Adult Chronic Immune Thrombocytopenic Purpura Research Articles

A Phase 1b Study of Eltrombopag and Azacitidine in Patients with High Risk Myelodysplastic Syndromes and Related Disorders

A Phase 1b Study of Eltrombopag and Azacitidine in Patients with High Risk Myelodysplastic Syndromes and Related Disorders

Interplaying of regulatory T-cells and related chemokines in immune thrombocytopenic purpura patients

BACKGROUND: Chronic immune thrombocytopenic purpura (ITP) is an immune-mediated bleeding disorder, in which platelets are opsonized by autoantibodies directed against platelet surface membrane glycoproteins, and prematurely cleared and destructed by Fc-receptors on the surface of macrophages in the reticuloendothelial system.OBJECTIVES: This work is designed to show the contribution of lymphocyte subsets and platelet destruction in adult chronic ITP and role of infection.MATERIALS AND METHODS: Transforming growth factor-β1 (TGF-β1) was measured using ELISA, and the frequency of regulatory T-cell (Treg) profile (CD4+CD25+CD127−) was investigated by FCM in blood samples of 50 Iraqi ITP patients (35 on-treatment ITP patients and 15 newly diagnosed) along with 20 age-matched healthy people that act as controls, as well as all patients were breath tested for detecting Helicobacter pylori using urea breath test. The study was carried out in the National Center of Hematology, Mustansiriyah University.RESULTS: The results showed that although there was a significant reduction in Treg number in ITP patients compared with the control individuals (P < 0.001), the effect of treatment has shown a restored count of Tregs in comparison to the newly diagnosed ones (P = 0.002), while the assessment of cytokine serum level revealed that TGF-β1 was significantly increased (P = 0.001) in the on-treatment group of patients (TGF-β1 = 3.24 ± 0.3 ng/μl) in comparison with the nontreated group of patients (TGF-β1 = 1.75 ± 0.2 ng/μl). However, it was still significantly (P < 0.001) less than their values in the apparently healthy individuals (TGF-β1 = 9.0 ± 0.2 ng/μ). Moreover, 25 out of 50 (50%) showed positive results for the presence of H. pylori.CONCLUSION: The present study revealed that Treg and its cytokines may play a fundamental role in the pathophysiology of adult chronic ITP since they contribute to the maintenance of peripheral immune tolerance. However, a causal link between H. pylori infection and ITP diseases is considerable.

The spleen dictates platelet destruction, anti-platelet antibody production, and lymphocyte distribution patterns in a murine model of immune thrombocytopenia.

For many years, splenectomy has been used to treat immune thrombocytopenia (ITP), and this procedure benefits approximately two-thirds of the treated patients. Although splenectomy may raise platelet counts, antibody-coated platelets and cytotoxic T lymphocytes appear to persist or can change over time. To better understand how the spleen may affect anti-platelet immune responses, we used a murine model of ITP demonstrating both antibody-mediated and T lymphocyte-mediated thrombocytopenia. Mice with severe combined immunodeficiency (SCID) were either splenectomized or not and transfused with splenocytes from CD61 (GPIIIa) knockout mice immunized against CD61(+) platelets. Platelet counts and anti-platelet antibody levels were performed weekly. After 4weeks, the mice were sacrificed, and lymphoid organs were harvested and examined by flow cytometry to quantify CD4(+)CD25(+)FoxP3(+) Tregs and conventional cross-presenting XCR1(+) and tolerizing SIRPα+ dendritic cells. The results indicate that compared with control non-splenectomized mice, thrombocytopenia was improved and anti-platelet antibody production was significantly diminished in all splenectomized mice that received immune splenocytes. Splenectomized SCID mice also had a marked reduction in Tregs in the thymus together with an increased proportion of both thymic dendritic cell subsets that correlated with increased platelet counts. Of interest, although splenectomy diminished anti-platelet antibody production and raised platelet counts, marrow megakaryocyte densities were still significantly reduced in mice that received immune splenocytes. These results suggest that the spleen in murine ITP not only is the primary site responsible for platelet destruction, but it also controls, to a significant extent, the antibody response against platelets and the migration patterns of lymphocyte subsets.

