Comparative analysis of primary immune thrombocytopenia and immune thrombocytopenia secondary to connective tissue diseases

To investigate the significance of detecting serum complement C3 and C4 in patients with multiple myeloma (MM) and to explore its correlation with myeloma bone disease (MBD). The levels of serum complement C3 and C4 in 69 MM patients and 30 healthy people were examined by scatter nephelometry. The bone density of L1-4 vertebral body, bilateral femoral neck and bilateral hip joints were measured by dual energy bone density meter (DXA). The levels of serum complement C3 and C4 in MM patients significantly increased in comparison with that in healthy people (P＜0.01). The patients in advanced clinical stage exhibited a higher levels of C3 and C4 than those in stable stage (P＜0.01). In addition, the patients with grade C of MBD had a higher levels of serum complement C3 and C4 than those in patients with grade A and B of MBD (P＜0.01). The levels of serum complement C3 and C4 in MM patients negatively correlated with bone density in L1-4 vertebral body, bilateral femoral necks and hip joints. The correlation coefficients were r=-0.938, r=-0.659, r=-0.745, r=-0.748, r=-0.596 in complement C3 and r=-0.908, r=-0.623, r=-0.710, r=-0.714, r=-0.595 in complement C4, respectively. The levels of complement C3 and C4 positively correlate with the severity of bone disease and bone density in MM patients, which suggests that complement C3 and C4 plays important roles in the development of MBD. The levels of serum C3 and C4 may be the sensitive biomarkers of MBD.

ObjectiveImmune thrombocytopenia (ITP) is well‐known as an antibody‐mediated autoimmune disease, and it is easy to get response but often turns to relapse or refractory. Cyclosporin is a traditional immunosuppressant and had a good effect on ITP patients. In this paper, we retrospectively analyze the immunological characteristics and therapeutic effect of cyclosporin in 220 patients with ITP.MethodsAll newly diagnosed ITP patients in the Department of Hematology, Tianjin Medical University General Hospital from June 2018 to December 2020 were enrolled and divided into four groups according to the expression of autoantibodies and the occurrence of prodromal infection. The basic data and immune indexes of ITP patients in each group were collected. The clinical immunological characteristics of patients in each group and the therapeutic effect of cyclosporin in each group were analyzed.ResultsMulti‐autoantibody ITP patients were more likely to have low serum albumin and high gamma globulin, and the ratio of albumin to globulin decreased. In addition, the level of IgA and IgG increased and the level of complement C3 and C4 decreased more frequently than those in other groups. The number of CD3+T lymphocytes, especially CD3+CD4+T lymphocytes, decreased in ANA+ITP patients. The number of CD16+CD56+NK cells, pDC/DC ratio, and pDC/mDC ratio were higher than those in other groups. The expression of IL‐6 and the proportion of CD19+B lymphocytes increased in two groups of ITP patients with abnormal autoantibodies. The patients of pro‐infected group were more likely to suffer from coagulation disorder. After treatment with cyclosporin, the response rate increased and the 3‐month relapse rate decreased in all ITP patients, and the therapeutic effect of patients with high megakaryocyte number was significantly higher than that of patients with low megakaryocyte number. The impact factors that influence the effect of glucocorticoid and(or) IVIG were the number of CD3+CD8+T lymphocytes, CD4/CD8 cell ratio, and the number of CD19+B lymphocytes. The independent impact factor of cyclosporin therapeutic response rate was the number of CD3+T lymphocytes.ConclusionsITP is a heterogeneous disease, recurrence may occur during or rapidly after treatment. Cyclosporine included treatment can improve the effective rate of ITP and reduce the relapse rate within 3 months. The number of CD3+T lymphocytes was the only impact factor that influence the therapeutic effect of cyclosporin in ITP patients.

