Chronic Primary Immune Thrombocytopenia Research Articles

Elevated NKT cell levels in adults with severe chronic immune thrombocytopenia

The aim of this study was to investigate the frequency of circulating natural killer T (NKT) cells and regulatory T cells (Tregs), as well as serum cytokine profiles, in adult chronic primary immune thrombocytopenia (ITP). The frequency of circulating T cell receptor (TCR) Vα24+Vβ11+CD3+ NKT cells and CD4+CD25+CD127−/low Tregs was measured using multi-color flow cytometry. The serum concentrations of 11 cytokines were determined with a cytometric bead assay. The frequency of circulating NKT cells in patients with ITP was 0.13±0.03%, whereas the frequency in healthy controls was 0.07±0.01% of CD3+ (P>0.05). However, the frequency of NKT cells in patients with ITP with platelet counts ≤20×109/l (0.22±0.05%) was significantly higher than that in patients with platelet counts >20×109/l (0.05±0.01%; P<0.05) and that in healthy controls (0.07±0.01%; P<0.05). The frequency of peripheral Tregs was comparable between patients with ITP (3.97±0.44% of CD4+) and healthy controls (3.69±0.31%; P>0.05). No significant differences were observed in the serum concentrations of 11 cytokines between patients with ITP and healthy controls, despite the fact that the serum levels of interleukin (IL)-12p70, IL-8, IL-4, interferon (IFN)-γ and tumor necrosis factor (TNF)-α in patients with ITP were higher than those in the healthy controls. The platelet count was negatively correlated with the frequency of circulating NKT cells in chronic ITP. These results indicate that NKT cells may be involved in ITP with severe thrombocytopenia, and NKT and Tregs may be important in cytokine deregulation in chronic ITP.

Rituximab versus splenectomy in persistent or chronic adult primary immune thrombocytopenia: an adjusted comparison of mortality and morbidity

Splenectomy and rituximab are both recommended as second-line treatment in immune thrombocytopenia (ITP), but they have never been directly compared. We compared their efficacy and serious adverse outcomes in a retrospective cohort of 105 adult primary ITP patients exposed to one or other of these treatments. Primary outcome was composite: death from hemorrhage or from infection and hospitalization for bleeding or for infection. Secondary outcomes were overall mortality, hospitalization for bleeding, hospitalization for infection, as well as response and complete response (international definitions). Analyses were adjusted on a propensity score. Patients treated with rituximab (n = 43) were older and had more comorbidities than the splenectomized patients (n = 62). Mean follow-up was, respectively, 3 and 8.4 years. After adjustment on the propensity score, there was no difference between the two groups regarding the primary and other clinical outcomes. In the multivariate analysis, only a history of mucosal bleeding (HR 3.2 95% CI [1.2-8.5]) and a Charlson score ≥1 (HR 4.2 95% CI [1.8-9.6]) were associated with the primary outcome. These two factors were also associated with hospitalization for bleeding. As expected, response, complete response and maintenance rates were higher in the splenectomy group. Splenectomy compared with rituximab was independently associated with a response at 12 months (OR 4.4, 95% CI [1.7-11.8]). Then, adjusted analyses in this real-life cohort confirmed the better results of splenectomy compared with rituximab.

Economic evaluation of Thrombopoietin Receptor Agonists in the treatment of chronic primary immune thrombocytopenia

To develop a tool to assist the decision-making for selection of Thrombopoyetin Receptor Agonists of adult patients with chronic immune primary thrombocytopenia (PTI). Stochastic cost-effectiveness analysis with a 6-Health- States Markov model: stable, bleeding type 2, 3 or 4, post-type 4 bleeding and death. Each simulation analyzes a randomly generated scenario that describes patients characteristics, results measured in quality adjusted life years (QALYs) and costs (in ?2011). Distributions were obtained from the Spanish data of the European health survey of 2009, the INE estimate of population for 2011 and the 6-months clinical studies for Eltrombopag and Romiplostim. Utility values were obtained from the literature and the costs from Spanish official rates lists. A set of 10.000 random scenarios were generated and the patients evolution of each scenario was simulated during a time horizon of five years (in 2-weeks cycles). National Health System Perspective was used and the annual discount rate was set at 3%. Eltrombopag showed more effectiveness in 9.983 scenarios and there was no difference in 17. In 7.048 scenarios the alternative Eltombopag was dominant. It was cost-effective in another 19 (threshold 30,000 ??/AVAC). Eltrombopag was the most cost-effective alternative in 70,67% of the simulated scenarios and its use could produce lower costs to the NHS.

