Pathogenic Mechanisms of Vaccine-Induced Immune Thrombotic Thrombocytopenia in People Receiving Anti-COVID-19 Adenoviral-Based Vaccines: A Proposal.

VITT is a rare, life-threatening syndrome characterized by thrombotic symptoms in combination with thrombocytopenia, which may occur in individuals receiving the first administration of adenoviral non replicating vectors (AVV) anti Covid19 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterized by high levels of serum IgG that bind PF4/polyanion complexes, thus triggering platelet activation. Therefore, identification of the fine pathophysiological mechanism by which vaccine components trigger platelet activation is mandatory. Herein, we propose a multistep mechanism involving both the AVV and the neo-synthetized Spike protein. The former can: i) spread rapidly into blood stream, ii), promote the early production of high levels of IL-6, iii) interact with erythrocytes, platelets, mast cells and endothelia, iv) favor the presence of extracellular DNA at the site of injection, v) activate platelets and mast cells to release PF4 and heparin. Moreover, AVV infection of mast cells may trigger aberrant inflammatory and immune responses in people affected by the mast cell activation syndrome (MCAS). The pre-existence of natural antibodies binding PF4/heparin complexes may amplify platelet activation and thrombotic events. Finally, neosynthesized Covid 19 Spike protein interacting with its ACE2 receptor on endothelia, platelets and leucocyte may trigger further thrombotic events unleashing the WITT syndrome.

Survival after acute episodes of immune-mediated thrombotic thrombocytopenic purpura (iTTP) - cognitive functioning and health-related quality of life impact: a descriptive cross-sectional survey of adults living with iTTP in the United Kingdom.

OBJECTIVES: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare life-threatening thrombotic microangiopathy affecting adults with unpredictable disease onset and acute presentation. This study aimed to describe the health-related quality of life (HRQoL), cognitive functioning and work productivity of survivors following acute episode(s) of iTTP in the United Kingdom (UK). METHODS: An online survey was developed in collaboration with the TTP Network. Descriptive statistics were calculated for the health questionnaire Short Form Survey-36 Version 2 (SF-36v2), the Hospital Anxiety and Depression Score (HADS), the PROMIS Cognitive Function Abilities Subset - Short Form 6a (PROMIS CFAS - SF6a), and the Work Productivity and Activity Index: Specific Health Problem (WPAI-SHP), along with several iTTP-specific bespoke questions. RESULTS: Fifty participants were recruited between July-November 2019. The mean (standard deviation [SD]) standardized SF-36v2 physical and mental component scores were 42.16 (9.59) and 33.61 (12.34), lower than population norms. The mean (SD) standardized PROMIS CFAS - SF6a score was 39.69 (7.86), lower than population norms. HADS mean (SD) scores of 12.18 (3.14) and 11.78 (2.36) indicated moderate levels of anxiety and depression, respectively. Of those employed (58%), approximately 42.73% of participants reported work productivity loss due to their iTTP. Participants also reported experiencing flashbacks, fatigue interference in family, social and intimate life, and fears of relapse. DISCUSSION AND CONCLUSION: Regardless of recency of the last acute episode, participant scores signified impairments in all domains. Remission from an acute episode of disease does not signify the conclusion of care, but rather the requirement for long-term healthcare particularly focused on psychological support.

Qualitative study to support the content validity of the immune thrombocytopenia (ITP) Life Quality Index (ILQI).

Immune thrombocytopenia (ITP) is an acquired immune-mediated disorder. Bleeding is the primary symptom that presents in varying severities. ITP has a negative impact on health-related quality of life (HRQoL). The ITP Life Quality Index (ILQI) was developed as a 10-item patient-reported outcome measure to assess impact on HRQoL in ITP. The objective of the present study was to confirm the content validity of the ILQI with a qualitative interview study in the UK involving 15 adult participants with ITP. Combined concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted to explore the symptoms and impacts associated with ITP and confirm content validity of the draft ILQI. The CE phase elicited 14 ITP symptom concepts, including: bruising (all 15 patients, 100%), fatigue (14, 93·3%) and bleeding gums/blood blisters (13, 86·7%). Impacts included decreased ability to participate in sport (all 15 patients, 100%) and anxiety (12, 80%). The CD phase resulted in an adjustment to the ILQI recall period from 1 week to 'the past month'. Updates were made to improve relevance and response options. The qualitative interviews support the content validity of the ILQI and confirm that the concepts assessed are relevant and consistently understood and interpreted by adult patients with ITP.

The Role of Leptin in Childhood Immune Thrombocytopenia (ITP): An Anti-Inflammatory Agent?

