Improvement In Platelet Count Research Articles

Thrombocytopenia among HIV infected patients attending a tertiary care hospital in India

Thrombocytopenia is a frequent hematological complication of human immunodeficiency virus infection which can occur at any stage of HIV infection. The various cytopenias correlate directly with the degree of immunosuppression. However, isolated thrombocytopenia, may be the initial presentation of HIV infection. Incidence of thrombocytopenia is around 10% - 40% and in some patient only thrombocytopenia may be the first sign of HIV infection or AIDS. Since few studies are available from Asian countries we decide to study thrombocytopenia in HIV infection or AIDS from India.The study was conducted at a teaching hospital in India after obtaining ethical permission from the institute. Subjects were recruited after taking written informed consent. Two hundred subjects of both sex and in the age group 18-60 years were recruited for study. Blood samples were collected and analysed on same day within two hours. Platelet count of < 1.5 lakh/mm was defined as thrombocytopenia. Data analysis was carried out using Statistical Package for Social Science (SPSS) version 16.0. p value < 0.05 considered as significant and p value > 0.05 non-significant. The mean platelet count was 2.06935lakh/ mmand highest and lowest platelet count were 4.1lakh/mm and 0.63lakh/mmrespectively. Out of two hundred, 8.5% subjects had thrombocytopenia. Females had a slightly higher prevalence as compared to males but it was not statistically significant (p=0.22). Likewise more of younger age group patients had thrombocytopenia. No significant relation was found between platelet count and ART status (p=0.773). Thrombocytopenia is a common finding in HIV infection. Peripheral destruction of platelets and ineffective platelet production leads to thrombocytopenia among HIV patients. ART improves platelet count and must be started as soon as possible.

Thrombosis in Patients with Immune Thrombocytopenia ,Review of Literature

Introduction ITP is characterized by low platelet count due to immune mediated destruction and bleeding tendency. However, during last few decades thromboembolic events have been reported in patients with ITP. This review is done to study the reported cases of thromboembolic phenomenon in patient with ITP in an attempt to assess the patient characteristics and to understand the underlying mechanism. Methods We searched google Scholar, PubMed about cases with ITP and thrombosis the summary is presented in the following table (Table 1). Results Around 30 reported cases of ITP with thrombotic events were identified and a total of 36 events were recognized in last 10 years. The ages ranged from 3 years to 81 years with a mean of 51 years. Most of the patients were young and middle aged (18-65 years of age), meanwhile around 9 patients were elderly (age > 65 years). Only 3 cases were observed in pediatric age. Almost equal incidence in both genders was recognized. Half of the patient had chronic ITP while in the rest it was diagnosed less than a year. 20 out of 36 (55.6%) events happened at platelet count less than 100*10^9. While 16 events were reported with platelet count higher than this or unknown. Majority of the patients (around 64%) developed arterial events while fewer developed venous thrombosis. For treatment, most of the patients (44%) were not receiving any particular treatment for ITP at the time of thrombotic event. While 6 events (17%) happened while being treated with IVIG and 10 events (28%') happened while on TPO-RA. Only 3 patients were treated with corticosteroids prior to the event. In patients treated with TPO-RAs arterial and venous events were almost similar (57% vs 43% respectively) while majority of the events happened at lower than normal platelet count (7/10 events). Almost half of the patients had one or more underlying risk factor predisposing to atherosclerosis and thrombosis. Most of the patients were treated appropriately for the events with either antiplatelet agents or anticoagulation while simultaneously treatment for ITP was given. Corticosteroids were most frequently used for ITP during the episode followed by IVIG (52% and 28% of total treated patients respectively). Only 1 patient was treated with TPO-RA after the event for low platelet counts while others received other treatments (Rituximab, Danazol and splenectomy). Discussion Thrombosis is a complex process involving arteries and veins. Accelerated atherosclerosis and plaque rupture is the underlying event for arterial thrombosis. While in venous thrombosis immobility and procoagulant states are the main factors. Immune thrombocytopenia is characterized by immune mediated destruction and impaired production of platelets predisposing to bleeding mostly. However, it is a unique pathological process that is linked to both bleeding and thrombosis. Multiple factors predispose patients to thrombosis in ITP. The patients with chronic and active disease are particularly at risk of paradoxical thrombosis due to accelerated atherosclerosis as in other autoimmune conditions, predisposing to arterial thrombotic events. Active disease is also characterized by increased turnover of platelets in bone marrow and higher levels of circulating platelets microparticles (PMPs) which promote thrombin formation and promote venous thrombosis. The patients treated with IVIG and TPO-RA are at higher risk as compared to other forms of treatment. IVIG is used in acute states as it prevents the destruction of platelets but simultaneously promotes thrombosis by increasing blood viscosity and thrombin production. TPO-RAs are agents which mimic the action of thrombopoietin on megakaryocytes promoting their growth and differentiation and increasing platelet production. Increasing platelet count above the normal target might contribute to thrombosis however megakaryocyte activation itself leads to increased risk of thrombosis, despite low platelet count. In patients with ITP and thrombotic events, judicious use of antiplatelet therapy and anticoagulation is indicated along with simultaneous therapy directed at improving platelet count. Conclusion Patient with active ITP are predisposed to thrombosis in addition to bleeding. A treating physician needs to be vigilant to diagnose early the events and then to institute proper use of antiplatelets and anticoagulation along with therapy directed at ITP. Figure Disclosures No relevant conflicts of interest to declare.

