Pathogenesis Of Thrombocytopenia Research Articles

A Comprehensive Review Article on Dengue Fever

Dengue fever is a contagion- caused complaint that is spread by mosquitoes. Dengue is an acute viral illness caused by RNA contagion of the family Flaviviridae and spread by Aedes mosquitoes. A womanish Aedes aegypti mosquito carrying a blood- mess from a mortal host through her honker which penetrates the host’s skin. That occurs in tropical and tropical areas of the world. The complaint is now endemic in farther than 100 countries in the WHO Regions, analogous as the Americas, Africa, the Middle East, Asia, and the Pacific islands & also other countries who can suffered these world wide spread complaint. About half of the world’s population is now at trouble of dengue with an estimated 100 – 400 million infections being each time. The severe form of dengue fever, also called dengue hemorrhagic fever, can beget serious bleeding, a unlooked-for drop in blood pressure (shock) and death. Symptoms include high fever, severe headache, joint and muscle pain, nausea, and puking. Treatment for dengue fever includes supportive care, analogous as rest and fluids. The complex pathogenesis of thrombocytopenia and increased vascular permeability in dengue illness is also mooted. The composition give a detailed overview on dengue contagion infection, medium, symptoms, discriminative opinion & prevention & treatment.

Research progress on pathogenesis of thrombocytopenia associated with TAVI

Research progress on pathogenesis of thrombocytopenia associated with TAVI

Gene mutations in the PI3K/Akt signaling pathway were related to immune thrombocytopenia pathogenesis.

Immune thrombocytopenic (ITP) is an autoimmune bleeding disease with genetic susceptibility. Twenty newly diagnosed active primary ITP patients who had not been treated with glucocorticosteroids, immune globulin or immunosuppressants prior to sampling were enrolled in this study. Bone marrow blood mononuclear cells were used for whole exome sequencing to further elucidation the variant genes of ITP. High-molecular-weight genomic DNA was extracted from freshly frozen bone marrow blood mononuclear cells from 20 active ITP patients. Next, the samples were subjected to molecular genetic analysis by whole-exome sequencing, and the results were confirmed by Sanger sequencing. The signaling pathways and cellular processes associated with the mutated genes were identified with gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. The results showed that there were 3998 missense mutations involving 2269 genes in more than 10 individuals. Unique genetic variants including phosphatase and tensin homolog, insulin receptor, and coagulation factor C homology were the most associated with the pathogenesis of ITP. Functional analysis revealed these mutation genes mainly affect Phosphatidylinositol 3 kinase/serine/threonine kinase B signaling pathways (signal transduction) and platelet activation (immune system). Our finding further demonstrates the functional connections between these variant genes and ITP. Although the substantial mechanism and the impact of genetic variation are required further investigation, the application of next generation sequencing in ITP in this paper is a valuable method to reveal the genetic susceptibility.

Introduction of direct-acting antiviral agents alters frequencies of anti-GPIIb/IIIa antibody-producing B cells in chronic hepatitis C patients with thrombocytopenia

The pathogenesis of thrombocytopenia in chronic hepatitis C (CHC) conceivably involves autoimmunity; however, the dynamics of autoantibodies and other autoimmune mechanisms remain unclear. In this study, we examined the changes in the frequency of anti-glycoprotein (GP) IIb/IIIa antibody-producing B cells and the levels of plasma B-cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL), and interleukin (IL)-21 following treatment of CHC with direct-acting antiviral agents (DAA). We recruited 28 patients with CHC who underwent treatment with DAA for 8–12 weeks and subsequently tested negative for serum hepatitis C virus RNA. Thirty healthy controls were recruited for comparison. Platelet counts increased significantly (p = .016), and the frequency of anti-GPIIb/IIIa antibody-producing B cells decreased significantly (p = .002) in CHC patients with thrombocytopenia at the end of treatment (EOT) than before DAA treatment (baseline). However, these changes were not observed in CHC patients without thrombocytopenia. Plasma BAFF levels in CHC patients with thrombocytopenia significantly decreased from baseline to EOT (p = .002). Anti-GPIIb/IIIa antibody-producing B cells were positively correlated with plasma BAFF levels in these patients (r = 0.669, p = .039). These results suggest that DAA treatment suppresses the autoimmune response against platelets and improves thrombocytopenia.

