Pathophysiology, Clinical Manifestations and Diagnosis of Immune Thrombocytopenia: Contextualization from a Historical Perspective.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated decrease in the platelet count and an increased risk of bleeding. The pathogenesis is complex, affecting multiple components of the immune system and causing both peripheral destruction of platelets and impaired central megakaryopoiesis and platelet production in the bone marrow. Here, we intend to contextualize the current knowledge on the pathophysiology, terminology, epidemiology, clinical manifestations, diagnosis, and prognosis of ITP from a historical perspective and the first references to the never-stopping garnering of knowledge about this entity. We highlight the necessity to better understand ITP in order to be able to provide ITP patients with personalized treatment options, improving disease prognosis and reducing the incidence or frequency of refractoriness.

Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109 /L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109 /L. Treatment-free response (TFR; platelet count ≥30 × 109 /L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109 /L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Case report: XMEN disease: a patient with recurrent Hodgkin lymphoma and immune thrombocytopenia.

Here we present the case of a 28-year-old man with X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) disease. He presented with immune thrombocytopenia within 1 year after successful autologous hematopoietic stem cell transplantation for recurrent EBV-associated classical Hodgkin lymphoma (CHL). The combination of EBV- associated malignancy, autoimmunity, recurrent airway infections at young age and bronchiectasis, prompted immunological investigation for an inborn error of immunity (IEI). Genetic testing revealed XMEN disease. XMEN disease is characterized by a glycosylation defect due to mutations in the MAGT1 gene. Germline mutations in the MAGT1 gene disrupt glycosylation of the NKG2D receptor in immune cells, including natural killer and CD8-positive T cells, vital for immune surveillance, especially against EBV. Consequently, individuals with XMEN disease, are prone to EBV-associated lymphoproliferative disorders in addition to auto-immunity. Early recognition of adult onset IEI-related B-lymphoproliferative disorders, including CHL is of vital importance for treatment decisions, including (allogeneic) haematopoietic stem cell transplantation and family screening.

Immune thrombocytopenic purpura after influenza vaccine administration; a systematic review and meta-analysis.

BACKGROUND: The American Society of Haematology defines immune thrombocytopenic purpura (ITP) as a common hematologic disorder characterized by a transient or long-term decrease in platelet counts (< 100 × 109/L.), purpura, and haemorrhagic episodes caused by antiplatelet autoantibodies, with the exclusion of other clinical conditions. We aimed to systematically determine the incidence of ITP in adults and children following influenza vaccination, the duration between vaccination and the occurrence of ITP, and to identify predictors of ITP after the vaccine. METHODS: We searched PubMed, Cochrane Library, Google Scholar, Web of Science, Scopus, and Science Direct. We included primary studies that assessed the occurrence of immune thrombocytopenia in individuals who had received any influenza vaccine (primary or booster dose), regardless of the dosage, preparation, time of administration, or age of the participants. We excluded studies that were (a) Narrative, scoping, and umbrella reviews ;(b) studies with no accessible full text, abstract-only studies, or (c) Overlapping or unreliable data. The risk of bias in the included studies was assessed using the Joanna Briggs Institute (JBI) tool. We categorized studies for qualitative analysis based on study design. Descriptive statistics were used to summarize quantitative data, including the incidence of ITP after influenza vaccination. RESULTS: Out of 729 articles retrieved from the database search, we included 24 studies. All patients identified and included in this systematic review presented with immune thrombocytopenia, determined by their platelet count. The period between vaccination and the occurrence of ITP ranged from (2:35 days). The mean duration was 13.5 days. The analysis revealed a statistically significant incidence rate ratio (IRR) = 1.85,95% CI [1.03-3.32] of ITP occurrence after 42 days. CONCLUSIONS: Influenza-associated ITP is uncommon, self-limiting, non-life-threatening, and curable. None of the patients reported having severe adverse events or death. Further studies are required to confirm the exact incidence of the ITP to better understand the pathophysiology of ITP development post-influenza vaccination.

Infant case of severe immune thrombocytopenia caused by COVID-19 infection.

Immune thrombocytopenia (ITP) is a common childhood acute autoimmune bleeding disorder caused by numerous viruses and characterized by isolated thrombocytopenia. Although cases of ITP caused by coronavirus disease 2019 (COVID-19) infection have been reported in adults, pediatric reports are limited. We present the case of a 1-year-old girl who developed COVID-19-infection-related ITP with a very low platelet count (0.0 × 104/µL). We searched for COVID-19-related pediatric ITP cases and found 10 other cases, with the majority having platelet counts of <1.0 × 104/µL. Although pediatric ITP cases caused by COVID-19 infection may be severe, further studies are needed.