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.

Second‐line treatments and outcomes for immune thrombocytopenia: A retrospective study with electronic health records

BackgroundSecond‐line treatment for immune thrombocytopenia (ITP) is not well reported for patients treated in real‐world clinical settings. ObjectiveThe purpose of this study was to compare outcomes of four second‐line treatments for ITP. Patients/methodsIncluded adult patients had at least two medical records containing ITP diagnoses and second‐line eltrombopag, romiplostim, rituximab, or splenectomy. Date of treatment initiation or splenectomy was set as index date, between July 1, 2008, and March 31, 2017. Patients had first‐line corticosteroid or intravenous immune globulin treatment and continuous database activity from 6 months before to 12 months after index. Patient characteristics, treatment patterns, platelet counts, bleeding‐related episodes (BREs), and thrombotic events (TEs) were compared by second‐line treatment cohort. ResultsThe sample included 3332 patients (mean age, 60.5 years; 52.3% female): eltrombopag (5.8%), romiplostim (9.9%), rituximab (73.3%), and splenectomy (11.0%). Patients having splenectomy were younger, more likely female and commercially insured, and less likely to require a third line of treatment than medical regimen cohorts. Proportions of patients having treatment‐free (≥180 days with no second‐line index or rescue agent) periods varied significantly (P = .01) by regimen: 33% for eltrombopag, 23% for romiplostim, 26% for rituximab, and 17% for splenectomy. All regimens significantly improved platelet counts, while TE and BRE rates differed significantly (P = .03 and P = .01, respectively) when all treatment groups were compared. ConclusionsOver an average 7‐year follow‐up, all second‐line regimens improved platelet counts, but eltrombopag yielded the highest proportion of patients with completely treatment‐free periods of at least 180 days.

Severe Immune Thrombocytopenia in Pregnancy: Intravenous Immunoglobulin Can Improve Platelet Count Significantly

Background: Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by isolated thrombocytopenia, which is related to an autoimmune process. ITP is considered a diagnosis of excl...

Platelet Count Improvement after Chronic Hepatitis C Treatment among Cirrhotic Patients Who Achieved Sustained Virological Response: Realworld Results from 2186 Patients in Egypt.