Long-Term Complications after Splenectomy in Adult Chronic Immune Thrombocytopenia with a Minimum Follow up of 10 Years. First Results from a Single-Center Case-Control Study in 140 Patients with Primary ITP

Introduction:Splenectomy was historically regarded as the gold standard for treatment in chronic adult immune thrombocytopenic purpura (ITP). However, the recent emergence of new drugs has deeply modified ITP management and splenectomy is no longer viewed as an unavoidable step in adult chronic ITP in many countries. The estimation of the risk over benefit of this potential curative treatment remains challenging both for patients and physicians. A retrospective Italian study focused on long-term outcome of patients splenectomized for ITP gave reassuring data concerning safety. A recent study from a large cohort of American veterans showed an increased risk of death due to septicemia, pulmonary embolism, coronary artery disease and cancer more than 10 years after splenectomy. We reported here the results of the first single center case-control study evaluating the long-term incidence of splenectomy complications with a minimum follow-up of 10 years.Methods:We retrospectively selected in a clinical computer database all primary ITP patients splenectomized more than 10 years ago in our unit. We matched 1 by 1 to non-splenectomized ITP patients based on date and age at ITP diagnosis and sex criteria. Clinical data were then completed from medical charts. All patients were interviewed by phone and a standardized questionnaire was used. Medical records from general practitioner or from Medical care center have been systematically obtained if necessary, especially for deceased patients. Comparison between groups were made using Fisher’s test for qualitative variables, Kaplan-Meier method to estimate incidence and Rank test for comparison of cumulative incidence, with p<0.05 defining significance.Results:Seventy splenectomized ITP patients were included (19men/51women) with a median age at ITP diagnosis of 37 years (range: 3-92). Sixty one (87%) initially responded to splenectomy but only 34(48.5%) maintained a sustained response after a median follow-up of 189 months (range:120-528). Matched non-splenectomized ITP patients had a median age at diagnosis of 40 years (range: 3-93) and a median follow-up since ITP diagnosis of 197 months (range: 96-504).Cumulative incidence of thromboembolic events was higher in the splenectomized group (p=0.029) (Figure1). Four (6%) episodes of post-operative portal vein thrombosis were observed, 3 were complicated by portal cavernoma requiring long-term anticoagulation. They tended to present with more thromboembolic events on a long-term (n=7) than non-splenectomized ITP patients (n=3, p=0.113). Two splenectomized (2.8%) and 1 non-splenectomized (1.4%) patients were diagnosed with post-embolic pulmonary arterial hypertension. The incidence of cardiovascular events was significantly higher in splenectomized group (9(13%) versus 2(2.8%), p=0.005) (Figure 2) with 6 transient and/or ischemic strokes in splenectomized patients (none in non-splenectomized).Infectious events were similar in the two groups (splenectomized: 12 (17%) vs 10 (14%)) but infections were more frequent and severe in splenectomized patients. Indeed, 12 splenectomized patients presented 20 infectious events requiring hospitalization, 13 of them were pneumonia (Streptococcus Pneumoniae: n=4, Haemophilus Influenzae: n=1, undocumented: n=9). Five complicated septic-shocks leading to 3 deaths. In non-splenectomized group, 10 patients had 10 infectious events (Pneumonia n=4, Streptococcus Pneumoniae n=1), 7 were hospitalized, none had septic-hock. Incidence of cancer was similar in the 2 groups (splenectomized: 11 (16%), non-splenectomized: 10 (14%).Finally, the mortality rate was not different between two groups (splenectomized: n=14 (20%), non-splenectomized n=9, 13%). Ten (38%) of the 36 non-responders patients deceased, 7 from hemorrhage and/or septic shock. Other splenectomized and non-splenectomized patients died from malignant cancer/hemopathy (n=5), coronary artery disease (n=2),other (n=6).Conclusion:Based on this case control single center study, we observed that long-term splenectomized patients have not only an increase risk of life-threatening infections, but also an increased risk of thromboembolic, and cardiovascular events. A long-term follow-up is therefore recommended in this patient population regardless the status of ITP in order to better prevent and manage such complications. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Use and effectiveness of eltrombopag in a tertiary hospital

BackgroundEltrombopag is authorised by the EMA for adult chronic immune thrombocytopenic purpura (ITP) splenectomised patients who are refractory to other treatments and as second-line treatment for non-splenectomised patients for whom...

