to 9% at a TPO concentration of 669 pg/mL. The reference range for TPO was established in serum samples from 118 apparently healthy individuals (58 males and 60 females) and was 7–99 pg/mL. The Wilcoxon test was used to compare continuous variables and the Fisher’s exact test was used to compare categorical variables. RESULTS:The patient population included 40 patients with a consumptive thrombocytopenia (38 with primary or secondary immune thrombocytopenic purpura (ITP), 2 with thrombotic thrombocytopenic purpura), 34 patients with myeloproliferative disorders (23 with essential thrombocytosis, 9 with polycythemia vera, 2 with an ill-defined myeloproliferative disorder), and 47 patients with hypoproliferative thrombocytopenia (29 with chemotherapy-related thrombocytopenia, 19 with primary or secondary bone marrow failure syndromes). Among the 38 patients with ITP, 11 were taking TPO agonists (9 on romiplostim, 2 on eltrombopag), 19 were taking immunomodulatory agents (16 on steroids alone or in combination with other therapies, 2 on azathioprine, 1 on danazol), and 12 were off ITP-specific therapy when the TPO level was measured. 9 out of 38 (24%) patients with ITP had undergone splenectomy and/or been previously treated with rituximab. The median serum TPO level in patients with consumptive thrombocytopenia was 64.5 pg/mL (interquartile range, 48.5–97.5 pg/mL) and the corresponding median platelet count was 68,000/μL (interquartile range, 27,000–144,500) (Figure). While patients with myeloproliferative disorders had similar TPO levels [median 87.0 pg/mL (38.0–125.5)], their platelet counts were significantly higher than those of patients with consumptive thrombocytopenia [median 549,500/mL (431,250–693,000] (P <0.0001). Contrastingly, comparable platelet counts [median 61,000/μL (31,000–118,000)] were observed among patients with hypoproliferative thrombocytopenia, but serum TPO levels were significantly higher than those of patients with consumptive thrombocytopenia [844 pg/mL (409.5–1551.5), P <0.0001]. [Display omitted] Among 22 evaluable patients meeting diagnostic criteria for primary or secondary ITP who had taken a TPO agonist for at least 1 month, serum TPO levels appeared to predict responsiveness to the drug. A clinical response to a TPO agonist was defined as achieving a platelet count ≥50,000/μL after starting the drug and maintaining it at or above that count in ≥50% of subsequent complete blood counts from initiation until discontinuation of the drug, loss to follow-up, or 6 months had passed, whichever was longest, without the need for recurrent rescue therapy. Whereas 14 out of 16 (88%) ITP patients with a TPO level <99 pg/mL met our definition for a clinical response to treatment with a TPO agonist, only 1 out of 6 patients (17%) with a TPO level >99 pg/mL responded (P <0.005 for the difference in clinical response to TPO agents.) CONCLUSIONS:TPO levels may have diagnostic utility in discriminating between patients with hypoproliferative and consumptive thrombocytopenia. High TPO levels among patients with ITP may predict a poor clinical response to treatment with TPO agonists. Further studies are required to confirm these data. Disclosures:Zhukov:Quest Diagnostics: Employment. Sahud:Quest Diagnostics: Employment. Kuter:Quest Diagnostics: Consultancy, Research Funding.

Alterations of serum erythropoietin and thrombopoietin levels in patients undergoing Coronary Artery Bypass Grafting (CABG)

The hormones erythropoietin (EPO) and thrombopoietin (TPO) are main regulators of erythro- and thrombopoiesis. Cell loss caused by operative procedures may alter serum levels of the hormones, resulting in well known phenomenons like reactice thrombocytosis. Blood samples from 10 patients (mean age 63 ± 9 years) were obtained before and at day 1, 5 and 10 after coronary artery bypass grafting (CABG). EPO and TPO levels were determined by commercially available ELISA-Kits (R&D Systems, Germany). In addition, platelet count (PC) and hemoglobin concentration (Hb) were determined. Prior to CABG, EPO (13.2 ± 8.2 mU/mL), TPO (189 ± 52 pg/mL), Hb (8.8 ± 1.1 mmol/L) and PC (254 ± 121/nL) were within a normal range. At day 1 after surgery, Hb and PC were significantly decreased to 6.6 ± 0.9 mmol/L and 138 ± 70/nL. In contrast, EPO and TPO were significantly elevated to 32 ± 18 mU/mL and 336 ± 96 pg/mL, respectively, in spite of hemodilution. In particular, TPO elevation was followed by a significant increase in PC (342 ± 144/nL) at day 10 after surgery compared to preoperative values. Appropriate to the decrease in hemoglobin concentration and platelet count, clear alterations of serum erythropoietin and thrombopoietin levels could postoperatively be observed. EPO levels showed an inverse correlation to hemoglobin concentrations, whereas a disturbed thrombopoietin feedback mechanism resulted in the phenomenon of reactive thrombocytosis.