This study aimed to assess the changes in platelet counts of patients with liver cirrhosis due to chronic HCV, who achieved sustained virological response (SVR) after taking direct acting antivirals (DAAs) in a large cohort study in Egypt. This multicenter observational retrospective study was carried out on 2500 chronic hepatitis C virus (HCV) infected patients who achieved (SVR) after treatment with direct acting antiviral drugs (DAA). HCV infection was confirmed by positive PCR for HCV RNA infection. SVR was defined as a negative PCR test for HCV-RNA 12 weeks after completion of DAA therapy. Platelets count was measured before therapy, during therapy, at the end of treatment, and 12 weeks after the end of the treatment. There were 2186 patients enrolled in the study; 1866 (85.4%) were treatment naïve. There were 1006 (46%) males and 1180 (54%) females. Mean age was 50.82± 11.66 years, 2142 (98%.0) patients achieved SVR, 2118 (96.9%) patients had Child -Pugh class A cirrhosis, and 68 (3.1%) had Child -Pugh class B liver cirrhosis. A significant increase in the platelets count was detected at the end of treatment in comparison to the pretreatment levels (P<0.001), and after achieving SVR (P <0.001) when compared to the pretreatment values. Improvement of platelets count occurs after HCV therapy with DAAS in patients with liver cirrhosis. These results suggested that HCV eradication may have a role in the improvement of platelet count.

The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis.

Approximately 20-50% patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKI) or with myelofibrosis (MF) treated with ruxolitinib develop grade ≥3 thrombocytopenia needing treatment interruptions and dose reductions. We conducted a non-randomized, phase II, single-arm study to determine the efficacy of eltrombopag for patients with CML or MF with persistent thrombocytopenia while on TKI or ruxolitinib. Eltrombopag was initiated at 50 mg/day, with dose escalation up to 300 mg daily allowed every 2 weeks. Twenty-one patients were enrolled (CML=15, MF=6); with a median age of 60 years (range, 31-97 years). The median platelet count was 44x109/L (range, 3-49x109/L) in CML and 62x109/L (range, 21-75x109/L) in MF. After a median of 18 months (range, 5-77 months), 12 of 15 patients with CML achieved complete platelet response. The median peak platelet count among responders was 154x109/L (range, 74-893x109/L). Among CML patients five could re-escalate the TKI dose and nine improved their response. None of the six patients with MF had a sustained response. Therapy was generally well tolerated. One patient discontinued therapy due to toxicity (elevated transaminases). One patient with CML developed significant thrombocytosis (>1,000x109/L). Another CML patient developed non occlusive deep venous thrombosis in the right upper extremity without thrombocytosis, and one MF patient had myocardial infarction. Eltrombopag may help improve platelet counts in CML patients receiving TKI with recurrent thrombocytopenia. Further studies are warranted (clinicaltrials gov. Identifier: NCT01428635).

Improved platelet counts during prolonged tranexamic therapy for Quebec platelet disorder implicate the underlying fibrinolytic defect as the cause of lower platelet counts

Improved platelet counts during prolonged tranexamic therapy for Quebec platelet disorder implicate the underlying fibrinolytic defect as the cause of lower platelet counts

Dynamics of Platelet Counts in Major Trauma: The Impact of Haemostatic Resuscitation and Effects of Platelet Transfusion-A Sub-Study of the Randomized Controlled RETIC Trial.

