Increased Platelet Production Research Articles

Clinical research progress of lusutrombopag for the treatment of thrombocytopenia in chronic liver disease

Thrombocytopenia is one of the common complications with the hematologic system in patients with chronic liver disease, which often causes poor quality of life and high risk of bleeding, thereby affecting their diagnosis, treatment, and prognosis. Platelet transfusion can improve the patient's declining platelet count to a certain extent, but it has problems such as high price and being easy to cause immune rejection. Thrombopoietin (TPO), as an important cytokine that affects platelet production, can bind to TPO receptors and activate megakaryocytes to produce platelets. Lusutrombopag is a newly developed small-molecule TPO receptor agonist that can induce bone marrow progenitor cells to differentiate into megakaryocytes and increase platelet production, posing characteristics of oral convenience, safety and effectiveness; thus, it has been used in many countries and regions for the treatment of patients with chronic liver diseases concurrent with thrombocytopenia. Herein, the pharmacological features and clinical research are reviewed.

Compound K Promotes Megakaryocytic Differentiation by NLRP3 Inflammasome Activation.

Platelets are essential blood components that maintain hemostasis, prevent excessive bleeding, and facilitate wound healing. Reduced platelet counts are implicated in various diseases, including leukemia, hepatitis, cancer, and Alzheimer's disease. Enhancing megakaryocytic differentiation is a promising strategy to increase platelet production. Compound K (CK), a major bioactive metabolite of ginsenosides from Panax ginseng, has demonstrated anti-cancer and neuroprotective properties. In this study, we investigated the effects of CK on megakaryocytic differentiation and apoptosis in chronic myeloid leukemia (CML) cell lines K562 and Meg-01. CK treatment significantly upregulated the mRNA expression of key megakaryocytic differentiation markers, including CD61, CD41, and CD42a, and promoted the formation of large, multinucleated cells in K562 cells. Additionally, flow cytometry analysis revealed that CK at 5 µM induced apoptosis, a critical process in thrombocytopoiesis, in both K562 and Meg-01 cells. RT2 Profiler PCR array analysis further identified a marked increase in the expression of genes associated with the activation of the NLRP3 inflammasome in CK-treated K562 and Meg-01 cells. This study is the first to demonstrate that CK promotes megakaryocytic differentiation and apoptosis through the activation of the ERK/EGR1 and NLRP3 inflammasome pathways. These findings suggest that CK may enhance platelet production, indicating its potential as a therapeutic candidate for platelet-related disorders and other associated diseases.

Thrombopoietin receptor agonists regulate myeloid-derived suppressor cell-mediated immunomodulatory effects in ITP.

TPO receptor agonists (TPO-RAs) are a class of clinical second-line regimens for the treatment of primary immune thrombocytopenia (ITP). It can promote megakaryocyte maturation and increase platelet production, but its effect on immunosuppressive cells in patients with ITP has not been explored. Sixty-two ITP patients and 34 healthy controls (HCs) were included in this study. The proportion and functions of myeloid-derived immunosuppressive cells (MDSCs) in ITP patients and HCs were investigated. We found that the proportion and function of MDSCs in ITP patients treated with TPO-RAs were significantly higher than those treated with glucocorticoids (GCs), which was correlated with the clinical efficacy. The proportion and function of cytotoxic Th1 cells and CD8+T cells decreased, while the proportion and immunosuppressive function of Treg cells increased in ITP patients treated with TPO-RAs. We further proved, through MDSC depletion tests, that the inhibitory effect of MDSCs on Th1 cells and the promotion of Treg cells in the original immune micro-environment of GCs-treated ITP patients were impaired; however, these MDSCs' functions were improved in TPO-RAs-treated patients. Finally, we found that the KLF9 gene in MDSCs cells of ITP patients treated with TPO-RAs was down-regulated, which contribute to the higher mRNA expression of GADD34 gene and improved function of MDSCs. These results demonstrate a novel mechanism of TPO-RAs for the treatment of ITP through the assessment of MDSCs and their subsequent impact on T cells, which provides a new basis for TPO-RAs as first-line treatment approach to the treatment of ITP.

