Bone Marrow Specimens From Patients with Immune Thrombocytopenia (ITP) Demonstrate Increased Megakaryocyte-Bound IgG and Increased T-Helper Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2233-2233
Author(s):  
Lisa J. Toltl ◽  
Catherine Ross ◽  
John G. Kelton ◽  
Donald M. Arnold
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Bone Marrow Biopsy ◽  
T Helper Cells ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
T Helper ◽  
Hematopoietic Growth Factors ◽  
Cell Numbers ◽  
Igg Binding

Abstract Abstract 2233 BACKGROUND: Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disease characterized by low platelet counts and platelet autoantibodies. The mechanisms of ITP remain unclear although recent evidence suggests that megakaryocytes may be the target of immune destruction. To test this hypothesis we evaluated IgG-binding to megakaryocytes and B- and T-cells in bone marrow specimens of ITP patients and non-thrombocytopenic controls. METHODS: Histological slides of bone marrow biopsies from ITP patients and control patients were prepared from stored paraffin-embedded tissue blocks for blinded pathological assessment. Adult ITP patients (N=19) had a platelet count less than 100 x109/L (range 2 – 76 x109/L) as measured within 4 weeks before the date of bone marrow biopsy procurement without splenomegaly, myelodysplastic syndrome, lymphoproliferative disease, HIV, hepatitis B or C, drug-induced thrombocytopenia or prior treatment with thrombopoietin receptor agonists or other hematopoietic growth factors. Control patients (N=15) were adults with limited stage lymphoma or monoclonal gammopathy of undetermined significance with a normal platelet count (150 – 400 x109/L) who had a bone marrow biopsy for staging purposes which was reported as normal. Patients with prior use of anti-neoplastic agents or hematopoietic growth factors were excluded. Coded bone marrow biopsy sections were labeled with rabbit polyclonal anti-IgG, anti-CD4, anti-CD8, anti-CD20, and CD61 in serial sections, followed by streptavidin-biotin labeling techniques. The intensity of staining was assessed semi-quantitatively by an experienced hematopathologist for megakaryocyte, B-cell and T-cell numbers (increased, decreased, within normal limits) and megakaryocyte-bound IgG (negative, below 50% of cells positive or more than 50% of cells positive) blinded to diagnosis and platelet count. RESULTS: ITP bone marrows demonstrated greater IgG binding to megakaryocytes compared with controls [12/19 (63.16%) vs. 4/15 (26.67%), p=0.02], increased CD4+ cells [15/19 (78.95%) vs. 5/15 (33.33%), p=0.003] and marginally increased CD8+ cells [11/19 (57.89%) vs. 4/15 (26.67%), p=0.05]. B-cell numbers were not different between groups. CONCLUSIONS: Using bone marrow specimens from carefully selected ITP patients and controls, our study shows that IgG-bound megakaryocytes and T cells, especially T-helper cells, are increased in bone marrow of ITP patients compared with controls. These data provide evidence of megakaryocyte injury in ITP. Additional labeling with caspase-3 and TUNEL stains is planned to identify markers of apoptosis. Disclosures: Kelton: Amgen: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Arnold:Amgen: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Talecris: Honoraria; Hoffmann-LaRoche: Research Funding.

scholarly journals Megakaryocyte Apoptosis in the Bone Marrow of Patients with Immune Thrombocytopenia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1379-1379
Author(s):  
John R Vrbensky ◽  
Ishac Nazy ◽  
Lisa J Toltl ◽  
Catherine Ross ◽  
John G. Kelton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Bone Marrow Biopsy ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Tunel Staining ◽  
Bone Marrow Biopsies ◽  
Entire Study ◽  
Platelet Counts ◽  
Normal Platelet