Romiplostim (AMG531, Nplate) for secondary failure of platelet recovery after allo-SCT

Romiplostim (Rm) (AMG531, Nplate), a protein that binds to and stimulates the TPO receptor, has been shown to increase and maintain platelet counts in splenectomized and non-splenectomized adult patients with chronic immune thrombocytopenic purpura (ITP), and few adverse events have been reported.1, 2, 3, 4, 5 An overall response, defined as platelet count 50 000/μL for 4 weeks, was observed in 83% of patients, and 49% of these had a durable response.3 Interestingly, no antibodies against Rm or endogenous TPO were detected.2, 3 The study by Kuter et al.3 suggested that Rm could increase BM reticulin in some patients, though there was improvement upon withdrawal of the drug. The clinical significance of this finding remains unclear and warrants further study.6 In addition, discontinuation of Rm can cause a rapid decrease in platelet count in many patients. However, the safety and efficacy of long-term Rm treatment has been established in patients for up to 156 weeks of treatment.4 Altogether, these data have led to the approval of Rm for adult chronic ITP therapy in North America, Australia and Europe.

Bone marrow reticulin and collagen content in patients with adult chronic immune thrombocytopenic purpura: A Danish nationwide study

We quantified and differentiated reticulin and collagen content in bone marrow specimens from chronic immune thrombocytopenic (ITP) patients and examined the correlation between some clinical characteristics and the fibrosis grading. Through the Danish National Patient Registry, we identified 378 patients with chronic ITP from 1997 until 2007. Of these, 253 (67%) had undergone at least one bone marrow biopsy, and we retrieved the bone marrow specimens from 187 (74%). We graded the bone marrow content of reticulin and collagen according to the Thiele scale (Grade 0-3). We also retrieved information on patients' clinical characteristics. We examined the prevalence of bone marrow fibrosis grading > 0 by patients' age (≤ 75 years and > 75 years), sex, platelet count at baseline (< 30 × 10⁹/L, and ≥ 30 × 10⁹/L), splenomegaly, hepatomegaly, and medications. In total 75 chronic ITP patients (40%) had a bone marrow grading >0. Of these, 72 (39%) had Grade 1 reticulin fibers present. Only three patients (< 2%) had collagen fibers present: two had Grade 2 and one had Grade 3. The prevalence of bone marrow grading > 0 was lower in patients aged > 75 years than ≤ 75 years (prevalence ratio = 0.64, 95% CI: 0.36-1.15) and lower in men than women (prevalence ratio = 0.70, 95% CI: 0.45-1.09), while a baseline platelet count ≥ 30 × 10⁹/L was associated with a higher prevalence of grading > 0 (prevalence ratio = 1.24, 95% CI: 0.81-1.86). Thus, bone marrow reticulin and collagen content in chronic ITP patients may be associated with some clinical characteristics.

New advances in the treatment of adult chronic immune thrombocytopenic purpura: role of thrombopoietin receptor-stimulating agents

New advances in the treatment of adult chronic immune thrombocytopenic purpura: role of thrombopoietin receptor-stimulating agents Ara Metjian1, Charles S Abrams21Department of Medicine, Duke University Medical Center, Durham, NC, USA; 2Department of Medicine, University of Pennsylvania, Philadelphia, PA, USAAbstract: Decades of basic science and clinical research have led to an increased understanding of the pathophysiology of immune thrombocytopenic purpura (ITP), the processes underlying thrombopoiesis, and the treatment of chronic ITP. Now, new agents are available to treat ITP in a nonimmunosuppressive fashion. Lessons learned from the clinical trials of recombinant human thrombopoietin (TPO) have led to the development of a novel class of compounds: nonimmunogenic agonists of the thrombopoietin receptor. Representing the first nonimmunosuppressive agents to treat chronic refractory ITP in decades, medications such as romiplostim and eltrombopag were recently approved by the US Food and Drug Administration. These new agents offer physicians a new tool for treating difficult cases of ITP in their medical armamentarium. Additional TPO mimetics are also being developed that show promise in vitro, and await future development.Keywords: thrombocytopenia, immune-mediated thrombocytopenia, eltrombopag, romiplostim, thrombopoietin, thrombopoietin receptor

New advances in the treatment of adult chronic immune thrombocytopenic purpura: role of thrombopoietin receptor-stimulating agents

Decades of basic science and clinical research have led to an increased understanding of the pathophysiology of immune thrombocytopenic purpura (ITP), the processes underlying thrombopoiesis, and the treatment of chronic ITP. Now, new agents are available to treat ITP in a nonimmunosuppressive fashion. Lessons learned from the clinical trials of recombinant human thrombopoietin (TPO) have led to the development of a novel class of compounds: nonimmunogenic agonists of the thrombopoietin receptor. Representing the first nonimmunosuppressive agents to treat chronic refractory ITP in decades, medications such as romiplostim and eltrombopag were recently approved by the US Food and Drug Administration. These new agents offer physicians a new tool for treating difficult cases of ITP in their medical armamentarium. Additional TPO mimetics are also being developed that show promise in vitro, and await future development.