Elevated TNF-α Induces Thrombophagocytosis by Mononuclear Cells in ex vivo Whole-Blood Co-Culture with Dengue Virus.

BackgroundInfection with dengue virus (DENV) causes hematological complications in dengue diseases characterized by thrombocytopenia accompanied by macrophage activation syndrome and hemophagocytosis in fatal patients.MethodsIn this study, we investigate the undefined mechanisms underlying the progression of thrombocytopenia caused by thrombophagocytosis based on an ex vivo whole-blood co-culture model of DENV infection for mimicking the acute febrile phase of infection.ResultsIn this model, complete blood count test showed a decrease in monocytes (p < 0.01), but not neutrophils nor other white blood cells, accompanied by a low thrombocyte count (p < 0.01) in DENV infection with a positive correlation (r = 0.636, p < 0.05). Furthermore, DENV exposure caused significant thrombophagocytosis in mononuclear cells (p < 0.05). Abnormal production of tumor necrosis factor (TNF)-α was highly associated with induction of thrombophagocytosis (r = 0.758, p < 0.01), decreased monocytes (r = −0.758, p < 0.01), and decreased thrombocyte (r = −0.728, p < 0.01). Neutralizing TNF-α considerably (p < 0.05) reversed such DENV-induced effects and was further validated by immunostaining-based flow cytometry analysis on mononuclear CD14 positive monocytes. Exogenous administration of TNF-α effectively caused thrombophagocytosis accompanied by decreased monocytes and thrombocytes, probably causing monocyte activation.ConclusionThese results demonstrate the potential pathogenesis of thrombocytopenia caused by TNF-α-induced thrombophagocytosis in monocytes during DENV infection.

Modern approach to the diagnosis and treatment of thrombocytopenia

Normally, the number of platelets in a healthy adult is in the range of 150-320 x 10⁹. A condition in which their number falls below 150x10⁹ is called thrombocytopenia. It can be both associated with a violation of the process of platelet formation in the bone marrow (in particular, with aplastic anemia, hemoblastosis, thrombocytopenic purpura), and be a concomitant pathology, for example, be a consequence of drug treatment of a number of somatic diseases. In the pathogenesis of thrombocytopenia, three main directions are distinguished: a decrease in platelet production, an acceleration of their decay and a violation of the distribution of the platelet pool with their sequestration in the spleen. Most often, drug thrombocytopenia develops against the background of the use of cytostatics, chloramphenicol, antithyroid drugs, NSAIDs. The decrease in the number of platelets can also be influenced by the regular use of alcohol, some infectious diseases, and immunodeficiency states. The main clinical manifestation of thrombocytopenia is hemorrhagic syndrome, proceeding as petechial rashes or ecchymosis, however, in some cases, clinical manifestations may be absent, and then the diagnosis is made on the basis of a clinical blood test. Treatment of thrombocytopenia is carried out taking into account the etiological factor that caused it.

Abstract 13784: Thrombopoietin Restores Megakaryopoiesis By Protecting Bone Marrow Endothelial Progenitor Cells Of Patients With Hematologic Malignancies Undergoing Chemotherapy