To investigate the effect of leptin in childhood ITP, we measured plasma leptin in 39 children with acute ITP, after treatment and in remission, and in 33 healthy age/BMI-matched controls. We also cultured ITP and control peripheral blood mononuclear cells (PBMCs) with recombinant leptin to assess its direct effect on pro/anti-inflammatory cytokine gene expression. A significant increase in leptin was observed in children with active disease compared to controls. A significant inverse correlation of leptin with platelet count was also observed in children with acute ITP. Leptin remained high after treatment with IVIg, whereas steroid treatment lowered leptin below control levels. In remission, leptin was in the control range. Cytokine gene expression was significantly increased in children with acute ITP compared with controls, with highest expression for IFN-γ and IL-10. IVIg/steroid treatment significantly decreased IFN-γ and IL-10 expression. In remission, IFN-γ and IL-10 expression remained low. Addition of leptin to PBMCs isolated from patients in remission resulted in a significant increase in IL-10 gene expression compared to controls. Further experiments with purified T-cells and monocytes identified monocytes as the source of leptin-induced IL-10. We suggest that leptin acts as an active anti-inflammatory agent in childhood ITP by promoting IL-10 secretion by monocytes.

Fostamatinib: A Review in Chronic Immune Thrombocytopenia.

Fostamatinib (Tavalisse®; Tavlesse®) is the first spleen tyrosine kinase (Syk) inhibitor approved for the treatment of chronic immune thrombocytopenia (ITP) in adult patients who have had an insufficient response to previous treatment. By inhibiting Syk activation in macrophages, fostamatinib blocks autoantibody-mediated platelet phagocytosis. In the placebo-controlled phase III FIT1 and FIT2 trials, 24 weeks of oral fostamatinib therapy increased platelet count in previously treated adults with ITP. A significantly higher proportion of patients achieved stable response with fostamatinib than with placebo in FIT1, but not in FIT2; however, pooled analyses of the two studies showed that fostamatinib produced significantly higher stable and overall response rates than placebo. Interim findings from the ongoing FIT3 open-label extension study suggested that the efficacy of fostamatinib was maintained with long-term treatment (up to 62 months; median duration 6 months), including in patients receiving fostamatinib as second- or later-line treatment. Fostamatinib had a generally manageable tolerability profile in all three FIT studies, with no serious safety risks. Fostamatinib therefore provides an alternative treatment option for chronic ITP in adult patients with an insufficient response to previous treatment.

Update on diagnosis and treatment of immune thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is a heterogeneous acquired disorder characterized by isolated thrombocytopenia whose exact pathogenesis is not yet clear. Depending upon the presence or absence of an underlying treatable cause, ITP can be categorized as primary or secondary. Primary ITP is a diagnosis of exclusion and there is no gold standard test for its confirmation. Recent drug intake, infections, lymphoproliferative disorders, and connective tissue disorders should be ruled out before labeling a patient as primary ITP. AREA COVERED: This review summarizes a comprehensive update on the diagnostic and therapeutic modalities for ITP. We reviewed the literature using GOOGLE SCHOLAR, PUBMED and ClinicalTrial.gov databases as needed to support the evidence. We searched the literature using the following keywords: 'immune thrombocytopenia,' 'idiopathic thrombocytopenic purpura,' 'thrombocytopenia,' 'immune thrombocytopenic purpura,' and 'isolated thrombocytopenia'. EXPERT OPINION: We believe that more detailed studies are required to understand the exact pathophysiology behind ITP. The first-line drugs like corticosteroids have both short-term and long-term adverse effects. This brings the need to explore effective alternative medications and to reconsider their role in ITP treatment algorithm if guidelines can be modified based on new studies.

Immune thrombocytopenia (ITP) World Impact Survey (I-WISh): Impact of ITP on health-related quality of life.

Immune thrombocytopenia (ITP) has a substantial, multifaceted impact on patients' health-related quality of life (HRQoL). Data describing which aspects of ITP physicians and patients perceive as having the greatest impact are limited. The ITP World Impact Survey (I-WISh) was a cross-sectional survey, including 1507 patients and 472 physicians, to establish the impact of ITP on HRQoL and productivity from patient and physician perspectives. Patients reported that ITP reduced their energy levels (85% of patients), capacity to exercise (77%), and limited their ability to perform daily tasks (75%). Eighty percent of physicians reported that ITP symptoms reduced patient HRQoL, with 66% reporting ITP-related fatigue substantially reduced patient HRQoL. Patients believed ITP had a substantial impact on emotional well-being (49%) and 63% worried their condition would worsen. Because of ITP, 49% of patients had already reduced, or seriously considered reducing their working hours, and 29% had considered terminating their employment. Thirty-six percent of patients employed at the time of the survey felt ITP decreased their work productivity, while 51% of patients with high/very high symptom burden reported that ITP affected their productivity. Note, I-WISh demonstrated substantive impact of ITP on patients' HRQoL both directly for patients and from the viewpoint of their physicians. Patients reported reduced energy levels, expressed fears their condition might worsen, and those who worked experienced reduced productivity. Physicians should be aware not only of platelet counts and bleeding but also the multi-dimensional impact of ITP on patients' lives as an integral component of disease management.