Although platelets play a central role in haemostasis, the dynamics of platelet counts during haemostatic resuscitation, the response to platelet transfusion, and effects on clinical outcome are poorly described for trauma patients. As a sub-study of the already published randomized controlled RETIC Study “Reversal of Trauma-induced Coagulopathy using First-line Coagulation Factor Concentrates or Fresh-Frozen Plasma” trial, we here analysed whether the type of first-line haemostatic resuscitation influences the frequency of platelet transfusion and determined the effects of platelet transfusion in coagulopathic patients with major trauma. Patients randomly received first-line plasma (FFP) or coagulation factor concentrates (CFC), mainly fibrinogen concentrate. In both groups, platelets were transfused to maintain platelet counts between 50 and 100 × 109/L. Transfusion rates were significantly higher in the FFP (n = 44) vs. CFC (n = 50) group (FFP 47.7% vs. CFC 26%); p = 0.0335. Logistic regression analysis adjusted for the stratification variables injury severity score (ISS) and brain injury confirmed that first-line FFP therapy increases the odds for platelet transfusion (odds ratio (OR) 5.79 (1.89 to 20.62), p = 0.0036) and this effect was larger than a 16-point increase in ISS (OR 4.33 (2.17 to 9.74), p = 0.0001). In conclusion, early fibrinogen supplementation exerted a platelet-saving effect while platelet transfusions did not substantially improve platelet count and might contribute to poor clinical outcome.

Impact of high plasma concentrations of linezolid in Taiwanese adult patients— therapeutic drug monitoring in improving adverse drug reactions

Previous studies have shown that the development of thrombocytopenia was associated with the elevated plasma concentration of linezolid, but little is known about the relationship between other uncommon adverse drug reactions (ADRs) and plasma concentration. The appropriate dosing adjustment has remained controversial. This prospective observational study was conducted to investigate the association between the plasma concentration of linezolid, ADRs, and clinical outcomes. Adult patients on linezolid treatment undergoing at least one therapeutic drug monitoring (TDM) were enrolled. The association between linezolid concentrations and ADRs was examined by multivariate Cox regression model. Predictors of linezolid concentrations was determined by linear regression model. The cut-off point of linezolid concentration and the effect of dosing adjustments based on TDM was also explored. Of 50 patients enrolled in the study, plasma concentrations were 1.5-3 times higher than what was described in the prescribing information. The median minimum concentration (Cmin) was significantly higher in patients with thrombocytopenia compared to patients without thrombocytopenia (13.0 vs. 7.2μg/mL, P=0.0273), and a higher median maximum concentration was also observed in patients with lactic acidosis (33.0 vs. 27.5μg/mL, P=0.0420). The Cmin was elevated in patients with advanced age and severely impaired renal function. Dosing adjustment tailored by early TDM with the upper limit of Cmin 9μg/mL may improve platelet counts. Elevated linezolid concentrations were associated with thrombocytopenia and lactic acidosis. TDM-guided dosing adjustment could be considered as a pragmatic way to mitigate thrombocytopenia.

Eltrombopag monotherapy can improve hematopoiesis in patients with low to intermediate risk-1 myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders characterized by low blood counts and a propensity to develop acute myeloid leukemia. The management of lowerrisk (LR) MDS with persistent cytopenias remains suboptimal. Eltrombopag, a thrombopoietin-receptor agonist, can improve platelet counts in LR-MDS and trilineage hematopoiesis in aplastic anemia. We conducted a phase II dose modification study to investigate the safety and efficacy of eltrombopag in LR-MDS. The eltrombopag dose was escalated from 50 mg/day to a maximum of 150 mg/day over a period of 16 weeks. The primary efficacy endpoint was hematologic response at 16-20 weeks. Eleven of 25 (44%) patients responded; five and six patients had uni- or bi-lineage hematologic responses, respectively. The predictors of response were presence of a paroxysmal nocturnal hemoglobinuria clone, marrow hypocellularity, thrombocytopenia, and elevated plasma thrombopoietin levels at study entry. The safety profile was consistent with that found in previous eltrombopag studies in aplastic anemia; no patients discontinued the drug due to adverse events. Three patients developed reversible grade 3 liver toxicity and one patient had increased reticulin fibrosis. Ten patients discontinued eltrombopag after achieving a robust response (median time 16 months); four of them reinitiated eltrombopag because of declining blood counts, and all attained a second robust response. Six patients had disease progression not associated with expansion of mutated clones and no patient progressed to develop acute myeloid leukemia on study. In conclusion, eltrombopag was well-tolerated and effective in restoring hematopoiesis in some patients with low or intermediate-1 risk MDS. This study was registered at clinicaltrials.gov as #NCT00932156.