SET domain containing 2 promotes megakaryocyte polyploidization and platelet generation through methylation of α-tubulin

BackgroundMegakaryocytes (MKs) are polyploid cells responsible for producing ∼1011 platelets daily in humans. Unraveling the mechanisms regulating megakaryopoiesis holds the promise for the production of clinical-grade platelets from stem cells, overcoming significant current limitations in platelet transfusion medicine. Previous work identified that loss of the epigenetic regulator SET domain containing 2 (SETD2) was associated with an increased platelet count in mice. However, the role of SETD2 in megakaryopoiesis remains unknown. ObjectivesHere, we examined how SETD2 regulated MK development and platelet production using complementary murine and human systems. MethodsWe manipulated the expression of SETD2 in multiple in vitro and ex vivo models to assess the ploidy of MKs and the function of platelets. ResultsThe genetic ablation of Setd2 increased the number of high-ploidy bone marrow MKs. Peripheral platelet counts in Setd2 knockout mice were significantly increased ∼2-fold, and platelets exhibited normal size, morphology, and function. By knocking down and overexpressing SETD2 in ex vivo human cell systems, we demonstrated that SETD2 negatively regulated MK polyploidization by controlling methylation of α-tubulin, microtubule polymerization, and MK nuclear division. Small-molecule inactivation of SETD2 significantly increased the production of high-ploidy MKs and platelets from human-induced pluripotent stem cells and cord blood CD34+ cells. ConclusionThese findings identify a previously unrecognized role for SETD2 in regulating megakaryopoiesis and highlight the potential of targeting SETD2 to increase platelet production from human cells for transfusion practices.

An Innovative Inducer of Platelet Production, Isochlorogenic Acid A, Is Uncovered through the Application of Deep Neural Networks.

(1) Background: Radiation-induced thrombocytopenia (RIT) often occurs in cancer patients undergoing radiation therapy, which can result in morbidity and even death. However, a notable deficiency exists in the availability of specific drugs designed for the treatment of RIT. (2) Methods: In our pursuit of new drugs for RIT treatment, we employed three deep learning (DL) algorithms: convolutional neural network (CNN), deep neural network (DNN), and a hybrid neural network that combines the computational characteristics of the two. These algorithms construct computational models that can screen compounds for drug activity by utilizing the distinct physicochemical properties of the molecules. The best model underwent testing using a set of 10 drugs endorsed by the US Food and Drug Administration (FDA) specifically for the treatment of thrombocytopenia. (3) Results: The Hybrid CNN+DNN (HCD) model demonstrated the most effective predictive performance on the test dataset, achieving an accuracy of 98.3% and a precision of 97.0%. Both metrics surpassed the performance of the other models, and the model predicted that seven FDA drugs would exhibit activity. Isochlorogenic acid A, identified through screening the Chinese Pharmacopoeia Natural Product Library, was subsequently subjected to experimental verification. The results indicated a substantial enhancement in the differentiation and maturation of megakaryocytes (MKs), along with a notable increase in platelet production. (4) Conclusions: This underscores the potential therapeutic efficacy of isochlorogenic acid A in addressing RIT.

Thrombopoietin receptor agonists use and risk of thrombotic events in patients with immune thrombocytopenic purpura: A systematic review and meta‑analysis of randomized controlled trials.