Thrombosis in patients with primary chronic immune thrombocytopenia

Patients with primary chronic immune thrombocytopenia (ITP) have immune-mediated platelet destruction and/or suppressed platelet production. ITP patients are, due to the thrombocytopenia, at increased risk of severe bleeding episodes. Paradoxically, these patients also seem to have an increased risk of venous thromboembolism (VTE). Findings from a Danish study including 391 patients with chronic ITP and 3,128 comparisons from the general population have suggested a more than twofold higher risk of VTE in patients with chronic ITP compared with the general population. VTEs may occur even in patients with low platelet count. The conclusion is therefore that clinicians should keep VTE in mind as a potential diagnosis in patients with chronic ITP.

Risk of arterial thrombosis in patients with primary chronic immune thrombocytopenia: a Danish population‐based cohort study

Risk of arterial thrombosis in patients with primary chronic immune thrombocytopenia: a Danish population‐based cohort study

Thrombopoietin receptor agonist therapy in primary immune thrombocytopenia is associated with bone marrow hypercellularity and mild reticulin fibrosis but not other stromal abnormalities

Primary immune thrombocytopenia is an acquired autoimmune disorder characterized by platelet count of <100 × 109/l in the absence of other causes of thrombocytopenia. Primary immune thrombocytopenia is defined as ‘chronic' when it has been present for more than 12 months without spontaneous remission or maintenance of complete response to therapy. Recently, thrombopoietin receptor agonists became available for treatment of chronic primary immune thrombocytopenia. Anecdotal reports have raised concerns about a possible association between therapy with thrombopoietin receptor agonists and an increase in bone marrow fibrosis. To investigate this association we studied eight patients with primary immune thrombocytopenia in detail comparing fibrosis and other morphological features in pre-therapy and on-therapy bone marrow biopsies, with the longest follow-up reported to date. A slight but significant increase to MF-1 in reticulin fibrosis was observed during therapy, but collagen was never present. On-therapy bone marrows were hypercellular due to panmyelosis with increased trilineage hematopoiesis. Megakaryocytes were increased in number, with acquisition of evident pleomorphism, nuclear hyperlobulation and tendency in some cases to form clusters. The overall picture of the on-therapy marrows was characterized by myeloproliferative neoplasm-like features, resembling essential thrombocythemia or occasionally early primary myelofibrosis. As thrombopoietin receptor agonists are becoming a mainstream treatment for primary immune thrombocytopenia, general pathologists and especially hematopathologists need to be aware of the characteristic morphological changes associated with use of these therapeutic agents, in order to avoid misdiagnosis of a myeloid neoplasm.

Spotlight on Eltrombopag in Treatment-Refractory Chronic Primary Immune Thrombocytopenia†

Eltrombopag (Revolade®) is an orally bioavailable, low molecular weight, synthetic nonpeptide thrombopoietin receptor agonist, which selectively binds to the transmembrane and juxtamembrane domains of the thrombopoietin receptor on the surface of platelets, megakaryocytes, and megakaryocyte precursor cells, resulting in responses similar to those induced by recombinant human thrombopoietin. Eltrombopag does not compete with thrombopoietin for its binding domain on the thrombopoietin receptor, and is highly selective. This article provides an overview of the pharmacological properties of eltrombopag and reviews the clinical efficacy and tolerability of the drug in adult patients with chronic primary immune thrombocytopenia (ITP). In well designed 6-week and 6-month trials, eltrombopag was more effective than placebo at increasing platelet count and decreasing the incidence of bleeding in patients with treatment-refractory chronic ITP, and was generally well tolerated in these patients. Long-term (median duration 100 weeks) data from a noncomparative trial support these results. Importantly, previous splenectomy did not appear to have an effect on the efficacy of eltrombopag. As the first licensed oral thrombopoietin receptor agonist, eltrombopag may be a more convenient option than other ITP medications; however, it may be a costly option long term, as platelet counts generally return to baseline levels following treatment cessation, implying that continued treatment may be advised. Long-term treatment is often necessary in patients with chronic ITP, as curative rates with any treatment are very low. Eltrombopag was generally well tolerated in clinical trials in patients with chronic ITP. Hepatobiliary abnormalities occurred in a greater proportion of eltrombopag than placebo recipients; however, these were usually mild and reversible. Other potential concerns, such as thromboembolic events, cataracts, and increased bone marrow reticulin, need to be further investigated. Eltrombopag is an effective treatment option for adult patients with chronic ITP and an increased risk of bleeding who are refractory to previous treatments, including splenectomy, as demonstrated in well designed clinical trials.