Effect and mechanism of low-dose chidamide on the treatment of primary immune thrombocytopenia

目的探讨低剂量（0.1 mg/kg）西达本胺治疗原发免疫性血小板减少症（ITP）的作用及机制。方法①应用C57BL/6J小鼠建立ITP被动模型，灌胃给予0、0.01、0.1、0.5、5.0 mg/kg西达本胺，观察治疗前后ITP小鼠模型外周血血小板计数。②应用C57BL/6J小鼠建立ITP主动模型，灌胃给予0.1 mg/kg西达本胺，观察治疗前后ITP小鼠模型外周血血小板计数；4周后处死小鼠，流式细胞术检测脾细胞中CD4+CD25+Foxp3+自然调节性T细胞（nTreg）比例并应用ELISA方法检测小鼠外周血IL-6水平。③分离ITP患者外周血单个核细胞，与低剂量西达本胺共培养72 h后检测nTreg细胞比例；免疫磁珠法分离CD4+CD25+调节性T细胞（Treg细胞）以及CD4+CD25−效应T细胞，将二者以1∶4比例混合共培养，加入低剂量西达本胺干预，检测Treg细胞对效应T细胞增殖的抑制作用。结果①低剂量西达本胺可明显提高ITP被动模型鼠外周血血小板水平。②低剂量西达本胺可显著提高ITP动物模型外周血血小板水平，降低出血相关死亡率。③低剂量西达本胺可显著提高ITP动物模型脾细胞中nTreg比例、降低血清IL-6水平。④低剂量西达本胺可显著提高ITP患者外周血单个核细胞培养体系中nTreg细胞比例、增强Treg细胞对效应T细胞增殖的抑制作用。结论低剂量西达本胺可促进nTreg生成、增强Treg细胞的免疫抑制功能、降低IL-6水平，促进免疫耐受，对ITP有较好的治疗作用。

Diagnóstico y manejo oportunos del síndrome HELLP

El síndrome HELLP (SH) es una complicación severa del embarazo caracterizada por hemólisis, enzimas hepáticas elevadas y plaquetopenia. Es una de las situaciones más graves del embarazo, provocando tasas elevadas de morbimortalidad maternoperinatal. La complicación más frecuente del SH es la hemorragia, necesitándose transfusión de sangre y/o hemoderivados para corregir la hipovolemia, anemia o coagulopatía, siendo la complicación más catastrófica el hematoma hepático espontáneo. El parto es el único tratamiento efectivo para el SH. La mortalidad perinatal está relacionada directamente con la edad gestacional. No se ha logrado consenso sobre el manejo del SH que ocurre antes de las 34 semanas de gestación, cuando las condiciones maternas y fetales son estables. El objetivo de la presente revisión es resumir la información existente sobre el manejo oportuno del SH. Se concluye que la vía del parto dependerá de las condiciones cervicales y la estabilidad materno-fetal. Se necesitan estudios adecuados para determinar si hay beneficio con el manejo expectante en gestaciones pretérmino, y la administración de corticoides para mejorar el recuento de plaquetas en el SH.

Dengue virus co-infections with multiple serotypes do not result in a different clinical outcome compared to mono-infections.