Abstract Introduction: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder in which autoantibodies promote the destruction and underproduction of platelets. Recent evidence suggests that immune-mediated destruction of bone marrow megakaryocytes is associated with the pathogenesis of this disease. In addition, the attenuation of megakaryocyte apoptosis can lead to platelet underproduction since this process appears to be involved in thrombopoiesis. In the current study, we investigated megakaryocyte apoptosis as a possible mechanism in the pathogenesis of ITP. Patients/Methods: Bone marrow biopsy sections from ITP patients and controls were stained with anti-human CD61 to enumerate megakaryocytes. Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining was performed as a measure of megakaryocyte apoptosis. The samples were coded and reviewed by an experienced hematopathologist who was blinded to the diagnosis. Adult primary ITP patients had isolated thrombocytopenia with no underlying cause and a platelet count less than 100 x109/L at the time of bone marrow biopsy procurement. Patients with secondary ITP (in the context of medications, lymphoproliferative disease, HIV, hepatitis B or C infection) were excluded, as were patients who received prior treatment with thrombopoietin receptor agonists or other hematopoietic growth factors. Thrombocytopenic controls were patients with myelodysplastic syndrome (MDS) who had platelet counts below 100 x109/L. Control patients with normal platelet counts had bone marrow biopsies performed as part of investigations for lymphoma or plasma cell dyscrasia with negative test results. Results: The average platelet count for ITP patients, MDS patients, and controls were 18 x109/L (range 2-76 x109/L), 29 x109/L (range 9-60 x109/L), and 281 x109/L (range 171-400 x109/L), respectively. Elevated megakaryocyte counts were observed in the bone marrow sections of 5/14 (36%) ITP patients, 0/8 (0%) MDS patients, and 2/11 (18%) controls. Megakaryocyte apoptosis was comparable between ITP patients and MDS patients [2/14 (14%) vs 1/8 (13%) (p=1.00)], while fewer ITP patients exhibited megakaryocyte apoptosis compared to controls with normal platelet counts [2/14 (14%) vs 7/11 (64%) (p=0.02)]. In the entire study cohort, the average platelet counts of patients with negative and positive TUNEL staining were 66 x109/L (range 2-378 x109/L) and 206 x109/L (range 20-400 x109/L), respectively (p=0.01). In addition, the normalized megakaryocyte counts (per high powered field) were 8.2 ± 5.5 and 5.4 ± 2.5 in patients with negative and positive TUNEL staining, respectively (p=0.05). Conclusion: Megakaryocyte apoptosis was reduced in ITP bone marrow samples compared to controls with normal platelet counts, but was also low in thrombocytopenic MDS patients. Reduced megakaryocyte apoptosis was found to be associated with a low platelet count, and may be related to thrombocytopenia regardless of etiology. Our study is consistent with the hypothesis that attenuated megakaryocyte apoptosis is relevant in the context of platelet underproduction in ITP. Disclosures Arnold: Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; UCB: Consultancy; Amgen: Consultancy, Research Funding.

The Utility of Bone Marrow Examinations for the Diagnosis of Immune Thrombocytopenia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3691-3691
Author(s):  
Vishwanath Kishan Mahabir ◽  
Cathy Ross ◽  
Snezana Popovic ◽  
Jacqueline Bourgeois ◽  
Grace Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Growth Factors ◽  
Bone Marrow Biopsy ◽  
Immune Thrombocytopenia ◽  
Hematopoietic Growth Factors ◽  
Bone Marrow Biopsies ◽  
Normal Limits ◽  
Control Bone ◽  
Marrow Cellularity