Childhood Immune Thrombocytopenia: A Changing Therapeutic Landscape

Childhood immune thrombocytopenia (ITP) is generally a benign self-limiting disorder of young children with <10% of cases requiring regular platelet enhancing therapy at 1 year following diagnosis. Increasingly, children with newly diagnosed ITP, who have isolated thrombocytopenia and no atypical features in the history or physical examination, are managed with minimal investigation and observation alone. The role of up-front, short-course corticosteroid therapy without bone marrow aspiration in this subgroup of cases merits further investigation. For children with clinically significant chronic ITP, the timing of elective splenectomy and the role of splenectomy-sparing strategies such as rituximab continues to be debated. Management of children with combined autoimmune cytopenias secondary to systemic lupus erythematosus, common variable immunodeficiency, and the autoimmune lymphoproliferative syndrome is often a challenge. Splenectomy should be avoided in cases with documented immunodeficiencies because of the increased risk of overwhelming sepsis postsplenectomy. For these cases, as well as for children with resistant primary chronic ITP who have failed splenectomy, the role of therapies such as mycophenolate mofetil, sirolimus, and the thrombopoietins remains to be determined.

The scintigraphic index spleen/liver at 30 minutes predicts the success of splenectomy in persistent and chronic primary immune thrombocytopenia

Splenectomy is considered the second-line of treatment in patients with chronic primary immune thrombocytopenia (ITP) in whom glucocorticoids have failed. Some patients do not respond to splenectomy or they have postoperative complications. Based on our previous experience using kinetic and scintigraphic parameters, we did a retrospective study with the aim of comparing all these parameters as a means of predicting the success of splenectomy in persistent and chronic primary ITP. Forty-one consecutive patients with chronic primary ITP refractory to prednisone, who had been splenectomized, were included in the study. The response to splenectomy was assessed by evaluating bleeding and platelet counts before and at different times after surgery. A complete platelet kinetic study was performed before the splenectomy using autologous (111) In-labeled platelets. The scintigraphic parameters measured included different indices between spleen/heart, liver/hearth, and spleen/liver. Thirty-six patients gave a complete response after splenectomy and five patients did not respond. A statistically significant difference between both groups was found with initial platelet recovery and with some scintigraphic indices which also showed a variable prediction value for the success of splenectomy. Among these indices, the spleen/liver at 30 minutes demonstrated a predictive value with a 100% of sensitivity and a 100% of specificity. some platelet kinetic parameters and scintigraphic indices, in particular the spleen/liver at 30 minutes, were useful to predict the outcome of splenectomy in persistent and chronic primary ITP and, therefore, they should be taken into account when deciding whether or not to perform a splenectomy.

Thrombopoietin-Receptor Agonists for Primary Immune Thrombocytopenia

A 26-year-old woman with a history of chronic primary immune thrombocytopenia presents for evaluation. Her condition was first diagnosed when she was 11 years of age. Her platelet count has typically been less than 10,000 per cubic millimeter. Her symptoms have not responded to glucocorticoids, and she has had only transient responses to intravenous immune globulin. Previous treatments have included a course of cyclosporine, a course of four doses of rituximab, and splenectomy. Her bleeding symptoms have consisted mainly of menorrhagia, resulting in iron-deficiency anemia. She is currently being treated with a thrombopoietin-receptor agonist, which has resulted in an increase in her platelet count to between 50,000 and 200,000 per cubic millimeter and resolution of her excessive menstrual bleeding, with normalization of her hemoglobin level after iron therapy. She is now inquiring about the longterm treatment of her condition.

Chronic adult primary immune thrombocytopenia (ITP) in the Asia-Pacific region

Patients with primary immune thrombocytopenia (ITP) from the Asia-Pacific region often exhibit characteristics distinct from those of patients from the West. Moreover, as the region itself is heterogeneous, the ITP landscape among individual Asia-Pacific countries can be diverse. The recently released international consensus report on ITP places new emphasis on ITP, but does not address the unique ITP landscape in the Asia-Pacific region, which is home to 60% of the world's population. In an attempt to characterize how the ITP landscape differs between the West and the Asia-Pacific region, an expert panel with representatives from Northeast Asia, Southeast Asia, and Australia was convened. Important differences were identified between the guidance provided in the international consensus report and experience in the Asia-Pacific region, namely diagnostic practices, incidence and approach to ITP secondary to H. pylori infection, systemic lupus erythematosus-related ITP, the use of bone marrow examination, initial treatment strategies, and the role of splenectomy, rituximab, and thrombopoietin receptor agonists.