Evaluation of Bleeding-Related Episodes in Patients with Chronic Immune Thrombocytopenic Purpura (ITP) Receiving Romiplostim or Medical Standard of Care.

Abstract 1311Poster Board I-334 BackgroundChronic ITP is an autoimmune disease characterized by low platelet counts and increased risk of bleeding that may be severe or even fatal. Rescue medications, most commonly intravenous immunoglobulins, are used to treat or prevent bleeding but produce only transient increases in platelet counts in most cases and may have issues with toxicity. Romiplostim is a peptibody protein designed to increase platelet production by binding to and activating the thrombopoietin receptor, and is approved for the treatment of adult chronic ITP. ObjectiveTo determine the effects of romiplostim treatment on bleeding outcomes during a phase 3b, randomized, open-label study, in adult nonsplenectomized ITP patients receiving either romiplostim or medical standard of care (SOC). We have developed a clinically-relevant composite endpoint, termed bleeding-related episode (BRE). A BRE was considered to be either an actual bleeding event, and/or the use of rescue medication to treat or prevent bleeding. MethodsPatients were randomized (2:1) to romiplostim or SOC. Eligible patients were required to have either a platelet count <50×109/L or have had their platelet count fall to <50×109/L during or after a clinically-indicated taper or discontinuation of current ITP therapy. Once-weekly subcutaneous romiplostim was administered with dose adjustments to target a platelet count between 50 and 200 × 109/L. SOC treatments were prescribed according to standard institutional practices or therapeutic guidelines. Since many types of ITP treatment could be administered in the SOC group, for the purpose of this analysis rescue medication was defined as any use of immunoglobulins (intravenous immunoglobulin or Anti-D), intravenous steroids, or platelet transfusions. In order to collapse related events into episodes, events (bleeding events and/or the use of rescue medication) that occurred concurrently or within 3 days of each other were considered a single clinical episode. Rates of BREs per 100 patient-weeks were calculated from the number of events/episodes divided by the number of patient-weeks on study treatment, multiplied by 100. ResultsDuring the 52-week treatment period, the total number of patient-weeks for the romiplostim group (N=154) was 7087, and for the SOC group (N=70) was 2571. During the treatment period, the rate of BREs was lower in the romiplostim group than the SOC group (see Table), with a 67% reduction in the rate of BREs in patients receiving romiplostim compared to SOC (95% CI, 60% to 73%). The rate of BREs involving the use of immunoglobulins was also lower in the romiplostim group, with a 95% reduction in the rate of BREs in patients receiving romiplostim compared to those receiving SOC (95% CI, 92% to 97%).TableRomiplostim N. of patients = 154 Patient-week=7087 r (n)SOC N. of patients = 70* Patient-week=2571 r (n)BREs3.1 (220)9.4 (241)BREs with immunoglobulins0.2 (17)4.8 (123)Events incorporated intoBREs**Bleeding3.7 (262)5.6 (144)Anti D0.0 (1)0.4 (9)IVIG0.3 (19)4.9 (127)IV steroids0.1 (8)0.4 (9)Transfusions0.3 (24)0.8 (20)Total4.4 (314)12.0 (309)Patient-week = Total patient weeks on study during treatment period, n = Number of events, r = duration-adjusted event rate per 100 patient-weeks ( n / Patient-week x 100)*5 of 75 patients randomized to SOC were excluded from this analysis due to use of rituximab at study entry**A single BRE could contain multiple events ConclusionsCompared to SOC, romiplostim was associated with a reduction in all BREs as well as BREs involving immunoglobulin use. DisclosuresStasi:Amgen Inc.: Honoraria, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau. Giagounidis:Amgen Inc.: Consultancy, Speakers Bureau. Janssens:Roche: Honoraria. Legg:Amgen Inc.: Employment, Equity Ownership. Danese:Amgen Inc.: Consultancy, Research Funding. Deuson:Amgen Inc.: Employment, Equity Ownership.