Thrombopoietin receptor agonists (TPO-RAs) have a role in second-line immune thrombocytopenic purpura (ITP) treatment, binding to and activating thrombopoietin receptors on megakaryocyte membranes in the bone marrow. This promotes megakaryocyte maturation and increases platelet production. Despite a 2-6% incidence of thrombotic events during TPO-RA treatment, it remains uncertain whether TPO-RAs elevate thrombosis rates. A comprehensive search of electronic databases was conducted using the relevant search criteria. To assess the risk of bias, the included studies were assessed using the revised Cochrane Risk of Bias Assessment Tool 2.0, and a meta-analysis was performed using RevMan 5.4.1. A total of 1,698 patients with ITP were included from randomized controlled trials (RCTs). There were 26 thromboembolic events in the TPO-RAs group and 4 in the control group. However, there was no significant difference in the incidence of thrombotic events between the two groups [odds ratio (OR)=1.76, 95% confidence interval (CI): 0.78-4.00, P=0.18], even if the duration of treatment was >12 weeks (OR=2.46, 95% CI: 0.81-7.43, P=0.11). Subgroup analysis showed that none of the four drugs significantly increased the incidence of thrombotic events (romiplostim: OR=0.92, 95% CI: 0.14-6.13, P=0.93; eltrombopag: OR=2.32, 95% CI: 0.64-8.47, P=0.20; avatrombopag: OR=4.15, 95% CI: 0.20-85.23, P=0.36; and hetrombopag: OR=0.76, 95% CI: 0.03-18.76, P=0.87). There was also no significant difference in the results of the double-blinded placebo-controlled RCTs (OR=1.21, 95% CI: 0.41-3.58, P=0.73). Compared to patients with ITP who did not receive TPO-RA treatment, those receiving TPO-RA treatment did not exhibit a significantly increased risk of thrombotic events.

Pharmacologic Reduction of Platelet Count Attenuates Whole Blood Hypofibrinolysis in a Mouse Model of Sickle Cell Disease

Increased risk of venous thrombosis is a hallmark of sickle cell disease (SCD). We previously reported that SCD dramatically alters the properties of venous clots, including resistance to tissue plasminogen activator (tPA)-mediated fibrinolysis. Using an internal fibrinolysis assay (tPA added to whole blood before clot formation), clot lysis time (CLT) was significantly (p<0.01) prolonged in clots formed ex vivo from whole blood of SCD patients (SS) (651±34 min) compared to race-matched controls (AA) (370±75). We then investigated how therapeutic RBC exchange affects CLT in SCD patients. Interestingly, despite hemoglobin A levels of approximately 50%, CLT for the pre-exchange SS clots (639±81 min) was similar to CLT recorded for blood clots from SS patients who did not undergo RBC exchange (see above). However, CLT for post-exchange SS clots was significantly shortened (240±34; p<0.05 vs pre-exchange) to the level observed for clots from AA controls. We noticed that the RBC exchange procedure not only changes the proportion of AA and SS RBCs, but also reduces both platelet counts and serum plasminogen activator inhibitor-1 (PAI-1) levels by approximately 50-60%. Importantly, exvivo restoration of the platelet number in post-exchange samples to the level observed in pre-exchange blood resulted in restoration of the hypofibrinolytic phenotype and a partial restoration of serum PAI-1 levels. Changes in platelet count after RBC exchange are quickly normalized. Therefore, in the current study, we investigated the effect of sustained reduction of platelet count on whole blood hypofibrinolysis in SCD mice. Using an external fibrinolysis assay (2.5 nM tPA added after clot formation) as described by Bonnard et al. (Sci Rep, 2017) we determined if hypofibrinolysis is also observed in Townes sickle cell mice (SS). Consistent with human SCD, the CLT was profoundly increased in ex vivo clots formed from whole blood of SS mice (n=13) compared to non-sickle (AA) control mice (n=12) (Figure 1A; first two bars). Next, we demonstrated that the cellular fraction of SS blood was responsible for resistance of the clots to tPA-mediated fibrinolysis, regardless of whether the plasma was from SS or AA mice (Figure 1A; last four bars). We then used a pharmacologic strategy to reduce platelet counts. Thrombopoietin (TPO) is a growth factor that promotes maturation of hematopoietic stem cells into megakaryocytes and thereby increases platelet production. We previously showed that silencing liver TPO expression using a liver-specific antisense oligonucleotide (TPO-ASO) resulted in a sustained 50% reduction in both plasma TPO levels and platelet counts without affecting hemostasis in both baboons and mice. In the present study, TPO-ASO (20 mg/kg subcutaneous) or vehicle control were administered to 3-month old AA and SS mice (n=3-6) on days 0, 3, 5 and 7, followed by weekly maintenance injections for the next 3 weeks. 4 weeks after initiation of treatment, mice were euthanized, and blood was collected to evaluate plasma levels of TPO and external whole blood fibrinolysis. Platelet, but no other cell count was significantly reduced in both AA (by 62%, p<0.05) and SS (by 47%, P<0.05) mice treated with TPO-ASO. Baseline plasma levels of TPO were reduced in SS mice (101±20 pg/ml) compared to AA controls (182±10; p<0.05). TPO-ASO treatment resulted in significant reduction of TPO plasma levels in both AA (21±16; p<0.01) and SS (17±9; p<0.05) mice. Interestingly, TPO-ASO-mediated reduction of platelet count did not affect CLT of ex vivo clots formed from whole blood of AA mice (Figure 1B). In contrast, TPO-ASO treatment dramatically reduced CLT in SS clots (p<0.05) (Figure 1B). In conclusion, we demonstrated that: (i) the resistance of ex vivo formed clots to tPA-mediated fibrinolysis observed in SCD patients can be reproduced in a mouse model of the disease; (i) the external fibrinolysis assay provides a robust and reliable model for studying whole blood hypofibrinolysis in SCD; (iii) hypofibrinolysis in SCD appears to be predominantly driven by the cellular fraction of blood; and (iv) platelets play an important role in the hypofibrinolytic phenotype in SCD, demonstrated by mitigation of the hypofibrinolytic phenotype in SS mice subjected to long-term reduction of platelet count. Further studies investigating the effect of platelet count reduction on venous thrombosis and vascular stasis in SS mice are currently ongoing.

Megakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels

Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of release is crucial for designing and interpreting cfDNA-based liquid biopsy assays. Using cell type-specific methylation markers as well as genome-wide methylation analysis, we determine that megakaryocytes, the precursors of anuclear platelets, are major contributors to cfDNA (~26%), while erythroblasts contribute 1–4% of cfDNA in healthy individuals. Surprisingly, we discover that platelets contain genomic DNA fragments originating in megakaryocytes, contrary to the general understanding that platelets lack genomic DNA. Megakaryocyte-derived cfDNA is increased in pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased upon reduced platelet production due to chemotherapy-induced bone marrow suppression. Similarly, erythroblast cfDNA is reflective of erythrocyte production and is elevated in patients with thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns can thus serve as biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis, which can aid in determining the etiology of aberrant levels of erythrocytes and platelets.

The Combination of Intravenous Immunoglobulin (IVIG) and Low Does Recombinant Human Thrombopoietin (rhTPO) for the Management of Corticosteroid/IVIG Monotherapy-Resistant Immune Thrombocytopenia in Pregnancy

Introduction Primary immune thrombocytopenia (ITP) is a common autoimmune disease characterized by a low platelet count resulting from antibody-mediated platelet destruction and insufficient platelet production. ITP, with a prevalence of 1 in 1000-10 000 pregnancies, accounts for approximately 3% of all causes of thrombocytopenia in pregnancy and is reported to be the most common cause of thrombocytopenia in the first and early second trimesters. It has been revealed that severe ITP is associated with devastating outcomes. It remains a challenge to manage pregnant patients with ITP. First-line treatment options in pregnant ITP patients currently include corticosteroids and intravenous immunoglobulin (IVIg). However, previous studies reported that the response rate of pregnant ITP patients to corticosteroids was less than 40% and that to IVIg was 38-56%, which was lower than that of nonpregnant ITP patients. The second-line treatment options are limited for pregnant ITP patients. Recombinant human thrombopoietin (rhTPO), a full-length and glycosylated TPO with a molecular weight of 90 000 Daltons developed by 3SBIO (Shenyang, China), has also been approved by the China State Food and Drug Administration as a second-line option for nonpregnant ITP patients. It cannot cross the placenta theoretically with such a large molecular weight, and thus, it has an apparent theoretical advantage over the two TPO mimetics since it would not impact the fetus. A study investigating the application of rhTPO in pregnancy suggested that rhTPO was a potentially effective and well-tolerated treatment option for ITP patients during pregnancy. It might be explained that the development of ITP was associated with increased platelet destruction and impaired platelet production, and the combination of IVIg and TPO mimetics impacts these two targets since IVIg could reduce platelet destruction, whereas TPO mimetics could increase platelet production. Therefore, we conducted a monocenter, single-arm, open-label study to investigate the efficacy and safety of low-dose rhTPO plus IVIg in pregnant corticosteroid/IVIg monotherapy-resistant ITP patients. Methods This study was registered at www.clinicaltrials.gov as NCT05634824.The following criteria were considered: patients have a diagnosis of primary ITP before or first onset during pregnancy; patients ≥ 18 years; patients complicated with bleeding manifestations and/or have a platelet count < 30 × 10^9/L and failed to respond to initial treatment of corticosteroids or intravenous immunoglobulin (IVIg) monotherapy or relapsed during the tapering or discontinuation of corticosteroids. For those patients, the initial combination therapy consisted of rhTPO at an initial dose of 150 U/kg once daily subcutaneously for 28 days and IVIg 400 mg/kg per day for 5 days. If the platelet count was in the range of 30 to 50 × 10^9/L, the combination therapy was repeated. To reduce the risk for thrombocytosis, patients received maintenance therapy consisting of rhTPO at a dose of 150 U/kg per day if the platelet count rose above 50 × 10^9/L, and treatment was discontinued when platelet counts exceeded 100 × 10^9/L. After delivery, the treatment consisted of rhTPO 150 U/kg per day, and the dose was maintained if the platelet count exceeded 30 × 10^9/L. In addition, IVIg 400 mg/kg per day for 5 days was added if the platelet count could not be maintained above 30 × 10^9/L. If patients did not achieve a count of 30 × 10^9/L within 4 weeks, treatment was also discontinued. Results The study included 19 patients with thrombocytopenia during pregnancy who were admitted to Peking University People's Hospital from December 1, 2022, to May 30, 2023, all of whom had failed hormone and IVIG treatment. The median age of those patients was 34 years old (range 20 to 42 years old), and the median platelet count before treatment was 13×10^9/L (range 1-30×10^9/L). The four-week response rate was 63.2% (12/19), and the median response time was 7.5 days (range 5 to 35 days). There were no treatment-related adverse reactions. Conclusions Low-dose rhTPO plus IVIg in pregnant corticosteroid/IVIg monotherapy-resistant ITP patients is effective and safe. These findings suggest that IVIg plus low-dose rhTPO may represent a potential combination therapy for pregnant patients with ITP.

Common-sense combination therapy in refractory immune thrombocytopaenia.

Common-sense combination therapy in refractory immune thrombocytopaenia.

High Immature Platelet Fraction is Associated with Early Neurological Deterioration in Acute Ischemic Stroke (P3-5.007)

<h3>Objective:</h3> To investigate the association between the level of immature platelet fraction (IPF) and the prevalence of early neurological deterioration (END) in acute ischemic stroke patients. <h3>Background:</h3> Early neurological deterioration (END) in acute ischemic stroke is a common event. However, the underlying pathophysiological bases are heterogenous and hard to explain. Immature platelet fraction (IPF) is the useful marker of increased platelet production and turnover which could occur in patients with increased platelet activation. High value of IPF was reported in acute coronary syndrome. <h3>Design/Methods:</h3> A total 1655 of acute ischemic stroke patients in single tertiary academic center was enrolled from January 2013 to October 2018 via stroke registry. IPF levels were quantified by whole blood flow cytometry with automated assays (Sysmex XE-2100™). High IPF was defined as the IPF level was more than 5%. Early neurological deterioration was defined as an increment change of at least one point in motor power or total National Institute of Health Stroke Scale (NIHSS) score deterioration ≥2 points within the first week after admission. <h3>Results:</h3> A total of 72 patients (4.4%) experienced END. END was more prevalent in the patients with high IPF [13 (11.7%) vs 59 (3.8%), p&lt;0.0001]. Multivariate logistic regression analysis showed high IPF was an independent predictor of the prevalence of END (adjust odds ratio = 1.32; 95% confidence interval = 1.03–1.70). <h3>Conclusions:</h3> A high IPF levels was associated with the prevalence of END in acute ischemic stroke patients. Future investigation might be needed to evaluate the effective treatment of the high IPF in acute phase of ischemic stroke. <b>Disclosure:</b> Bang-Hoon Cho has nothing to disclose. The institution of Sung-Wook Yu has received research support from Yuhan.

