Thrombopoietin Analogs In ITP Patients Daily Practice: Treatment Profile, Efficacy and Safety

Immune Thrombocytopenia during Childhood: New Approaches to Classification and Management

To investigate the expression and clinical significance of high mobility group box 1(HMGB1) in spleen of adult patients with chronic and refractory immune thrombocytopenia(ITP). Twenty chronic and refactory ITP patients received splenectomy were enrolled in ITP group and 20 cases of traumatic spleen rupture were enrolled in control group. The splenectomy efficacy in ITP patients was analyzed retrospectively. The HMGB1 expression in spleen tissue was detected by immunohistochemistry, and the correlation between different expression levels of HMGB1 and splenectomy efficacy were analysed. Meanwhile, the protein expression levels of HMGB1 in peripheral blood serum and mononuclear cells(PBMNC) of 25 patients with chronic and refractory ITP were detected by ELISA and Western blot. The median platelet count before splenectomy was 7.5 (0-20) ×109/L; all the patients showed that the initial response to splenectomy within the first month after operation was 100%, the median time of response was 1 day (1-6 days). The median peak platelet count post splenectomy was 448.5 (161-1272)×109/L. In the median time of 10(3-30) months, the platelets count in 8 patients was reduced to varying degrees. After a median follow-up of 69.5 months (22-195), complete response was found in 12 patients, 4 cases showed response and 4 did not. The HMGB1 expression positive rate in spleen of ITP patients was significantly higher than that in control group (85.0% vs 15.0%)(P<0.001). There were a negative correlation between the HMGB1 expression in ITP and therapeutic outcome after splenectomy (r=-0.791, P<0.01). In addition, HMGB1 expression levels in serum and PBMNC of the patients with chronic refractory ITP were also significantly higher than that in healthy controls (P<0.01). The splenectomy has been found to be effective therapeutic method for patients with ITP, the HMGB1 highly express in the spleen of the patients with chronic refractory ITP, but negatively correlats with the therapeutic outcome after splenectomy.

Th1 Polarization of Cytokine and Cytokine Receptor Polymorphisms Affect the Susceptibility and Severity of ITP