Acute Immune Thrombocytopenia Following Influenza Vaccination in a Patient With Untreated Helicobacter pylori Infection.

A 70-year-old man with previously normal comprehensive blood counts (CBCs) was referred to our hospital for acute thrombocytopenia. Following a negative workup for secondary causes, we diagnosed immune thrombocytopenia (ITP). Aside from the influenza vaccine administered six days before presentation, there was no discernable precipitant on history. His only risk factor for ITP was untreated Helicobacter â€‹â€‹â€‹â€‹â€‹â€‹pylori diagnosed over two months prior. With treatment, the patient's platelets normalized within three days. ITP following influenza vaccination has been documented in the literature and reported to regulatory bodies. Our case indicates that individuals with untreated H. pylori infection might be particularly vulnerable to such occurrences.

Comparative Analysis of De Novo Immune Thrombocytopenia Following mRNA COVID-19 Vaccine Versus Non-mRNA Vaccines and COVID-19: A Global Database Analysis.

Introduction Autoimmune diseases have been linked to COVID-19 vaccines. An increasing number of cases have reported de novo immune thrombocytopenia (ITP) following mRNA COVID-19 vaccines. This study aims to investigate the incidence of de novo ITP following the mRNA COVID-19 vaccine in comparison to other non-mRNA vaccines and COVID-19. Methods Data were collected from the TriNetX global health research network, which covers over 117 million patients. Four different patient cohorts were included: those who received the mRNA COVID-19 vaccine (between 12/15/2020 - 5/1/2023), the influenza vaccine (between 01/01/2010 - 01/01/2020), tetanus, diphtheria, and pertussis/tetanus and diphtheria (Tdap/Td) vaccines (between 01/01/2010 - 01/01/2020), and those who had COVID-19 (between 01/01/2020 - 05/01/2023). A comparative analysis was conducted to examine the occurrence of de novo ITP within three weeks after receiving mRNA COVID-19 vaccine, non-mRNA vaccines, or upon diagnosis of COVID-19. Additionally, a comparative analysis was performed after 1:1 propensity score matching to balance baseline characteristics (age, sex, and race). Results The overall event rate was 0.07 per 10,000 for the mRNA COVID-19 vaccine, 0.25 per 10,000 for the influenza vaccine, and 0.28 per 10,000 for the Tdap/Td vaccines. Additionally, the incidence of de novo ITP following COVID-19 was 0.30 per 10,000. Those who received the influenza vaccine and Tdap/Td vaccines had higher rates of de novo ITP compared to the mRNA COVID-19 vaccine group, with a relative risk of 3.48 and 3.88, respectively. The occurrence of de novo ITP following COVID-19 was significantly higher compared to that following the mRNA COVID-19 vaccine, with a relative risk of 4.27. Post-propensity score matching analysis produced similar outcomes. Conclusions The findings of this study suggest that the incidence of de novo ITP is significantly lower following mRNA-based COVID-19 vaccines compared to non-mRNA vaccines and COVID-19.

Treatment of immune thrombocytopenia with hetrombopag olamine tablets in a Kabuki syndrome patient with new KMT2D mutations.

Kabuki syndrome (KS) is a rare multisystem-affecting genetic disorder, and usually accompanied with autoimmune disorders such as immune thrombocytopenic purpura (ITP). Here, we report a 16-year-old patient with Kabuki syndrome with ITP and observe the therapeutic effect of TPO agonist hetrombopag olamine tablets. The duration of maintenance therapy and follow up were both 17 months. Whole exon sequencing (WES) of the patient's peripheral blood showed c.5775_5778del (p. Leu1926LysfsTer120) heterozygous mutation in the KMT2D gene, which was not reported before.

Mitochondrial ROS-dependent CD4+PD-1+T cells are pathological expansion in patients with primary immune thrombocytopenia.