Iron is a modifier of the phenotypes of JAK2-mutant myeloproliferative neoplasms

AbstractJAK2-V617F mutation causes myeloproliferative neoplasms (MPNs) that can manifest as polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis. At diagnosis, patients with PV already exhibited iron deficiency, whereas patients with ET had normal iron stores. We examined the influence of iron availability on MPN phenotype in mice expressing JAK2-V617F and in mice expressing JAK2 with an N542-E543del mutation in exon 12 (E12). At baseline, on a control diet, all JAK2-mutant mouse models with a PV-like phenotype displayed iron deficiency, although E12 mice maintained more iron for augmented erythropoiesis than JAK2-V617F mutant mice. In contrast, JAK2-V617F mutant mice with an ET-like phenotype had normal iron stores comparable with that of wild-type (WT) mice. On a low-iron diet, JAK2-mutant mice and WT controls increased platelet production at the expense of erythrocytes. Mice with a PV phenotype responded to parenteral iron injections by decreasing platelet counts and further increasing hemoglobin and hematocrit, whereas no changes were observed in WT controls. Alterations of iron availability primarily affected the premegakaryocyte-erythrocyte progenitors, which constitute the iron-responsive stage of hematopoiesis in JAK2-mutant mice. The orally administered ferroportin inhibitor vamifeport and the minihepcidin PR73 normalized hematocrit and hemoglobin levels in JAK2-V617F and E12 mutant mouse models of PV, suggesting that ferroportin inhibitors and minihepcidins could be used in the treatment for patients with PV.

Eltrombopag Causes Cell Cycle Arrest of T Cells through Iron Chelation and Could Modulate the Immune Response in ITP

Background Thrombopoietin receptor agonists (TPO-RAs) are the recommended second line treatment in most guidelines for immune thrombocytopenia (ITP) allowing patients to avoid immunosuppressive treatments (Provan et al and Neunert et al 2019). Three different TPO-RAs are licensed for use in ITP. Real world evidence has shown that if patients do not respond to one agent, they may respond to another. This is thought to relate to different signalling pathways, and possibly one TPO-RA creating a stronger signal than another (Olnes et al, 2012; D'Arena et al, 2013). Nonetheless, it is difficult to fully explain responses on switching agents, especially a response to Eltrombopag (ELT) when Romiplostim (ROMI) has failed. In addition to being a TPO-RA, ELT is a small molecule peptide, which chelates cations, in particular iron and calcium. We have previously shown its ability to shuttle iron out of cells, and the impact this has on liver, cardiac and megakaryocyte cells in vitro (Roth et al, 2012; Vlachodimitropoulou et al, 2016, Liu et al 2022). We previously reported that ELT has an anti-proliferative effect on stimulated Jurkat and primary T cells, and demonstrated that patients on ELT have a reduced frequency of terminally differentiated effector (TEMRA) CD8 T cells compared to patients on ROMI (Sayed et al, ASH, 2019). We propose that this is related to an intracellular iron chelation effect, which could either explain or be additive to its megakaryocyte stimulating effect in ITP. In this study, we further explored the immunomodulatory effect of ELT on CD8 T cells in ITP. Methods Primary T cells were stimulated with Dynabeads Human T-Activator CD3/CD28 in the presence of ELT, ROMI, Deferoxamine (DFX) or human recombinant TPO (rhTPO) at increasing doses based on their calculated therapeutic serum levels. DFX and rhTPO act as positive control for iron chelation and TPO-R, respectively. Cell cycle was measured using Propidium Iodide (PI) and analysed using flow cytometry. To explore the in vivo effect of ELT, we measured CD8 TEMRA cells before and after treatment in a cohort of patients with ITP treated with ELT. Results Primary T cells treated with ELT resulted in cell cycle arrest to G1 phase. This effect was more pronounced with increasing doses of ELT. DFX exhibited similar effect on primary T cells, however, the induction of G1 phase cell cycle arrest was less potent than ELT. ROMI and rhTPO did not affect cell cycle progression of primary T cells (Figure 1). To confirm whether this cell cycle arrest was due to the iron chelating properties of ELT, we treated the arrested primary T cells with ammonium iron (III) for 24 hours, and found that cell cycle was able to be rescued. We further investigated the immunomodulatory effect of ELT in patients with ITP by assessing CD8 TEMRA cells (CD45RA+CD62L-) before and after ELT treatment. We found that patients who responded to ELT had a reduction in the frequency of TEMRA cells correlating to their platelet count. An example shown in Figure 2 of a patient who had previously failed ROMI, Mycophenolate Mofetil (MMF) and Rituximab, and subsequently responded to ELT. Prior to ELT, at low platelet count, patient presented with high frequency of CD8 TEMRA cells. Response to ELT resulted in an increased platelet count and a corresponding fall in CD8 TEMRA cells. Discussion Here we show that ELT suppresses the proliferation of T cells, through cell cycle arrest via its iron chelating properties. We propose that this could have a dual impact in patients with ITP, increasing platelet production as well as dampening down the immune response, hence explaining why switching to ELT could be effective if other TPO-RAs have failed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune Thrombocytopenia (Itp) In Emergency Medicine