Abstract Abstract 3691 Background: The utility of bone marrow examinations for the investigation of patients with immune thrombocytopenia (ITP) is a matter of debate. We designed an agreement study to evaluate the inter-rater reliability of bone marrow biopsies and aspirates for the diagnosis of ITP. Methods: Histological slides of bone marrow biopsies from patients with ITP and controls were prepared from stored tissue blocks and corresponding aspirate slides were retrieved for blinded, duplicate, independent pathological review. Patients had a diagnosis of primary ITP, were 18 years of age or older with a platelet count less than 100 ×109/L as measured within 4 weeks before the date of bone marrow biopsy procurement. Patients with splenomegaly, myelodysplastic syndrome, lymphoproliferative disease, HIV, hepatitis B or C, drug-induced thrombocytopenia or previous treatment with hematopoietic growth factors or thrombopoietin receptor agonists were excluded. Control bone marrow samples were selected from patients 18 years of age or older with stage I to III lymphoma or monoclonal gammopathy of undetermined significance who had a normal platelet count within 4 weeks before bone marrow biopsy procurement. Prior treatment with anti-neoplastic agents or hematopoietic growth factors were exclusions. Bone marrow slides from ITP patients and controls were coded and arranged in random order. A standardized pathological assessment form was used to capture bone marrow cellularity (in deciles), diagnosis [‘ITP’ or ‘within normal limits (wnl)’], megakaryocyte number (increased, decreased or wnl), morphology (abnormal or wnl), distribution (abnormal or wnl) and megakaryocyte assessment on aspirate (abnormal or wnl). The form was piloted by a third independent hematopathologist (n=10 bone marrow examinations) and revised prior to duplicate review. All reviewers were pathologists with at least 5 years experience reading bone marrows. Chance-corrected agreement between reviewers was calculated using kappa (k) and chance-independent agreement was calculated using phi (φ) with 95% confidence intervals (CI). Results: Bone marrow slides were prepared from 30 ITP patients and 53 controls. Agreement on marrow cellularity (to within 20%), which was used to ensure calibration of assessors, was good (k= 0.75, 95% CI. 0.65–0.85). Of 81 evaluable bone marrows, pathologists agreed on the diagnosis for 69 cases (85.2%); overall agreement was fair (φ = 0.52; 95% CI: 0.10–0.78). Of the 30 ITP bone marrows, pathologists correctly agreed on the diagnosis in 2 (6.7%) cases, incorrectly agreed on 20 (66.7%) and disagreed on 8 (26.7%). Of the 51 control bone marrows, pathologists correctly agreed on the diagnosis in 46 (90.2%) cases, incorrectly agreed on 1 (2.0%) and disagreed on 4 (7.8%). Agreement on megakaryocyte number, morphology and distribution was fair. Conclusions: Inter-rater reliability of bone marrow examinations for the diagnosis of ITP was fair. Pathologists often incorrectly agreed that ITP bone marrows were considered to be within normal limits. These data suggest that ITP bone marrows often do not exhibit any distinguishing features. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Association between Megakaryocyte Abnormalities on Bone Marrow Smear and Response to Thrombopoietin Receptor Agonists in Adult Patients with Primary Immune Thrombocytopenia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3160-3160
Author(s):  
Ondine Walter ◽  
Agnès Ribes ◽  
Johanne Germain ◽  
Jean-Baptiste Rieu ◽  
Thibault Comont ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Adult Patients ◽  
Second Line ◽  
Bone Marrow Smear ◽  
Advisory Committees ◽  
Thrombopoietin Receptor