Introduction and Objective: Thrombocytopenia is the most common side effect of patients with hematologic malignancies undergoing chemotherapy. Platelet production depends on a good bone marrow (BM) microenvironment, especially the endothelial progenitor cells (EPC), which play an important role in angiogenesis and thus supporting megakaryopoiesis. However, little is known regarding the function of EPC in patients with hematologic malignancies. Therefore, the present study aimed to examine the role of EPC in angiogenesis and megakaryopoiesis, and the effect of thrombopoietin (TPO) on EPC in patients with hematologic malignancies. Methods: Twenty-three patients with ALL or AML, and ten age-matched healthy donors were recruited in the present study. EPCs were isolated from BM mononuclear cells. The cell count, proliferation, migration, and tube formation assays were conducted. Megakaryocytes were quantified by flow cytometry after coculturing with EPC in the absence and presence of TPO (100 ng/ml). In addition, transgenic zebrafish with vascular endothelial cells expressing EGFP [Tg(fli-1:EGFP)] were used to examine the angiogenic effect of TPO. Simvastatin was used to induce vascular defects in zebrafish embryos. The embryos were then treated with or without TPO (10 -3 U/μl) by intravenous injection before fluorescent images were captured. Results: The number of BM EPC was significantly smaller in patients with ALL and AML than in healthy donors. The BM EPCs from patients showed significantly reduced proliferation, migration and tube formation when compared to those from healthy donors. TPO (100 ng/ml) significantly improved those functions of EPC, and significantly increased the number of megakaryocytes after coculture. In Tg(fli-1:EGFP) zebrafish embryos, TPO (10 -3 U/μl) significantly increased the SIV vascularized area in the presence of simvastatin. Conclusion: The present study shows that dysfunctional BM EPC contributes to the pathogenesis of thrombocytopenia in patients with hematologic malignancies undergoing chemotherapy; and such impaired functions of BM EPC could be restored by TPO. In addition, TPO increases the number of megakaryocytes after coculture with EPC in vitro and promotes angiogenesis in zebrafish embryos.

Thrombocytopenia in COVID-19: Focused Summary of Current Understanding of Mechanisms and Clinical Implications.

Thrombocytopenia is noted in corona virus disease-2019 (COVID-19) with a prevalence of 5% to 41%, and has been observed to be associated with inferior outcomes. The pathogenesis of thrombocytopenia in COVID-19 is unique and differs from other viral syndromes in terms of clinical presentation and causative mechanisms. Platelets act as both targets and the initial defense against severe acute respiratory syndrome-coronavirus 2 and work in concert with the underlying thrombophilic mechanisms to modulate the final disease phenotype. Understanding these mechanisms may possibly allow targeting of a key component of COVID-19 pathogenesis. We provide a focused review of the current mechanisms implicated in development of thrombocytopenia in COVID-19 and therapeutic implications of the same.

M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity

Dysfunctional megakaryopoiesis hampers platelet production, which is closely associated with thrombocytopenia (PT). Macrophages (MФs) are crucial cellular components in the bone marrow (BM) microenvironment. However, the specific effects of M1 MФs or M2 MФs on regulating megakaryocytes (MKs) are largely unknown. In the current study, aberrant BM-M1/M2 MФ polarization, characterized by increased M1 MФs and decreased M2 MФs and accompanied by impaired megakaryopoiesis-supporting abilities, was found in patients with PT post-allotransplant. RNA-seq and western blot analysis showed that the PI3K-AKT pathway was downregulated in the BM MФs of PT patients. Moreover, in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MФs from PT patients. Furthermore, we found M1 MФs suppress, whereas M2 MФs support MK maturation and platelet formation in humans. Chemical inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MФs, as indicated by decreased MK count, colony-forming unit number, high-ploidy distribution, and platelet count. Importantly, genetic knockdown of the PI3K-AKT pathway impaired the megakaryopoiesis-supporting ability of MФs both in vitro and in a MФ-specific PI3K-knockdown murine model, indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 MФs. Furthermore, our preliminary data indicated that TGF-β released by M2 MФs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in MKs. Taken together, our data reveal that M1 and M2 MФs have opposing effects on MKs in a PI3K-AKT pathway-dependent manner, which may lead to new insights into the pathogenesis of thrombocytopenia and provide a potential therapeutic strategy to promote megakaryopoiesis.