New therapeutic options for adult chronic immune thrombocytopenic purpura: a brief review

Patients with chronic immune thrombocytopenic purpura (ITP) only require treatment if they are bleeding, or prior to scheduled operations. Patients are also treated if platelet counts are very low. Some patients become refractory, relapse or do not respond to treatment with steroids. Splenectomy is effective in raising the platelet count in most patients, but as spontaneous remission may occur even after 1 year or more, it is justified to defer splenectomy. Furthermore, splenectomy and/or first-line treatment modalities may not suit all patients. Therefore, alternatives are desirable. This review will focus on anti-B cell therapy with rituximab, and two thrombopoietin mimetic agents that have entered clinical trials, AMG 531 and eltrombopag. These therapeutics have been studied in patients who were refractory to first-line treatment and/or splenectomy, and to defer splenectomy. There are no controlled trials with rituximab, but clinical experience has shown a success rate of 40% to 60%. Encouraging phase 1 and 2 data have been published for both thrombopoietin mimetics; preliminary data from an open-label extension trial with AMG 531 and from phase 3 studies with eltrombopag further confirm their efficacy. Clinical experience will ultimately determine the appropriate indications of these new treatments for ITP.

Health-Related Quality of Life (HRQoL) in Patients (Pts) with Chronic Immune Thrombocytopenic Purpura (ITP): Results from Two Placebo-Controlled Phase 3 Studies of AMG 531.

Pt-reported outcomes (PROs) are important tools for understanding the effects of treatment for various diseases. We developed the ITP Pt Assessment Questionnaire (ITP-PAQ) as the first disease-specific PRO instrument for adult chronic ITP. Further evaluation of its validity was assessed in ITP pts receiving AMG 531. AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin receptor. The ITP-PAQ was used to examine HRQoL changes in both splenectomized and nonsplenectomized pts from 2 randomized, double blind, placebo-controlled Phase 3 studies of AMG 531 in adult pts with chronic ITP. It contains 44 items and 10 scales including Symptoms, Bother, Fatigue, Activity, Fear, Psychological, Work, Social Activity, Women's Reproductive Health, and Overall Quality of Life. Pts were blinded to their platelet counts before completing the ITP-PAQ. Changes in mean scores from baseline to week 24 were calculated for each ITP-PAQ scale by treatment arm, with positive values indicating improvement in HRQoL. Independent two-tailed t-tests were used to test differences. Specific items within each scale were also analyzed to provide further insights into the disease-specific areas of most concern for pts. Of the 125 pts enrolled, 63 were splenectomized (placebo, 21; AMG 531, 42), and 62 were nonsplenectomized (placebo, 21; AMG 531, 41). At baseline, splenectomized pts had lower scores on all ITP-PAQ scales than nonsplenectomized pts, especially Bother (51.0 vs 66.7), Fear (69.4 vs 81.3), Work (62.4 vs 77.5), and Overall Quality of Life (40.3 vs 56.5). Over the 24-week study, AMG 531-treated pts reported significantly greater improvement relative to placebo on 5 of 10 scales. Among splenectomized pts, significantly greater improvements in mean scores from baseline were found in the AMG 531 arm for Symptoms (placebo vs AMG 531; 0.2 vs 10.8, p=0.02), Bother (4.5 vs 24.6, p=0.009), Social Activity (−2.1 vs 16.9, p=0.017), and Women's Reproductive Health (−11.9 vs 10.1, p=0.027). Among nonsplenectomized pts, significantly greater improvement was found in AMG 531 pts for Activity (−1.8 vs 23.7, p=0.016). Particular improvements in items shown by both splenectomized and nonsplenectomized AMG 531-treated pts included bleeding (Symptoms), bruising (Symptoms), feeling unattractive due to bruising (Bother), and fear of infections (Fear). In summary, lower HRQoL was reported in splenectomized compared to nonsplenectomized pts with ITP, reflecting potentially different clinical needs for these 2 pt populations. Pts treated with AMG 531 showed greater improvement in HRQoL relative to placebo pts on most ITP-PAQ scales, and significant improvements were more common in splenectomized pts. Results from these 2 trials have provided further validation of the ITP-PAQ and can inform selection of key endpoints for future studies.

Health-Related Quality of Life (HRQoL) in Patients with Chronic Immune Thrombocytopenic Purpura (ITP): Interim Results from an Open-Label Study of AMG 531.