Abstract Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease due to peripheral destruction but also impaired central production of platelets. Autoimmune reaction directed against megakaryocytes (MKs) has been described, and may explain morphological abnormalities of MKs observed in some patients with primary ITP. Thrombopoietin receptor agonists (TPO-RAs) are indicated as second-line treatments for ITP, but no predictive factors of response used in clinical routine practice has been demonstrated. The utility of systematic bone marrow smears (BMS) at ITP diagnosis is discussed. Howerer, it is usually recommended before second-line treatments. Two studies have suggested an association between MK abnormalities and response to corticosteroids in primary ITP, but none have investigated this association for TPO-RAs. This study aimed to investigate the association between MK abnormalities and response to TPO-RAs in adult patients with primary ITP. Methods: The source of population was the CARMEN registry. The CARMEN (Cytopénies Auto-immunes: Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) with incident ITP in routine visit or hospital stay. ITP was defined by international definition (platelet count <100 x 10 9/L and exclusion of other causes of thrombocytopenia). The study population consisted in all patients included in the CARMEN registry between June 2013 and March 2018 with primary ITP, treated by TPO-RA and with a BMS before initiating TPO-RA. We excluded the patients with a number of MKs <10 MK on the BMS. Morphological abnormalities were established based on literature and defined by consensus among 3 expert cytologists (AR, JBR and VDM). All MKs present on each smear were analyzed. MKs were categorized by the presence of dysplasia (monolobed MK and/or separated nuclei and/or microMKs), and according to their stage of maturation (basophilic, granular and thrombocytogenic). All patients' medical charts were reviewed by two experts in ITP (OW and GM) to determine the response to TPO-RAs. Response was defined by a platelet count between 30 and 100 G/L with at least a doubling of basal platelet count according to the international definition. In case of subsequent exposure to both TPORAs in a single patient, response was defined by response to at least one TPO-RA in the main analysis. We performed a subgroup analysis by TPORAs. Results: During the study period, 451 patients with incident ITP were included in CARMEN-registry. Among them, 105 had been treated by TPO-RAs, including 65 with BMS before the exposure to TPORA. We then excluded 20 patients with secondary ITP and 7 with less than 10 MKs on the BMS. We finally included 38 patients in the analysis. Median age at diagnosis was 71 years (interquartile range - IQR: 31 - 94) and 34.2% were women. Thirty-three patients were treated with eltrombopag, 17 with romiplostim including 13 who were exposed to both TPORAs. Thirty-four (89.4%) achieved response. The median number of MKs analyzed per patient was 137 (IQR: 50 - 265). All results are presented in Table 1. In the main analysis, there was no significant difference in the median percentage of dysplastic MKs in responders (4.0%, 95% confidence interval - CI: 2.3 - 6.4) and non-responders (4.5%, 95% CI: 0.7 - 7.1). There was a trend for a higher proportion of granular MKs (4.5%, 95% CI: 3 - 6) and basophilic MKs (30.1%, 95% CI: 21.9 - 39.1) in non-responders comparing to responders (granular: 2.0%, 95% CI: 0 - 4.1; basophilic: 21.3%, 95% CI: 11.4 - 40.7). Results were similar in the subgroup of patients treated with eltrombopag (data not shown; the low number of patients treated with romiplostim precluded any analysis). Conclusion: In this study, neither MK abnormalities nor the pattern of MK maturation stages were significantly associated with response to TPO-RAs. These results do not support a systematic bone marrow smear in patients with primary ITP to look for morphological predictive factors of response to TPO-RA. Figure 1 Figure 1. Disclosures Comont: AstraZeneca: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Retrospective Multicenter Case Study Evaluating the Characteristics, Management and Outcome of Acquired Amegakaryocytic Thrombocytopenia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3167-3167
Author(s):  
Anais Roeser ◽  
Guillaume Moulis ◽  
Mikael Ebbo ◽  
Louis Terriou ◽  
Elsa Poullot ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Aplastic Anemia ◽  
Board Of Directors ◽  
Bone Marrow Biopsy ◽  
Research Funding ◽  
Advisory Committees ◽  
Overall Response ◽  
Acquired Amegakaryocytic Thrombocytopenia