Update οn the diagnosis and management of systemic lupus erythematosus.

Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is-by and large-a systemic disease, occasionally it can be organ-dominant, posing diagnostic challenges. To date, diagnosis of SLE remains clinical with a few cases being negative for serologic tests. Diagnostic criteria are not available and classification criteria are often used for diagnosis, yet with significant caveats. Newer sets of criteria (European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019) enable earlier and more accurate classification of SLE. Several disease endotypes have been recognised over the years. There is increased recognition of milder cases at presentation, but almost half of them progress overtime to more severe disease. Approximately 70% of patients follow a relapsing-remitting course, the remaining divided equally between a prolonged remission and a persistently active disease. Treatment goals include long-term patient survival, prevention of flares and organ damage, and optimisation of health-related quality of life. For organ-threatening or life-threatening SLE, treatment usually includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses. Management of disease-related and treatment-related comorbidities, especially infections and atherosclerosis, is of paramount importance. New disease-modifying conventional and biologic agents-used alone, in combination or sequentially-have improved rates of achieving both short-term and long-term treatment goals, including minimisation of glucocorticoid use.

An update on the pathophysiology of immune thrombocytopenia.

: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder mediated by antiplatelet autoantibodies and antigen-specific T cells that either destroy platelets peripherally in the spleen or impair platelet production in the bone marrow. There have been a plethora of publications relating to the pathophysiology of ITP and since January of 2019, at least 50 papers have been published on ITP pathophysiology. PURPOSE OF REVIEW: To summarize the literature relating to the pathophysiology of ITP including the working mechanisms of therapies, T-cell and B-cell physiology, protein/RNA/DNA biochemistry, and animal models in an attempt to unify the perceived abnormal immune processes. RECENT FINDINGS: The most recent pathophysiologic irregularities associated with ITP relate to abnormal T-cell responses, particularly, defective T regulatory cell activity and how therapeutics can restore these responses. The robust literature on T cells in ITP points to the notion that ITP is a disease initiated by faulty self-tolerance mechanisms very much like that of other organ-specific autoimmune diseases. There is also a large literature on new and existing animal models of ITP and these will be discussed. It appears that understanding how to specifically modulate T cells in patients with ITP will undoubtedly lead to effective antigen-specific therapeutics. CONCLUSIONS: ITP is predominately a T cell disorder which leads to a breakdown in self tolerance mechanisms and allows for the generation of anti-platelet autoantibodies and T cells. Novel therapeutics that target T cells may be the most effective way to perhaps cure this disorder.

Systematic Identification of lncRNA-Associated ceRNA Networks in Immune Thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an autoimmune disease. However, the molecular mechanisms underlying ITP remained to be further investigated. In the present study, we analyzed a series of public datasets (including GSE43177 and GSE43178) and identified 468 upregulated mRNAs, 272 downregulated mRNAs, 134 upregulated lncRNAs, 23 downregulated lncRNAs, 29 upregulated miRNAs, and 39 downregulated miRNAs in ITP patients. Then, we constructed protein-protein interaction networks, miRNA-mRNA and lncRNA coexpression networks in ITP. Bioinformatics analysis showed these genes regulated multiple biological processes in ITP, such as mRNA nonsense-mediated decay, translation, cell-cell adhesion, proteasome-mediated ubiquitin, and mRNA splicing. We thought the present study could broaden our insights into the mechanism underlying the progression of ITP and provide a potential biomarker for the prognosis of ITP.

Pathogenesis of immune thrombocytopenia in common variable immunodeficiency.