Immune Thrombocytopenia (ITP) is an autoimmune disorder characterised by a low platelet countless than 100? ×? 10^9/L, purpura, and hemorrhagic episodes induced by antiplatelet autoantibodies without anemia or leukopenia. Immune thrombocytopenia (ITP) occurs in 2 to 4/100? 000 adults. A wide range of signs and symptoms, from modest mucocutaneous petechiae to severe, life-threatening organ haemorrhage, are seen in ITP patients. they may present to the emergency department (ED) with life-threatening bleeding as a result of their thrombocytopenia. ITP has two distinct clinical syndromes, manifesting as an acute condition in children and a chronic condition in adults. IgG autoantibodies make circulating platelets more sensitive. It causes these cells to be removed more quickly by antigen-presenting cells (macrophages) of the spleen, and occasionally the liver or other components of the monocyte-macrophage system. Current evidence supports alternatives to splenectomy for second-line management of patients with persistently low platelet counts and bleeding. By increasing platelet production, bone marrow compensates for platelet breakdown. Immune Thrombocytopenia most commonly arises within a few weeks after a viral infection in healthy children and young adults. Immunosuppressive treatment is usually effective in treating ITP. Many patients with ITP require no emergent treatment. However, the emergency physician should start treatment with a platelet transfusion, corticosteroids, and intravenous immune globulin (IVIG) as soon as the patient with suspected ITP arrives at the ED with serious haemorrhage.The diagnosis is usually made by ruling out all known causes of thrombocytopenia. This review aims to summarize current evidences regarding prevalence, causes, diagnosis and management of immune thrombocytopenia. Keywords:,,,

Thrombocytopenia in chronic liver disease: Physiopathology and new therapeutic strategies before invasive procedures.

Chronic liver disease is characterized by several hematological derangements resulting in a complex and barely rebalanced haemostatic environment. Thrombocytopenia is the most common abnormality observed in these patients and recent advances have led to researchers focus the attention on the multifactorial origin of thrombocytopenia and on the key role of thrombopoietin (TPO) in its physiopathology. Severe thrombocytopenia (platelet count < 50000/μL) complicates the management of patients with chronic liver disease by increasing the potential risk of bleeding for invasive procedures, which may be therefore delayed or canceled even if lifesaving. In the very last years, the development of new drugs which exceed the limits of the current standard of care (platelet transfusions, either immediately before or during the procedure) paves the way to a new scenario in the management of this population of patients. Novel agents, such as the TPO-receptor agonists avatrombopag and lusutrombopag, have been developed in order to increase platelet production as an alternative to platelet transfusions. These agents have demonstrated a good profile in terms of efficacy and safety and will hopefully allow reducing limitations and risks associated with platelet transfusion, without any delay in scheduled interventions. Altogether, it is expected that patients with chronic liver disease will be able to face invasive procedures with one more string in their bow.