Eltrombopag

Eltrombopag (Revolade(®)) is an orally bioavailable, low molecular weight, synthetic nonpeptide thrombopoietin receptor agonist, which selectively binds to the transmembrane and juxtamembrane domains of the thrombopoietin receptor on the surface of platelets, megakaryocytes and megakaryocyte precursor cells, resulting in responses similar to those induced by recombinant human thrombopoietin. Eltrombopag does not compete with thrombopoietin for its binding domain on the thrombopoietin receptor, and is highly selective. This article provides an overview of the pharmacological properties of eltrombopag and reviews the clinical efficacy and tolerability of the drug in adult patients with chronic primary immune thrombocytopenia (ITP). In well designed, 6-week and 6-month trials, eltrombopag was more effective than placebo at increasing platelet count and decreasing the incidence of bleeding in patients with treatment-refractory chronic ITP, and was generally well tolerated in these patients. Long-term (median duration 100 weeks) data from a noncomparative trial support these results. Importantly, previous splenectomy did not appear to have an effect on the efficacy of eltrombopag. As the first licensed oral thrombopoietin receptor agonist, eltrombopag may be a more convenient option than other ITP medications; however, it may be a costly option long term, as platelet counts generally return to baseline levels following treatment cessation, implying that continued treatment may be advised. Long-term treatment is often necessary in patients with chronic ITP, as curative rates with any treatment are very low. Eltrombopag was generally well tolerated in clinical trials in patients with chronic ITP. Hepatobiliary abnormalities occurred in a greater proportion of eltrombopag than placebo recipients; however, these were usually mild and reversible. Other potential concerns, such as thromboembolic events, cataracts and increased bone marrow reticulin, need to be further investigated. Eltrombopag is an effective treatment option for adult patients with chronic ITP and an increased risk of bleeding who are refractory to previous treatments, including splenectomy, as demonstrated in well designed clinical trials.

Reduced expression of transforming growth factor‐β1 and correlated elevation of interleukin‐17 and interferon‐γ in pediatric patients with chronic primary immune thrombocytopenia (ITP)

Dysregulated T helper (Th) cells are considered important in the pathophysiology of chronic primary immune thrombocytopenia (ITP). The present study investigated whether levels of Th cytokines in pediatric patients with chronic ITP were different compared with healthy controls. Fifty-seven pediatric patients with chronic ITP and 28 healthy controls were enrolled. Patients were divided into three groups based on their platelet counts at the time of the study: (i) active disease <50 × 10(9) /l (n = 23), (ii) stable disease 50-150 × 10(9) /l (n = 23), and (iii) in remission >150 × 10(9) /l (n = 11). Plasma concentration of Th1 [interferon gamma (INF-γ), interleukin 2 (IL-2)], Th2 (IL-4, IL-10), Th3 [transforming growth factor-β1 (TGF-β1)], and Th17 (IL-17) cytokines were investigated by enzyme-linked immunosorbent assay. IFN-γ was increased in patients with active (P < 0.001) and stable disease (P = 0.026) when compared with controls. The IL-17 level was significantly higher in all of the 3 patient groups. In addition, there was a positive correlation between IL-17 and IFN-γ levels in chronic ITP patients (r = 0.640, P < 0.001). Reduced TGF-β1 expression was observed in patients with active (P < 0.001) and stable disease (P = 0.001) in comparison with controls. Moreover, TGF-β1 level in patients was positively correlated with the platelet count (r = 0.355, P = 0.007). Elevation of IL-17 and IFN-γ may be an important dysregulation of cellular immunity in pediatric patients with chronic ITP. The disease activity is associated with reduced production of TGF-β1.

Hepatobiliary laboratory abnormalities among patients with chronic or persistent immune thrombocytopenia (ITP)