Immature Platelet Fraction: Its Clinical Utility in Thrombocytopenia Patients

Objectives Etiology of thrombocytopenia is multifactorial and its pathogenesis should be distinguished for appropriate management. Newly formed immature platelets are called reticulated platelets (RPs) and can be estimated in peripheral blood using automated hematology analyzers, which express them as immature platelet fraction (IPF). In the present study we intend to assess and establish the clinical utility of IPF in differentiating the two major causes of thrombocytopenia—decreased production and increased destruction of platelets—along with determining its significance in monitoring patients with thrombocytopenia. Materials and Methods Sixty-one cases of thrombocytopenia and 101 healthy controls with normal platelet count were included in the study. IPF and all the other usual blood cell parameters were measured using a fully automated hematology analyzer. Based on the pathogenesis of thrombocytopenia, the cases were divided into groups and the difference in IPF value between the groups was evaluated. Results The reference range of IPF among healthy controls was estimated to be 0.7 to 5.7%. The mean IPF was significantly higher in patients with increased peripheral destruction of platelets (13.4%) as compared to patients with decreased production of platelets (4.6%). The optimal cutoff value of IPF for differentiating patients with increased peripheral destruction of platelets from patients with decreased production of platelets was 5.95% with a sensitivity of 88% and specificity of 75.9%. Conclusion Measurement of IPF is useful for detecting evidence of increased platelet production and helps in the initial evaluation of thrombocytopenia patients. It is a novel diagnostic method which can be used to differentiate patients with thrombocytopenia due to increased destruction of platelets from patients with thrombocytopenia due to bone marrow failure/suppression.

Apoptosis in platelets from adult patients with chronic idiopathic thrombocytopenic purpura.

Adult chronic idiopathic thrombocytopenic purpura (cITP) is a chronic and usually life-long haemorrhagic disorder in which enhanced platelet destruction and weakened platelet production lead to thrombocytopenia. Platelets were isolated from blood samples collected from 40 adult patients with cITP and 40 healthy volunteers. Mitochondrial membrane potential (ΔΨm) and plasma membrane phosphatidylserine externalization were determined by flow cytometry, and activation of caspase-3 and expressions of Bax, Bak and Bcl-xL were analysed by western blotting. Flow cytometry showed increased mitochondrial depolarization and lower ΔΨm in platelets from adult patients with cITP. In addition, plasma membrane phosphatidylserine externalization was observed on platelets from adult patients with cITP, but rarely from healthy volunteers. Western blot analysis of platelet proteins revealed that, in adult cITP patients, caspase-3 was activated, which cleaved gelsolin and to release a 47-kDa fragment. Moreover, the expressions of Bax and Bak were elevated, and Bcl-xL was decreased markedly in platelets from adult patients with cITP. Our findings reveal, based on loss of mitochondrial membrane potential (Δψm), phosphatidylserine exposure, caspase-3 activation, enhanced expression of Bax and Bak, and attenuated expression of Bcl-xL, that platelet death in the pathogenesis of thrombocytopenia in chronic ITP in adults is apoptotic.

Kupffer cell receptor CLEC4F is important for the destruction of desialylated platelets in mice

The liver has recently been identified as a major organ for destruction of desialylated platelets. However, the underlying mechanism remains unclear. Kupffer cells, which are professional phagocytic cells in the liver, comprise the largest population of resident tissue macrophages in the body. Kupffer cells express a C-type lectin receptor, CLEC4F, that recognizes desialylated glycans with an unclear in vivo role in mediating platelet destruction. In this study, we generated a CLEC4F-deficient mouse model (Clec4f−/−) and found that CLEC4F was specifically expressed by Kupffer cells. Using the Clec4f−/− mice and a newly generated platelet-specific reporter mouse line, we revealed a critical role for CLEC4F on Kupffer cells in mediating destruction of desialylated platelets in the liver in vivo. Platelet clearance experiments and ultrastructural analysis revealed that desialylated platelets were phagocytized predominantly by Kupffer cells in a CLEC4F-dependent manner in mice. Collectively, these findings identify CLEC4F as a Kupffer cell receptor important for the destruction of desialylated platelets induced by bacteria-derived neuraminidases, which provide new insights into the pathogenesis of thrombocytopenia in disease conditions such as sepsis.