Immune thrombocytopenia (ITP) is recognised as the most common autoimmune cytopenic disorder and has been defined as a process associated with accelerated platelet destruction and decreased platelet production. Demographically, ITP affects adults and children with a bimodal distribution, involving cohorts aged <18 and 75–84 years.1 The most consequential clinical manifestation of ITP is its increased risk of bleeding; however, sparse data exist to characterise this risk at the older extreme of the ageing spectrum. When diagnosed in adulthood, most patients will eventually develop chronic disease and require long-term treatment strategies. The prevalence of ITP in adults is estimated to be 12 per 100 000 adults in the United States and data from the French National Health Insurance System has cited a prevalence of chronic ITP up to nine per 100 000 person-years in men aged >75 years.2, 3 More recently, data from the Nordic Country Patient Registry for Romiplostim estimated the prevalence of chronic ITP as 10–10·7 per 100 000 adults in Denmark and Sweden;4 however, we believe these are likely underestimates. In their paper Sokal et al.5 present data from the Cytopénies Auto-immunes: Registre Midi-PyréneEN (CARMEN)-France registry that expand and our understanding of the real-world presentation, risk factors for bleeding, and management of primary ITP in elderly patients (EPs), defined as those aged 65–79 years, as compared with the very EPs (VEPs) aged ≥80 years. The results complement the findings from other large ITP registries that have focussed on EPs and VEPs6, 7 and confirm the expectation that VEPs have a greater number of comorbidities and experience more severe bleeding events and higher mortality compared to younger cohorts. Interestingly, findings were similar between VEP and EP groups as far as the need for and response to first-line treatment, receipt of second-line treatment modalities, development of persistent disease, and complications of ITP and its treatment, including any bleeding occurrence, infection, and thrombosis. First-line therapy in VEPs more frequently utilised a combination of corticosteroids and intravenous immunoglobulin (IVIg) as opposed to single-agent corticosteroids. Factors associated with bleeding in VEPs included female sex, platelet count of <20 × 109/l and exposure to anticoagulants. Despite the insights provided by the Sokal et al.5 study and other large ITP registries that have examined EPs and VEPs, significant gaps in our knowledge persist. We lack prospective randomised controlled treatment trials for these age cohorts and recognise that elderly adults were typically excluded from clinical registration trials, due to age-related entry criteria, medical comorbidities, and, most important, selection bias exercised by investigators. Thus, we are relegated to analyse and apply the results generated from robust observational, registry-based studies to track the natural history of ITP and treatment responses in various subcohorts. In the study by Sokal et al.,5 which purports to describe the prospective real-world experience of primary ITP in France between 2013 and 2018, 251 of the 541 patients enrolled in the CARMEN-France registry were EPs or VEPs. However, an additional selection occurred such that 67 patients were subsequently excluded from the study group. The size of this excluded group (26·6%) is significant when compared with 97 in the EP group and 87 in the VEP group. A further analysis of these patients might identify potential pitfalls in the diagnosis and management of primary versus secondary ITP in the elderly. Of particular interest is whether their exclusion was related to bone marrow pathology or cytogenetic/mutational abnormalities. If their ITP was deemed secondary rather than primary this would have implications for how we should approach the diagnosis and follow-up of EPs and VEPs. Guidelines for the evaluation of isolated thrombocytopenia and ruling out secondary causes of ITP are not standardised and, as a primary example, the routine performance of bone marrow aspiration and biopsy is controversial. In the Italian Hematology Centers Registry,6 bone marrow biopsy was performed in only half of the studied patients. Per the International Working Group guidelines, a bone marrow biopsy is not recommended when the thrombocytopenia is isolated and there are no abnormalities on physical examination or on the peripheral blood film.8 And yet, age is a risk factor for clonal cytopenias and neoplasms. Studies indicate that 12% of myelodysplastic syndrome (MDS) may present with isolated thrombocytopenia of <100 × 109/l,9 the most common cytogenetic profile being normal. Up to 80% of secondary MDS have abnormal karyotypes, while <50% of patients with de novo MDS will have an abnormal karyocyte.10 Thus, next-generation sequencing on bone marrow aspirates may become a useful