Circulation of multiple dengue virus (DENV) serotypes in a locale has resulted in individuals becoming infected with mixed serotypes. This research was undertaken to study the clinical presentation, presence of DENV serotypes and serological characteristics of DENV infected patients with co-infections from three Provinces of Sri Lanka where DENV-1 and -2 predominated during the study. A reverse transcription polymerase chain reaction was performed on 1249 patient samples and 301 were positive for DENV (24.1%). DENV-1 was the predominant serotype detected in 137 (45.51%) followed by DENV-2 in 65 (21.59%), DENV-3 in 59 (19.6%) and DENV-4 in 4 (1.32%) patients with mono-infections. Thirty-three patients (10.96%) had DENV co-infections with two or more serotypes. The highest number of co-infections was noted between DENV-1 and DENV-2 (57.57%) suggesting co-infection is driven by the frequency of the circulating serotypes. Platelet counts were significantly higher in DENV co-infected patients although clinical disease severity or white blood cell count, packed cell volume or viraemia were not significantly different in the co-infected compared to the mono-infected patients. Thus co-infection with multiple DENV serotypes does occur but with the exception of improved platelet counts in co-infected patients, there is no evidence that clinical or laboratory measures of disease are altered.

Improvement of human platelet aggregation post-splenectomy with paraesophagogastric devascularization in chronic hepatitis B patients with cirrhotic hypersplenism

Thrombocytopenia is a common hematological abnormality in patients with cirrhotic hypersplenism. Splenectomy with paraesophagogastric devascularization (SPD) is a conventional surgical therapy which can reverse pancytopenia in these patients. Platelets are traditionally recognized for their central role in hemostasis. However, the status of platelet aggregation in chronic hepatitis B patients with cirrhotic hypersplenism before and after SPD has not been reported yet. A total of 41 cirrhotic patients and 31 healthy controls were included in this study. Platelet aggregation was detected by AggRAM® Advanced Modular System (Helena Laboratories, USA). ELISA was used to detect the cytokines closely related to platelet aggregation. Expressions of platelet membrane glycoproteins (GPs) were evaluated by flow cytometric analysis. Platelet aggregation was found to be decreased distinctly in the cirrhotic patients, and to be restored to normal level after SPD. The cirrhotic patients showed higher plasma levels of the cytokines HMGB1, PEDF, vWF, cAMP and cGMP, which also improved partially after SPD. Moreover, the cirrhotic patients had much lower expression of GPIIb/IIIa, GPIbα and P-selectin than either the healthy controls or SPD patients at basal or activated level. Generally, SPD benefits cirrhotic patients with bleeding tendencies by improving platelet counts and aggregation. GPIIb/IIIa may be the key membrane protein responsible for the change in platelet aggregation before and after SPD.

Retrospective EHR Study on Effectiveness of Eltrombopag in Cancer Treatment-Related Thrombocytopenia