Current approaches to the use of antiplatelet and anticoagulant drugs in pregnant women with thrombocytopenia caused by hemostasis activation

Introduction. At present, hemostasis disorders still hold one of the lead places in the pathogenesis of reproductive losses associated with high risk of miscarriage and remain one of the major causes for developing serious obstetric complications. Relevance, efficacy and safety of using drugs containing acetylsalicylic acid (ASA) and low molecular weight heparins (LMWH) in pregnant women with thrombocytopenia comorbid with intravascular coagulation activation remain pressing issues. The study of thrombocytopenia pathogenesis during pregnancy and search for new methods of hemostasis correction are accounted for by high risk of developing diverse perinatal complications and necessity to conduct prophylactic measures for their prevention.Aim: to study hemostasis changes and clinical outcomes in pregnant women with thrombocytopenia, to substantiate the use of antiplatelet agents and anticoagulants in pregnant women with activated intravascular blood coagulation for preventing development of thromboembolic and placenta-associated complications of pregnancy.Materials and Methods. A multicenter prospective study was conducted by enrolling 299 pregnant women at a gestational age of22.85 [22.00; 25.00] weeks, whose average age was 31.06 [27.75; 35.00] years. There were distinguished three groups: main group (n = 124) consisted of pregnant women with lowered platelet count and activated intravascular blood coagulation, who received ASA preparations and LMWH in prophylactic doses for 4 weeks; pregnant comparison groups (n = 125) received no such drugs; control group (n = 50) consisted of women with normal platelet counts during physiological pregnancy. All patients underwent clinical, anamnestic and laboratory examination, and the clinical outcomes of pregnancy were assessed.Results. It was found that use of ASA (a combined drug: ASA 75 mg + magnesium hydroxide 15.2 mg/day) and LMWH (enoxaparin sodium) in pregnant women from the main group were noted to improve hemostasis parameters: via markedly increased platelet count, decreased fibrinogen level, prothrombin index as well as normalized antithrombin III level (p &lt; 0.01). It was also found during treatment that the D-dimer level and the rate (83.6 ± 2.3 % and 72.4 ± 2.7 %) and the degree (86.4 ± 2.7 % and 74.4 ±2.8 %) of platelet aggregation in the main group (in contrast with comparison group) were significantly decreased (p &lt; 0.01). The frequency of detected chronic placental insufficiency was significantly higher (p &lt; 0.01) in the comparison group (n = 50; 41.32 %) vs. the main group after receiving ASA and LMWH (n = 20; 16.52 %). The incidence of moderate (p = 0.016) and severe (p = 0.018) preeclampsia was significantly higher in the comparison group vs. the main group. While comparing the volume of blood loss during delivery, there were no differences between the main group and the comparison group (p = 0.46); it was noted only a statistically significant difference compared to the control group (p = 0.04), in which the lowest blood loss was found (337.9 [200.0; 600.0] ml) in comparison with the other two groups (p1,3 = 0.05; p2,3 = 0.04). It should be noted that the volume of blood loss in all groups remained within the physiological permissible range.Conclusion. Our clinical and laboratory study allowed to substantiate relevance of using ASA and LMWH drugs in pregnant women with thrombocytopenia comorbid with confirmed activation of intravascular blood coagulation, for prevention of thromboembolic and placenta-associated complications of pregnancy as well as proved safety of such drugs during pregnancy.

Discussion issues of management of pregnant women with thrombocytopenia

The study of the pathogenesis of thrombocytopenia during pregnancy remains a very important problem, since hemostatic abnormalities continue to occupy one of the leading places among the causes of infertility, miscarriage and a large number of perinatal complications. Pregnant women with thrombocytopenia constitute a risk group for the development of bleeding events and thrombotic complications during pregnancy, in childbirth, and in the postpartum period. This article reviews literature data on the pathogenic causes of thrombocytopenia during pregnancy and on the main methods of treatment of the disease.