Abstract Introduction Acquired amegakaryocytic thrombocytopenia (AAT) is an extremely rare disease characterized by acquired megakaryocytic aplasia or hypoplasia with no other lineage abnormalities. Given limited evidence, the first aim of this study was to describe the characteristics, management and outcome of patients with AAT, the second aim was to examine the therapeutic response through a systematic review of published case reports. Patients and Methods We carried out a retrospective multicenter study through the French Reference Network for Adult Autoimmune Cytopenias, including patients aged > 18 years with acquired thrombocytopenia with a platelet count < 50 x 10 9/L, associated with a megakaryocytes / granulocytes ratio < 50 % on bone marrow, diagnosed from July 2007 to February 2020. Exclusion criteria were: abnormal granular lineage, evidence of dysplasia, bone marrow infiltration by tumor cells or hematologic malignancy, significant karyotype abnormality, and significant paroxysmal nocturnal hemoglobinuria clone. Bone marrow biopsy were centrally reviewed. Patients' medical charts were collected using the standardized form of the referral center for adult immune thrombocytopenia (ITP). Response to treatment was defined according to standardized international criteria for ITP: response (R) and complete response (CR) were respectively defined as platelet count of > 30 × 10 9/L with at least a doubling of the baseline value, and platelet count of > 100 × 10 9/L ; overall response as either R or CR. We performed a systematic review conducted through Medline and Scopus databases from 1970 to April 2021. Cases were included in the analysis if initial platelet count was < 50 x 10 9/L and bone marrow examination was available, demonstrating a megakaryocyte hypoplasia or aplasia with no alternate diagnosis. Results We screened 23 patients reported as thrombocytopenia with absence or decreased megakaryocytes. Eleven patients were excluded because of: presence of megakaryocytes on bone marrow biopsy despite megakaryocytic aplasia on bone marrow aspirate (n=2), absence of bone marrow biopsy (n=4), aplastic or hypoplastic bone marrow (n=3), moderate thrombocytopenia > 50 x 10 9/L (n=1), lack of data (n=1). Twelve patients were included in the analysis. AAT patients had a median age of 52.5 years, 5/12 (41.7%) were female, 6/12 (50%) had a preexisting autoimmune disease (Table 1). All bone marrow biopsies reviewed to date contained CD8+ T-cell infiltrates. Eight patients received a first line treatment with corticosteroids and/or intravenous immunoglobulins (IVIg), a single response was observed. Ten patients received cyclosporine in monotherapy resulting in 4CR, and 1R or in combination with diverse agents with heterogenous responses. Six had received a single therapy with thrombopoietin receptor agonists (TPO-RAs) inducing 4 CR. Eventually, 9 patients (75%) achieved a CR under therapy, obtained with ciclosporin alone in 3 cases, ciclosporin in association with TPO-RA or ATG in 2 cases, cyclophosphamide followed-up by mycophenolate mofetil in 1 case, and TPO-RAs alone in 4 patients (of whom 3 had previously received at least on immunosuppressive therapy). After a median follow up time of 4.0 years (range 1.2 - 11.9), 2 (16%) patients eventually developed an aplastic anemia, 7 and 41.5 months respectively after initial AAT diagnosis. The literature search yielded 108 articles, of which 75 articles reporting 85 cases were included in the final analysis. The pooled analysis of newly reported and historic cases included 97 cases. Overall response rates to corticosteroids and IVIg were respectively 22.4 % and 5.3 % (Table 2). Ciclosporin was used as single agent in 37.1 % of patients, with an overall response rate of 66.7 %. TPO-RAs were used in 9 cases, with a CR in 7 patients (77.8%). Overall, 9/97 patients (9.3 %) experienced an aplastic anemia during the follow-up. The presence of a thymoma was associated with a higher risk of aplastic anemia (OR 6.83 (95%CI 1.22-34.00, p=0.020)). Conclusion Distinguishing AAT from ITP is of significance as the outcome and response to therapy strongly differ. Aplastic anemia may occur in the follow-up but remain rare. Corticosteroids and IVIg are inefficient in most cases, ciclosporin appear to be very effective, TPO-RA could also be an option, as single therapy or in associations. Further data will be needed to define the respective place of these treatments. Figure 1 Figure 1. Disclosures Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenix: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees. Ebbo: Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Attendance Grant; Amgen: Honoraria; Sobi: Other: Attendance Grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haioun: Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding. Michel: Amgen,Novartis,UCB,Argenx,Rigel: Honoraria. Godeau: Amgen: Consultancy; Novartis: Consultancy; Grifols: Consultancy; Sobi: Consultancy. Mahevas: GSK: Research Funding; Amgen: Honoraria.

The Importance of a Bone Marrow Biopsy to Distinguish Primary Immune Thrombocytopenia From Indolent Haematological Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4676-4676
Author(s):  
Sif Gudbrandsdottir ◽  
Hans Carl Hasselbalch ◽  
Henrik Frederiksen
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Low Grade ◽  
Haematological Malignancies ◽  
Drug Induced ◽  
Advisory Committees ◽  
Primary Immune Thrombocytopenia