Administration of vinca alkaloids (VA) to chronic corticosteroid refractory immune thrombocytopenia (ITP) patients results in a temporary increase of platelet count. The aim of the study was to evaluate the efficacy of vinca alkaloids in preparing adult corticosteroid refractory chronic ITP patients for splenectomy as well as to compare the costs of this method with costs of applying intravenous immunoglobulins. The study included 12 chronic ITP patients refractory to corticosteroids applied for 3-144 months. The patients were prepared for splenectomy with average 3.0 (from 1 to 4) 2-h intravenous infusions of vinca alkaloids at 7 day intervals. In eight patients, vincristin was used in a total dose of 6 mg (2 mg per infusion), in two patients, vinblastin was used in total dose of 30 mg (10 mg per infusion), and in two patients, vincristin and vinblastin infusions were administered alternatively. In nine of the 12 treated patients (75%) the platelet count increased to > or = 80 x 10(9)/l, which allowed safe splenectomy. Three patients unreactive to VA treatment were prepared for splenectomy with intravenous gammaglobulin infusions. Splenectomy was performed in 12 patients, in eight with laparoscopic method, in four with classic method. No complications during surgical intervention were observed. In none of the VA treated patients was myelosupression or liver or/and kidney dysfunction observed. Splenectomy resulted in normalization of platelet count in all patients after operation and in six of nine patients followed up for 10 months (on the average). Matching of VA costs with treatment efficacy and comparison with similar costs for intravenous immunoglobulin treatment revealed many fold lower costs of the former method.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by platelet counts less than 100 × 109/l.11 Clinical symptoms can manifest as petechiae, purpura, mucosal bleedings or, more rarely, as intracranial hemorrhages.14 Therapeutic management of ITP remains challenging due to the heterogeneity in patients caused by the diverse individual patient factors and the several phases of the disease course, such as newly diagnosed, persistent and chronic ITP. First-line treatments for ITP include corticosteroids such as glucocorticoids (GCs), intravenous immunoglobulin and anti-D immunoglobulin, while second-line treatments include rituximab or splenectomy, and third-line treatment options may be thrombopoietin receptor agonists (TPO-RA).8 The pathogenesis of ITP has proven to be complex, with multiple factors and various cell types contributing to the immune imbalance that leads to destruction of platelets in the circulation.6, 12, 14 General mechanisms include anti-platelet antibody mediated platelet-phagocytosis via Fcγ-receptors on monocytes and macrophages9, 12, 14 and/or T cell mediated platelet destruction.10 Moreover, a plethora of studies have clearly demonstrated that the pathophysiology of ITP is characterized by abnormal T cell responses, predominantly signified by an impairment in T regulatory cells (Tregs).12 In addition, dendritic cells and myeloid-derived suppressor cells (MDSCs) have also been shown to be impaired in ITP.2, 12 The working mechanism of certain ITP therapeutics has been demonstrated to be related to restoring these abnormal T cell,5 dendritic cell3, 4 and MDSC responses.1, 2 Looking specifically at treatment with GCs, CD39+ Tregs were shown to be decreased in newly diagnosed ITP patients and, upon treatment with the high-dose GC dexamethasone, Treg numbers increased in responding patients, with an improvement of the Treg-immunosuppressive function.5 Similarly, it was previously shown that Tregs were deficient in adult chronic ITP patients and that treatment with high-dose dexamethasone resulted in increased numbers of circulating Tregs as well as myeloid dendritic cells with decreased CD11c expression, while, in contrast, plasmacytoid dendritic cells were decreased in number.4 Furthermore, it was demonstrated that both the numbers of MDSCs and their suppressive functions were impaired in peripheral blood and spleens of adult ITP patients, and that high-dose dexamethasone treatment could increase the numbers of MDSCs while also enhancing their suppressive functions.2 The immunosuppressive capacity of GCs in ITP may not only impact Tregs, dendritic cells and MDSCs, but also monocytes, as demonstrated by Williams and colleagues in this issue of the British Journal of Haematology.13 Williams et al. investigate the percentage of monocyte subsets (and their cell surface phenotype) from peripheral blood mononuclear cells isolated from newly diagnosed ITP patients prior to and following GC-treatment. They interestingly observe intermediate monocytes (CD14++, CD16+) to be increased in newly diagnosed untreated ITP patients, with these cells displaying an inflammatory phenotype of enhanced surface CD64 and CD80 expression. GC-treatment subsequently reduced the proportion of intermediate monocytes and enhanced the expression of the anti-inflammatory markers CD206 and CD163. These GC-induced phenotypic effects were not observed in chronic ITP patients receiving TPO-RA. The authors conclude that intermediate monocytes may have a role in the ITP pathogenesis with a clinical response to GC-treatment. Notably, Manzano et al. recently found that intermediate monocytes were not increased in their cohort of ITP patients.7 However, these patients suffered from ITP for a minimum of 6 months (some greater than 12 months), while the study by Williams et al. focused on newly diagnosed (acute) ITP with on average lower platelet counts of less than 30 × 109/l. Besides the intermediate monocytes, Williams et al. also found a potentially important role for non-classical monocytes (CD14+, CD16++). The non-classical monocyte population was not increased in untreated ITP patients but was found to be strongly reduced upon GC-treatment, with an increase in CD206 and CD163 surface expression. Overall, it would be interesting to monitor GC-treated newly diagnosed ITP patients over a longer period of time and investigate if the percentage and phenotype of monocyte subsets may change and thereby serve as a potential indicator as to whether to switch to another therapeutic approach. On a functional level, it can be hypothesized that GC-primed monocytes may shape T cell responses in ITP, but it may also be possible that they inhibit antibody-mediated platelet phagocytosis. FcγRI (CD64) and FcγRIII (CD16) have been shown to be important for antibody-mediated platelet phagocytosis in ITP.9 Williams and colleagues observed that GC-treatment generally reduced the expression of CD64 on monocytes and reduced the total fraction of CD16 expressing monocytes. How GC-primed monocytes may restore ITP-responses could, for instance, be researched in T cell and platelet phagocytosis assays, with and without GC-treatment. In conclusion, Williams et al. identify a GC-induced reduction in monocyte subsets in combination with cell surface phenotype alterations in clinically responding, newly diagnosed ITP patients. Further research should focus on monitoring these GC-induced monocyte effects throughout the ITP disease course to assess if they may change and potentially provide a novel predictive clue for adjusting therapeutic strategy. In addition, the pathogenic role of the different monocyte subsets in ITP, with and without GC-treatment, should be further mechanistically investigated.

Association of Interleukin-18 Gene Polymorphism with Severity of Chronic Immune Thrombocytopenia (ITP).