Plasmacytoid Dendritic Cells Surveil Megakaryocyte Sialic Acid to Regulate Thrombopoiesis

The Thomsen-Friedenreich antigen (TF-antigen) occurs during exposure of the underlying Core-1 disaccharide (Gal-beta(1,3)GalNAc) through the loss of its capping sialic acid (Sia). Exposure of the cryptic TF-antigen occurs during inflammation, during acute infections with influenza viruses or bacteria, in malignancies, and is associated with thrombocytopenia. Exposure of the TF-antigen on circulating blood cells, including platelets and red blood cells (RBC), can lead to severe thrombocytopenia or hemolysis in hemolytic uremic syndrome and other immune diseases. Recent data suggest that altered Sia may cause platelet destruction because treatment with the sialidase inhibitor Tamiflu increases platelet count in healthy and thrombocytopenic patients. In humans, genetic mutations involving Sia synthesis and transport, and atypical cell surface sialylation, unrelated to any genetic mutation, are associated with reduced platelet count, supporting the role of Sia in regulating platelet count. Immune cells, including classical dendritic cells (cDCs), plasmacytoid dendritic cells (pDCs), and subsets of T cells (CD8+, CD4+, and Treg cells) can also affect immune thrombocytopenia pathogenesis. Like many other immune cells, cDCs, and pDCs express Siglecs (sialic-acid-binding immunoglobulin-like lectins), which often contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that act as immunosuppressors. Whether BM immune cells monitor MKs via glycan-lectin receptors, including Siglecs and Sia interactions, to control platelet production is unclear. To investigate the role of the TF-antigen in thrombopoiesis, we generated St3gal1MK-KO mice (Pf4-Cre) that display increased TF-antigen specifically in megakaryocytes (MK) and platelets. St3gal1MK-KO mice developed significant thrombocytopenia, but had normal platelet half-life, suggesting that the TF-antigen affected BM thrombopoiesis. In vitro MK maturation and proplatelet production from primary ST3Gal1MK-KO mouse BM cells were also normal, pointing to extrinsic factors in the BM environment affecting thrombopoiesis. Platelet counts of St3gal1MK-KO mice were restored to wild-type levels by 1) crossing St3gal1MK-KO mice with Jak3KO mice that have impaired of lymphoid cell development, 2) by treatment with anti-inflammatory dexamethasone, and 3) treatment with a depleting anti-CD4 antibody. Immunofluorescence staining of the St3gal1MK-KO BM revealed proplatelet structures positive for GPIba+ and the TF-antigen, being infiltrated by mononuclear cells resembling lymphocytes. We speculated that immune cells surveil megakaryocytes to control thrombopoiesis. Bulk RNAseq of CD4+ cells in St3gal1MK-KO BM confirmed a population bias for Type I interferon (IFN-I)-releasing pDCs, a cell type regulated by unique sialic acid binding lectins (Siglecs). Inhibition of IFN-I activity, by a blocking receptor antibody improved platelet counts in St3gal1MK-KO mice. Co-cultures of pDCs with MKs show inhibited pro-platelet formation when TF-antigen is present on MKs with elevated IFN-I levels. Gene set enrichment analysis of BM pDCs single cell RNASeq (scRNAseq) data further confirmed that TF-antigen exposure by MKs up-regulates IFN-I transcripts. scRNAseq also reveals a new population of immune cells with pDC transcript signature and concomitant upregulation of immunoglobulin re-arrangement gene transcripts Igkc and Ighm. In conclusion, the data shows that recognition of aberrant MK sialylation by pDCs regulates thrombopoiesis through IFN-I secretion. Disclosures No relevant conflicts of interest to declare.

Pathogenesis of Thrombocytopenia in Chronic HCV Infection: A Review.