The ITP Patient Assessment Questionnaire (ITP-PAQ) was developed to complement clinical data by assessing multiple facets of disease-specific HRQoL in adult patients with chronic ITP (Mathias et al., Health Qual Life Outcomes, 2007). Here we present interim results from an ongoing, open-label extension study that will evaluate the ability of AMG 531 to improve their HRQoL in the long-term. AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin receptor. Adult chronic ITP patients receiving AMG 531 completed the ITP- PAQ at baseline, and weeks 4, 12, 24, and every 12 weeks thereafter. The ITP-PAQ consists of 44 items and 10 scales. Data have been assessed for this interim analysis through week 48, a time-point with reasonable patient numbers at the time of the data cut-off. Mean scores at each assessment, and changes in mean scores from baseline to week 48 were calculated, with positive changes in mean score indicating improvement in HRQoL. Compliance rates for the ITP-PAQ were 95% at baseline, 93% at week 4, and 83% at week 48. Over the 48-week period, results demonstrated an upward trend for the scale scores (see Table). The greatest improvements were reported in the Symptoms, Bother, Activity, Reproductive Health, and Overall Quality of Life scales, particularly during the first 4 weeks of the study. Changes in mean score from baseline to week 48 were significantly increased for Symptoms, Bother, Fatigue, Activity, Fear, Psychological Health, Work, Social Activity, and Overall Quality of Life. ITP patients receiving AMG 531 had an initial, yet sustained, improvement in ITP-PAQ scores. Subsequent analyses of results collected in this ongoing study will be used to substantiate our findings, and the therapeutic benefit of AMG 531 on HRQoL in patients with chronic ITP will be provided by correlations with clinical data. [Display omitted]

Self‐reported health‐related quality of life in adults with chronic immune thrombocytopenic purpura

Adult chronic immune thrombocytopenic purpura (ITP) is a disorder manifested by varying degrees of purpura and mucosal bleeding, rarely including intracranial hemorrhage. Therapy is aimed at increasing the patient's platelet count to safe levels and includes a wide variety of treatments. While the diagnosis, treatment, and prognosis of chronic ITP have been extensively discussed, the effect of ITP and its treatment on patient quality of life has not been evaluated in adults. In this study, the Short-Form 36 questionnaire was used to evaluate the health-related quality of life (HRQOL) of 73 adult ITP patients compared with that of the general U.S. population and of patients with six other relatively common chronic disorders. This study shows that the HRQOL of adult patients with ITP is significantly worse than that of the general U.S. population. It is also worse than that of patients with hypertension, arthritis, or cancer; similar to that of patients with diabetes; but better than that of patients with congestive heart failure or a missing or paralyzed limb. Future studies need to address the effects of treatment not only on the platelet count and bleeding but also on HRQOL.

Eltrombopag, a novel, oral platelet growth factor, increases platelet counts in thrombocytopenic patients and healthy subjects

8602 Background: Eltrombopag (SB-497115) is a novel, first in class, orally bioavailable, thrombopoietin receptor agonist that induces differentiation and proliferation of megakaryocyte progenitors and has been shown to increase platelet counts in preclinical and clinical studies. Methods: In two randomized, placebo-controlled trials, eltrombopag was administered as oral tablets, once daily for 10 days to 73 healthy male subjects at doses of 5–75mg in an ascending dose cohort study, and to 103 (64 female/39 male) adult chronic immune thrombocytopenic purpura (ITP) patients, with a platelet count of &lt;30×109/L, once daily for 6 weeks at doses of 30–75mg in a parallel dose cohort study. The primary efficacy endpoint in the Phase II ITP trial was the proportion of subjects with a platelet count &gt;50×109/L after 6 weeks of dosing. Results: In healthy subjects, eltrombopag induced a dose dependent increase in the platelet counts. Mean maximal platelet count increases were 24.1 % at 30mg, 42.9 % at 50mg, and 50.4 % at 75mg. In 95 eligible ITP patients, platelet counts increased from &lt;30 to &gt;50×109/L in 16% (4/25) of subjects on placebo, and in the eltrombopag groups in 28% (7/25, p=ns) on 30mg, 67% (16/24, p&lt;0.001) on 50mg and 86% (18/21, p&lt;0.001) on 75mg eltrombopag. The median platelet counts in each treatment arm after 6 weeks of dosing were 16×109/L on placebo, 29×109/L on 30mg, 132×109L on 50mg, and 202×109/L on 75mg. The dose dependent effect was not significantly affected by the splenectomy status, background immunosuppressant use, or baseline platelet count (greater than or less than 15×109/L). Conclusions: The platelet count data from these clinical studies suggests that eltrombopag could be an effective therapy for the treatment of thrombocytopenia. Eltrombopag is being tested in further studies involving patients with ITP and chronic liver disease, and cancer patients receiving thrombocytopenic chemotherapy. [Table: see text]