Immune Thrombocitopenic Purpura (ITP) is an autoimmune disease characterized by antibody-mediated platelet destruction and variable reduced platelet production. Besides antibody-mediated platelet destruction, new pathogenic mechanisms have been reported to be involved in reducing platelet count. Among these, desialylation is one of the most recent and innovative mechanisms that has been found to be implied, at least in part, in non-antibody mediated platelet clearance. Common Variable Immunodeficiency (CVID) is the most common Primary Immunodeficiency seen in clinical practice. About 25-30% of CVID patients are affected by autoimmune manifestation, among which ITP is the most common. Little is know about pathophysiological mechanisms that lead to ITP in CVID. Given the poor antibody production typical of CVID patients, we aimed at verifying whether platelet desialylation could be responsible for CVID associated thrombocytopenia. According to our results, we may suggest that in CVID patients, ITP is due to a decreased bone marrow platelets production, rather than an increased peripheral platelet destruction, which is more common in patients with primary ITP. An increased platelet desialylation does not appear to be implicated in the thrombocytopenia secondary to CVID, while it is implicated in the pathogenesis of primary ITP. Nevertheless an intriguing aspect has emerged from this study: regardless the presence of thrombocytopenia, the majority of CVID patients present a double platelet population as far as desialylation concerns, whilst no one of the healthy donors and of the patients with primary ITP shows a similar characteristic.

Downregulation of microRNA-155-5p prevents immune thrombocytopenia by promoting macrophage M2 polarization via the SOCS1-dependent PD1/PDL1 pathway.

AIMS: We set about to investigate the potential role of microRNA-155-5p (miR-155-5p) in the development of immune thrombocytopenia (ITP), an idiopathic deficiency of blood platelets. MAIN METHODS: Initially, RT-qPCR and Western blot analyses were carried out to determine the expression of miR-155-5p and SOCS1 in peripheral blood mononuclear cells (PBMCs) and macrophages from ITP patients. We undertook gain- and loss- function methods by transfection of macrophages and PBMCs with treated plasmids. The expression patterns of platelet-related factors were measured by ELISA, and the expressions of PD1, PDL1, and macrophage M2 marker CD206 and CD86 were also measured. The relationship between miR-155-5p and SOCS1 was determined using the dual-luciferase reporter gene assay. We also established an ITP mouse model to explore the roles of miR-155-5p and SOCS1 in vivo. KEY FINDINGS: miR-155-5p was up-regulated, while SOCS1 was down-regulated in PBMCs and macrophages from ITP patients. SOCS1 was indicated as a target of miR-155-5p. Inhibition of miR-155-5p or up-regulation of SOCS1 facilitated macrophage M2 polarization as demonstrated by an increased M2/M1 ratio and suppressed expression of platelet-related factors. Furthermore, silencing of SOCS1 promoted ITP progression through blocking the PD1/PDL1 pathway, whilst upregulation of miR-155-5p remarkably increased the platelet abundance and suppressed SOCS1 expression in ITP model mice. SIGNIFICANCE: Silencing of miR-155-5p could promote PD1/PDL1 pathway-mediated macrophage M2 polarization and prevent ITP via up-regulation of SOCS1, thus relieving ITP.

Acute immune thrombocytopaenic purpura in a patient with COVID-19 and decompensated cirrhosis.

We report on a patient with coronavirus disease 2019 (COVID-19) and decompensated cirrhosis who experienced a favourable outcome of severe immune thrombocytopaenic purpura (ITP) after administration of intravenous immunoglobulin and high-dose dexamethasone. The present case suggests that it is reasonable to evoke ITP in case of profound thrombocytopaenia in a patient with COVID-19.

Fatigue in children and adolescents with immune thrombocytopenia.

Immune thrombocytopenia (ITP), an acquired autoimmune disorder of low platelets and risk of bleeding, has a substantial impact on health-related quality of life (HRQoL). Patients with ITP often report significant fatigue, although the pathophysiology of this is poorly understood. In this observational cohort of 120 children receiving second-line therapies for ITP, we assessed reports of fatigue using the Hockenberry Fatigue Scale. Children and adolescents with ITP reported a similarly high level of fatigue with 54% (29/54) of children and 62% (26/42) of adolescents reporting moderate-to-severe fatigue. There was no correlation between fatigue and age or gender. Adolescents with newly diagnosed and persistent ITP had higher mean fatigue scores than those with chronic ITP (P = 0·03). Fatigue significantly improved in children and adolescents by 1 month after starting second-line treatments, and this improvement continued to be present at 12 months after starting treatment. Fatigue scores at all time-points correlated with general HRQoL using the Kids ITP Tool, but did not correlate with bleeding symptoms, platelet count, or platelet response to treatment. Fatigue is common in children and adolescents with ITP and may benefit from ITP-directed treatment even in the absence of bleeding symptoms.