A large proportion of patients with chronic hepatitis C have associated thrombocytopenia (TCP). Due to bleeding risks, TCP, when severe, can limit diagnostic and therapeutic procedures, treatments, and increases risk of complications, especially excessive bleeding. It is important to understand the mechanisms that cause TCP in order to manage it. In general, TCP can be due to increased destruction or decreased production. Proposed mechanisms of increased destruction include autoantibodies to platelets and hypersplenism with sequestration. Proposed mechanisms of decreased production include virus-induced bone marrow suppression and decreased TPO production. Autoantibodies directed against platelet surface antigens have demonstrated an inverse correlation with platelet counts. Hypersplenism with sequestration involves the interaction of portal hypertension, splenomegaly, and platelet destruction. Decreased production mechanisms involve appropriate and inappropriate levels of TPO secretion. There is limited evidence to support viral-induced bone marrow suppression. In contrast, there is strong evidence to support low levels of TPO in liver failure as a major cause of TCP. TPO-agonists, specifically eltrombopag, have been shown in hepatitis C patients to increase platelet counts without reducing portal hypertension or splenomegaly. We conclude that TCP in hepatitis C virus-induced liver disease is often multifactorial, but an understanding of the mechanisms can lead to judicious use of new drugs for treatment.

Immature platelet fraction related parameters in the differential diagnosis of thrombocytopenia

The pathogenesis of thrombocytopenia can be divided into increased destruction (ID) of platelets in the peripheral blood and decreased production (DP) of platelets in the bone marrow. This study aimed to analyze the efficacy of immature platelet fraction (IPF) related parameters, including the IPF count (IPF#), IPF percentage (IPF%) and highly fluorescence IPF percentage (H-IPF%), measured by XN-9000, in the differential diagnosis of thrombocytopenia. One hundred and twenty healthy volunteers were enrolled in the healthy control (HC) group, and 180 thrombocytopenia patients were grouped into either the increased destruction (ID) group or the decreased production (DP) group according to their final diagnosis. IPF# was significantly lower in the DP group than in the ID and HC groups (P < .01). Among the three groups, the ID group had the highest IPF% and H-IPF%, and the HC group had the lowest IPF% and H-IPF%. The differences between the three groups were all statistically significant (P < .01). In differentiating the ID patients from the DP patients, the areas under the operating characteristics curve of IPF#, IPF% and H-IPF% were 0.859, 0.944 and 0.930, respectively. False positive rates were below 0.04 when IPF#, IPF% and H-IPF% were above 2.65, 7.55 and 2.35, respectively. IPF related parameters showed high efficacy in the differential diagnosis of thrombocytopenia. However, due to the small numerical values of the IPF related parameters in some thrombocytopenia patients, the fluctuations of IPF% and H-IPF% should also be taken into consideration. Though H-IPF% is a new parameter, its effectiveness in the differential diagnosis of thrombocytopenia is not better than IPF%’s.

PS1486 INTERLEUKIN‐33 IN PEDIATRIC PATIENTS WITH IMMUNE THROMBOCYTOPENIA: RELATION TO PROGNOSIS AND TREATMENT OUTCOME

Background:The pathogenesis of thrombocytopenia in immune thrombocytopenia (ITP) has shifted from the traditional view of increased platelet destruction mediated by autoantibodies to more complex mechanisms where both impaired platelet production and T‐cell‐mediated effects play a role. Interleukin‐33 (IL‐33) is a newly identified cytokine of the IL‐1 family. There is increasing evidence to suggest that IL‐33 is a key inflammatory mediator in a complex network of immune cells and non‐immune cells. IL‐33 signals via its ST2 receptor and is involved in several autoimmune diseases by regulating T cell immune responses.Aims:To assess the level of IL‐33 in children and adolescents with ITP and correlate it with disease severity, treatment response and outcome.Methods:Fifty young patients with ITP were compared with 40 age‐ and sex‐matched healthy controls. Patients were studied stressing on bleeding manifestations, organomegaly/lymphadenopathy and therapy. Bleeding score was calculated to each patient according to the ITP Bleeding Scale (IBLS). The studied ITP Patients were further classified into 3 subgroups: “newly diagnosed ITP” (ITP within 3 months from diagnosis), “persistent ITP” (ongoing ITP between 3 and 12 months from diagnosis), and “chronic ITP” (ITP lasting more than 12 months). ITP Patients were also classified into active ITP defined as platelet count below 100 x 109/L accompanying with or without bleeding episode or complete response (CR) which was defined as any platelet count of at least 100 × 109/L and absence of bleeding.Results:IL‐33 levels were significantly lower in ITP patients than controls (median [IQR], 150 [100 – 230] versus 210 [180–260] pg/mL; p = 0.011). Levels were also lower in chronic than newly diagnosed ITP. IL‐33 levels are lower among active ITP (median [IQR], 105 [85 – 120] pg/mL) compared with those in complete remission (median [IQR], 240 [200 – 250] pg/mL) and healthy controls (p &lt; 0.001) while no significant difference was found among the two latter groups (p = 0.197). Patients who had splenectomy had lower IL‐33 levels than non‐splenectomized ones. Lower IL‐33 levels were found among patients with corticosteroid‐dependence and relapse (p &lt; 0.05). No significant difference as regards IL‐33 between treated and un‐treated patients with active ITP. IL‐33 was positively correlated to platelet count at sampling (r = 0.714, p &lt; 0.001).Summary/Conclusion:Conclusions: Alterations of IL‐33 levels in pediatric patients with ITP highlight the role of T‐cell immune response in the pathogenesis of ITP. It may be considered as a potential prognostic marker for the development of chronic ITP as it correlates with disease activity. Further studies investigating the role of IL‐33 in the pathogenesis of ITP may provide a new therapeutic target for ITP.

