Diagnosis of immune thrombocytopenia, including secondary forms, and selection of second-line treatment

This article summarizes our approach to the diagnosis of immune thrombocytopenia (ITP), its secondary forms, and choice of second-line treatment options. We very briefly summarize first-line treatment and then utilize a case-based approach. We first explore persistent, chronic ITP in a younger female. We consider many possibilities beyond primary ITP e.g., hypogammaglobulinemia, chronic infection, and anemia, and how to approach their diagnosis and management. The journey continues throughout pregnancy and the post-partum period and eventually includes fourth-line treatment after a late relapse. We then consider an older male, emphasizing differences in diagnostic considerations and management. The focus is on initiation and continuation of second-line treatment, the pros and cons of each option, and briefly the impact of treatment choices related to the endemic presence of severe acute respiratory syndrome coronavirus 2. During the review of potential second-line treatment options, we also briefly touch upon novel treatments. Finally, there is a short section on refractory disease drawn from our previous extensive review published in February 2020.1 The clinical nature of the discussions, replete with figures and tables and with the interspersion of pearls regarding efficacy and toxicity at different ages and genders, will serve the reader in the management of “typical” adult patients who develop persistent and chronic ITP

A disease-specific measure of health-related quality of life for use in adults with immune thrombocytopenic purpura: Its development and validation

BACKGROUND: No validated disease-specific measures are available to assess health-related quality of life (HRQoL) in adult subjects with immune thrombocytopenic purpura (ITP). Therefore, we sought to develop and validate the ITP-Patient Assessment Questionnaire (ITP-PAQ) for adult subjects with ITP. METHODS: Information from literature reviews, focus groups with subjects, and clinicians were used to develop 50 ITP-PAQ items. Factor analyses were conducted to develop the scale structure and reduce the number of items. The final 44-item ITP-PAQ, which includes ten scales [Symptoms (S), Bother-Physical Health (B), Fatigue/Sleep (FT), Activity (A), Fear (FR), Psychological Health (PH), Work (W), Social Activity (SA), Women's Reproductive Health (RH), and Overall (QoL)], was self-administered to adult ITP subjects at baseline and 7–10 days later. Test-retest reliability, internal consistency reliability, construct and known groups validity of the final ITP-PAQ were evaluated. RESULTS: Seventy-three subjects with ITP completed the questionnaire twice. Test-retest reliability, as measured by the intra-class correlation, ranged from 0.52–0.90. Internal consistency reliability was demonstrated with Cronbach's alpha for all scales above the acceptable level of 0.70 (range: 0.71–0.92), except for RH (0.66). Construct validity, assessed by correlating ITP-PAQ scales with established measures (Short Form-36 v.1, SF-36 and Center for Epidemiologic Studies Depression Scale, CES-D), was demonstrated through moderate correlations between the ITP-PAQ SA and SF-36 Social Function scales (r = 0.67), and between ITP-PAQ PH and SF-36 Mental Health Scales (r = 0.63). Moderate to strong inter-scale correlations were reported between ITP-PAQ scales and the CES-D, except for the RH scale. Known groups validity was evaluated by comparing mean scores for groups that differed clinically. Statistically significant differences (p < 0.01) were observed when subjects were categorized by treatment status [S, FT, B, A, PH, and QoL, perceived effectiveness of ITP treatment [S], and time elapsed since ITP diagnosis [PH]. CONCLUSION: Results provide preliminary evidence of the reliability and validity of the ITP-PAQ in adult subjects with ITP. Further work should be conducted to assess the responsiveness and to estimate the minimal clinical important difference of the ITP-PAQ to more fully understand the impact of ITP and its treatments on HRQoL

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

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CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance

Hyper-IgM (HIGM) syndromes are primary immunodeficiencies characterized by defects of class switch recombination and somatic hypermutation. HIGM patients who carry mutations in the CD40-ligand (CD40L) gene expressed by CD4+ T cells suffer from recurrent infections and often develop autoimmune disorders. To investigate the impact of CD40L–CD40 interactions on human B cell tolerance, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from three CD40L-deficient patients. Antibody characteristics and reactivity from CD40L-deficient new emigrant B cells were similar to those from healthy donors, suggesting that CD40L–CD40 interactions do not regulate central B cell tolerance. In contrast, mature naive B cells from CD40L-deficient patients expressed a high proportion of autoreactive antibodies, including antinuclear antibodies. Thus, CD40L–CD40 interactions are essential for peripheral B cell tolerance. In addition, a patient with the bare lymphocyte syndrome who could not express MHC class II molecules failed to counterselect autoreactive mature naive B cells, suggesting that peripheral B cell tolerance also depends on major histocompatibility complex (MHC) class II–T cell receptor (TCR) interactions. The decreased frequency of MHC class II–restricted CD4+ regulatory T cells in CD40L-deficient patients suggests that these T cells may mediate peripheral B cell tolerance through CD40L–CD40 and MHC class II–TCR interactions

Impact of chronic Immune Thrombocytopenic Purpura (ITP) on health-related quality of life: a conceptual model starting with the patient perspective

<p>Abstract</p> <p>Background</p> <p>Immune thrombocytopenic purpura (ITP), a condition characterized by autoimmune-mediated platelet destruction and suboptimal platelet production, is associated with symptoms such as bruising, epistaxis, menorrhagia, mucosal bleeding from the gastrointestinal and urinary tracts and, rarely central nervous system bleeding. The aim of this research is to develop a conceptual model to describe the impact of ITP and its treatment on patients' health-related quality of life (HRQoL).</p> <p>Methods</p> <p>A literature search and focus groups with adult ITP patients were conducted to identify areas of HRQoL affected by ITP. Published literature was reviewed to identify key HRQoL issues and existing questionnaires used to assess HRQoL. Focus group transcripts were reviewed, and common themes were extracted by grouping conceptual categories that described the impact on HRQoL.</p> <p>Results</p> <p>The literature synthesis and themes from the focus group data suggest that decreased platelet counts, disease symptoms, and treatment side effects influence multiple domains of HRQoL for ITP patients. Key areas affected by ITP and its treatments include emotional and functional health, work life, social and leisure activities, and reproductive health.</p> <p>Conclusion</p> <p>ITP affects various areas of HRQoL. This conceptual model will help inform the evaluation of therapeutic strategies for ITP.</p

Physician decision making in selection of second-line treatments in immune thrombocytopenia in children.

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians

The role of CD8+ T cell clones in immune thrombocytopenia

Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multi-dimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterised patients with ITP and compared them to age-matched controls using immunophenotyping, next-generation sequencing of T cell receptor (TCR) genes, single-cell RNA sequencing, and functional T cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L-) expressing intracellular interferon-g, tumour necrosis factor-a, and Granzyme B defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the T cell receptor showed expanded T cell clones in patients with ITP. T cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon-g and trigger platelet activation and apoptosis through TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP

IDENTIFICATION OF OCCULT CEREBRAL MICROBLEEDS IN ADULTS WITH IMMUNE THROMBOCYTOPENIA

Management of symptoms and prevention of life-threatening hemorrhage in immune thrombocytopenia (ITP) must be balanced against adverse effects of therapies. Because current treatment guidelines based on platelet count are confounded by variable bleeding phenotypes, there is a need to identify new objective markers of disease severity for treatment stratification. In this cross-sectional prospective study of 49 patients with ITP and nadir platelet counts <30 × 109/L and 18 aged-matched healthy controls, we used susceptibility-weighted magnetic resonance imaging to detect cerebral microbleeds (CMBs) as a marker of occult hemorrhage. CMBs were detected using a semiautomated method and correlated with clinical metadata using multivariate regression analysis. No CMBs were detected in health controls. In contrast, lobar CMBs were identified in 43% (21 of 49) of patients with ITP; prevalence increased with decreasing nadir platelet count (0/4, ≥15 × 109/L; 2/9, 10-14 × 109/L; 4/11, 5-9 × 109/L; 15/25 <5 × 109/L) and was associated with longer disease duration (P = 7 × 10−6), lower nadir platelet count (P = .005), lower platelet count at time of neuroimaging (P = .029), and higher organ bleeding scores (P = .028). Mucosal and skin bleeding scores, number of previous treatments, age, and sex were not associated with CMBs. Occult cerebral microhemorrhage is common in patients with moderate to severe ITP. Strong associations with ITP duration may reflect CMB accrual over time or more refractory disease. Further longitudinal studies in children and adults will allow greater understanding of the natural history and clinical and prognostic significance of CMBs