tool in EPs and VEPs with suspected ITP. Published clinical trials have typically considered the diagnosis of primary ITP to represent a ‘single’ disease entity, characterised by a ‘common’ thrombocytopenic phenotype. On the other hand, it is increasingly apparent that ITP is actually a heterogeneous disorder with disparate underlying pathophysiology and immunological triggers, which change with normal ageing and become exaggerated with extreme ageing. We lack ITP clinical trials that examine baseline and post-treatment changes in immunological repertoires; however, given the increased number of medical co-morbidities and changes to the immune milieu with age, it would not be surprising if nearly all primary ITP in EPs and VEPs results from secondary immunological phenomena. As observed by Cines et al.,11 primary ITP will comprise an ever-decreasing proportion of patients as specific inciting events and immune defects are better identified. Currently, we lack specific assays to define immunological dysfunction and immunosenescence, validated predictive biomarkers, or knowledge of their prevalence in different patient subpopulations. Nor do we have a complete understanding of the coagulation profiles in EPs with ITP that give rise to bleeding or, more rarely, thrombosis. The propensity for haemorrhagic or thrombotic complications is further confounded by concurrent comorbidities and antiplatelet and systemic anticoagulation strategies prevalent in EP and VEP cohorts. This issue speaks directly to the safety of various treatment modalities and how treatment decisions will be made in the EP and VEP. The currently available clinical guidelines do not specifically address treatment of ITP in EPs or VEPs, suggesting that the recommendations can be extrapolated across all adult age cohorts.8, 12 The lack of high-quality, prospective efficacy and safety data specific to EPs remains a major challenge when making clinical treatment decisions and clinicians must balance risk of harm with the promise of response. For example, corticosteroids remain an important front-line ITP therapy. Sokal et al.5 report higher than expected response rates to corticosteroids ± IVIg in VEPs and EPs. Yet, corticosteroids can incite or exacerbate problems already associated with ageing, including hypertension, hyperglycaemia, mood disturbances and agitation, and gastrointestinal (GI) bleeding. VEPs were particularly vulnerable to GI bleeding in this study (five of nine of the most serious bleeding events). Another knowledge gap involves the safety and efficacy in VEPs and EPs of the thrombopoietin receptor agonists (TPO-RAs). As observed in the French registry, and consistent with evolving guidelines in the management of ITP, TPO-RAs were the preferred second-line agent. However, age >60 years was a risk factor for venous thromboembolism (VTE) and VTE-associated mortality. The TPO-RAs have been associated with excess arterial thromboses, which is an important consideration in VEPs and EPs with underlying atrial fibrillation and peripheral arterial disease. The Italian Registry for elderly ITP reported the incidence of thromboses during TPO-RA treatment to be 3·6 per 100 patient-years, with a significant incidence of progression or recurrence, even in patients with severe thrombocytopenia or receiving concurrent antiplatelet/anticoagulant therapy.13 Clinical registration drug trials with the various TPO-RAs have included very few EPs and even fewer if any VEPs. There are no comparative safety or efficacy trial data among the TPO-RAs for any age groups but there are provocative data suggesting that the TPO-RAs may influence immune modulation by increasing regulatory T-cell activity and by decreasing release of certain inflammatory cytokines.14 This may be pertinent in EPs and VEPs, in whom dysfunction of regulatory T cells and dysregulation of immune homeostasis are involved in the development of different autoimmune diseases in old age.15 As we move into the future of treating patients with ITP of all ages, the immunoheterogeneity of this disease entity will need to be considered, particularly in EPs and VEPs. Ideally, these different profiles could lead to immune stratification in adequately powered randomised controlled trials in EP- and VEP-related ITP and may provide predictive biomarkers for safety and efficacy of new therapies. The success of this approach will require international collaboration. In this spirit, the Sokal et al.5 paper can serve as a ‘call to action’ for the creation of a single longitudinal, international registry, employing standardised definitions of diagnosis and safety and efficacy, and this effort should be combined with a biorepository to study the immunoregulation of ITP in all age cohorts. This aspirational endeavour offers the potential to understand real-world primary ITP versus ‘masked’ secondary ITP in the elderly.