INTRODUCTION:Cancer treatment-related thrombocytopenia is a serious problem in patients treated for cancer. Literature indicates the incidence of chemotherapy and radiation induced thrombocytopenia can be as high as 50%, based on underlying cancer type and treatment. This study describes patients treated with eltrombopag, a thrombopoietin receptor agonist, for cancer treatment -related thrombocytopenia. METHODS: Patients, who initiated treatment with eltrombopag and met all inclusion criteria, were identified from the Optum EHR database between 1st Jan 2009 to 31st Mar 2018. The earliest order date for eltrombopag was considered the index date. Inclusion criteria were: 18 years of age and older; male or female; diagnosis of solid or lymphoid malignancy prior to the index date; receipt of systemic chemotherapy 4 months prior or 1 month after the index date; platelets 100,000/mm3 pre index date; no evidence of prior use of eltrombopag; no evidence of therapy with rituximab; and, active in the database for at least 4 months prior to and at least 14 days following index date. Outcomes evaluated were (1) pre-index date minimum and mean platelet values, (2) post index date maximum and mean platelet values during the index chemotherapy cycle of eltrombopag treatment and line of therapy (LOT) time periods. RESULTS: The study cohort consisted of 107 patients, with mean age of 63.7 years (SD: 17.9), 59.8% male, 40.2% female, and 32.7% had commercial insurance. The mean Charlson Comorbidity index (CCI) score was 4.0 (SD: 2.6). Top cancer diagnoses were malignant neoplasms of lymphoid and histiocytic tissue (14.0%), malignant neoplasm of female breast (9.4%), and malignant neoplasm of trachea, bronchus and lung (5.6%). Top chemotherapy regimens used in the cohort were: decitabine (9.4%); azacitidine (8.5%); lenalidomide (6.6%); ruxolitinib (3.8%), and carboplatin plus gemcitabine, daunorubin plus cytarabine, hydroxyurea, and radiation (2.8% for each regimen). The mean index cycle duration was 2.3 months (SD: 2.4 months) and median was 1.2 months, while the mean index LOT duration was 3.3 months (SD: 2.6 months) and median was 3 months. The pre and post mean platelet values, shown in the figure, indicated an increase in the mean platelet values post treatment in the mean and maximum values from the mean and minimum pre-index values, within both the index cycle and the LOT treatment period. CONCLUSIONS:The results of this retrospective analysis of patients with cancer treatment-related thrombocytopenia treated with eltrombopag are consistent with eltrombopag's known profile in improving platelet counts, as evidenced for other approved indications. Further studies are needed to determine the specific patient population who will benefit most from eltrombopag in this type of secondary thrombocytopenia. Figure1: Pre and Post Index Cycle and LOT Mean Platelet Values Disclosures Pawar: Novartis: Consultancy. Velcheti:AstraZeneca: Consultancy; Foundation Medicine: Consultancy; Merck: Consultancy; Boston Scientific: Consultancy; BMS: Consultancy; Novartis: Consultancy; Reddy Labs: Consultancy; Alkermes: Consultancy; Genentech: Consultancy. Lal:Optum: Employment. Le:Optum: Employment. Andrade:Optum: Employment. Desai:Precision Xtract: Employment. Patwardhan:Novartis Pharmaceuticals: Employment. OffLabel Disclosure: Eltrombopag for chemotherapy or radiation induced thrombocytopenia

Sustained Improvements in Markers of Liver Disease Severity After Hepatitis C Treatment

Although serological markers of disease severity improve after hepatitis C virus (HCV) treatment, it is unclear if all patients experience sustained improvement. We aim to evaluate longitudinal changes in aspartate (AST), alanine (ALT) aminotransferase, platelet count (PLT), and fibrosis-4 (FIB-4) after HCV treatment. All adult chronic HCV patients who received antiviral therapy from January 2011 to February 2017at four large urban hospital systems were evaluated to assess changes in AST, ALT, PLT, and FIB-4 from pre-treatment to post-treatment annually up to 4 years after HCV therapy. Comparisons used Student's t-test and analysis of variance, and were stratified by sex, race, ethnicity, age, body mass index (BMI), and diabetes mellitus. Among 2691 patients (62.2% men, 76.9% aged 45-65 years, 56.5% white), all markers of disease severity demonstrated sustained improvements from pre-treatment to 4 years post-treatment (AST 53 U/L to 27.5 U/L, ALT 53 U/L to 29 U/L, PLT 168×103 to 176×103, FIB-4 2.51 to 1.68). However, Hispanics and patients with BMI >30kg/m2 experienced rebound increases in AST, ALT, and FIB-4 at 4 years post-treatment after experiencing initial improvements in these serological markers in the first-year post-treatment. Sustained improvements in PLT were observed in all groups, including Hispanics and patients with BMI >30kg/m2. HCV treatment in a large community-based cohort demonstrated sustained improvements in AST, ALT, PLT, and FIB-4. Rebound increases in AST, ALT, and FIB-4 observed in Hispanics and those with BMI >30kg/m2 may reflect persisting nonalcoholic fatty liver disease.