Sequence of Splenectomy and Rituximab for the Treatment of Steroid-Refractory Immune Thrombocytopenia: Does It Matter?

OBJECTIVE: To evaluate the impact of the sequence of treatment with rituximab and/or splenectomy on time to relapse for patients with steroid-refractory immune thrombocytopenia (ITP). PATIENTS AND METHODS: Patients 18 years or older with steroid-refractory immune thrombocytopenia who underwent treatment with splenectomy or rituximab from January 1, 2002, through December 31, 2015, at Mayo Clinic. Evaluation included freedom from relapse (FFR) and response rates after treatment with rituximab or splenectomy as single or sequential interventions. RESULTS: A total of 218 eligible patients with ITP who were treated according to standard of care were included in this analysis. Patients failing steroids treated with splenectomy had a higher 5-year FFR than did those treated with rituximab (67.4% vs 19.2%; P<.001, propensity-score matched). Patients who failed splenectomy and were then treated with rituximab had a 2-year FFR similar to that of patients who failed rituximab and were then treated with splenectomy (73.4% vs 59.9%; P=.52). Patients treated with rituximab after splenectomy had a longer 2-year FFR than did patients treated with rituximab as a second-line treatment (73.4% vs 29.0%; P<.001). CONCLUSION: For patients with ITP that relapse after treatment with steroids, splenectomy provides longer FFR than rituximab as a second-line therapy. Among patients who fail second-line treatment with splenectomy or rituximab, those who end up receiving sequential splenectomy-rituximab or rituximab-splenectomy therapy seem to derive similar benefit in the long term. Patients who received rituximab after splenectomy seem to derive superior benefit than do those who are treated with rituximab with an intact spleen.

[Guideline for diagnosis and treatment of immune thrombocytopenia]. / Trombocitopenia inmune. Guía de diagnóstico y tratamiento.

Management, outcome, diagnosis, prognosis and treatment of immune thrombocytopenia are controversial. Several guidelines stating different experts' opinions have been published; however, no worldwide consensus regarding the management of the disease has still been reached. This guideline defines diagnostic criteria, states initial laboratory tests, establishes differential diagnosis, develops topics concerning outcome and prognosis, and enumerates available treatments for acute and chronic disease, as well as for management of life-threatening bleeding.

El manejo de la trombocitopenia inmune es motivo de discusión en lo concerniente a evolución, diagnóstico, pronóstico y tratamiento. Se han publicado varias guías que expresan distintas opiniones de expertos, pero no existe aún consenso mundial sobre cuál es el manejo más adecuado de la enfermedad. Esta guía establece los criterios para definir el diagnóstico; detalla el plan de estudios de laboratorio por realizar inicialmente; plantea los distintos diagnósticos diferenciales; desarrolla aspectos relativos a evolución y pronóstico, y enumera los tratamientos disponibles para las formas agudas y las crónicas, así como para el manejo de las emergencias y en algunas situaciones especiales.

Platelet to Lymphocyte Ratio and Glucocorticoid Resistance in Newly Diagnosed Primary Immune Thrombocytopenia: A Retrospective Cohort Study.

BACKGROUND In China, evidence regarding to the association between platelet to lymphocyte ratio (PLR) and glucocorticoid (GC) resistance in participants with primary newly identified immune thrombocytopenia (ITP) is limited. We aimed to investigate whether PLR is independently linked with GC-resistant ITP. MATERIAL AND METHODS We non-selectively and consecutively collected 154 newly diagnosed ITPs. The start enrollment time and the end enrollment time were from March 2013 to June 2017. The independent and dependent variables were PLR measured at diagnosis and GC non-response. Other variables involved in the present work can be summarized as demographic data and factors that were correlated with PLR reported by published studies. Univariate and multivariate binary logistic regression model and sensitivity analysis were used to evaluate the associations between PLR and GC resistance. RESULTS After adjusting covariates, PLR level was negatively associated with GC non-response [odds ratio (OR)=0.89, 95% confidence intervals (CI): 0.80 to 0.98], and supported by propensity score matching model (OR=0.74, 95%CI: 0.57 to 0.96]. Nonlinearity of PLR and GC resistance was observed whose inflection point was 5.08 (by 2-piecewise model). The OR and 95%CI on both sides of inflection point were 3.14 (0.81 to 12.21) and 0.81 (0.69 to 0.95), respectively. Subgroup analysis showed no significant differences from subgroups. CONCLUSIONS Threshold effect on PLR and GC resistance is observed. When PLR is larger than 5.08, a unit increase of PLR is independently associated with 19% reduction of GC resistance.