Real World Use of Thrombopoietin-Receptor Agonists in the Management of Immune Thrombocytopenia in the United Kingdom: Results from the TRAIT Study

Background: Immune thrombocytopenia (ITP) is characterized by non-chronic (transient, <12 months) and chronic (≥12 months) decline in the number of platelets. Herpes virus infections have been shown, in many studies, to be associated with the development of ITP. However, it remains unclear whether the herpes virus infection status is associated with the chronic ITP.Methods: We reviewed 480 primary pediatric patients with ITP in the period from January 2017 to December 2019. The prevalence of herpes virus antibodies including the Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV-1), Herpes simplex virus 2 (HSV-2), and Epstein Barr virus were recorded. The levels of serum complement C3 and C4, T (CD3+, CD4+, CD8+), B (CD19+) lymphocytes, and natural killer (CD16+ 56+) cells were also analyzed. Multivariate analysis was used to evaluate the associations between chronic ITP and herpes virus infection status.Results: Compared with non-chronic, patients with chronic ITP had older age (≥3 years), lower levels of hemoglobin and complement C3, and lower probability of CMV and HSV-2 infections (IgM positive; p < 0.05). Patients with herpes virus infection had lower serum platelet counts (p < 0.001), lower complement C3 levels and lower CD4+/CD8+ cells ratio (p < 0.05). Furthermore, platelet counts were positively correlated with CD4+/CD8+ cells ratios (r = 0.519; p = 0.0078), and negatively correlated with T cells (CD3+: r = −0.458, p = 0.0213; CD8+: r = −0.489, p = 0.0131). Multivariate analysis showed that age (OR, 1.644; 95%CI, 1.007–2.684; p = 0.047) was an adverse risk factor for chronic ITP and CMV IgM positive (OR, 0.241; 95%CI, 0.072–0.814; p = 0.022) had lower risk of chronic ITP development, while other herpes virus infection statuses and clinical features were not.Conclusion: Although herpes virus infections were associated with the onset of ITP, our findings indicated that herpes virus infection status might not be a risk factor for chronic ITP.

Predicting Chronic Immune Thrombocytopenia in Pediatric Patients at Disease Presentation: Leveraging Clinical and Laboratory Characteristics Via Machine Learning Models

To investigate the expression of programmed death receptor-1 (PD-1) and inducible costimulator (ICOS) on the surface of CD8+ T cells in peripheral blood of patients with primary immune thrombocytopenia (ITP), and explore the roles of PD-1 and ICOS in the occurrence and development of ITP. A total of 28 ITP patients treated in Tianjin Medical University General Hospital from September to December 2020 were selected, including 13 patients with newly diagnosed ITP, 15 patients with chronic ITP, and 22 healthy volunteers were recruited as control group. Flow cytometry was used to detect the expression levels of PD-1 and ICOS, and evaluate their correlation with clinical indicators. The percentage of CD8 + T cells in ITP patients of chronic group was higher than that of the newly diagnosed group and the control group (P<0.05). The expression level of PD-1 on CD8+ T cells in ITP patients of newly diagnosed group and chronic group were significantly lower than that of the control group (P<0.05), while the expression level of ICOS were significantly higher (P<0.05). In ITP patients, PD-1 was negatively correlated with platelet count (r=-0.4942, P<0.01), but positively with ICOS (r=0.4342). PD-1 and ICOS were both negatively correlated with lymphocyte count (rPD-1=-0.4374; rICOS=-0.4492). In ITP patients, the unbalanced expression of PD-1 and ICOS may interfere with the immune homeostasis of the body, which can be used as a therapeutic target for ITP patients.

Antinuclear antibody (ANA) can be positive in children with primary immune thrombocytopenia (ITP), but the effect of ANA titre and its variation on outcomes of children with primary ITP remains unclear. Here, we conducted a single-centre retrospective cohort study of children with primary ITP at the Peking Union Medical College Hospital in China. A total of 324 children with primary ITP included in this study were followed for a median time of 25 months. In this cohort, 39.2% had an ANA titre of 1:160 or higher. Results from a generalized estimating equation model revealed that patients with higher ANA titres had lower platelet counts at onset but a higher recovery rate of subsequent platelet counts. Results from Cox regression models adjusted for potential confounders revealed that patients with ANA titres of 1:160 or more were more likely to develop to autoimmune disease (AID) than those without, and the risk of AID development increased with the rise of ANA titres (p value for trend less than 0.001). These data highlight the predictive value of ANA titre for platelet counts and the risk of AID development in children with primary ITP.

Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review: comment

Hepatitis C virus leads to chronic liver disease, cirrhosis and hepatocellular cancer. Viral markers and other laboratory tests used in the diagnosis and follow-up of chronic hepatitis C do not correlate well with disease activity and liver histopathology. Therefore, alternative tests that indicate disease activity and relate with liver biopsy findings are needed. We aimed to investigate the relationship between serum complement levels and biopsy findings in patients with chronic hepatitis C. One hundred cases (70 patients, 30 healthy controls) were included in the study. Patients were divided into two groups: chronic hepatitis C patients with high transaminase levels were evaluated as the first group and patients with normal transaminase levels as the second group. Patients with a high transaminase level were biopsied and activity scores were evaluated against complement C3c and C4 levels. In addition, demographic data and laboratory tests were evaluated. Patients with chronic hepatitis C without proteinuria, acute phase response, cirrhosis, or coinfection with another hepatitis virus were included in the prospective study. Serum complement C3c (p<0.01) and C4 (p<0.01) levels were significantly lower in the first group than the second group. Serum complement C3c levels did not correlate with laboratory tests, hepatitis C virus-RNA levels, histological activity index, or fibrosis scores in patients with high transaminase levels, whereas complement C4 levels showed significant correlation with alanine aminotransferase (r: -0.368, p: 0.001) and histological activity index (r: -0.639, p: 0.001). We could not find any relation between serum complement C4 level and fibrosis. Serum complement C4 levels correlate with the histological activity index of the Knodell scoring system.

Efficacy and Safety of Intravenous Efgartigimod 10 Mg/Kg in Adult Patients with Primary Immune Thrombocytopenia: Advance, a Phase 3 Clinical Trial in Progress

Combination of Recombinant Factor VIIa and Fibrinogen Corrects Clot Formation in Primary Immune Thrombocytopenia At Very Low Platelet Counts