Abstract Abstract 4676 Background Primary immune thrombocytopenia (ITP) is characterised by an immune-mediated destruction of platelets and impaired platelet production [1, 2]. The diagnosis is one of exclusion, and any disorder presenting with isolated thrombocytopenia can mimic ITP [3]. Aims To identify and describe patients initially diagnosed with ITP and included in an on-going clinical trial, when further diagnostics revealed other underlying disorders as the aetiology to the low platelet counts. Methods Patients were identified from the on-going clinical trial ‘A randomised fase III study of the efficacy of rituximab in combination with dexamethasone vs dexamethasone in newly diagnosed patients with ITP’. All patients had given their written informed consent. The diagnosis of ITP was defined as isolated thrombocytopenia, normal bone marrow biopsy, no splenomegaly assessed by ultrasound, normal TSH-levels and exclusion of secondary immune-, viral- or drug-induced thrombocytopenia. Patients who were enrolled in the study but subsequently diagnosed with other underlying disorders and excluded from the protocol are described in the following. Results 116 patients had been enrolled in the clinical study at the time of these analyses. 9 patients were subsequently diagnosed with other disorders and excluded from the study. The median time from inclusion in the ITP-protocol to diagnosis of the underlying disorder was 11 days (range 3 – 486 days). 4 patients were diagnosed with other haematological disorders (debut symptoms, see figure 1). 4 patients with CMV presented median platelet count of 6 ×109/L (range 4–12 ×109/L), petechiae (4 patients) and mucosal bleeding (3 patients). 1 patient had flu-like symptoms and elevated leucocyte count. CMV was diagnosed by positive IgM titer after a median of 17,5 days (range 7 –29). 1 patient was diagnosed with antiphospholipid syndrome 17 days after inclusion. Conclusion The diagnosis of ITP is one of exclusion, and it is essential that patients presenting with isolated thrombocytopenia be thoroughly tested for underlying disorders. The present study has shown that a bone marrow biopsy may be a prerequisite and the only diagnostic tool to distinguish ITP from MDS or other low-grade malignancies. A bone marrow biopsy is recommended in all elderly patients in whom indolent haematological malignancies initially may mimick ITP. Disclosures: Gudbrandsdottir: GlaxoSmithKline: Research Funding; Amgen: Research Funding. Frederiksen:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2352-2352
Author(s):  
Tomas Jose Gonzalez-Lopez ◽  
Fernando Fernandez-Fuertes ◽  
Maria Cristina Pascual Izquierdo ◽  
Isabel Caparros ◽  
Silvia Bernat ◽  
...  
Keyword(s):  
Platelet Count ◽  
Median Time ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Previous Treatment ◽  
Complete Response ◽  
Platelet Response ◽  
Platelet Counts

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

scholarly journals Regulation of thrombopoiesis: effects of the degree of thrombocytopenia on megakaryocyte ploidy and platelet volume

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 177-185 ◽  
Author(s):  
L Corash ◽  
HY Chen ◽  
J Levin ◽  
G Baker ◽  
H Lu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Immune Thrombocytopenia ◽  
Temporal Relationship ◽  
Recovery Phase ◽  
Severe Thrombocytopenia ◽  
Detectable Change ◽  
Platelet Volume ◽  
Murine Bone Marrow ◽  
Ploidy Class

Abstract We have established a murine model and techniques with which to serially study thrombocytopoiesis after induction of experimental immune thrombocytopenia of variable severity and duration. Bone marrow megakaryocyte ploidy distribution was determined by using unfractionated bone marrow, a polyclonal megakaryocyte-specific probe, and two-color, fluorescence-activated flow cytometry. With these techniques, the modal megakaryocyte ploidy class in normal murine bone marrow was 16N. Serial studies of bone marrow megakaryocyte ploidy after the induction of acute, severe thrombocytopenia (platelet count, less than 0.05 X 10(6) microL) demonstrated no detectable change in the ploidy distribution at 12, 24, and 36 hours after the onset of thrombocytopenia. At 48 hours, the modal ploidy class shifted from 16N to 32N, and the 64N class increased significantly (P less than .001). The ploidy distribution returned to normal 120 hours after the onset of thrombocytopenia. A lesser degree of thrombocytopenia (platelet count reduction to 0.100 to 0.200 X 10(6)/microL) delayed the modal ploidy class shift from 16N to 32N until 72 hours after the onset of thrombocytopenia. Chronic, severe thrombocytopenia (platelet count, less than 0.05 X 10(6)/microL for seven days) resulted in a modal ploidy class shift from 16N to 32N during the thrombocytopenic phase and an enhanced increase in the 64N megakaryocyte class during the recovery phase. Mean platelet volume (MPV) was simultaneously measured on isolated total platelet populations after induction of thrombocytopenia. MPV was significantly increased (P less than .001) as early as eight hours after the onset of acute, severe thrombocytopenia, 40 hours before a shift in the ploidy distribution. Mild thrombocytopenia (platelet count reduction to 0.400 X 10(6)/microL) was not associated with a ploidy shift but did result in a significantly increased MPV (P less than .001). These studies demonstrate that the temporal relationship and magnitude of the effects of thrombocytopenia upon megakaryocyte ploidy distribution are dependent upon the degree and the duration of the thrombocytopenic stimulus and that the effects of experimental thrombocytopenia on platelet volume and megakaryocyte ploidy are dissociated.