Eltrombopag for Immune Thrombocytopenia Adult Patients in the Real-Life Practice in France. Interim Results of the Elextra Study

Rapid assessment of platelet production would distinguish between thrombocytopenia due to decreased platelet production or increased peripheral platelet destruction. We evaluated the value of immature platelet fraction (IPF) in differentiating immune thrombocytopenia (ITP) from thrombocytopenia secondary to bone marrow failure and its potential use as a prognostic marker. Forty-one young patients with ITP were compared with 14 patients with hematological malignancies under chemotherapy, representing a control group with thrombocytopenia due to bone marrow suppression and 30 age- and sex-matched healthy controls. Patients were studied stressing on bleeding manifestations, organomegaly/lymphadenopathy and therapy. Complete blood count including IPF was performed using Sysmex XE-2100. ITP patients were classified into two subgroups: acute ITP with spontaneous resolution within 3 months from diagnosis and chronic ITP that lasted ≥1 year from diagnosis. Median IPF was 11.8% in patients with ITP, 7% in those with hematological malignancy and 3% in the control group (p < 0.001). ITP patients had significantly higher mean platelet volume (MPV), platelet distribution width (PDW), platelet large cell ratio (P-LCR) and IPF compared with patients with malignancy or healthy controls, while plateletcrit (PCT) was significantly lower in ITP patients than other groups (p < 0.001). IPF was increased in patients with chronic ITP compared with acute ITP group (p < 0.001). Patients with active ITP had the highest IPF followed by those in partial remission, while ITP patients in remission had the lowest IPF. IPF was positively correlated to the number of lines of treatment used, MPV, PDW and P-LCR, while negatively correlated to platelet count and PCT among ITP patients (p < 0.001). Multiple regression analysis showed that platelet count and P-LCR were independently related to IPF. ROC curve analysis revealed that the cut-off value of IPF at 9.4% could be diagnostic for ITP patients with a sensitivity of 88% and a specificity of 85.7%. We suggest that IPF may be a rapid and inexpensive automated marker for etiology of thrombocytopenia and can be integrated as a standard parameter to evaluate the thrombopoietic state of the bone marrow. It may be considered as a potential prognostic marker for the development of chronic ITP.

Dysregulated T helper (Th) cells are considered important in the pathophysiology of chronic primary immune thrombocytopenia (ITP). The present study investigated whether levels of Th cytokines in pediatric patients with chronic ITP were different compared with healthy controls. Fifty-seven pediatric patients with chronic ITP and 28 healthy controls were enrolled. Patients were divided into three groups based on their platelet counts at the time of the study: (i) active disease <50 × 10(9) /l (n = 23), (ii) stable disease 50-150 × 10(9) /l (n = 23), and (iii) in remission >150 × 10(9) /l (n = 11). Plasma concentration of Th1 [interferon gamma (INF-γ), interleukin 2 (IL-2)], Th2 (IL-4, IL-10), Th3 [transforming growth factor-β1 (TGF-β1)], and Th17 (IL-17) cytokines were investigated by enzyme-linked immunosorbent assay. IFN-γ was increased in patients with active (P < 0.001) and stable disease (P = 0.026) when compared with controls. The IL-17 level was significantly higher in all of the 3 patient groups. In addition, there was a positive correlation between IL-17 and IFN-γ levels in chronic ITP patients (r = 0.640, P < 0.001). Reduced TGF-β1 expression was observed in patients with active (P < 0.001) and stable disease (P = 0.001) in comparison with controls. Moreover, TGF-β1 level in patients was positively correlated with the platelet count (r = 0.355, P = 0.007). Elevation of IL-17 and IFN-γ may be an important dysregulation of cellular immunity in pediatric patients with chronic ITP. The disease activity is associated with reduced production of TGF-β1.

HMGB1 is increased in patients with immune thrombocytopenia and negatively associates with Tregs

