Identifying Drugs Implicated in Drug-Induced Immune Thrombocytopenia Using Levels of Evidence Applied to Laboratory Tests,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3304-3304
Author(s):  
Donald M. Arnold ◽  
Theodore E. Warkentin ◽  
James W. Smith ◽  
Aliya Esmail ◽  
Sadiya Kukaswadia ◽  
...  
Keyword(s):  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Methodological Approach ◽  
Test Methods ◽  
Third Party ◽  
Validity And Reliability ◽  
Drug Induced ◽  
Level Of Evidence ◽  
Clinical Criteria ◽  
Igg Binding

Abstract Abstract 3304 Introduction: Many drugs can cause platelet counts to decrease. However, only relatively few cause severe drug-induced immune thrombocytopenia (DITP), a hemorrhagic syndrome characterized by drug-dependent, platelet-reactive antibodies. Laboratory testing for DITP is important to confirm the diagnosis, however test methods have evolved over the years and results are often difficult to interpret. We applied hierarchical grading methodology to published reports of DITP test methods to evaluate their validity and reliability. Using this grading system, we identified drugs that were implicated in DITP reactions with the highest level of evidence. Methods: All drugs implicated in DITP reactions based on clinical criteria were compiled from a previous systematic review (Swisher KK, Drug Safety 2009). Primary publications and additional reports associated with each drug were retrieved by searching MEDLINE and EMBASE to identify those drugs for which in vitro DITP testing had been performed. In duplicate and independently, the validity of DITP test methods was assessed based on whether or not they demonstrated: 1) drug or drug metabolite-dependence; 2) platelet specificity; and 3) IgG-binding. Reliability of test methods was assessed based on whether or not DITP test results were confirmed by more than one laboratory. Discrepancies were adjudicated by a third party. Assessors were experienced in DITP test methods. Results: We identified 149 drugs that were associated with DITP reactions by clinical criteria alone. Of those, 92 were excluded because testing was either not performed or was negative, or primary reports were irretrievable. Publications associated with the remaining 57 drugs were reviewed in duplicate. Of those, 27 were excluded because testing did not confirm drug-dependence (N= 15), platelet specificity (N=1) or IgG binding (N=11); 19 were included; and 11 were sent for adjudication. In the end, 22 drugs (abciximab, acetaminophen, cephamandole, diazepam, diphenylhydantoin, eptifibatide, gold, ibuprofen, mirtazapine, naproxen, oxaliplatin, penicillin, quinidine, quinine, rifampin, rosiglitazole, roxifiban, sulfisoxazole, tirofiban, tranilast, trimethoprim/sulfamethoxazole and vancomycin) met all validity criteria. Only 6 (gold, quinine, quinidine, tirofiban, rifampin and vancomycin) were confirmed positive by more than one laboratory. Conclusion: Based on assessments of validity and reproducibility of laboratory test methods, we identified 6 drugs – gold, quinine, quinidine, tirofiban, rifampin and vancomycin – that have been implicated in DITP reactions with a high level of evidence. This type of methodological approach can improve the likelihood of DITP diagnosis with a given drug. Disclosures: Warkentin: Sanofi-Aventis: Speakers Bureau; Pfizer Canada: Speakers Bureau; GlaxoSmithKline: Consultancy, Research Funding; GTI Diagnostics: Consultancy, Research Funding; Canyon Pharma: Consultancy, Speakers Bureau; Informa: Patents & Royalties.

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.

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 Diagnosis of Anosmia and Hyposmia: A Systematic Review

2021 ◽  
Vol 12 ◽  
pp. 215265672110265
Author(s):  
Abdul K. Saltagi ◽  
Mohamad Z. Saltagi ◽  
Amit K. Nag ◽  
Arthur W. Wu ◽  
Thomas S. Higgins ◽  
...  
Keyword(s):  
English Language ◽  
Viral Infections ◽  
Original Data ◽  
Olfactory Dysfunction ◽  
Imaging Modalities ◽  
Diagnostic Tools ◽  
Validity And Reliability ◽  
Medical Subject Headings ◽  
Level Of Evidence ◽  
Smell Tests

Background Anosmia and hyposmia have many etiologies, including trauma, chronic sinusitis, neoplasms, and respiratory viral infections such as rhinovirus and SARS-CoV-2. We aimed to systematically review the literature on the diagnostic evaluation of anosmia/hyposmia. Methods PubMed, EMBASE, and Cochrane databases were searched for articles published since January 1990 using terms combined with Medical Subject Headings (MeSH). We included articles evaluating diagnostic modalities for anosmia, written in the English language, used original data, and had two or more patients. Results A total of 2065 unique titles were returned upon the initial search. Of these, 226 abstracts were examined, yielding 27 full-text articles meeting inclusion criteria (Level of evidence ranging from 1 to 4; most level 2). The studies included a total of 13,577 patients. The most utilized diagnostic tools were orthonasal smell tests (such as the Sniffin’ Sticks and the UPSIT, along with validated abridged smell tests). Though various imaging modalities (including MRI and CT) were frequently mentioned in the workup of olfactory dysfunction, routine imaging was not used to primarily diagnose smell loss. Conclusion The literature includes several studies on validity and reliability for various smell tests in diagnosing anosmia. Along with a thorough history and physical, validated orthonasal smell tests should be part of the workup of the patient with suspected olfactory dysfunction. The most widely studied modality was MRI, but criteria for the timing and sequence of imaging modalities was heterogenous.