Plasma thrombopoietin level and platelet indices in hemodialysis patients receiving recombinant human erythropoietin

We focused on thrombocytopenia in hemodialysis patients (HD) receiving recombinant human erythropoietin (rHuEPO) and investigated thrombopoietin (TPO) level and platelet indices. We analyzed platelet parameters including mean platelet volume (MPV), platelet-crit (PCT), mean platelet component (MPC) concentration and platelet count (PLT) using ADVIA 2120 in 375 HD patients. This study included 25 HD patients undergoing treatment with rHuEPO at 9000 IU/week. These patients were divided into two groups by reference PLT of 130 x 10(9)/l [eight patients with low PLT (L-PLT group) and 17 patients with normal PLT (N-PLT group)], and TPO level and platelet indices in each group were compared with those in nine HD patients not receiving rHuEPO. In HD patients, the mean value of MPV was slightly higher and the mean values of PLT, PCT, and MPC were significantly lower than those in healthy controls. TPO levels were significantly higher in patients receiving rHuEPO than in patients not receiving rHuEPO. However, no significant difference was found between TPO levels in patients in the L-PLT group and patients in the N-PLT group. TPO levels were not correlated with PLT in these patients and that MPC levels decreased remarkably regardless of PLT.

Alteration of serum thrombopoietin levels in patients with chronic hepatitis C under interferon therapy

Thrombocytopenia is commonly observed during interferon-alpha (IFN-alpha) therapy in patients with chronic hepatitis C. Since thrombopoietin (TPO) is the main regulator of thrombopoiesis, thrombocytopenia may partially be due to a reduced TPO generation. Because of the developments of the second generation of TPO mimetic drugs patients with reduced TPO levels should be identified possibly having a benefit by medicinal stimulation of thrombopoiesis. Therefore, platelet count and serum TPO concentration of patients receiving an interferon-alpha therapy were determined.Twelve patients treated with IFN-alpha (daily 10 x 106 IU s.c. for four weeks) in cause of chronic hepatitis C were examined during the first month of therapy. Serum TPO concentration significantly decreased from 80.8+/-48.0 to 34.6+/-24.5 pg/ml (p<0.05, Mann-Whitney test), and platelet count declined from 214,417+/-48,292 to 151,333+/-44,726 platelets/microl. During the following three weeks platelet count remained at a low level, while serum TPO increased to normal range.In conclusion, an interferon treatment causes reduced serum TPO level during the first week of therapy accompanied by decreased platelet count. The reduction in TPO synthesis contributes to the development of thrombocytopenia in patients during interferon therapy.

Thrombopoietin level in patients with chronic liver diseases: Original Article

Thrombocytopenia and oxidative stress are the most frequent problems in patients with chronic liver diseases as viral cirrhosis and schistosomiasis. So, this study aimed to evaluate the role of thrombopoietin (TPO) on the occurrence of thrombocytopenia and in differentiation between these diseases. It also aimed to investigate the relation between TPO, oxidative stress and antioxidant status in these two types of chronic liver disease. So, We measured serum TPO level, lipid peroxide (MDA) and serum total antioxidant activity (TAO) in 40 patients with cirrhosis caused by hepatitis C virus and 37 patients with schistosomiasis from The Specialized Medical Hospital, Mansoura University. Results: Both serum TPO level and serum TAO activity were significantly lower (p < 0.05) in thrombocytopenic patients with viral cirrhosis when compared to both non thrombocytopenic and control groups. In contrast, TPO level was within the normal range in the patients with scistosomiasis either thrombocytopenic or not. while serum TAO activity was significantly lower (p < 0.05) in both thrombocytopenic and non thrombocytopenic patients with schistosomiasis in comparison to control subjects with no significant difference between these two subgroups. Serum MDA concentration was increased significantly (p < 0.05) in all diseased groups when compared to controls with significant increase in thrombocytopenic patients as compared to non thrombocytopenic. Conclusion: TPO hypoproduction played a role in the pathogenesis and treatment of viral cirrhosis associated with thrombocytopenia. Also, total antioxidant activity and MDA are useful markers for monitoring patients with these chronic liver diseases.

Diagnosis and Quantitation of Fibrosis

Hepatic fibrosis is the final common pathway for many different liver insults. Originally considered to be irreversible, hepatic fibrosis is now known to be a dynamic process with a significant potential for resolution. The diagnosis and quantitation of fibrosis have traditionally relied on liver biopsy. However, there are a number of drawbacks including the invasive nature of the procedure, sampling error, and interobserver variability. This article reviews the current role of liver biopsy in the assessment of hepatic fibrosis and discusses the role of the newer noninvasive methods including serum markers and radiologic tests.