Objective To investigate the diagnosis, treatment and prognosis of hemophilia A combined with primary immune thrombocytopenia (ITP). Methods The hemophilia A patient with ITP (male, 30 years old)admitted to the Department of Hematology, Xuzhou Medical University Affiliated Hospital on February 21, 2017 was selected as the study subject. During hospitalization, he was repeatedly treated with coagulation factor replacement therapy strategy, as well as symptomatic treatment measures such as hemostasis, platelet transfusion, intravenous infusion of glucocorticoids, and intravenous immunoglobulin (IVIG). By retrospective analysis, his clinical data were collected, and the clinical features, diagnosis and treatment were summarized. This study met the requirements of the Helsinki Declaration of the World Medical Association revised in 2013, and the informed consent of the subjects was obtained, and informed consent was signed with him. Results ① This patient was diagnosed as hemophilia A more than 20 years ago. During that period, the patient achieved a obvious effect by cryoprecipitation and recombinant human FⅧ infusion. About a month ago, without obvious inducement, the patient developed hematuria, epistaxis and oral hemorrhage. His activity of FⅧ was only 21.3%, and the platelet count was just 3×109/L. The patient received phenethylamine, recombinant human FⅧ, methylprednisolone, and intravenous immunoglobulin (IVIG) , but which was not effective for him. ② After admission to our hospital on February 21, 2017, the results of laboratory tests showed that the patient′s platelet count was very low, only for 2×109/L. His activity of FⅧ was 14.3%, and activity of FⅨwas 49.8%. Activated partial thromboplastin time (APTT) prolonged to 50.2 s, APTT was 32.1 s after correction, APTT (incubated at 37 ℃ for 2 h) prolonged to 50.0 s, and APTT (incubated at 37 ℃ for 2 h) was 37.9 s after correction. Morphological examination of bone marrow cells showed that bone marrow cells proliferated actively, granulocytes and erythroid line cells were proliferated, and the morphology was normal, as well as megakaryocyte maturation was accompanied by thrombocytopenia. Abdominal ultrasound results showed that the liver area was dense, the gallbladder wall was rough, and the spleen was not large (about 9.7 cm × 7.0 cm). ③ After admission, combining with previous medical history, results of relevant laboratory examinations and auxiliary examinations, the patient was diagnosed as hemophilia A combined with ITP by excluding other secondary diseases which caused thrombocytopenia. ④ After admission, the patient was repeatedly treated with recombinant human FⅧ. But the patient′s highest activity of FⅧ was only 25.8%, and APTT prolonged to 45.0 s, which suggested that the patient was partially tolerant to treatment. After receiving multiple platelet transfusions, the patient′s platelet count was still low, and did not exceed to 20×109/L, which suggested that the treatment is invalid. On May 5, 2017, the patient started oral eltrombopag (75 mg/d). After 3 months of treatment, the patient′s platelet count was up to 55×109/L, and the evaluation of efficacy was effective. However, after one month of discontinuation of eltrombopag, the patient′s platelet count fell to 10×109/L, which suggested that his disease relapsed. Conclusions Patients with hemophilia A combined with ITP, were clotting factor deficiency and thrombocytopenia, the risk of bleeding of them were high, and the treatment is difficult. In addition to infusion of recombinant human FⅧ, glucocorticoid and other drugs should be given to elevate platelet count, but the prognosis of this patient is not good. Patients with hemophilia A combined with ITP are rare in clinic, and its standard and effective treatment strategy requires a large sample size and multi-center study to further explore. Key words: Hemophilia A; Purpura, thrombocytopenic, idiopathic; Hemorrhage; Drug therapy; Prognosis; Primary immune thrombocytopenia

Rate of Bleeding-Rated Episodes (BREs) in Elderly Patients with Primary Immune Thrombocytopenia (ITP): A Population-Based Retrospective Cohort Study Using Medicare 20% Sample Data

Background: Immune thrombocytopenia (ITP) is characterized by non-chronic (transient, <12 months) and chronic (≥12 months) decline in the number of platelets. Herpes virus infections have been shown, in many studies, to be associated with the development of ITP. However, it remains unclear whether the herpes virus infection status is associated with the chronic ITP. Methods: We reviewed 480 primary pediatric patients with ITP in the period from January 2017 to December 2019. The prevalence of herpes virus antibodies including the Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV-1), Herpes simplex virus 2 (HSV-2), and Epstein Barr virus were recorded. The levels of serum complement C3 and C4, T (CD3+, CD4+, CD8+), B (CD19+) lymphocytes, and natural killer (CD16+ 56+) cells were also analyzed. Multivariate analysis was used to evaluate the associations between chronic ITP and herpes virus infection status. Results: Compared with non-chronic ITP, patient with chronic had older age (≥ 3 years), low level of hemoglobin and complement C3, and lower probability of CMV and HSV-2 infections (IgM positive; p<0.05). Patients with herpes virus infection had lower serum platelet counts (p<0.001), lower complement C3 levels and lower CD4+/CD8+ cells ratio (p<0.05). Furthermore, platelet counts were positively correlated with CD4+/CD8+ cells ratios (r=0.519; p=0.0078), and negatively correlated with T cells (CD3+: r=-0.458, p=0.0213; CD8+: r=-0.489, p=0.0131). Multivariate analysis showed that age (OR,1.644;95%CI, 1.007~2.684; p=0.047) was an adverse risk factor for chronic ITP and CMV IgM positive (OR,0.241;95%CI, 0.072~0.814; p=0.022) had lower risk of chronic ITP development, while other herpes virus infection status and clinical features were not. Conclusion: Although herpes virus infections were associated with the onset of ITP, our findings indicated that herpes virus infections status might not be a risk factor for chronic ITP.