OBJECTIVE: Aberrant-activated T cells, especially CD4+T cells, play a crucial part in the pathogenetic progress of immune thrombocytopenia (ITP). PD-1-mediated signals play a negative part in the activation of CD4+T cells. However, knowledge is limited on the pathogenic characteristics and function of CD4+PD-1+T cells in ITP. MATERIALS AND METHODS: The frequency and phenotype including cell activation, apoptosis, and cytokine production of CD4+PD-1+T cells were evaluated by flow cytometry. PD-1 Ligation Assay was performed to assess the function of PD-1 pathway in CD4+T cells. Mitochondrial reactive oxygen species (mtROS) were detected by MitoSOX Red probe. RESULTS: Compared with healthy controls (HC), the frequencies of CD4+PD-1+T cells were significantly increased in ITP patients. However, these cells are not exhausted despite PD-1 expression. Besides retaining cytokine-producing potential, these CD4+PD-1+T cells also had a possible B-cell helper function including expressing ICOS, CD84, and CD40L. Moreover, the CD4+PD-1+T cell subset contained higher levels of mitochondrial ROS than CD4+PD-1-T cell subset in patients with ITP. And mtROS inhibition could reduce the secretion of the inflammatory cytokines and regulate the function of CD4+PD-1+T cells. Upon in-vitro T cell receptor (TCR) stimulation of CD4+T cells in the presence of plate-bound PD-L1 fusion protein (PD-L1-Ig), CD4+T cells from ITP patients appeared resistant to such PD-1-mediated inhibition of interferon (IFN)-γ secretion. CONCLUSIONS: The CD4+PD-1+T cells were more abundant in patients with ITP. Additionally, this CD4+PD-1+T cell subset may be a potential etiology of ITP and a potential immune therapeutic target for ITP patients in the future.

Primary and secondary immune thrombocytopenia (ITP): Time for a rethink.

There are not many publications that provide a holistic view of the management of primary and secondary ITP as a whole, reflecting the similarities and differences between the two. Given the lack of major clinical trials, we believe that comprehensive reviews are much needed to guide the diagnosis and treatment of ITP today. Therefore, our review addresses the contemporary diagnosis and treatment of ITP in adult patients. With respect to primary ITP we especially focus on establishing the management of ITP based on the different and successive lines of treatment. Life-threatening situations, "bridge therapy" to surgery or invasive procedures and refractory ITP are also comprehensively reviewed here. Secondary ITP is studied according to its pathogenesis by establishing three major differential groups: Immune Thrombocytopenia due to Central Defects, Immune Thrombocytopenia due to Blocked Differentiation and Immune Thrombocytopenia due to Defective Peripheral Immune Response. Here we provide an up-to-date snapshot of the current diagnosis and treatment of ITP, including a special interest in addressing rare causes of this disease in our daily clinical practice. The target population of this review is adult patients only and the target audience is medical professionals.

Mixed Warm and Cold Autoimmune Hemolytic Anemia With Concomitant Immune Thrombocytopenia Following Recent SARS-CoV-2 Infection and Ongoing Rhinovirus Infection.

Mixed-type autoimmune hemolytic anemia (AIHA) is a term used to describe hemolysis occurring in the context of both warm and cold reactive autoantibodies to red blood cells. Immune thrombocytopenia (ITP) is an acquired form of thrombocytopenia potentially complicated by hemorrhage due to autoantibodies reactive with platelets and megakaryocytes. Diagnosis of ITP requires exclusion of other known causes of thrombocytopenia. AIHA and ITP may be primary disorders or associated with lymphoproliferative, autoimmune, or viral infections. Here, we report a rare case of simultaneous mixed-type autoimmune hemolytic anemia with immune thrombocytopenia following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection treated with Paxlovid followed by Rhinovirus infection.

Successful Systemic Lysis Therapy of a Floating Carotid Thrombus in an Acute Stroke Patient with Known Immune Thrombocytopenia (ITP) on Ongoing Eltrombopag Therapy and Acute COVID-19 Infection: a Case Report.

Patients with immune thrombocytopenia (ITP) under eltrombopag therapy are vulnerable to thrombotic disbalance, both due to the disease itself and therapy-related hypercoagulability. Vascular events such as the development of a free-floating carotid thrombus are known rare complications of acute COVID-19 infections due to endothelial inflammation and presumptive underlying hypercoagulable state. In patients at risk, the onset of new focal neurological symptoms should prompt immediate angiographic diagnostics and, if necessary, appropriate treatment. Here, we report a case of a 38-year-old female with a medical history of ITP and the presence of COVID-19 infection presenting an acute sensorimotor hemiparesis of the right side while on eltrombopag therapy. Initial CT angiography revealed a free-floating thrombus in the left common carotid artery. Upon admission, the patient's platelet count was significantly elevated at 896 × 109/l. After systemic lysis therapy, the thrombus was fully dissolved. Follow-up diffusion-weighted imaging revealed multilocular cortical infarction of the left MCA territory. The patient soon recovered and was discharged with residual mild sensorimotor deficits in the right arm. Eltrombopag was paused at admission, and the patient's platelet count was quickly returning to normal. She was discharged with a daily intake of acetylsalicylic acid, a reduced daily dose of eltrombopag, and weekly monitoring of her platelet count for the next three months. This unique case highlights the need for caution in patients at vascular risk who contract COVID-19 and discusses thrombocytic derailment under thrombopoietin receptor agonist therapy in the context of an acute COVID-19 infection.