Increased Number of B-Cells In the Red Pulp of the Spleen In ITP

Background: Coronavirus disease 2019 (COVID-19) is a serious health problem in many parts of the world. COVID-19 may trigger a new presentation of Immune Thrombocytopenia (ITP) or may cause relapse in patients with chronic ITP. Treatment of ITP in COVID-19 patients has the risk of worsening the condition of COVID-19 itself. Case presentation: A 32-year-old male with a history of chronic Immune Thrombocytopenia (ITP) was confirmed with COVID-19. The condition of ITP is controlled with low-dose steroids, presents with very low platelets, and does not respond to previous treatment; it was later discovered that the patient was infected with COVID-19. COVID-19 is known to aggravate thrombocytopenia in patients with ITP and can lead to new ITP conditions. Recent guidelines state that intravenous immunoglobulin (IvIg) is the first choice in ITP patients who have COVID-19 infection, and thrombopoietin receptor agonist (TPO-RA) was another alternative treatment, in this case, the patient received platelet transfusion therapy and TPO-RA, reported that the patient's platelets were well controlled with the use of TPO-RA and COVID-19 infection also improved with the treatment. Conclusion: Swift diagnosis is needed to improve the quality of life of patients and minimize the occurrence of potential complications caused by COVID-19 in chronic ITP patients. Latar Belakang: Coronavirus disease 2019 (COVID-19) merupakan masalah kesehatan yang serius di berbagai belahan dunia dan Organisasi Kesehatan Dunia (WHO) telah menetapkan COVID-19 sebagai pandemi. COVID-19 diketahui menyebabkan gejala pernafasan dengan manifestasi ringan hingga berat dan melibatkan berbagai sistem tubuh seperti hematologi, neurologi, dan sistem kekebalan tubuh. Presentasi kasus: Seorang laki-laki berusia 32 tahun dengan riwayat Immune Thrombocytopenia (ITP) kronis terkonfirmasi mengidap COVID-19. Kondisi ITP dikendalikan dengan steroid dosis rendah dan datang dengan trombosit yang sangat rendah serta tidak merespons pengobatan sebelumnya, kemudian diketahui bahwa pasien tersebut terinfeksi COVID-19. COVID-19 diketahui memperburuk trombositopenia pada pasien ITP dan dapat menyebabkan kondisi ITP baru. Pedoman terbaru menyatakan bahwa imunoglobulin intravena (IvIg) merupakan pilihan pertama pada pasien ITP yang mengalami infeksi COVID-19, dan agonis reseptor trombopoietin (TPO-RA) merupakan pengobatan alternatif lain, dalam hal ini pasien mendapat terapi transfusi trombosit dan TPO-RA. Setelah terapi dilaporkan bahwa trombosit pasien terkontrol dengan baik dengan penggunaan TPO-RA dan infeksi COVID-19 juga membaik dengan pengobatan. Kesimpulan: Diagnosis yang cepat diperlukan untuk meningkatkan kualitas hidup pasien dan meminimalisir terjadinya potensi komplikasi akibat COVID-19 pada pasien ITP kronis.

Primary immune thrombocytopenia: understanding pathogenesis is the key to better treatments.

The aim of this study was to investigate the effect of C-reactive protein (CRP) on the prognosis of adult patients with Immune thrombocytopenia purpura (ITP). A retrospective study of 628 adult ITP patients, as well as 100 healthy and 100 infected patients, attending the Affiliated Hospital of Xuzhou Medical University from January 2017 to June 2022 was performed. The ITP patients were grouped according to their CRP levels, and the differences in clinical characteristics of each group and the influencing factors of efficacy in newly diagnosed ITP patients were analyzed. CRP levels were significantly higher in the ITP and infected groups compared with healthy controls (P < 0.001), and platelet counts were significantly lower in the ITP group (P < 0.001). Between the CRP normal and elevated group, their age, white blood cell count, neutrophil count, lymphocyte count, red blood cell count, hemoglobin, platelet count, complement C3 and C4, PAIgG, bleeding score, proportion of severe ITP, and proportion of refractory ITP were significantly different (P < 0.05). Patients of severe ITP (P < 0.001), refractory ITP (P = 0.002), and with active bleeding (P < 0.001) had significantly higher CRP levels. Patients with no response after treatment had significantly higher CRP levels than those who achieved CR or R (P < 0.001). Platelet counts (r = - 0.261, P < 0.001) in newly diagnosed ITP patients and treatment outcomes (r = - 0.221, P < 0.001) were negatively correlated with CRP levels, and bleeding score was positively correlated with CRP levels (r = 0.207, P < 0.001). Treatment outcome was positively correlated with decrease in CRP levels (r = 0.313, P = 0.027). A multifactorial regression analysis of the influencing factors of treatment outcomes on newly diagnosed patients found that CRP was an independent risk factor of the prognosis (P = 0.011). In conclusion, CRP can help assess the severity and predict the prognosis of ITP patients.

Somatic Mutations in CD8+ T Cells in Patients with Chronic Immune Thrombocytopenia Are Associated with Increased Clonality and Cytotoxic Phenotype of CD8+ T Cells