scholarly journals Case Report: Oxaliplatin-Induced Immune-Mediated Thrombocytopenia

2018 ◽  
Vol 11 (3) ◽  
pp. 880-882 ◽  
Author(s):  
Elizabeth Pan ◽  
Eric Hsieh ◽  
Caroline Piatek
Keyword(s):  
Case Report ◽  
Cancer Therapy ◽  
Cancer Patients ◽  
Immune Thrombocytopenia ◽  
Drug Induced ◽  
Gastrointestinal Malignancies ◽  
Common Cause ◽  
Immune Mediated ◽  
Chemotherapy Agents ◽  
Platinum Derivative

Thrombocytopenia is a frequent complication of cancer may be due to a variety of causes including malignancy itself, acute disease processes, or cancer therapy. Systemic cancer therapy is the most common cause of thrombocytopenia in cancer patients observed nearly two-thirds of patients with solid tumors. Thrombocytopenia with traditional chemotherapy agents is most frequently the result of megakaryocyte cytotoxicity. Oxaliplatin is a platinum derivative commonly used in gastrointestinal malignancies and is associated with drug-induced immune thrombocytopenia.

scholarly journals Approach to the Diagnosis and Management of Drug-Induced Immune Thrombocytopenia

2013 ◽  
Vol 27 (3) ◽  
pp. 137-145 ◽  
Author(s):  
Donald M. Arnold ◽  
Ishac Nazi ◽  
Theodore E. Warkentin ◽  
James W. Smith ◽  
Lisa J. Toltl ◽  
...  
Keyword(s):  
Immune Thrombocytopenia ◽  
Drug Induced ◽  
Diagnosis And Management

scholarly journals Drug-induced thrombocytopenia: pathogenesis, evaluation, and management

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 153-158 ◽  
Author(s):  
James N. George ◽  
Richard H. Aster
Keyword(s):  
Single Dose ◽  
Causal Relation ◽  
Severe Thrombocytopenia ◽  
Antithrombotic Agents ◽  
Drug Induced ◽  
Level Of Evidence ◽  
Common Cause ◽  
Fibrinogen Binding ◽  
Immune Mediated ◽  
Drug Dependent

AbstractAlthough drugs are a common cause of acute immune-mediated thrombocytopenia in adults, the drug etiology is often initially unrecognized. Most cases of drug-induced thrombocytopenia (DITP) are caused by drug-dependent antibodies that are specific for the drug structure and bind tightly to platelets by their Fab regions but only in the presence of the drug. A comprehensive database of 1301 published reports describing 317 drugs, available at www.ouhsc.edu/platelets, provides information on the level of evidence for a causal relation to thrombocytopenia. Typically, DITP occurs 1 to 2 weeks after beginning a new drug or suddenly after a single dose when a drug has previously been taken intermittently. However, severe thrombocytopenia can occur immediately after the first administration of antithrombotic agents that block fibrinogen binding to platelet GP IIb-IIIa, such as abciximab, tirofiban, and eptifibatide. Recovery from DITP usually begins within 1 to 2 days of stopping the drug and is typically complete within a week. Drug-dependent antibodies can persist for many years; therefore, it is important that the drug etiology be confirmed and the drug be avoided thereafter.

scholarly journals Career Satisfaction Based on Trust and Proactive Personality

2020 ◽  
Vol 9 (1) ◽  
pp. 35-45
Author(s):  
Iwan Sunardi ◽  
Vini Wiratno Putri
Keyword(s):  
Career Satisfaction ◽  
Analytical Data ◽  
Sampling Technique ◽  
Test Methods ◽  
Validity And Reliability ◽  
Career Needs ◽  
Relationship Of ◽  
The Relationship ◽  
The City

The purpose of this study was to examine the effect of the trust of co-workers and proactive personalities on career satisfaction by exchanging leader-members as mediation on employees of bus assembly companies in the city of Semarang. Career satisfaction is the phase in which employees’ long-term career needs are aligned with what they get while working. Employees will always look for opportunities and trust in the organization and people who will help them in achieving career satisfaction. The sampling method uses a purposive sampling technique in the category of staff and foreman employees who have worked for more than five years with a sample of 160 employees. The analytical data in this study uses descriptive statistical test methods, instinctual tests include validity and reliability, and hypothesis testing. The tool used to test in this study uses SmartPLS 3.0. The results of this study, colleague trust cannot directly influence career satisfaction. However, it can be mediated by the exchange of leader members and produce significant influence. For further researchers, they can re-examine the relationship of coworkers’ trust with career satisfaction. And can expand the object of research or respondents under study.

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.

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