Gut microbiota were altered with platelet count and red blood cell count in immune thrombocytopenia patients with different treatments.

The gut microbiome is clearly linked to the development of various autoimmune diseases, however, its association with immune thrombocytopenia (ITP) is less well understood. The current study collected 73 samples, including 36 from healthy individuals and 37 from ITP patients. The gut microbial community was assessed using 16s rRNA sequencing. Findings illustrated that the abundance of key microbiota was significantly higher in the ITP group. This group was further divided into three subgroups that received different treatments for ITP. A random forest model was used to predict the key microbiota and the identified bacteria were shown to easily distinguish between the healthy and the ITP treatment groups. Microbial function annotation and difference analysis showed that drug treatment changed the gut microbiota and may play a role in inducing host autoimmune responses by changing microbial metabolism pathways. Clinical indices also correlated negatively with changes in the microbiota after treatment. In summary, ITP patients who received drug treatment had significant differences in their microbiota along with a high abundance of bacteria. Thus, the microbiome could be used as a biomarker to distinguish between healthy and ITB groups. The key differential bacteria could help to regulate the number of platelets in ITP patients and provide a red blood cell overstock.

Maintenence rituximab following induction in autoimmune cytopenias.

About 50% of immune thrombocytopenia (ITP) patients respond to rituximab induction, but most relapse. The effectiveness of rituximab maintenance remains untested. This study included autoimmune cytopenia patients who had previously responded to rituximab induction but subsequently relapsed. After re-induction, patients received rituximab maintenance regimen consisting of a single 375 mg/m2 dose administered at 4 month intervals, with a maximum of 6 doses. Primary endpoints were duration of response and safety. Sixteen patients: ITP (9), autoimmune haemolytic anaemia (2), and Evans syndrome (5) received rituximab maintenance. 15/16 achieved complete response (CR); 8/15 CR + 1 partial reponse remain in remission. Median response: 43 months; estimated 5-year relapse-free >50%. Three developed hypogammaglobulinemia. Rituximab maintenance led to prolonged remissions in patients with autoimmune cytopenias who had previously responded to rituximab induction.

Use of tranexamic acid in dogs with primary immune thrombocytopenia: A feasibility study.

Objective: The aim of this feasibility study is to evaluate the use of tranexamic acid and its safe use alongside standard therapy in dogs with primary immune thrombocytopenia (ITP). Design: This is a cohort feasibility study involving 10 dogs diagnosed with primary ITP that received standard therapy for ITP including corticosteroids, a single dose of vincristine, and omeprazole. Dogs were randomly divided into either the control group (n = 6) or the group receiving tranexamic acid (TXA group, n = 4). Key findings: The mean time from the start of treatment until remission was 5 days in the TXA group and 6 days in the control group (P = 0.69). Two dogs, one in each group, did not achieve remission. Clinical bleeding scores were not significantly different between both groups (p = 0.43), and the median blood volume administered was 37.5 ml/kg for the TXA group and 9.72 ml/kg for the control group (p = 0.084). Three out of the four dogs receiving TXA of 20 mg/kg IV started vomiting within 15 min of administration and were given a reduced dose of 15 or 10 mg/kg IV. Conclusion: Tranexamic acid did not confer a clinical benefit in this small cohort study and was associated with a high incidence of vomiting. This study provides useful information for the design of future trials in dogs with ITP receiving tranexamic acid including outcome measures and safety.

Severe maternal thrombocytopenia and prenatal invasive procedures: still a grey zone.