Thrombocytopenia in solid tumors: Prognostic significance.

Solid tumors are a heterogeneous group of malignancies that result from out-of-control proliferation of cells. Thrombocytopenia is a common complication among patients with solid tumors that predispose them to bleeding disorders. The aim of this review article is to investigate the underlying mechanisms of the risk and incidence of thrombocytopenia in solid tumors. It can be argued that thrombocytopenia is a poor prognostic factor in solid tumors that can result from several factors such as polymorphism and mutation in some transcription factors and cytokines involved in megakaryocytic maturation or from the adverse effects of treatment. Therefore, an understanding of the exact mechanism of thrombocytopenia pathogenesis in each stage of solid tumors can help in developing therapeutic strategies to decrease bleeding complications in these malignancies.

Current Advance in Thrombopoietin Receptor Agonists in the Management of Thrombocytopenia Associated With Chronic Liver Disease: Focus on Avatrombopag.

Chronic liver disease (CLD) is a condition that progresses over time toward advanced disease state which is known as liver cirrhosis. Liver cirrhosis leads to dangerous health problems among people living across the world. One such problem that observed in about 75% of cirrhotic patients is thrombocytopenia; which in turn associated with poor prognosis and recovery from CLD. Beyond these, thrombocytopenia in cirrhotic patients led to impairment of coagulation cascade and significantly influenced the utilization of effective mechanism in the management of CLD. By nature, treatment of CLD involves invasive diagnostic and treatment procedures; therefore, in the presence of thrombocytopenia implementing these methods put the lives of patients in a critical health problem due to increased risk of bleeding and mortality. Because of these reasons, prophylactic transfusion of platelets is considered to be one of the most effective options that reduce the risk of bleeding in patients with CLD that required to undergo an invasive procedure. Although platelet transfusion presented with significant advantages in facilitating the invasive procedure in patients with CLD, refractoriness with repeated use and various problems associated with its transfusion limit the continuous utilization of this important option. With these challenges and current advance in the knowledge of thrombopoiesis, the development of relatively safe and alternative drugs that enhance the production of platelets by interacting with thrombopoietin receptor agonists provides a promising option to platelet transfusion. The discovery and approval of romiplostim and eltrombopag in August 2008 and November 2008, respectively, for the treatment of chronic immune thrombocytopenia paved a way and followed by the Food and Drug Administration (FDA) approval of 2 potentially advantageous drugs, lusutrombopag, and avatrombopag, in 2018 for the treatment of thrombocytopenia in patients with CLD that required to undergo elective surgery. Therefore, this review aims to assess pathogenesis of thrombocytopenia and its challenges in the management of liver-related issues and, more importantly, gives emphasis to address the potential use of avatrombopag in the treatment of thrombocytopenia underlying CLD, its pharmacokinetics and pharmacodynamics, as well as its toxicological profiles by presenting the most commonly reported adverse events in various trials.