Anchoring IgG-degrading enzymes to the surface of platelets selectively neutralizes antiplatelet antibodies

AbstractImmune thrombocytopenia (ITP) is an acquired bleeding disorder characterized by immunoglobulin G (IgG)–mediated platelet destruction. Current therapies primarily focus on reducing antiplatelet antibodies using immunosuppression or increasing platelet production with thrombopoietin mimetics. However, there are no universally safe and effective treatments for patients presenting with severe life-threatening bleeding. The IgG-degrading enzyme of Streptococcus pyogenes (IdeS), a protease with strict specificity for IgG, prevents IgG-driven immune disorders in murine models, including ITP. In clinical trials, IdeS prevented IgG-mediated kidney transplant rejection; however, the concentration of IdeS used to remove pathogenic antibodies causes profound hypogammaglobulinemia, and IdeS is immunogenic, which limits its use. Therefore, this study sought to determine whether targeting IdeS to FcγRIIA, a low-affinity IgG receptor on the surface of platelets, neutrophils, and monocytes, would be a viable strategy to decrease the pathogenesis of antiplatelet IgG and reduce treatment-related complications of nontargeted IdeS. We generated a recombinant protein conjugate by site-specifically linking the C-terminus of a single-chain variable fragment from an FcγRIIA antibody, clone IV.3, to the N-terminus of IdeS (scIV.3-IdeS). Platelets treated with scIV.3-IdeS had reduced binding of antiplatelet IgG from patients with ITP and decreased platelet phagocytosis in vitro, with no decrease in normal IgG. Treatment of mice expressing human FcγRIIA with scIV.3-IdeS reduced thrombocytopenia in a model of ITP and significantly improved the half-life of transfused platelets expressing human FcγRIIA. Together, these data suggest that scIV.3-IdeS can selectively remove pathogenic antiplatelet IgG and may be a potential treatment for patients with ITP and severe bleeding.

CORRELATION BETWEEN PLATELET COUNT, D-DIMER AND DISEASE OUTCOME IN PATIENTS ADMITTED WITH COVID 19 DISEASE IN A TERTIARY CARE CENTRE

Corona virus disease 2019 (COVID 19) is a novel infectious disease which causes a spectrum of disease with respiratory and systemic inammation which leads to severe disease in 10 – 15 % of patients. Some patients develop a severe proinammatory state which can be associated with a unique coagulopathy leading to complications like ARDS and DIC. COVID 19 is a disease which lacks established laboratory markers available to evaluate illness severity and disease outcome. COVID 19 patients often have thrombocytopenia (5-41%) and appear to have increased platelet consumption, together with a corresponding increase in platelet production. The degree of D-dimer elevation positively correlates with morbidity in COVID 19 patients. Platelet count and D-dimer may be used as biomarkers to assess disease severity and may be useful for triaging patients and predicting the outcome of disease in resource limited settings.

A Phase II Study to Investigate the Efficacy and Safety of Eltrombopag in Combination with Dexamethasone As First-Line Treatment in Adults Patients with Newly Diagnosed Primary ITP (XPAG-ITP)

A Phase II Study to Investigate the Efficacy and Safety of Eltrombopag in Combination with Dexamethasone As First-Line Treatment in Adults Patients with Newly Diagnosed Primary ITP (XPAG-ITP)

THE USE OF ROMIPLOSTIM IN AN INFANT

Immune thrombocytopenia (ITP) is the most common platelet disorder in children, peaking between the ages of 1-7.The first line therapy consists of intravenous immunoglobulin, anti-D immunoglobulin or corticosteroids. Second-line treatment options are immunosuppressive therapy, Rituximab.Thrombopoietin receptor agonists are used, which increase platelet production in the bone marrow. Our case report on a child with refractory chronic ITP, who failed the first and second line therapy.

Immature platelet fraction is associated with early neurological deterioration in acute ischemic stroke

Early neurological deterioration (END) in acute ischemic stroke occurs frequently. This phenomenon has a heterogeneous pathomechanism. Immature platelet fraction (IPF) is known as the useful marker of increased platelet production and turnover which could occur in patients with increased platelet activation. We investigated whether the IPF is associated with the prevalence of END in acute ischemic stroke patients.