Therapies for immune thrombocytopenia (ITP) may be associated with abnormal hepatobiliary laboratory (HBL) values, but the epidemiology of these abnormalities is unknown in the ITP population. The study aim was to provide prevalence and incidence rates, as well as risk factors for abnormal HBL values among a cohort of patients with chronic or persistent primary ITP. Health insurance claims data from 3,244 patients with chronic or persistent ITP was examined to estimate the prevalence of abnormal HBL values: elevated levels of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), total bilirubin, and Alkaline Phosphatase (ALP). Incidence of abnormal HBL values was estimated in a sub cohort of 2557 (79%) patients without evidence of comorbidities related to secondary thrombocytopenia, liver disease, or abnormal HBL values during the 12-month baseline period. The baseline prevalence of ALT and AST > 3x the upper limit of normal (ULN) was 4.6 and 3.7%, respectively. The baseline prevalence of total bilirubin and ALP >1.5x ULN was 4.2 and 3.2%, respectively. The incidence rate of new HBL abnormalities (HBLA) was 1.24/1,000 person- years (95% CI: 0.52-2.56) for ALT>3x ULN and 0.41/1,000 person-years (95% CI: 0.08-1.32) for AST>3x ULN. HBLAs were significantly associated with male gender, liver disease, diabetes, congestive heart failure, lupus, hematological cancers, and HIV infection. In conclusion, the prevalence of HBLA, specifically ALT>3x ULN, among the ITP population is relatively high compared with atrial fibrillation, though within the confidence interval for that estimate. HBLAs were significantly associated with male gender, liver disease, and several other comorbidities, thus, distinguishing drug-induced liver injury in this population is clinically challenging.

Long-term clinical outcomes of patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study

AbstractFew data exist on the long-term prognosis of patients with chronic primary chronic immune thrombocytopenia (ITP). We examined the risk of infections, hemorrhage resulting in hospitalization, hematologic malignancies, and total and cause-specific mortality among patients with ITP compared with the general population. We used population-based medical databases to identify 407 patients with primary chronic ITP diagnosed during 1996 to 2007 and 4069 general population members individually matched on age, sex, and comorbidity level. We used Cox regression analysis to estimate rate ratios (RRs) adjusted for age (≤ 60 or > 60 years), sex, calendar year, and level of comorbidity. The adjusted 1-year RR of infection was 4.5 (95% confidence interval [CI], 3.3-6.1) for patients with chronic ITP compared with the general population cohort. The adjusted RR decreased to 1.8 (95% CI, 1.3-2.5) for the second to fifth year of follow-up. The adjusted 5-year RR was 3.2 (95% CI, 1.2-9.0) for hospitalized intracranial hemorrhage, 4.4 (95% CI, 2.3-8.3) for other hospitalized hemorrhages, and 4.7 (95% CI, 1.7-12.7) for hematologic malignancy. The 5-year all-cause mortality RR was 2.3 (95% CI, 1.8-3.0). In summary, primary chronic ITP was associated with substantially increased long-term risk of infections, hemorrhagic episodes requiring hospitalization, hematologic malignancies, and mortality.

Evidence-Based Mini-Review: Is Indium-Labeled Autologous Platelet Scanning Predictive of Response to Splenectomy in Patients With Chronic Immune Thrombocytopenia?

Clinical scenario: An otherwise healthy 25-year-old woman returns to your office for management of chronic primary immune thrombocytopenia. She was diagnosed 6 months earlier and continues to require prednisone 15 mg daily and periodic infusions of intravenous immunoglobulin to maintain a hemostatic platelet count. You discuss second-line treatment options, including splenectomy. The patient asks if there are any means by which to predict likelihood of response to splenectomy. You have heard about the use of indium-labeled autologous platelet scanning for this purpose and wonder what the evidence shows.

Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population‐based cohort study

Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population‐based cohort study

Predictors for splenectomy among patients with primary chronic immune thrombocytopenia: a population-based cohort study from Denmark

We conducted a nationwide cohort study of adult Danish patients with primary chronic immune thrombocytopenia (cITP) to examine selected patient and clinical characteristics as predictors for splenectomy. We analyzed data from the Danish National Patient Registry and patient medical records from 1996 to 2007. Using Cox regression analyses, we calculated incidence rate ratios (IRRs) and associated 95% confidence intervals (CI) for splenectomy. We included 371 adult cITP patients. Of these, 87 patients (23%) underwent a splenectomy during a median of 3.6 years of follow-up. The majority (84%) of cITP patients who underwent splenectomy had splenectomy within the first year after cITP diagnosis. Predictors for splenectomy included age ≤ 75 years (adjusted 1-year IRR = 6.79 (95% CI, 2.10-21.90)) at least one platelet count ≤ 30 × 10(9)/L (i.e., high disease activity; adjusted 1-year IRR = 2.67 (95% CI, 1.37-5.22)) during follow-up and year of cITP diagnosis in early period (1996-2001; adjusted 1 year IRR = 2.37 (95% CI, 1.46-3.85)). Presence of chronic comorbidity was associated with lower rates of splenectomy (adjusted 1 year IRR = 0.58 (95% CI, 0.33-1.05)). Our findings suggest that high disease activity and absence of chronic comorbidity may be associated with higher rates of splenectomy, and that contraindications for splenectomy (i.e., patients' perceived frailty) cause the physicians to use the procedure cautiously.