Use of a New Rotary Powered Device for Bone Marrow Aspiration and Biopsy Yields Excellent Specimens Quickly and Efficiently.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4544-4544
Author(s):  
Ronan T. Swords ◽  
Kevin R. Kelly ◽  
Devalingam Mahalingam ◽  
Stephen C. Cohen ◽  
Larry J. Miller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Clinical Evaluation ◽  
Research Funding ◽  
Bone Marrow Aspiration ◽  
Swine Model ◽  
Employment Equity ◽  
Equity Ownership ◽  
Specimen Quality ◽  
The Mean

Abstract Abstract 4544 Background The importance of bone marrow aspiration and biopsy in the evaluation of hematopoietic and non-hematopoietic disorders is well established. Recently, a new FDA-cleared battery powered bone marrow biopsy system was developed to allow operators access to the bone marrow space quickly and efficiently. Aims The first aim of this study was to evaluate the quality of core specimens using the new powered device compared to specimens obtained using the traditional manual technique in a swine model. The second aim was to evaluate the safety and efficacy of the device in patients presenting for outpatient hematology clinic visits. Materials and Methods For the pre-clinical evaluation of the device, three anesthetized pigs were used for the study. The powered device (OnControl, Vidacare Corporation, San Antonio, TX, USA) was comprised of a battery powered driver and needle set. The manual device used was a T-Handle Jamshidi bone marrow biopsy needle (Cardinal Health, Dublin, OH, USA). Core biopsy samples obtained were assessed for length and sample quality and then submitted for analysis to a pathologist blinded to the device used. The clinical evaluation of the device was conducted in accordance with practice guidelines and directions for use. Data collection included insertion success, time from insertion to removal, specimen quality, operator satisfaction with control/function of the device and overall operator satisfaction based on a scoring system (0-5; 0=totally unacceptable, 5=outstanding). Results Twenty six samples were collected from the swine model (19 samples using the powered device and 9 using the manual technique). No cellular artifact or thermal damage was reported in any of the samples obtained. The mean lengths for samples obtained using the powered and manual techniques were respectively 19.4mm±1.6mm and 18.6mm±5.3mm. For the clinical evaluation of the device, 16 patients were recruited from 2 centers. Mean insertion time was 11.25±3.39 seconds and mean time from needle contact with skin to needle removal was 38.5±13.94 seconds. No complications were reported. Five operators rated the overall use of the device as outstanding in 75% of cases. Conclusions In this study, the manual and powered samples were equivalent in specimen quality. The powered device however, captured longer biopsies when compared to the manual technique. In the patients evaluated, the device was easy to use as well as being safe and effective. The mean procedural time was significantly faster than previously reported with a manual technique. A randomized study of the powered device compared to the manual technique is underway. Disclosures: Swords: Vidacare Corporation: Research Funding. Kelly:Vidacare Corporation: Research Funding. Mahalingam:Vidacare Corporation: Research Funding. Cohen:Vidacare Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Miller:Vidacare Corporation: Employment, Equity Ownership. Philbeck:Vidacare Corporation: Employment, Equity Ownership. Brenner:Vidacare Corporation: Consultancy, Research Funding. Giles:Vidacare Corporation: Research Funding.