Hepatitis C virus‐related thrombocytopenia: clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura

Thrombocytopenia can be a complication of hepatitis C viral (HCV) infection. However, there is little published data regarding the clinical and laboratory manifestations of HCV-related thrombocytopenia (HCV-TP) compared with adult chronic immune thrombocytopenic purpura (CITP). We reviewed the medical records for all patients evaluated for chronic thrombocytopenia by the Haematology Service between January 1996 and June 2000. All patients were screened for HCV infection at the time of initial diagnosis. Of 250 patients who fulfilled American Society of Hematology criteria for CITP, 76 (30%) were HCV seropositive. HCV-TP patients were older [mean age (+/-SD) 54.9 +/- 8 years vs. 40.3 +/- 8 years, P </= 0.001] and equally distributed between both sexes. HCV-TP patients had less severe thrombocytopenia, defined as platelet count </=10 x 10(9)/l (4% vs. 46% for CITP, P </= 0.001). However, 56 (74%) had a platelet count </=50 x 10(9)/l. Symptoms and signs of thrombocytopenia were less frequent in HCV-TP, but major bleeding was more frequent (25% vs. 10%, P = 0.0059). Serum cryoglobulins and anticardiolipin antibodies were more frequent in HCV-TP (90% and 62% respectively), but rare in CITP (7% and 15%, P </= 0.001 compared with HCV-TP). HCV infection can be associated with significant thrombocytopenia and appears to be a distinct clinical entity.

Prospective evaluation of the immunobead assay for the diagnosis of adult chronic immune thrombocytopenic purpura (ITP)

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by antibody-induced platelet destruction. To better define the role of antigen-specific assays in adult chronic ITP, we prospectively measured platelet-associated autoantibody against either glycoprotein (GP) IIb/IIIa or GPIb/IX in 282 patients with chronic ITP and 289 patients with thrombocytopenia of other causes. We divided chronic ITP into four subgroups: presplenectomy, mild (platelet count >30 000 micro (L-1) requiring no therapy), presplenectomy, severe (platelet count <30 000 micro L(-1) requiring therapy but not splenectomy), postsplenectomy, remission (postsplenectomy partial or complete remission without further therapy) and postsplenectomy refractory (required therapy after splenectomy failure). Positive results: total ITP group, 55.4%; presplenectomy, mild, 31.1%; presplenectomy, severe, 42.6%; postsplenectomy, remission, 50.0%; and postsplenectomy, refractory, 87.8%. In addition, the degree of positivity increased with the severity of the patient's disease. The assay had a minimum specificity of 84.4% if clinical factors, consistent with immune thrombocytopenia, were not considered in patients with thrombocytopenia associated with other diseases. However, if clinical factors consistent with immune thrombocytopenia were considered and only patients with questionable immune thrombocytopenia and patients 'lost to follow-up' were included in the false-positive group the specificity was 93.1%. We conclude that the presence of immune thrombocytopenia is highly probable if the immunobead assay is positive and that antigen-specific assays are diagnostically useful in adult chronic ITP.

Therapy for adults with refractory chronic immune thrombocytopenic purpura.

Adult chronic immune thrombocytopenic purpura (ITP) is a common hematologic disorder; about 14,000 to 16,000 new cases occur each year in the United States. Initial treatment with corticosteroids and splenectomy results in normal or "safe" platelet counts in more than 70% of patients. Treatment of patients refractory to these two treatments is difficult. This paper describes a structured approach to therapy that is based on a literature review and personal experience, including experience with treatment of chronic ITP in special situations (such as emergent bleeding, pregnancy, and central nervous system bleeding). Treatment of most patients with chronic ITP is fairly straightforward, but management of patients refractory to corticosteroids and splenectomy can be difficult. Large, randomized studies are clearly needed to better evaluate the many types of treatment that are recommended for refractory patients.