Management of severe thrombocytopenia, particularly of ITP, in pregnancy is mainly based on expert consensus and clinical experience while there are no clear indications about the minimum platelet count requested for prenatal diagnosis invasive procedures. Since the lack of specific recommendations we reported our clinical management of a patient suffering from severe thrombocytopenia, undergoing amniocentesis. Due to the anecdotic possibility of maternal and fetal bleeding in case of severe thrombocytopenia, prophylaxis with IVIG or even corticosteroids could be considered as a safer strategy to prevent post-procedural adverse outcomes.

Severe Thrombocytopenia in a 30-Year-Old African American Male With Newly Diagnosed Sarcoidosis: A Case Report.

Sarcoidosis is a multisystem inflammatory disorder characterized by the formation of non-caseating granulomas. Hematological manifestations such as thrombocytopenia are unusual presentations of the disease. Various theories have been proposed for the development of thrombocytopenia in patients with sarcoidosis such as decreased production in bone marrow caused by granuloma formation, hypersplenism, and immune thrombocytopenia (ITP). We present a case of a 30-year-old African American male with ITP secondary to sarcoidosis who presented with a sudden onset of buccal mucosa and mucocutaneous bleeding and was found to have severe thrombocytopenia with values reaching as low as 1000/uL without prior history of easy bruising or bleeding. Overall, our patient had dyspnea, mucocutaneous bleeding, and was found to have mediastinal and hilar adenopathy, isolated thrombocytopenia, no splenomegaly, and non-necrotizing granulomas in the lymph nodes. The patient received platelet transfusions without initial response and received intravenous immunoglobulin (IVIG), romiplostim, and steroids with subsequent improvement in the platelet count after sufficient administration of a treatment regimen of approximately one week. Confounding factors that resulted in diagnostic uncertainty of our patient presentation included travel history with prophylactic antimalarial medications, doxycycline usage, only slightly elevated Angiotensin-Converting Enzyme (ACE) levels, and imaging features concerning metastatic disease vs. lymphoma. The clinical diversity of sarcoidosis often leads to diagnostic uncertainty and treatment delays due to its resemblance to other more common disorders. This is a novel case report of the earliest temporal presentation of severe thrombocytopenia and sarcoidosis in an African American male reported in the literature.

Humoral response to mRNA-based COVID-19 vaccine in patients with immune thrombocytopenia.

Data for COVID-19 vaccine response in patients with immune thrombocytopenia (ITP) are very limited. In a study of 28 patients with ITP, anti-severe acute respiratory syndrome coronavirus 2 spike antibody titres were measured after vaccination. The seroconversion rate for ITP patients was 91.3%, comparable to that in healthy controls (HCs). However, the antibody titre in ITP patients was significantly lower than that in HCs and declined with ageing. Furthermore, the antibody titre in ITP patients who received a minimum prednisolone dose of at least 5 mg/day at any time-point at or after initial vaccination was lower than that in other patients.

Effects of COVID-19 vaccination on platelet counts and bleeding in children, adolescents, and young adults with immune thrombocytopenia.

Coronavirus disease 2019 (COVID-19) vaccines rarely cause de novo immune thrombocytopenia (ITP) but may worsen preexisting ITP in adults. Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines impact platelet counts and bleeding in children, adolescents, and young adults (C-AYA) with preexisting ITP is unknown. We report here the very limited effect of COVID-19 vaccination on platelet counts and bleeding in a single-center series of 2 C-AYA with ITP. No patient experienced worsening bleeding and only one child had a significant decrease in platelet count which improved spontaneously to her baseline without intervention. SARS-CoV2 vaccination was safe in C-AYA with ITP in this small cohort.

Combination of two target agonists of the thrombopoietin and thrombopoietin receptor in the treatment of elderly patients with refractory immune thrombocytopenia.

Immune thrombocytopenia (ITP) is common in the elderly. Because of the coexistence of multiple diseases, there are many reservations regarding corticosteroid use in the elderly. Thrombopoietin (TPO) and its analogs can promote platelet production, but it is often difficult to correct TP in a short period. Recombinant human TPO (rh-TPO) acting on the cell membrane and the small-molecule TPO-receptor (MPL) agonist acting on the transmembrane receptor may have synergistic effects and accelerate platelet production because of different sites of action in the signaling pathway. In this study, two elderly patients with refractory ITP were successfully treated with two TPO-MPL signaling pathway agonists: recombinant human thrombopoietin (rh-TPO) and eltrombopag. This combination is safe with rapid and lasting effects. However, in elderly patients with refractory, recurrent, and glucocorticoid contraindications, the combination of different TPO agonists' clinical efficacy and adverse reactions needs to be further evaluated.