A New Rotary Powered Device for Bone Marrow Aspiration and Biopsy Yields Superior Specimens with Less Pain: Results of a Randomized Clinical Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1529-1529 ◽  
Author(s):  
Ronan Swords ◽  
Javier Anguita ◽  
Russell A. Higgins ◽  
Andrea Yunes ◽  
Michael Naski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Research Funding ◽  
Bone Marrow Aspiration ◽  
Morbidity And Mortality ◽  
Procedure Time ◽  
Medullary Bone ◽  
Biopsy Device ◽  
The Mean

Abstract Abstract 1529 Introduction: The importance of bone marrow aspiration and biopsy in the evaluation of hematopoietic and non-hematopoietic disorders is well established. However, this technique is associated with morbidity and mortality risks.1 Recently, a battery-powered bone marrow biopsy system was developed to allow operators to safely, quickly and efficiently access the marrow space. We previously evaluated this device in swine models and in patients needing routine hematology outpatient evaluation.2 In the current study we compared the powered device to the traditional manual technique by relatively assessing pain scores, procedure times, biopsy capture rates, quality of material retrieved, safety and operator satisfaction. Methods: Two large academic medical centers participated in this trial (San Antonio, TX and Madrid, Spain). The study protocol was approved by each center's institutional review board. Adult patients requiring bone marrow biopsies were considered for the study. Following informed consent, patients were randomized to have procedures using a manual biopsy device (T-handle Jamshidi bone marrow biopsy and aspiration set, Cardinal Health, Dublin, OH) or the Powered device (OnControl 11 gauge/102mm Bone Marrow Biopsy System, Vidacare Corporation, Shavano Park, TX). After infiltration of the skin and medullary bone with local anesthesia, a visual analog scale (VAS) pain score was recorded immediately following skin puncture and once again at the end of the procedure for each patient. Procedure time was measured from skin puncture to core specimen ejection from the needle. Pathologic assessment of 30 randomized samples was carried out. Operator satisfaction with devices was measured on a scale of 0–10, with 10 as the highest rating. Statistics were calculated using t-test and chi-square, with an alpha-level of 0.05. Results: Five operators from 2 sites enrolled 50 patients (Powered, n=25; Manual, n=25). Of those patients, 58% were male and 42% were female; and had a mean age of 56.0±18.0 years. The mean height was 167.5 ± 10.5cm and the mean weight was 78.7 ± 22.7kg. Forty percent were lymphoma patients—the largest diagnostic group. Between patient groups, there were no significant differences in the means for these variables. See Table below for quantitative results, including pathology analysis. For the pathology qualitative analysis, there was no difference between groups for hemorrhage, clot/particle spicules, or smear spicules. Conclusions: Results of this trial suggest that the use of a Powered bone marrow biopsy device significantly reduces needle insertion pain. While not reflected in the results, overall pain may be better tolerated due to the important difference in procedure time. Moreover, the superior size and overall quality of core specimens retrieved by the Powered device provides more material for pathologic evaluation, thereby increasing diagnostic yield and reducing the need for repeat procedures. Cohesiveness of the medullary bone sampled was comparable for both techniques; however, the Powered system was less likely to recover non-hematopoietic tissue (e.g. cortical bone and soft tissue). Artifact was slightly more common with the Powered device (aspiration, hemorrhage and crush) but this did not impact on the diagnostic quality of the sample. No differences in safety data were noted for either technique and operator satisfaction favored the Powered device. 1. Bain BJ. Bone marrow biopsy morbidity and mortality. British Journal of Haematology 2003;121:949-51. 2. Swords RT, Kelly KR, Cohen SC et al. Rotary powered device for bone marrow aspiration and biopsy yields excellent specimens quickly and efficiently. J Clin Pathol 2010;63:562-5. Disclosures: Swords: Vidacare Corporation: Research Funding. Anguita:Vidacare Corporation: Research Funding. Kelly:Vidacare Corporation: Research Funding. Philbeck:Vidacare Corporation: Employment. Miller:Vidacare Corporation: Employment, Equity Ownership. Brenner:Vidacare Corporation: Research Funding.

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