Partial Splenic Artery Embolization in 35 Cancer Patients: Results of a Single Institution Retrospective Study

PurposeTo evaluate the safety and efficacy of partial splenic embolization (PSE) in cancer patients with different etiologies of splenomegaly/hypersplenism. Materials and MethodsThe medical records of 35 cancer patients who underwent 39 PSE procedures were analyzed. The splenomegaly/hypersplenism was due to chemotherapy (n = 17), portal hypertension (n = 10), or hematologic malignancy (n = 8). After the first 11 PSEs, celiac plexus neurolysis, corticosteroids, and non-steroid anti-inflammatory drugs (NSAIDs) were included in the post-procedural management. ResultsPSE led to 59 ± 16% (mean ± standard deviation) splenic infarcts. The infarct volume per 1 mL 300–500 μm tris-acryl gelatin microspheres was not significantly different between the chemotherapy-induced group (264 ± 89 cm3) and the portal hypertension group (285 ± 139 cm3) but was significantly higher in the hematology group (582 ± 345 cm3). Platelet count increased from 65.7 ± 19.7 k/μl to a peak platelet count of 221 ± 83 k/μl at 2 weeks after PSE. Patients with a follow-up period of more than 1 year had the most recent platelet count of 174 ± 113 k/μl. Platelet count increase was significantly higher in the chemotherapy-induced group than the portal hypertension group. Adding celiac plexus neurolysis, corticosteroids, and NSAIDs to the post-procedural management resulted in a decreased rate of major complications from 73% to 46% and a decrease in the rate of moderate or severe pain from 92% to 20%. ConclusionsPSE improved platelet counts in cancer patients despite different etiologies of splenomegaly. The addition of celiac plexus neurolysis, corticosteroids, and NSAIDS to the post-PSE treatment protocol reduced complications. Data from this study could help to predict the amount of 300–500 μm tris-acryl gelatin microspheres required to achieve a planned infarct size.

Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study

SummaryBackgroundWiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC) gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy.MethodsWe did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP) expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462) and EudraCT (number 2009-017346-32).FindingsBetween April 20, 2010, and Feb 26, 2015, nine patients (all male) were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1–12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5–5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8–35·6) before gene therapy to 66·7% (55·7–98·6) at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1–31·0) to 76·6% (53·1–98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44–3·72) per patient-year of observation (PYO) in the year before gene therapy to 0·31 (0·04–1·11) per PYO in the second year after gene therapy and 0·17 (0·00–0·93) per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 109 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20–50 × 109 per L in one patient, 50–100 × 109 per L in five patients, and more than 100 × 109 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%) of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy.InterpretationData from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available.FundingItalian Telethon Foundation, GlaxoSmithKline, and Orchard Therapeutics.

Mesenchymal stem cells improve platelet counts in mice with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder. The breakdown of immune tolerance (regulatory T [Treg] cells and suppressor cytokines) plays an important role in ITP pathophysiology, especially in refractory ITP. Bone marrow-derived mesenchymal stem cells (BM-MSCs) show immunomodulatory properties and have been extensively utilized for autoimmune diseases. However, it has not been fully elucidated how BM-MSCs affect ITP. In this study, we explore the therapeutic mechanism of BM-MSCs on ITP in mice. Dose-escalation passive ITP mice were inducted by injection of MWReg30. BALB/c mice were randomly divided into two groups: ITP with BM-MSC transplantation and ITP controls. The serum levels of cytokines (interleukin 10 [IL-10] and transforming growth factor-β1 [TGF-β1]) were examined by enzyme-linked immunosorbent assays. The frequency of Treg cells in both peripheral blood and spleen mononuclear cells was analyzed by flow cytometry, and the forkhead box P3 (Foxp3) messenger RNA (mRNA) level was measured by real-time polymerase chain reaction. After BM-MSC treatment, the platelet (PLT) counts were significantly elevated. Meanwhile, cytokines (TGF-β1 and IL-10), the ratios of Treg cells, and the Foxp3 mRNA expression level were significantly higher in the BM-MSC group. Our results show that BM-MSCs can improve PLT counts mainly by secreting suppressive cytokines and upregulating Tregs, which may provide new therapeutic potential for human ITP.